Virtual Library

  • +

    IASLC General Assembly (ID 364)

    • Event: WCLC 2019
    • Type: General Assembly
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/10/2019, 08:00 - 08:45, Tokyo (1982)
  • +

    ES03 - BAP-1 and Other Novel Molecular and Metabolic Targets in Mesothelioma (ID 6)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Mesothelioma
    • Presentations: 5
    • Now Available
    • +

      ES03.01 - Targeting Altered microRNA Expression in Mesothelioma (Now Available) (ID 3161)

      10:30 - 12:00  |  Presenting Author(s): Glen Reid

      • Abstract
      • Presentation
      • Slides

      Abstract

      MicroRNAs (miRNAs) are an important class of noncoding RNA that post-transcriptionally regulate the expression of most protein-coding genes. In addition to central roles in normal biology, their aberrant expression in tumours contributes to all of the hallmarks of cancer. In common with other tumour types, changes in miRNA expression in malignant pleural mesothelioma (MPM) are characterised by a global downregulation, although elevated levels of some miRNAs are also found. While altered expression has been demonstrated for many miRNAs in MPM, relatively few have been functionally characterised. Early studies reported modest tumour suppressive activities of, among others, miR-29c, miR-31 and miR-145. More recently, miR-16, miR-193a and the miR-34 family were shown to have clear tumour suppressor activity; restoring the levels of these miRNAs leads to a range of effects including inhibition of cell growth, induction of apoptosis, reversal of drug resistance and reduced migration and invasion. In the case of miR-16 and miR-193a, targeted delivery of mimics to tumours in a xenograft model led to significant inhibitory effects on tumour growth. These results laid the foundation for the phase I MesomiR-1 trial, investigating the safety and optimal dose of a miR-16-based mimic delivered in anti-EGFR antibody-targeted bacterial minicells. This trial of 27 patients demonstrated safety of the treatment as well as initial signs of activity, with one objective response and stable disease in a further 15 patients. With miR-16 also impacting response to pemetrexed and contributing to PD-L1 regulation in vitro, restoration of miR-16 levels in combination with chemo or immunotherapy are potential future applications of this approach. Other miRNAs with pronounced tumour suppressor activity, including miR-137 and miR-193a, are further candidates for clinical development. The lower levels of miR-193a recently found to be associated with shorter overall survival in the TCGA study lend support to this notion.

      In contrast to the use of mimics to restore levels of miRNAs downregulated in MPM, inhibition of overexpressed miRNAs with antisense oligonucleotides is an alternative strategy for modulating miRNA levels. This approach is attractive as it may be amenable to local delivery, avoiding the problems associated with tumour targeting via systemic administration. While the number of miRNAs found to be consistently overexpressed in MPM is relatively small, recent studies suggest that their inhibition can have profound effects on MPM growth. One such example was the report of the effects of inhibiting the overexpressed miR-182 and miR-183. They are upregulated in MPM cell lines where they promote proliferation and invasion, at least in part due to suppression of FOXO1. Reducing their levels with miRNA inhibitors reversed these effects, with dual inhibition showing additive effects. An oncogenic role for miR-182 was first demonstrated in melanoma, in which this miRNA enhances migration, invasion and metastasis via inhibition of FOXO3 and MITF. Upregulation of miR-182 in melanoma is due to amplification (at 7q31) of a miRNA cluster which also contains the related miR-183 and miR-96. As this region appears to be more frequently lost in MPM, the mechanism for overexpression remains to be determined. Another miRNA with oncogenic activity in MPM is miR-24, which was identified via a screen of polysome-associated miRNAs and is upregulated in cell lines and tumour samples. This miRNA regulates a range of genes involved in cell adhesion and communication, many of which are associated with good prognosis, and miR-24 knockdown reduced migration and invasion in vitro and in vivo. Although the targets of miR-24 identified in this study had no obvious link to MPM biology, it is intriguing that in other cancers miR-24 regulates both transcripts produced by the CDKN2A locus. Whether other well known oncogenic miRNAs such as miR-155, miR-10b and miR-21 promote MPM tumour progression remains to be seen, but the initial results with miR-182, miR-183 and miR-24 warrant further pre-clinical development.

      Despite progress in the development of miRNAs as therapeutic targets for MPM, outstanding questions remain. Of particular relevance is the question of the cell of origin of dysregulated miRNAs. As tumour samples consist of a mix of cancer, stroma and immune cells, the source of miRNA contributing to changes in expression is unknown and thus impacts the interpretation of results. For example, altered expression of miR-223 was linked to changes in migratory behaviour of MPM, but in xenograft studies this miRNA is clearly derived from the stroma. Another confounding observation concerns the apparent contradictory findings from studies of the same miRNA. For example, miR-137 has clear tumour suppressor function in MPM cells in vitro, but its expression varies widely across MPM lines and is found at higher levels in tumours from patients with shorter survival. Similarly, miR-31 has growth inhibitory activity but higher expression is associated with poor prognosis in sarcomatoid tumours. There are also cases of different miRNAs showing apparent differences in MPM compared with other cancers. A prime example of this is miR-21; an oncomiR in most cancer types, but growth inhibitory when overexpressed MPM cell lines. Finally, because the activity of miRNAs typically leads to modest reductions in target genes, demonstrating in vivo effects is not trivial. In addition, because the miRNA being restored (or inhibited) is usually identical to its endogenous miRNA counterpart, measuring delivery can be difficult. Due to their short size, even novel sequences such as that used in the TargomiR study are difficult to definitively measure by RT-qPCR or RNA-seq.

      In summary, the changes in miRNA expression in MPM provide avenues to develop new therapetuic approaches. The successful phase I trial of TargomiRs demonstrated that miRNA targeting is feasible in MPM and while the majority of miRNA studies in MPM have focused on miRNA mimics, recent studies suggest that antisense inhibitors have similar potential. Notwithstanding the ongoing difficulties in delivering nucleic acid-based drugs, the recent FDA approval of the first siRNA therapy – together with ongoing clinical trials of a number of miRNA mimic drugs – means that gene silencing drugs have moved from concept to reality. Continued preclinical studies and early phase clinical trials are needed to determine the true potential of miRNA targeting in MPM treatment.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES03.02 - Targeting CDKN2A in Mesothelioma (Now Available) (ID 3162)

      10:30 - 12:00  |  Presenting Author(s): Dean Anthony Fennell

      • Abstract
      • Presentation
      • Slides

      Abstract

      Interrogation of the genomic landscape in mesothelioma has revealed considerable inter-patient genomic heterogeneity, however development of molecularly targeted stratified therapy is currently in its infancy.

      Somatic copy number loss involving the chromosome 9p21-3 locus occurs at high frequency (45% deep deletion in the TCGA cohort), and its expression may be further suppressed by DNA methylation. 9p21-3 harbours CDKN2A. Conditional Knockout of CDKN2A is sufficient to initiate mesotheliomas in vivo consistent with a role in tumorigenesis. This is supported by emerging phylogenetic analysis in which 9p21-3 occurs as an early (clonal or truncal) homozygous event during tumour evolution, in around 20% of cases. Late homozygous and heterogzyous losses also occur, with evidence of parallel evolution. Importantly, CDKN2A is a major negative prognostic factor associated with earlier progression following surgical resection.

      CDKN2A encodes two genes; 1, the inhibitor of cyclin dependent kinases 4 and 6 known as p16ink4A, and 2. MDM2, an inhibitor of the p53-MDM2 interaction. Early preclinical studies showed that re-introducing p16ink4A transgene in a CDKN2A negative mesothelioma exhibited anti-tumour activity. Small molecule inhibition of CDK4/6 essentially phenocopies p16ink4a (in the presence of wild type RB1). Large scale drug-gene interaction studies have revealed CDKN2A dependent sensitivity to CDK4/6 inhibition suggesting a possible strategy in mesothelioma. We have therefore developed the MiST stratified umbrella trial (NCT NCT03654833) is therefore evaluating the CDK4/6 inhibitor abemaciclib in p16ink4a negative relapsed mesothelioma (arm 2)

      Loss of p14ARF expression promotes MDM2, an E3 ubiquin ligase targeting p53. Given the low mutation rate for p53 in mesothelioma (around 16% in the TCGA), MDM2 inhibitors may, in the context of p14ARF loss, de-repress p53 to mediate tumour suppression. Preclinical data supports this hypothesis which has translational potential.

      Co-deletion of the gene MTAP with CDKN2A is common, and coincident with around 80% of CDKN2A losses. MTAP (methylthioadenosine phosphorylase) may represent a potential molecular target in 9p21-3 deleted mesothelioma. This tumour suppressor salvages the essential amino acid methionine, as well as adenine, and plays a critical role in the polyamine salvage pathway. Recently it has been shown that loss of MTAP leads to an increase level in its substrate, methylthioadenosine (MTA). This metabolite directly interacts with and inhibits the epigenetic modifier, PRMT5 (protein arginine methyltransferase 5) that mediates symmetrical arginine di-methylation of histone H4 (H4R3me2s). A direct consequence of this is a reduction in the pool of functional PRMT5 enzyme, revealing a vulnerability to 1. Inhibition of PRMT5 expression or 2. Inhibition of PRMT5 substrate (SAM) synthesis via MAT2A (which converts methionine to SAM). 1st generation small molecule PRMT5 inhibitors are currently undergoing phase 1 clinical evaluation, however MTA dependent allosteric antagonism of such inhibitors presents a challenge to achieving efficacy. Small molecule transcriptional suppression may present a solution. Accordingly, using the connectivity map, we have identified quinacine as a PRMT5 transcriptional suppressor capable of suppressing PRMT5 transcription (which is c-jun dependent), mediating MTAP selective loss of viability with commensurate reduction in H4R3me2s, consistent with an on-target effect.

      In summary, 9p21-3 loss encompassing CDKN2A and MTAP is one of the most common genomic aberrations in mesothelioma. Novel strategies are emerging with significant translational potential to deliver targeted therapies for mesothelioma.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES03.03 - Targeting NF2 in Mesothelioma (Now Available) (ID 3163)

      10:30 - 12:00  |  Presenting Author(s): Yoshitaka Sekido

      • Abstract
      • Presentation
      • Slides

      Abstract

      Malignant mesothelioma (MM), which arises from the pleural or peritoneal cavities, is a very aggressive tumor that is highly refractory to conventional therapies. Several key genetic alterations, including mutations of the CDKN2A/ARF, NF2, and BAP1 tumor-suppressor genes, are associated with the development and progression of MM. Notably, activating oncogene mutations are very rare; thus, it is difficult to develop effective inhibitors to treat MM.

      Neurofibromatosis type 2 (NF2) encodes the tumor suppressor protein moesin-ezrin-radixin-like protein (merlin), which is a member of the Band 4.1 family of cytoskeletal linker proteins. NF2-inactivating mutations, deletions, or rearrangements are harbored in 40%–50% of MMs and result in bi-allelic loss of protein function. Somatic NF2 mutations are also frequently detected in sporadic schwannomas, meningiomas, ependymomas, and to a lesser extent, in other types of solid tumors. Merlin/NF2 primarily localizes to the plasma membrane where it mediates contact-dependent inhibition of proliferation in normal cells. Merlin/NF2 has also been shown to regulate multiple cell-signaling cascades including the Hippo pathway.

      The Hippo signaling pathway is involved in critical biological processes, including organ size-control, development, differentiation, tissue regeneration (via cell-growth restriction), cell division regulation, apoptosis, and cancer development. The 4 core components in this pathway, MST1/2, SAV1 (also called WW45), MOB1, and LATS1/2, have all been shown to act as tumor suppressors. Since MMs also exhibit genetic or epigenetic inactivation of Hippo pathway components, including MST1/2 and LATS1/2, merlin-Hippo pathway dysregulation is thought to play a key role in MM development and progression.

      Hippo pathway inactivation results in inactivation of the LATS1/2 kinases, which, in turn, induces constitutive activation (via underphosphorylation) of YAP1 and TAZ transcriptional coactivators. Underphosphorylation stabilizes YAP1 and TAZ and enables them to enter the nucleus where they bind to distinct transcription factors, including TEAD1-4, and regulate transcription of numerous target genes. We, along with other groups, have shown that constitutive activation of YAP1 and TAZ in vitro and in vivo confer malignant phenotypes in mesothelial cells, whereas their knockdown suppresses these phenotypes. Critical YAP1/TAZ target genes include prooncogenic cyclin D1 (CCDN1), forkhead box M1 (FOXM1), connective tissue growth factor (CTGF), and cytokine-encoding genes such as IL1B, which have also been shown to enhance the malignant phenotypes of MM cells.

      Currently, several small molecules have been developed to directly target YAP1/TAZ coactivators, including YAP1-TEAD binding inhibitors. Targeting key YAP1/TAZ-inducible downstream genes, such as IL1B and CTGF, in the dysregulated Hippo pathway may also represent an alternative approach to inhibit MM progression. Furthermore, targeting stimulatory or inhibitory signaling pathways within the Hippo pathway, which include TGF-beta, Wnt, G-protein-coupled receptor (GPCR), mammalian target of rapamycin (mTOR) and mevalonate pathways, may be considered. Collectively, these evidences indicate that the Hippo pathway is a promising therapeutic target for MM treatment, particularly with regard to NF2-Hippo pathway inactivation, and supports the development of new strategies to effectively target YAP1/TAZ activation status as a promising therapeutic modality for this formidable disease.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES03.04 - Pegargiminase to Treat Mesothelioma (Now Available) (ID 3164)

      10:30 - 12:00  |  Presenting Author(s): Peter Szlosarek

      • Abstract
      • Presentation
      • Slides

      Abstract

      Treatments based on targeting metabolism remain central to the management of malignant mesothelioma, an intractable malignancy with a median overall survival (OS) of ~12 months. The standard of care since 2003 is an antifolate drug (pemetrexed or raltitrexed) paired with a platinum salt which provides a 2-3 month median survival benefit. Arginine metabolism is dysregulated in mesothelioma with deficiency of the rate limiting enzyme argininosuccinate synthetase 1 (ASS1) three-fold higher in sarcomatoid and biphasic compared to epithelioid tumours. ASS1 inactivation via promoter methylation diverts the precursor aspartate for enhanced pyrimidine synthesis via carbamoyl-phosphate synthetase 2 (CAD), accounting in part for increased tumorigenesis. However, loss of ASS1 generates a collateral dependence on exogenous arginine for growth (auxotrophy) that may be exploited with arginine-degrading enzymes, such as arginine deiminase and arginase.

      A randomised phase 2 trial of pegargiminase (ADI-PEG20, pegylated arginine deiminase) monotherapy delivered as a weekly intramuscular (IM) injection (36mg/m2) in patients with ASS1-deficient mesothelioma (ADAM study; NCT01279967) revealed a 1.2 month progression-free survival benefit over best-supportive care (BSC) only (3.2 versus 2.0 months; hazard ratio of 0.56; and p=0.03). The restricted mean survival for OS, calculated due to early survival curve cross-over, was 15.7 months for the pegargiminase group versus 12.1 months for the BSC group, for a difference of 3.6 months (p=0.13). Pegargiminase was well-tolerated with a 13.6% grade 3-4 allergic rate, including anaphylactoid reactions and serum sickness, which were readily reversible and a low frequency of grade 1-2 reactions, mostly local skin irritation and discomfort due to the IM therapy. Pharmacodynamically, pegargiminase suppressed arginine plasma levels (measured on the day of and prior to drug dosing) for 4 weeks before a return to baseline with a reciprocal change in the degradation product, citrulline, a consequence of the production of drug-neutralising antibodies. Partial metabolic responses were documented by FDG-PET in almost 50% of patients by the third week of pegargiminase administration. Thus, while the PFS primary endpoint was modest, the ADAM trial is the first proof of principle study to show a survival benefit using an ASS1 biomarker-directed strategy.

      More recent efforts in the arginine deprivation field have focused on rational drug combinations. Preclinically, pegargiminase reduces intracellular thymidine pools via inhibition of enzymes involved in de novo synthesis, specifically thymidylate synthetase and dihydrofolate reductase, and pyrimidine salvage via thymidine kinase 1, collectively enhancing pemetrexed cytotoxicity in arginine-auxotrophic tumour cell lines, including mesothelioma. This was tested in the phase 1 TRAP study (NCT02029690) combining pegargiminase with pemetrexed and cisplatin (ADIPemCis) in patients with ASS1-deficient mesothelioma (n=5) and non-squamous non-small cell lung cancer (NSCLC, n=4). The dose-escalation portion of the study revealed ADIPemCis was safe with a 78% (n=7/9) partial response rate and an overall 100% disease control rate. Moreover, partial responses were seen in biphasic and sarcomatoid mesothelioma considered to be largely chemorefractory. The overall PFS and OS in this small study was 7.5 and 13.9 months, respectively. A dose expansion cohort in mesothelioma at the maximum tolerated dose confirmed a similarly high disease control rate of 93.5% (29/31) and, with two-thirds of patients with non-epithelioid mesothelioma (10 biphasic and 10 sarcomatoid), an overall median PFS of 5.6 and OS of 10.1 months was observed. Although, a small series there was a 3 fold-higher survival at 12 months for patients with sarcomatoid mesothelioma compared with historical controls (30% versus 10% survival). These data supported the opening of a randomised double-blind phase 2/3 trial called ATOMIC-meso and the first to focus on the most aggressive subtypes of mesothelioma that is expected to report initial results by 2020 (NCT02709512).

      Mesothelioma therapeutics are at a crossroads with increasing evidence for a key role of immunotherapy in a subset of patients. Objective responses of 10-30% have been reported in several phase 1-2 studies of PD1/PD-L1 antagonists with or without CTLA4 blockade in patients with mesothelioma. Pegargiminase increases PD-L1 expression on mesothelioma cells and leads to an influx of T cells in immunocompetent murine tumour models. Furthermore, urea cycle dysregulated cancers with increased aspartate flux and pyrimidine synthesis are hypothesized to generate genomic signatures more amenable to immune checkpoint blockade. Preliminary results of a phase 1 study of pegargiminase and pembrolizumab reveal activity in arginine auxotrophic cancers with good safety and tolerability (NCT03254732). Similarly, a first-in-man trial of platinum, pemetrexed combined with pegargiminase and atezolizumab (iTRAP study) is planned to start in 2019 focusing on patients with ASS1-deficient non-squamous NSCLC (NCT03498222). Pending these early data, and further ASS1 and PD-L1 biomarker analyses, additional studies are planned in patients with mesothelioma.

      Recent preclinical work in our laboratory has revealed that arginine deprivation has a key role in remodulating the tumour microenvironment with an increase in macrophages involved in resistance to pegargiminase. Mesothelioma cells co-cultured with macrophages released several proinflammatory cytokines including IL-1alpha and the CXCR-2 dependent chemokines IL-8, CXCL2 and CXCL8 with a co-ordinate increase in ASS1 and ASL in macrophages and tumour cells, respectively bypassing sensitivity to pegargiminase. Moreover, analysis of blood from the ADAM study revealed an increase in argininosuccinate in the plasma of early metabolic progressors and paired biopsies from the TRAP mesothelioma expansion cohort revealed an influx of macrophages consistent with the preclinical work. Thus, re-education of macrophages with chemokine or “don’t’ eat me” inhibitors may be a viable strategy in mitigating stromal resistance to pegargiminase. Further optimisation of pegargiminase for the treatment of mesothelioma may come from manipulation of additional resistance pathways. Thus, antimalarial agents such as chloroquine inhibit autophagy, a common escape mechanism to nutrient deprivation, and have enhanced the effect of arginine depletion in various ASS1 negative tumour cell lines including mesothelioma. Lastly, synthetic lethal approaches targeting polyamine metabolism in ASS1-negative mesothelioma cells, also merit clinical investigation in combination with pegargiminase and may lead to deeper and more durable metabolic responses.

      In summary, bench-to-bedside studies of pegargiminase have progressed to a phase 2/3 trial in mesothelioma. Combinations of pegargiminase with immune checkpoint blockade and modulators of resistance pathways appear promising areas for further development.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES03.05 - Inherited Predisposition to Mesothelioma, Biological and Clinical Differences with Sporadic Mesothelioma (Now Available) (ID 3165)

      10:30 - 12:00  |  Presenting Author(s): Jane E. Churpek

      • Abstract
      • Presentation
      • Slides

      Abstract

      Why less than 5% of those exposed to asbestos develop malignant mesothelioma,1 has long fueled the hypothesis that inherited genetic factors may contribute to risk. Studies in erionite exposed households in Turkey suggested that inherited genetic factors cooperate with shared exposures in mesothelioma development.2 In 2011, the discovery of inherited mutations in the gene BAP1 in families clustering multiple cases of mesothelioma3 and demonstration of further proof of causation in a mouse model, showing that mice with one abnormal copy of Bap1 develop mesothelioma more quickly, with lower asbestos doses, and at a higher proportion than wild-type mice4, 5 solidified the role of inherited genetics in mesothelioma risk. Failure to detect inherited BAP1 mutations in a substantial subset of cancer-prone and sporadic mesothelioma cases suggested, however, that BAP1 was not the only gene involved. A strong family history of many types of cancer has also been observed, suggesting that other broad cancer susceptibility genes were involved.6, 7 Recently, our group as well as groups at the NCI and in Italy all published results of targeted panel-based genomic sequencing of three unselected series of mesothelioma cases (Table 1).8-10 We all found a similar overall germline mutation frequency of 10-12%, placing mesothelioma among a growing number of solid tumors, such as metastatic prostate cancer, with mutation frequencies in this range. Clinical predictors of a germline mutation from all three series include: peritoneal compared with pleural disease, younger age, those with a personal history of other cancers, female gender, and lower level of prior asbestos exposure. By gene, BAP1 accounted for the most mutations, but overall more than half of those carrying a germline mutation carried a mutation in a gene other than BAP1. Biologically, most of these genes function predominantly in DNA repair pathways, especially the homologous recombination pathway involved in double strand break repair. These data may explain prior observations of complex cytogenetics and other features of genomic instability in mesothelioma tumors9-11 and could explain platinum sensitivity, a chemotherapy drug known to have increased efficacy in solid tumors, such as ovarian cancer, in those with germline mutations in genes in the same pathway. To investigate this possibility, we combined our data with data from the NCI series and together, our groups found that a germline mutation in any DNA repair gene was associated with improved OS after platinum based chemotherapy and that this effect was independent of age at diagnosis and gender, two key known prognostic factors.9 Interestingly, this effect was only present in those with pleural disease, in whom mutation carriers had a median OS of 7.9 vs 2.4 years in non-mutation carriers (p=0.0012). Further, among germline mutation carriers, OS for those with pleural or peritoneal disease was similar suggesting a similar biology is a more important predictor of OS than site in those cases. These data support the investigation of other DNA repair based therapies, such as PARP inhibitors, in patients with mesothelioma, especially among those with a relevant germline mutation. Further investigation of the full spectrum of inherited risk factors in mesothelioma, their interaction with response to various therapies, as well as how patterns of acquired mutations in mesothelioma tumors differ by germline mutation status and whether those without a germline mutation but whose tumors acquire similar gene mutations respond to similar therapies are all yet to be determined.

      REFERENCES

      1. Carbone M, Kratzke RA, Testa JR. The pathogenesis of mesothelioma. Semin Oncol. 2002;29: 2-17.

      2. Roushdy-Hammady I, Siegel J, Emri S, Testa JR, Carbone M. Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey. Lancet. 2001;357: 444-445.

      3. Testa JR, Cheung M, Pei J, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43: 1022-1025.

      4. Xu J, Kadariya Y, Cheung M, et al. Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma. Cancer Res. 2014;74: 4388-4397.

      5. Napolitano A, Pellegrini L, Dey A, et al. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene. 2016;35: 1996-2002.

      6. Ugolini D, Neri M, Ceppi M, et al. Genetic susceptibility to malignant mesothelioma and exposure to asbestos: the influence of the familial factor. Mutat Res. 2008;658: 162-171.

      7. Ohar JA, Cheung M, Talarchek J, et al. Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer. Cancer Res. 2016;76: 206-215.

      8. Betti M, Casalone E, Ferrante D, et al. Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma. Cancer Lett. 2017;405: 38-45.

      9. Hassan R, Morrow B, Thomas A, et al. Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy. Proc Natl Acad Sci U S A. 2019;116: 9008-9013.

      10. Panou V, Gadiraju M, Wolin A, et al. Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma. J Clin Oncol. 2018;36: 2863-2871.

      11. Betti M, Aspesi A, Ferrante D, et al. Sensitivity to asbestos is increased in patients with mesothelioma and pathogenic germline variants in BAP1 or other DNA repair genes. Genes Chromosomes Cancer. 2018;57: 573-583.

      table 1.png

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

  • +

    ES09 - How I Do It - Real World Issues in the Diagnosis and Treatment of Metastatic NSCLC (ID 12)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 5
    • Now Available
    • +

      ES09.01 - How I Optimize Tissue Specimen Processing for Histopathological and Molecular Profiling (Now Available) (ID 3199)

      13:30 - 15:00  |  Presenting Author(s): Amanjit Bal

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is the most common cancer in males worldwide, and the most common cause of cancer related mortality in both sexes. There have been significant advances in the treatment of non-small cell lung cancer (NSCLC) in the last several years, which require careful biopsy sample acquisition and processing. Approximately 70% lung cancer patients present in advanced stage, thus most diagnosis of lung cancer are offered on cytology specimens and small biopsies.

      Specimens for diagnosing lung cancer

      For diagnosis of lung cancer, the specimens received in pathology laboratory includes; Effusions and FNAC samples from which cell blocks can be prepared, endobronchial biopsies, transbronchial lung biopsies, CT/PET guided core biopsies and biopsies from metastatic sites like lymph nodes, bone etc. Since tissue is an issue in diagnosis and management of lung cancer, thus strategies to manage limited tissues have been developed:

      The pre-analytical steps involved in handling, fixing and processing these precious tissue samples are critically controlled to obtain accurate and meaningful biomarker tests.

      For molecular testing two block setting is used: One block for diagnostic immunostains and second block is reserved for molecular workup.

      Pathological analysis of NSCLC on small biopsies:

      Histological Sub-typing of NSCLC:The subtyping of NSCLC on small biopsies has poor inter-observer agreement. WHO 2015 classification recommends use of ancillary techniques like mucin histochemsitry and immunohistochemistry for cases that cannot be classified based on light microscopy and minimize the use of term NSCLC-NOS.1To refine separation of squamous from adenocarcinoma; use of one adenocarcinoma marker and one squamous marker is suggested to preserve tissue for further molecular testing.For adenocarcinoma, TTF-1, Keratin 7 and napsin and for squamous, P40, p63 and keratin5/6 are used. Cocktails of nuclear and cytoplasmic antibodies like, TTF1/CK5/6 and napsin/p63 are also available. For neuroendocrine tumours, the specific markers include; neuron-specific enolase, chromogranin, synaptophysin, and CD56. With the use of immunohistochemistry the NSCLC-NOS category has been reduced from 10% to 5% in our setup.2

      Morphological Patterns of Adenocarcinoma:The histologic patterns of adenocarcinoma described in WHO 2015 classification include; lepidic predominant, acinar predominant, papillary predominant, solid predominant and micropapillary predominant pattern. These histological patterns though described for resection specimens, should be reported on small biopsies as they provide prognostic information; Lepidic pattern is associated with favorable prognosis, acinar and papillary with intermediate prognosis whereas the solid and micropapillary patterns have poor prognosis.3

      Genetics for personalized medicine in lung cancer

      Epidermal Growth Factor Receptor gene (EGFR) mutation:Most common mutations in young Asian females and/or never smokers and involves exons 18-21 of EGFR gene, the encoding a portion of the tyrosine kinase domain. Ninety percent of EGFR mutations are exon 19 deletions or missense point mutation in L858P in exon 21. Additional mutations in EGFR (T790M in exon 20) as well as mutations in other genes such as MET have been responsible for resistance to EGFR inhibitors.

      Anaplastic Lymphoma Kinase (ALK) rearrangement:EML4-ALK translocation of the transcription activation domain of ALK and the dimerization domain of EML4, leads to interstitial inversion in the short arm of chromosome 2. EML4-ALK translocation is seen in 5-8% of adenocarcinomas and is detected by break apart FISH or by IHC (D5F3 clone on Ventana system).

      Overall incidence of EGFR mutations in our set up is 22.3% and for ALK re-arrangement is 9.5%.3,4

      ROS1 re-arrangement: Similar to ALK mutations, ROS1 re-arranged tumours respond to tyrosine kinase inhibitor therapyandaccounts for 1-2% of pulmonary adenocarcinomas. ROS1 expression is screened by immunohistochemistry (D4D6 clone from Cell signaling) and break-apart FISH confirms the positive cases.

      Rare genetic changes:Other rare mutations reported in lung cancer includes; HER2 mutations (1%); BRAF mutations (2%); RET and NTRK rearrangements reported in 1.9% and 0.9%, respectively

      Immunotherapy

      In addition to targetable mutations, immune checkpoint inhibitors have revolutionized the treatment of lung cancer. The programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) have monoclonal antibodies directed towards them, which have shown promise with regards to overall survival in advanced NSCLC. PD-L1 expression status as assessed by immunohistochemistry is important in predicting response to PD-1/PD-L1 inhibitors. However, there are challenges in PD-L1 testing that includes; four different IHC clones on different staining platforms, due to limited tissue all assays cannot be performed, heterogeneity of staining and the need for standardization of interpretation and scoring criteria.

      Recent advances

      Since tissue is an issue in molecular testing of lung cancer, targeted next generation sequencing panels are available for testing all relevant molecular changes in one go. Oncomine Dx is one such panel for lung cancer that has got FDA approval. In absence of available tissue especially in setting of relapse, cell free DNA is an alternative for detecting molecular alterations.

      Conclusions

      The exact histological subtyping of NSCLC, thus reducing the ‘NOS’ rate, analysis of genetic alterations for targeted therapy and evaluation of targets for immune checkpoint inhibitors has significantly impacted the treatment and prognosis of lung cancer patients. Thus procurement of adequate tissue and its judicious use is of utmost importance. As the number of clinically significant targetable mutations and chromosomal rearrangements continues to grow, the next generation sequencing becomes the need of the day.

      References

      Travis WD, Brambilla E, Nicholson AG et al. The 2015 World Health Organization classification of lung tumors: Impact of genetic, clinical and radiologic advances since the 2004 classification.J Thorac Oncol 2015;10(9):1243 60.

      Kaur H, Sehgal IS, Bal A et al. Evolving epidemiology of lung cancer in India: Reducing non-small cell lung cancer-not otherwise specified and quantifying tobacco smoke exposure are the key. Indian J Cancer 2017;54:285-90.

      Maturu VN, Singh N, Bal A, et al. Relationship of epidermal growth factor receptor activating mutations with histologic subtyping according to International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society 2011 adenocarcinoma classification and their impact on overall survival.Lung India 2016;33:257-66.

      Bal A, Singh N, Agarwal P et al. ALK gene rearranged lung adenocarcinomas: molecular genetics and morphology in cohort of patients from North India.APMIS. 2016;124(10):832-8.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES09.02 - How I Report Imaging for Assessment of Responses to Targeted Therapies vs. Immune Checkpoint Inhibitors vs. Chemotherapy (Now Available) (ID 3200)

      13:30 - 15:00  |  Presenting Author(s): Ritu R Gill

      • Abstract
      • Presentation
      • Slides

      Abstract

      How I Report Imaging for Assessment of Responses to Targeted Therapies vs. Immune Checkpoint Inhibitors vs. Chemotherapy

      Response assessment is an integral part of radiological reporting in tumor imaging. Our daily workflow includes diagnostic evalaution, determining resectability and response assessment. The radiology template and format is determined by the indication of the exam, and the clinical report may not include detail of all the lesions, but is a synopsis of the findings and an overview of the disease state and longitudinal change on the current therapy. In general our clinical reports do not have details related to detailed response categories and criteria. Response assessment is reported through a separate portal, which is generally overseen by the clinical trials office.

      Response to therapy is the primary endpoint in most Phase I and II clinical trials. The response criteria to be used and primary and secondary endpoints are detailed in the study protocols based on the type of drug being used. In the era of precision medicine, the traditional response criteria have been evaluated and modified to assess response in targeted and immune therapies. The immune response criteria were developed to follow delayed healing and pseudoprogression. This presentation will discuss details on how I assess response in the context of chemotherapy, targeted therapy and immunotherapy.

      Assessment of response to chemotherapy was performed using RECIST initially published in 2000 and revised in 2009(1,2). In the current practice RECIST 1.1 is used unless specified by the study protocol. The study protocol will detail the modality technique, duration and reporting criteria. In general the detailed protocol will prove information on the modality of choice. In traditional chemotherapy, the effect of cytotoxic drugs results in gross rumor reduction in most cases. Most trials require more than I independent reviewers, and may have an onsite review and a central review for confirmation of response.

      Targeted therapies require matching the right gene mutation to the right pharmaceutical agent, which improves the efficacy and the effectiveness of therapy. Response assessment is on similar lines as chemotherapy. However, response beyond RECIST progression may be allowed on investigator discretion, if the tumor is progressing very slowly and the subject is asymptomatic. In patients with EGFR-mutant NSCLC treated with EGFRTKI, continued EGFR-TKI therapy may be indicated in those patients with progressive disease as these tumors grow slowly over many months and some tumor cells may remain sensitive to EGFR-TKI (3). Erlotinib and crizotinib are commonly continued beyond RECIST progression, because of an initial dramatic response followed by slow progression over many months in relatively asymptomatic patients.

      Immunotherapy trials are assessed using immune response criteria (iRECIST), the main difference between iRECIST and RECIST, is that the patients are allowed to continue on therapy once disease progresses (PD) for another cycle is continued PD, to ensure it is not pseudoprogression(4). Response assessment in immune therapy trials, allows an extra cycle at 4 to 5 weeks after progression is documented before a decision is made to change therapy. Progression is confirmed at the following cycle or with pathology confirmation.

      Additional criteria from PETCT and MRI and CT using volumetric assessment is used in the research arena, but not yet used universally for clinical trials. Modified RECIST(5) is more appropriate for pleural tumors as it improves reproducibility of measurements across reviewers and time points. Volumetric assessment is thought to more representative of the morphological changes but definite cut offs as surrogate of the response need validation(6). MRI can assess both size and cellularity and function and hence MR based response assessment derived from apparent diffusion coefficient and pharmacokinetic parameters such as area under the curve, permeability coefficient and elimination coefficient can provide anatomical and functional response to therapy(7,8).

      It is vital to make a note of any atypical findings and also to recognize adverse events related to the drug and help with timely management. The presentation will detail how I assess response in the real world with case specific examples and illustration of some atypical responses and lesions that can mimic progression.

      slide1.jpg

      References:

      1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New Guidelines to Evaluate the Response to Treatment. J Natl Cancer Inst. 2000;92(3):205–16.

      2. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.

      3. Mok TSK. Living with imperfection. Journal of Clinical Oncology. 2010;28(2):191–2.

      4. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Vol. 18, The Lancet Oncology. 2017. p. e143–52.

      5. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol. 2004;15(2):257–60.

      6. Frauenfelder T, Tutic M, Weder W, Götti RP, Stahel RA, Seifert B, et al. Volumetry: An alternative to assess therapy response for malignant pleural mesothelioma? Eur Respir J. 2011;38(1):162–8.

      7. Ohno Y, Koyama H, Onishi Y, Takenaka D, Nogami M, Yoshikawa T, et al. Non–Small Cell Lung Cancer: Whole-Body MR Examination for M-Stage Assessment—Utility for Whole-Body Diffusion-weighted Imaging Compared with Integrated FDG PET/CT. Radiology. 2008;248(2):643–54.

      8. Giesel FL, Choyke PL, Mehndiratta A, Zechmann CM, von Tengg-Kobligk H, Kayser K, et al. Pharmacokinetic analysis of malignant pleural mesothelioma-initial results of tumor microcirculation and its correlation to microvessel density (CD-34). Acad Radiol [Internet]. 2008 May [cited 2014 Oct 2];15(5):563–70.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES09.03 - How I Decide 1st Line Treatment Options for Metastatic NSCLC Without Driver Mutations - Balancing Efficacy, Toxicity and Cost (Now Available) (ID 3201)

      13:30 - 15:00  |  Presenting Author(s): Martin NA Frueh

      • Abstract
      • Presentation
      • Slides

      Abstract

      Chemotherapy alone has been the accepted standard treatment for patients with stage IV non-small cell lung cancer (NSCLC) for more than two decades based on trials demonstrating a survival benefit and improved quality of life. In the first line setting, the addition of the anti-VEGF antibody (AB) bevacizumab and anti-EGFR ABs cetuximab and necitumumab resulted in modest improvement of survival. Recently, immune-checkpoint inhibitors (ICI) have revolutionized systemic treatment approaches of patients with EGFR/ALK wild type NSCLC in the first and further line setting, mainly due to their ability to achieve long-term tumor control in a subset of patients. Although a considerable proportion of patients doesn`t respond to ICI, immunotherapy is now widely used in combination with chemotherapy as first line treatment in an increasing number of patients as a result of the absence of a reliable predictive biomarker. This situation leaves physicians in the dilemma of balancing the benefit of potential long term disease control in a limited number of patients with the harms which include not only toxicities but also costs. The implementation of novel ICI treatment options in the first line treatment of metastatic NSCLC into current clinical practise will be discussed.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES09.04 - How I Decide 2nd Line Treatment Options for Relapsed/Refractory Metastatic NSCLC (Now Available) (ID 3202)

      13:30 - 15:00  |  Presenting Author(s): Navneet Singh

      • Abstract
      • Presentation
      • Slides

      Abstract

      Management of advanced and metastatic non-small cell lung cancer (NSCLC) has been revolutionized in the past decade with the advent of testing for ‘druggable’ molecular driver alterations and availability of therapies for the same. More recently, immunotherapy (in particular PD-1/PD-L1 immune check point inhibitors) have opened up a fifth frontier for the treatment of this disease. However, barring exceptions, patients with advanced/metastatic NSCLC relapse irrespective of whether they received a targeted therapy or chemotherapy (with/without immunotherapy) or immuno(mono)therapy in the front line setting. This is understandable as cures are uncommon in metastatic disease although sustained and durable responses to immunotherapy and targeted therapies are well known. Treatment of relapsed disease presents a greater challenge as performance status, ability to bear cost of treatment and finally wishes of patients and caregivers often change as opposed to the treatment naïve state. Additional factors also come into play in low and middle income group countries (LMICs) and resource constrained settings.

      Practicing precision medicine remains the goal even for the relapsed setting. However, finding additional targets or drugs for identified secondary targets mandates rebiopsy which may be limited by ease of access to the desired site for rebiopsy as well as patients’ willingness to undergo the same. Liquid biopsy (typically blood and less commonly other body fluids) appears to be an increasingly promising alternative to conventional tissue biopsy with the availability of highly sensitive testing platforms (especially NGS) and the ability of the former to provide ‘global’ assessment of biomarker status as opposed to the latter. Tissue heterogeneity is more pronounced in the setting of relapsed disease as compared to treatment naïve settings.

      In case of EGFR mutated NSCLC, the advent of T790M inhibitors (osimertinib) was the preferred treatment approach for patients progressing on 1st/2nd generation EGFR TKIs and with a demonstrable exon 20 T790M mutation on either tissue or liquid biopsy (AURA trial). However, the FLAURA trial led to osimertinib moving to the frontline setting and therefore relapses on osimertinib is typically followed by chemotherapy unless specific mechanisms of resistance can be demonstrated which can be further targeted by available drugs. It is likely that 4th generation TKIs will be available for patients in the coming few years thus providing an opportunity to use another TKI following progression on osimertinib.

      For ALK rearranged NSCLC, there is a similar story. 2nd generation ALK inhibitors (alectinib, ceritinib and brigatinib) were developed and initially approved for patients intolerant to or having progressed on the 1st generation ALK inhibitor crizotinib. The ALEX/J-ALEX trials (for alectinib) and ASCEND-4 trial (for ceritinib) meant that these drugs moved to the front-line setting. In particular data from ASCEND-8 trial showed that 450 mg of ceritinib with a low-fat meal was as effective and better tolerated than the conventional 750 mg taken empty stomach. For resource constrained settings, this has an additional implication of lower cost of treatment. Lorlatinib, a 3rd generation ALK inhibitor, approved for use following progression on the 1st/2nd generation ALK inhibitors described above is also attempting to move to the frontline setting pending results of ongoing trials for this purpose.

      For both EGFR and ALK, the debate on using the best and most effective drug first vs. sequencing lower followed by higher generation drugs continues to be hotly debated as treatment options for progressors on 3rd generation TKIs given upfront are mostly limited to chemotherapy or experimental therapies as part of ongoing clinical trials.

      Platinum based doublet chemotherapy (pemetrexed based for non-squamous histology and gemcitabine/paclitaxel/nab-paclitaxel for squamous histology) was the cornerstone of treatment for patients without a targetable genetic alteration. Docetaxel single agent was the standard 2nd line treatment option and attempts were made to enhance its efficacy by combining it with VEGF inhibitors like ramucirumab (REVEL trial) or nintedanib (non-squamous only; LUME LUNG-1). Simultaneous time period saw the results of PD-1 inhibitors (nivolumab; CheckMate 017 and 057 and pembrolizumab; KEYNOTE 001 & 010) as well as PD-L1 inhibitor (atezolizumab; OAK) and thus these drugs become the preferred and standard 2nd line treatment. However, a similar story as for EGFR and ALK happened herein as well with the KEYNOTE 024 trial (pembrolizumab monotherapy for PD-L1 expression of 50% or higher) and KEYNOTE 189 and 407 trials (pembrolizumab combined with chemotherapy irrespective of PD-L1 expression) leading this drug to be part of front line treatment. Atezolizumab as part of a 4 drug regiment (paclitaxel-carboplatin-bevacizumab-atezolizumab) also appeared to provide similar efficacy in the front line setting (IMPOWER 150) for non-squamous NSCLC although concerns about toxicity remain. The effect of immunotherapy coming to the front line treatment setting (alone or in combination with chemotherapy) also implies that these drugs have no proven role in relapse as there is no data currently that patients treated initially with immune check point inhibitors benefit from the same class of drugs on relapse.

      Patients in LMICs and resource constrained settings tend to get treatment in more conventional ways than listed above as newer drugs and regimens are either not available or are not approved as fast as in the US/Europe or are very expensive. Hence it is fairly common for EGFR mutated patients to receive 1st generation EGFR TKIs, for ALK rearranged patients to receive crizotinib and for those without any driver mutations/rearrangements to receive only platinum doublet chemotherapy in the first line setting. This sort of represents a time lag compared to what is applicable in the US/Europe. The need to provide affordable yet effective treatment remains the primary aim of clinical oncologists in LMICs and precision medicine is therefore informally and practically adapted to the available resources.

      Navneet Singh MD DM

      Email: navneetchd@hotmail.com; singh.navneet@pgimer.edu.in

      [The author is a thoracic medical oncologist and pulmonologist currently working as an Additional Professor of Pulmonary Medicine at PGIMER, Chandigarh, India. He is a member of IASLC’s Staging & Prognostic Factors Committee; Publications and its Regent for South Asia. Additionally, he is Chair of American Society of Clinical Oncology’s(ASCO) International-Development-and-Education-Award(IDEA) Working Group and Thoracic-Cancer Guideline Advisory Group. His detailed profile is accessible at http://www.linkedin.com/in/navneet-singh-160012.]

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES09.05 - Limitations in the Availability of Radiotherapy (Now Available) (ID 3203)

      13:30 - 15:00  |  Presenting Author(s): Jamal Saleh Khader

      • Abstract
      • Presentation
      • Slides

      Abstract

      Limitations in the Availability of Radiotherapy

      Abstract

      The annual global incidence of cancer, according to Globocan 2018 report is 18 million new cancer cases, and the number is projected to rise in 2035 to 25 million cases (13 million deaths), with 70% occurring in low- and middle -income countries (LMICs), where there is a severe shortfall in the availability of radiotherapy (1). Radiotherapy is an essential component of overall curative and palliative cancer care. It is estimated that about half of cancer patients would benefit from radiotherapy for treatment of localized disease, local control, and palliation (2). Yet, this crucial component of the response to cancer has been largely absent from global health discourse, and has received limited domestic and international funding. As a result, there is a worldwide shortfall of radiotherapy services; with more than 90% of the population in low-income countries, lacking access to radiotherapy(2). The growing burden of cancer will place increased demand on the already-scarce radiotherapy services worldwide. A 2015 report by the Global Task Force on Radiotherapy for Cancer Control estimated that by 2035 at least 5000 additional megavolt treatment machines would be needed to meet LMIC demands, together with about 30 000 radiation oncologists, 22 000 medical physicists and 80 000 radiation therapy technologists(3).

      Many of the challenges in delivering radiotherapy in LMICs that were identified including: (a) a shortage of good-quality radiotherapy equipment capable of both simple and more complex radiotherapy treatment delivery, (b) the challenge of servicing the linacs, both for preventative maintenance and upon equipment breakdown and (c) the chronic shortage of adequately trained personnel(3). In LMICs, the costs of equipment, building and salaries are 81, 9 and 10% of the total cost of the facility, respectively, compared with 30, 6 and 64% in high-income countries. Some of the challenges facing LMICs are also related radiofrequency power systems, linac beam production and control, durable and sustainable power supplies, computer applications in radiation therapy & linac safety and operability(4). Investment in radiotherapy is crucial and an imperative in low-income and middle-income countries, if unnecessary cancer deaths and suffering are to be avoided. Investment in radiotherapy is timely for many reasons, including evidence from The Lancet Commission on Investing in Health (5) showing the benefits of investing in health to achieve convergence in health outcomes between low-income countries and upper-middle-income countries, the momentum for investing in low-income and middle-income countries to expand surgery,(6) and the UN resolution on sustainable development, which recognises that “universal health coverage is a key instrument to enhancing health, social cohesion and sustainable human and economic development”.(7)

      Conclusion

      It is a call for action to enhance population-based cancer control plans, expansion of access to radiotherapy, human resources for radiotherapy, sustainable financing to expand access to radiotherapy and align radiotherapy access with universal health coverage.

      References

      1.Freddie B et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.

      CA CANCER J CLIN 2018;68:394–424

      2.Barton MB et al. Estimating the demand for radiotherapy from the evidence: a review of changes from 2003 to 2012. Radiother Oncol 2014; 112: 140–44.

      3.Atun R, et al. Expanding global access to radiotherapy. Lancet Oncol 2015;16(10):1153e1186

      4. Dosanjh M et al. Developing Innovative,Robust and Affordable Medical Linear

      Accelerators for Challenging Environments, Clin Oncol , 2019 Jun; 31(6):352-355

      5.Jamison DT et al. Global health 2035: A world converging within a generation.

      Lancet 2013; 382: 1898–955.

      6. Meara JG et al. Global Surgery 2030: evidence and solutions for achieving health,

      welfare, and economic development. Lancet 2015; 386: 569–624.

      7. UN. Sustainable development, the Future We Want, UN General Assembly

      Resolution, A/66/L.56, para 138–141. http://www.uncsd2012.org/content/documents/

      (accessed July 5, 2015).

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

  • +

    ES17 - Molecular Alterations and Heterogeneity in Mesothelioma (ID 20)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Mesothelioma
    • Presentations: 4
    • Now Available
    • +

      ES17.01 - Mesothelioma Evolution (Now Available) (ID 3247)

      11:00 - 12:30  |  Presenting Author(s): Edward J. Hollox

      • Abstract
      • Presentation
      • Slides

      Abstract

      Malignant pleural mesothelioma (MPM) is mostly caused by prior exposure to asbestos fibres. It has a long but variable latency period following exposure, with a median of around 40 years but a range between 20-70 years, possibly reflecting the length and level of asbestos exposure as well as other environmental and genetic causes. Upon diagnosis, there are limited treatment options, and median survival time is a year, although, again, this is highly variable.

      Understanding the genetic events in the mesothelium between asbestos exposure and diagnosis of MPM is important for two reasons. Firstly, it will inform the biology of MPM tumour growth and potentially highlight different environmental and genetic factors that cause the variation in latency. Secondly, it will help identify key early driver mutations in MPM informing biology and candidate changes for developing approaches for early detection of the cancer.

      Evolutionary genetics is based on inferring past events from current genetic/genomic sequences. It has long been recognised that the development of cancer is an evolutionary process, and the availability of large amounts of DNA sequence data have facilitated an understanding of evolution of tumours using methods mostly borrowed from evolutionary genetics. One powerful approach compares a matched tumour and normal genome, infers the somatic mutations in the tumour, and uses the ratio of mutations that change an amino acid to mutations that don’t change an amino acid (dN/dS ratio) across all genes to identify particular genes that have been positively selected during tumour evolution. This approach can also shed light on overall evolutionary processes that have occurred in the tumour.

      Genomic sequences from multiple regions of the same tumour not only emphasise the molecular heterogeneity of tumours but allow an explicit phylogenetic tree of the evolution of the tumour for each patient, distinguishing somatic mutations that happened early in the tumour's evolution (and are therefore present throughout the tumour) from those that happened late in the tumour evolution.

      Here, I report preliminary findings from a British Lung Foundation/Mesothelioma UK-funded project entitled MEDUSA - Mesothelioma Evolution: Deciphering drUgable Somatic Alterations as potential targets for synthetic lethal therapy. This project uses multiregional sampling of MPMs, together with matched whole blood, to infer a phylogenetic tree of MPMs. The preliminary data presented focuses on the first 20 patients, with between 4 and 5 regions of the tumour analysed per patient. Using whole exome sequencing, the project aims to identify truncal changes, that is, mutations that happened early in the tumour and are present throughout the tumour that can be potential targets for drugs, with the aim of developing personalised, effective tumour treatment for each patient. We focus on copy number changes (deletions and duplications of genes) and confirm that MPM is highly heterogeneous with extensive copy number changes in the genome. We focus on truncal copy number changes in ~20-25% of patients affecting the known mesothelioma tumour suppressor genes BAP1, MTOR, CDKN2A and SETD1. Distinguishing patients that have truncal copy number changes in these genes, in contrast to those patients with copy number changes in the terminal branches of the evolution of the tumour, helps to tailor individualised drug therapies. Our approach emphasises the importance of multiregional sampling of tumours to account for MPM heterogeneity. For example, by sampling the posterior costophenic angle of these MPM from these 20 patients, we would find 10 deletions of CDKN2A, of which only 5 are truncal, with the other five localised to only part of the tumour.

      Multiregional genomic analysis and evolutionary genetics approaches can illuminate the history of a tumour and have the potential to guide therapy. They also provide the framework for follow-on studies in a patient, such as analysing the origin of metastases and identifying the effects on the tumour of treatment. The extra information provided by multiregional sampling supports the idea that this approach should become routine in tailoring the treatment to the tumour in MPM.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES17.02 - Molecular Heterogeneity (Now Available) (ID 3248)

      11:00 - 12:30  |  Presenting Author(s): Didier Jean

      • Abstract
      • Presentation
      • Slides

      Abstract

      Molecular heterogeneity in Malignant Pleural Mesothelioma

      Malignant Pleural Mesothelioma (MPM), a rare thoracic tumor strongly linked to asbestos exposure, is one of the most aggressive cancer with a very poor prognosis. Clinical trials have highlighted MPM diversity in terms of prognosis and patients’ response to anti-cancer agents, suggesting an underlying tumor heterogeneity. As current treatment options are rarely curative, a better characterization of inter and intra-tumor heterogeneity is essential for the identification of new therapeutic strategies, and for the implementation of precision medicine with the aim to improve the cure to this dreadful cancer.

      The first level of inter-tumor heterogeneity in MPM is histologic with three main histologic types i.e. epithelioid, sarcomatoid and biphasic. The latter is also an evidence of intra-tumor heterogeneity as the biphasic histologic type is a mix of variable proportion of epithelioid and sarcomatoid tumor cells. The histologic heterogeneity is even more complex with the characterization of several histologic subtypes (1).

      Large-scale omics and NGS (Next Generation Sequencing) studies also highlighted MPM heterogeneity at the molecular level. MPM show a complex pattern of chromosomal abnormalities and mutations, so it is difficult to take into account this molecular heterogeneity of MPM solely on the basis of chromosomal or genetic alterations. We and others, using unsupervised hierarchical clustering based on transcriptomic or integrated multi-omics data, defined molecular classification in 2 and 4 tumor subtypes (2-4). These molecular subtypes are related to histology and associated to prognosis, to specific mutations in genes such as BAP1 and to the deregulation of specific signal pathways such as epithelial-mesenchymal transition (EMT). Smaller and highly homogeneous subtypes were also defined by taking into account molecular subtypes and mutation profiles such as the one characterized by a double inactivation in the two tumor suppressor genes related to Hippo signal pathway, NF2 and LATS2 (5). Interestingly, based on preclinical studies, a potential target therapy has been proposed for this subtype illustrating the interest to define homogenous tumor subtypes in order to develop new therapeutic approaches.

      However, these molecular classifications in subtypes have some limitations. First, they take into account only inter-tumor heterogeneity but not intra-tumor heterogeneity, which is poorly described at the molecular level in MPM (6). Second, a meta-analysis comparing all molecular subtypes obtained by unsupervised hierarchical clustering of several different transcriptomic dataset highlighted only two main subtypes, which are highly correlated in all datasets. Apart from these two opposite subtypes corresponding to pure epithelioid and sarcomatoid phenotypes, intermediate subtypes could simply reflect various cut-offs of a continuum combining epithelioid and sarcomatoid entities, which could be better defined using molecular gradients (7).

      For these reasons with the aim to better characterize MPM molecular heterogeneity, we used a deconvolution method that decomposes the MPM transcriptomic profile of each tumor as a combination of epithelioid and sarcomatoid components. We determined the proportion of these epithelioid and sarcomatoid components (E.score and S.score, respectively) in large series of tumors. These two opposite histo-molecular gradients were related to histology types and to subtypes of MPM molecular classification (7).

      The underlying oncogenic pathways driving the establishment of the epithelioid and sarcomatoid related cell entities were specified. Integration of transcriptome, methylome and miRNome data showed the strong contribution of epigenetic regulation. We also highlighted the link between the histo-molecular gradients and the tumor microenvironment and the immune contexts. A strong positive correlation was observed between the S.score and the infiltration of T lymphocytes, monocytes, fibroblasts and endothelial cells, while the E.score was linked to natural killer cells infiltration and complement pathway. These results suggested the presence of an adaptive immune response in tumors with a high S-score and of an innate immune response in tumors with a high E-score. The S.score was also strongly correlated with high expression of most immune checkpoint inhibitors, including CD274 (PDL1) and CTLA4 (7).

      More importantly, we highlighted the potent clinical impact of histo-molecular gradients on prognosis and on personalized therapeutic strategies in MPM. First, we showed that the S.score has a strong prognostic value, higher than histologic and molecular classifications. Second, our data supported that these histo-molecular gradients might be used to guide therapeutic strategies such as targeted therapies by performing preclinical studies. Third, the strong correlation of the S.score with T lymphocytes infiltration and immune checkpoint inhibitors expression supports that a high S.score could be predictive of immunotherapy based on anti-PDL1 and anti-CTLA4 inhibitors (7). Prediction of patients responding to these inhibitors is particularly important given the recent promising results of this immunotherapy for some MPM patients (8).

      More recently, we have performed a genetic profiling, focusing on the main key genes altered in mesothelial carcinogenesis, of a large collection of MPM with complete clinical annotations and well-characterized for heterogeneity using current available tumor classifications. The unpublished results provided a comprehensive overview of the genetic landscape of MPM taking into account the histologic and molecular heterogeneities.

      References:

      1. Husain A. N. et al. Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med. 2013, 137: 647-667.

      2. Bueno R. et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet. 2016, 48: 407-416.

      3. de Reynies A. et al. Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition. Clin Cancer Res. 2014, 20: 1323-1334.

      4. Hmeljak J. et al. Integrative Molecular Characterization of Malignant Pleural Mesothelioma. Cancer Discov. 2018, 8: 1548-1565.

      5. Tranchant R. et al. Co-occurring mutations of tumor suppressor genes, LATS2 and NF2, in malignant pleural mesothelioma. Clin Cancer Res. 2017, 23: 3191-3202.

      6. Oehl K. et al. Heterogeneity in Malignant Pleural Mesothelioma. Int J Mol Sci. 2018, 19.

      7. Blum Y. et al. Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications. Nat Commun. 2019, 10: 1333.

      8. Scherpereel A. et al. Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial. Lancet Oncol. 2019, 20: 239-253.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES17.03 - Heterogeneity & Immune Checkpoint Expression (Now Available) (ID 3249)

      11:00 - 12:30  |  Presenting Author(s): Aaron S. Mansfield

      • Abstract
      • Presentation
      • Slides

      Abstract

      Mesothelioma is a spatially complex malignancy. Morphologic heterogeneity is commonly identified, especially with surgical resection that can unmask distinct histologic components across sites of disease. Molecular analyses of HUMARA methylation patterns on the X-chromosome, CDKN2A deletions, and single nucleotide variants from multiple tumor sites all suggest that mesothelioma is polyclonal with multiple genetic subclones within each tumor. Temporal histologic heterogeneity has also been reported with sarcomatoid differentiation during progression of disease. The selective pressures of the microenvironment and therapies may further drive tumor heterogeneity. With the application of immune checkpoint inhibitors for the treatment of this disease, the expression of immune checkpoints and the immunologic milieu of mesothelioma has been increasingly investigated. Whereas most studies report immune checkpoint expression from a single site of disease obtained from a single time point, distinct immunologic patterns have been observed within tumors from different sites. The molecular and immunologic heterogeneity of mesothelioma may have prognostic and therapeutic implications.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES17.04 - New Insights into the Molecular Characteristics and Intra-Tumor Heterogeneity of Malignant Pleural Mesothelioma from the MESOMICS Project (Now Available) (ID 3250)

      11:00 - 12:30  |  Presenting Author(s): Lynnette Fernandez-Cuesta

      • Abstract
      • Presentation
      • Slides

      Abstract

      Malignant pleural mesothelioma (MPM) is a rare but deadly disease, which molecular characteristics have only recently been uncovered through large-scale genomic studies (Bueno Nat Genet 2016; Hmeljak Cancer Discov 2018). Although insightful and important, many questions are still unanswered, which could be addressed with additional comprehensive and integrative genomic analyses. In addition, we have recently performed a reanalysis of the transcriptome data of the two aforementioned cohorts with no assumption of discretness, in which we have uncovered the importance of angiogenesis and the immune system for understanding the diversity of MPM molecular phenotypes (Alcala et al. under review). Intra-tumour heterogeneity (ITH) is commonly reported in MPM at the histopathological level; however, the question of the molecular ITH of this disease has not been comprehensively addressed so far. Only one recent study has highlighted the enormous ITH at the microenvironment level (Thapa et al. JTO 2017), suggesting that MPM experience spatially heterogeneous selective pressures, or possibly that there exist MPM clones that differentially alter their micro-environment.

      In close collaboration with the French MESOBANK/MESOPATH, we have started the MESOMICS project aiming at performing a molecular characterization of a large series of MPM through the integration of muti-omic data and detailed epidemiological and clinical information in order to better understand this understudied and deadly disease. For this we have collected 130 fresh frozen tumors and their matched-normals from all the three MPM types (epithelioid, biphasic, sarcomatoid) and the main morphological subtypes of the epithelioid MPM. We have performed whole-genome sequencing, transcriptome sequencing and 850K methylation arrays in all these samples. For 12 of them we had access to several regions of the tumor, which allowed us to perform ITH analyses. The preliminary analyses of these data will be presented and discussed.

      Website: RareCancersGenomics.com

      Twitter: @CancersRare

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

  • +

    ES19 - Recently Diagnosed Malignant Pleural Effusion (ID 22)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Interventional Diagnostics/Pulmonology
    • Presentations: 5
    • Now Available
    • +

      ES19.01 - Benefits and Limitations of Systemic Therapy for Malignant Pleural Effusion (Now Available) (ID 3258)

      14:00 - 15:30  |  Presenting Author(s): Anne Tsao

      • Abstract
      • Presentation
      • Slides

      Abstract

      Systemic therapy for metastatic non-small cell lung cancer is directed by molecular profiling. Ideally, genetic sequencing and PD-L1 immunohistochemistry should be performed on tumor cells obtained from malignant pleural effusions where the diagnosis of non-small cell lung cancer is evident. This discussion will review the recommended up to date testing practices and the subsequent systemic therapy decisions for patients with metastatic non-small cell lung cancer.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES19.02 - Best Endoscopic Tools for the Best Results (Now Available) (ID 3257)

      14:00 - 15:30  |  Presenting Author(s): Mohammed Munavvar

      • Abstract
      • Presentation
      • Slides

      Abstract

      Best Endoscopic Tools for the Best Results

      Dr M Munavvar

      Lancashire Teaching Hospitals, Preston, UK

      Introduction

      Undiagnosed pleural effusion is an increasingly common clinical problem and represents significant burden of disease both to patients and healthcare resources. With the increase in annual incidence of both primary and secondary pleural malignancies, better diagnostics and treatment options are very much needed.

      Medical thoracoscopy, also known as local anaesthetic thoracoscopy [2], is a procedure where a rigid or semi-rigid scope is inserted into the pleural cavity via a port for direct visualisation of the pleura and biopsy of abnormal areas, besides completion of talc poudrage, where appropriate. It is usually performed under conscious sedation and local anaesthesia. This procedure avoids risks of general anaesthesia and single lung ventilation, required for video-assisted thoracoscopic surgery (VATS) and therefore can be performed in patients who are unfit for anaesthesia/surgery. The procedure of thoracoscopy is performed in a controlled environment such as in an operating theatre setting, endoscopy suite or treatment room with adequate staffing.

      Diagnostic advantage

      A significant number of cases of pleural effusion are undiagnosed after a single diagnostic pleural aspiration and the diagnostic yield of pleural fluid cytology is only approximately 60% [3]. A second aspiration only modestly increases diagnostic yield by 15% and a third sample is non-contributory [3]. A blind pleural biopsy (also known as closed pleural biopsy) increases the diagnostic yield above pleural fluid cytology by only 7-27% [3]. In mesothelioma however, the diagnostic yield of pleural fluid cytology is even lower, at around 32% [4]. A blind pleural biopsy only increases sensitivity to around 50% [5].

      Medical thoracoscopy is substantially superior in diagnostic power compared to pleural fluid cytology and blind pleural biopsy. As it allows direct visual assessment of the pleura and subsequent biopsy of the abnormal areas, it maximises diagnostic yield to >90% in malignant pleural diseases [5,6]. Rigid thoracoscopy generates similar diagnostic yield compared to semirigid thoracoscopy in exudative pleural effusions but larger biopsy samples can be obtained during rigid thoracoscopy [5,6].The sensitivity of medical thoracoscopy in malignant mesothelioma appears to be equally good and the efficacy of rigid medical thoracoscopy in regards to diagnosis in pleural malignancy is as high as VATS [2].

      With the increasing need to secure an accurate diagnosis and plan optimal treatment in possible pleural malignancy, medical thoracoscopy offers a high diagnostic yield earlier in the patient journey. Therefore, this is the preferred procedure where the option exists and helps to reduce the need for repeated diagnostic procedures and reduces the time taken to establish diagnosis and commence appropriate treatment.

      Medical thoracoscopy as a therapeutic procedure

      Another advantage of medical thoracoscopy is that it is a diagnostic and therapeutic procedure in the same setting. Complete drainage of pleural fluid can be achieved during the procedure and talc poudrage can also be performed during medical thoracoscopy. It is a highly effective method of pleurodesis with an efficacy of 84% at 1 month, which is at least equivalent to talc slurry via a seldinger chest drain, with possibly increased efficacy in the subgroup of patients who have breast or lung carcinoma and without trapped lung [2].

      Medical thoracoscopy is also effective in the management of TB pleurisy and empyema. Septations and adhesions in complex infected effusions can be divided during thoracoscopy which can facilitate accurate chest tube placement and drainage.

      Advanced Thoracoscopy Techniques

      Narrow Band Imaging- using Semirigid Thoracoscope

      Autofluorescence Rigid Thoracoscopy

      Biopsy- with Insulated Tip Diathermy Knife

      Cryobiopsy- using Semirigid Thoracoscope

      Rigid Thoracoscope

      Semi-rigid Thoracoscope

      References:

      Diacon AH, Van de Wal BW, Wyser C, et al. Diagnostic tools in tuberculous pleurisy: a direct comparative study. Eur Respir J 2003;22:589e91.

      Rahman NM, Ali NJ, Brown G, Chapman SJ, O’Davies RJ, Downer NJ, Gleeson FV, Howes TQ, Treasure T, SinghS and Phillips GD Local anaesthetics thoracoscopy: British Thoracic Society pleural disease guideline 2010. Thorax 2010;65(Suppl 2):ii54-ii60

      Mohan A, Chandra S, Agarwal D, Naik S and Munavvar M. Utility of semirigid thoracoscopy in the diagnosis of pleural effusions: a systematic review. Journal of Bronchology and Interventional Pulmonology 17 (3), 195-201

      Munavvar M, Khan MAI, Edwards J, Waqaruddin Z and Mills J. The autoclavable semirigid thoracoscope: the way forward in pleural disease? Eur Respir J 2007; 29: 571-574

      Dhooria S, Singh N, Agarwal AN, Gupta D and Agarwal R. A randomized trial comparing the diagnostic yield of rigid and semirigid thoracoscopy in undiagnosed pleural effusion. Respir Care 2014:59 (5), 756-764

      Rozman A, Camlek L, Marc-Malovrh M, Triller N, Kern I. Rigid versus semi-rigid thoracoscopy for diagnosis of pleural disease: a randomized pilot study. Respirology, 2013 May;18(4):704-10.

      Loddenkemper R, Lee P, Noppen M, Mathur PN. Medical thoracoscopy/pleuroscopy: step by step. Breathe. 2011;8(2):156-67.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES19.03 - RCT's on Malignant Pleural Effusion Talc Pleurodesis Managment (Now Available) (ID 3260)

      14:00 - 15:30  |  Presenting Author(s): Nick Maskell

      • Abstract
      • Presentation
      • Slides

      Abstract

      This talk will focus on 2 recently completed multicentre RCT's in talc pleurodesis for malignant pleural effusions; IPC plus trial (NEJM 2018) and the TAPPS trial (in submission). A summary of these 2 trials is below:

      IPC Plus - Methods: Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evi- dence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial ob- struction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo through the indwelling pleural catheter on an outpatient basis. Talc or placebo was administered on a single-blind basis. Follow-up lasted for 70 days. The primary outcome was successful pleurodesis at day 35 after randomization. Results: The target of 154 patients undergoing randomization was reached after 584 patients were approached. At day 35, a total of 30 of 69 patients (43%) in the talc group had successful pleurodesis, as compared with 16 of 70 (23%) in the placebo group (haz- ard ratio, 2.20; 95% confidence interval, 1.23 to 3.92; P=0.008). No significant be- tween-group differences in effusion size and complexity, number of inpatient days, mortality, or number of adverse events were identified. No significant excess of blockages of the indwelling pleural catheter was noted in the talc group. Conclusions: Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects. (Funded by Becton Dickinson; EudraCT number, 2012-000599-40.)

      TAPPS - Methods We recruited patients with malignant pleural effusion from 17 United Kingdom hospitals over 5 years. On an open-label basis, patients were randomly assigned to receive either 4g talc poudrage at thoracoscopy under conscious sedation, or chest tube insertion under local anesthetic followed by 4g talc slurry. Follow-up lasted for six months. The primary outcome was pleurodesis failure rate three months after randomization, defined as the need for further pleural intervention during follow-up. Secondary outcomes including mortality and cost-effectiveness were also assessed. Results The target of 330 patients was reached after 583 were approached. At three months, pleurodesis failure rate was 36/161 (22%) with poudrage and 38/159 (24%) with slurry (adjusted odds ratio (OR) 0.91, 95% confidence interval (CI) 0.54-1.55, p=0.74). No statistically significant differences were noted in any secondary outcome. Numbers of adverse events were similar between groups. Using a standard threshold, poudrage had a 36% probability of being cost-effective. Conclusions In patients with malignant pleural effusion, there appears to be no additional clinical or cost-effectiveness benefit to choosing talc poudrage at physician-led thoracoscopy over talc slurry through chest tube. (Funded by the United Kingdom National Institute for Health Research).

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES19.04 - How to Deal with a Trapped Lung (Now Available) (ID 3259)

      14:00 - 15:30  |  Presenting Author(s): Y C Gary Lee

      • Abstract
      • Presentation
      • Slides

      Abstract

      TRAPPED LUNG AND MALIGNANT PLEURAL EFFUSIONS

      Y C Gary Lee MBChB PhD FRACP FRCP FCCP

      Professor of Respiratory Medicine, University of Western Australia

      Trapped lung, now also called nonexpandable lung, refers to the observation when an underlying lung fails to fully expand upon removal of pleural fluid or air [1]. It occurs in ~30% of patients with malignant pleural effusions (MPEs) and may arise from thickened visceral pleura (inhibiting lung expansion) or from endobronchial tumor obstruction. The pleural space in patients with nonexpandable lung is usually under high negative pressure. This can lead to transudative fluid accumulation by Starling’s equation, in addition to the underlying MPE formation. This condition is often difficult to manage as fluid often keep recurring to fill up the trapped lung space.

      Patients with MPE and trapped lung often present with breathlessness. It is important to recognize that removal of the fluid can still provide symptom relief despite the nonexpendable underlying lung [2]. A trial of fluid drainage to determine if the patient has symptoms benefits is worthwhile. The current belief is that breathlessness from MPE is a result of altered respiratory mechanics when the hemithorax expands to accommodate the volume of the effusion (see our review [2] for details).

      Patients with nonexpandable lungs usually do not benefit from pleurodesis due to the lack of apposition of the visceral and parietal pleura. Indwelling pleural catheter (IPC) is now a recognized first choice management of MPE in patients with a nonexpendable lung, as recommended in the latest American thoracic Society MPE guidelines (2018) [3]. Several large randomized studies in recent years have testified to the benefits of IPC management of MPEs. The TIME-2 study [4] showed that IPC offered benefits to breathlessness and chest pain similar to conventional talc slurry pleurodesis. The AMPLE trial [5] showed that patients with MPE managed with IPC spent fewer days in hospital and required fewer pleural invasive procedures in their remaining life while enjoying the same level of symptom and quality-of-life improvements as those patients treated with talc pleurodesis. The recently published AMPLE-2 study [6] compared daily catheter drainage vs symptom-guided drainage in patients with MPEs and an IPC. Interestingly 50% of those with initial trapped lung who underwent daily drainage eventually developed spontaneous pleurodesis that allow removal of the catheter. The numbers however were small and the results require verification.

      Conventionally it is believed that surgical decortication of the lung in MPE patients with visceral pleural thickening may allow the lung to re-expand and thus permit successful pleurodesis. Limited objective data exist to support this belief (see our recent review [7]). In the VATS-Meso trial [8] and other observational series, patient who underwent VATS pleurodesis +/- pleurectomy have higher risks of complications especially prolonged post-operative air-leak and thus hospitalization. The planned AMPLE-3 randomized trial will compare IPC treatment with surgical pleurodesis for MPE.

      Patients with MPEs and underlying nonexpandable lung are often excluded in clinical trials and thus their optimal management remains unclear. They represent a sizeable subset of MPE patients and deserve specific attention in future research.

      REFERENCES

      1. Light RW, Lee YCG. Textbook of Pleural Dieaseas. 3rd ed. USA: Taylor & Francis; 2016.

      2. Thomas R, Jenkins S, Eastwood PR, et al. Physiology of breathlessness associated with pleural effusions. Curr Opin Pulm Med. 2015;21(4):338-45.

      3. Feller-Kopman DJ, Reddy CB, DeCamp MM, et al. Management of Malignant Pleural Effusions. An Official ATS/STS/STR Clinical Practice Guideline. Am J Respir Crit Care Med. 2018;198(7):839-49.

      4. Davies HE, Mishra EK, Kahan BC, et al. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. JAMA. 2012;307(22):2383-9.

      5. Thomas R, Fysh ETH, Smith NA, et al. Effect of an Indwelling Pleural Catheter vs Talc Pleurodesis on Hospitalization Days in Patients With Malignant Pleural Effusion: The AMPLE Randomized Clinical Trial. JAMA. 2017;318(19):1903-12.

      6. Muruganandan S, Azzopardi M, Fitzgerald DB, et al. Aggressive versus symptom-guided drainage of malignant pleural effusion via indwelling pleural catheters (AMPLE-2): an open-label randomised trial. Lancet Respir Med. 2018;6(9):671-80.

      7. Fitzgerald DB, Koegelenberg CFN, Yasufuku K, et al. Surgical and non-surgical management of malignant pleural effusions. Expert Rev Respir Med. 2018;12(1):15-26.

      8. Rintoul RC, Ritchie AJ, Edwards JG, et al. Efficacy and cost of video-assisted thoracoscopic partial pleurectomy versus talc pleurodesis in patients with malignant pleural mesothelioma (MesoVATS): an open-label, randomised, controlled trial. Lancet. 2014;384(9948):1118-27.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      ES19.05 - Surgical Management of Malignant Pleural Effusion (Now Available) (ID 3261)

      14:00 - 15:30  |  Presenting Author(s): Alan D Sihoe

      • Abstract
      • Presentation
      • Slides

      Abstract

      At first glance, it would seem that the thoracic surgeon has little role to play nowadays in the management of malignant pleural effusion (MPE). Substantial advances have been made in the understanding of the pathophysiology of MPE and its diagnosis. There is broad consensus that pleurodesis should generally be given at the bedside rather than in the operating theatre, while intractable cases can be managed with indwelling catheters. Even where interventions into the chest are required, the advent of ‘medical’ thoracoscopy appears to have diminished the role of surgeons in managing MPE.

      However, it would be wrong to presume that thoracic surgeons may be completely excluded from the MPE scene. There remain situations were surgery is still required for a definitive diagnosis or effective palliation. Surgeons continue to have more extensive experience with biopsy, drainage, and ‘rapid pleurodesis’ – yielding high rates of success. More importantly, minimally invasive Video-Assisted Thoracic Surgery (VATS) has evolved significantly in recent years. Uniportal VATS is becoming increasingly utilized, and is often complemented by technological advances such as non-intubated anesthesia. The latest advances in minimally invasive thoracic surgery have ensured that the high success rate of surgery is now coupled with surprisingly little – if any – functional or physiological ‘cost’ to the patient with MPE. The ‘VATS’ available today is not the same VATS from even a few years ago.

      This presentation provides an overview of the current surgical options available in the management of MPE. The modern thoracic surgeon remains fully equipped and prepared to contribute to the multi-disciplinary care of patients with this complication.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

  • +

    IBS01 - My Oligometastatic Oncogene Driven Patient (Ticketed Session) (ID 32)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Targeted Therapy
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 07:00 - 08:00, Tokyo (1982)
    • +

      IBS01.01 - Systemic or Local Treatment: What to Do First? (Now Available) (ID 3315)

      07:00 - 08:00  |  Presenting Author(s): Benjamin J Solomon

      • Abstract
      • Presentation
      • Slides

      Abstract

      In the era of increasingly effective systemic treatments including EGFR and ALK tyrosine kinase inhibitors we will review the rationale for aggressive treatment of oligometastatic or oligopersistent disease in order to improve long term treatment outcomes. In the setting of oligometastatic disease to the brain, treatment of one or more sites of brain metastases with effective systemic treatment with stereotactic radiotherapy may allow whole brain radiation to be avoided or delayed. For extracranial disease, locally ablative therapies to solitary sites of metastases may enable potentially curative approaches to primary tumours. Further, benefit for treatment of oligo-persistent sites of disease after intial systemic treatment with local consolidative therapy has been demonstrated. Central to aggressive local approaches are appropriate staging investigations including MRI Brain and FDG-PET scan to determine the extent of metastatic disease.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      IBS01.02 - Strategies Treatment After Oligoprogression (Now Available) (ID 3316)

      07:00 - 08:00  |  Presenting Author(s): Federico Cappuzzo  |  Author(s): Lorenza Landi

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer remains the leading cause of cancer-related mortality with more than 50% of the cases diagnosed at advanced stage. For decades, metastatic Non-Small-Cell Lung Cancer (NSCLC) has been considered as incurable disease with limited therapeutic opportunities. In such context, local ablative therapies (LAT), mainly represented by surgical metastasectomy, was the sole treatment with curative intent for selected patients with single brain or adrenal lesion.

      However, improvements in the knowledge of cancer biology coupled with progresses in systemic therapy positively impacted the duration and quality of life. This is the case of NSCLC carrying epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) rearrangement, where targeted therapies have changed the natural history of the disease, with median survival exceeding 4 years. Beyond EGFRmutations and ALKrearrangement, additional actionable alterations have been identified, includingBRAFmutations or ROS1rearrangements as the latest entered in clinical practice. Specific therapies are now available in clinic for all of these aberrations, with osimertinib, alectinib, crizotinib or the combination of dabrafenib and trametinib as the best first-line option for individuals harboring alterations respectively in the EGFR, ALK, ROS1or BRAF. Unfortunately, after an initial response all patients eventually progress. From a clinical point of view, there are two main patterns of progression including rapid and systemic progression or slow, limited and often indolent progression. In the first scenario, shift to a second line therapy is recommended. In the other case (oligoprogressive disease), LAT plus continuation of front-line inhibitor given beyond progression seems the best option.

      The oligoprogressive state is characterized by a limited number of sites in progression, implying that the other sites remain controlled and therefore sensitive to systemic treatments. The advent of non-invasive techniques such as stereotactic radiotherapy, radiofrequency, and mini-invasive surgery has led to a precise re-evaluation of LATs in this situation. Local treatment of the oligoprogressive lesions may allow modification of the natural history of the disease, maintenance of effective systemic targeted treatment and, ultimately, to improved survival. In addition, some LATs have the advantage that can be repeated over time in difficult-to-treat organs as brain. Data validating an aggressive local therapeutic approach in oligoprogressive NSCLC patients are currently limited and essentially retrospective. Several international trials are ongoing and their results could contributing in better defining the role of radical local treatment in oligoprogressive advanced NSCLC patients.

      Unfortunately, even if the addition of a LAT contributes in disease control, majority of patients finally relapse and die for additional metastatic spread. Therapy options at the time of oligometastatic progression are largely influenced by previous therapies, site of progression and molecular portrait of the disease. Molecular characteristics are of particular relevance for defining the possibility of sequential use of additional target agents. This is the case of T790M EGFR mutation occurring in the vast majority of patients progressing after old generation EGFR TKIs for which osimertinib is superior to standard platinum-doublet chemotherapy. Viceversa, in absence of the acquired mutation (T790M negative), chemotherapy or combinations of chemotherapy and immunotherapy should be the preferred choice.

      In conclusion, molecular target therapies and more recently immunotherapy significantly improved survival of patients presenting with metastatic disease at diagnosis. However, acquired resistance inevitably occurs, limiting patient survival. A subset of patients presenting oligometastic disease represent a unique subgroup of patients who can benefit from LAT followed by continuation of systemic therapy. Randomized clinical trials are needed the role of LAT in this context.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

  • +

    IBS18 - Essentials in Biomarker Testing for Lung Cancer (Ticketed Session) (ID 49)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Pathology
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 07:00 - 08:00, Tokyo (1982)
    • +

      IBS18.01 - Testing Guidelines in 2019 (Now Available) (ID 3369)

      07:00 - 08:00  |  Presenting Author(s): Mary Beth Beasley

      • Abstract
      • Presentation
      • Slides

      Abstract

      Molecular alterations occurring in lung cancer which are either amenable or potentially amenable to treatment with targeted therapies have been identified at an exponential rate in the past decade. Consequently, an increasing number of post-treatment resistance mechanisms have also been identified. Adequate molecular testing is therefore critical for the identification of such alterations for appropriate treatment planning. As such, the first joint CAP/IASLC/AMP molecular testing guidelines were published in 2013 and were expanded in the updated 2018 guidelines. The necessity for this was due not only to the rapid advances in identification of targetable mutations but also to improved technologies with which genetic variants could be identified. Briefly, the 2018 guidelines recommend that, at a minimum, testing for EGFR hot-spot mutations as well as ALK and ROS translocations must be performed. Testing for BRAF, RET, ERBB2, KRAS and MET alterations were not recommended as stand-alone assays but were deemed appropriate as part of larger multiplex panels. EGFR T790M testing was the only strong recommendation for patients with targetable mutations who relapsed on targeted therapy. The guidelines were recommended for advanced stage adenocarcinomas or tumors with an adenocarcinoma component. Much latitude was left to individual practices in regard to testing early stage cancers and tumors with non-adenocarcinoma histology. European guidelines from ESMO provide similar recommendations regarding EGFR and ALK testing.

      In the time since the publications of these guidelines in 2018, the number of therapeutic targets has continued to increase. Additionally, there has been increased focus on neoadjuvant use of targeted therapies. While these neoadjuvant trials primarily focus on EGFR, ALK and ROS abnormalities, some extend beyond this scope to include mutations in genes such as MET, which are not part of the 2018 minimal testing criteria. All of these factors contribute to the increasing challenges of providing sufficient testing for optimal patient care. Coverage of the ever-expanding list of targetable alterations is somewhat ameliorated by the recommendation of multiplexed next-generation sequencing panels (NGS) over single gene testing in order to identify treatment options beyond the minimal recommendations. NGS allows for a larger number of tests to be performed on a smaller amount of material, which is particularly critical given that most patients are diagnosed at an advanced stage and may only have a small biopsy or cytology specimen available as opposed to a resection. While misconceptions remain, cytology specimens are perfectly adequate for molecular testing provided sufficient material is present, an issue which can be a factor in any small biopsy specimen. Molecular testing on cytology specimens is typically performed on cell block preparations; however, results have also been achieved from other types of cytology preparations and supernatant material. In spite of these advances, it is recognized that significant knowledge gaps and limitations exists in regard to testing. As such, a significant number of lung cancer specimens do not undergo appropriate molecular testing. Further, access to testing, debates regarding cost-effectiveness, issues with reimbursement and optimal approaches in resource-limited areas remain a challenge.

      Selected references:

      Bellevicine C, Troncone G. The cytopathologist's expanding role in the 2018updated molecular testing guidelines for lung cancer. Cancer Cytopathol. 2018 Sep;126(9):753-755.

      Kerr KM, Bubendorf L, Edelman MJ, Marchetti A, Mok T, Novello S, O'Byrne K,Stahel R, Peters S, Felip E; Panel Members; Panel Members. Second ESMO consensusconference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol. 2014 Sep;25(9):1681-90.

      Lindeman NI, Cagle PT, Aisner DL, Arcila ME, Beasley MB, Bernicker EH,et al.Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018 Mar;142(3):321-346.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      IBS18.02 - Tests by Next Generation Sequencing (Now Available) (ID 3370)

      07:00 - 08:00  |  Presenting Author(s): Lynette M Sholl

      • Abstract
      • Presentation
      • Slides

      Abstract

      Next generation sequencing (NGS) encompasses a family of technologies that effectively multiplex and digitize nucleic acid sequencing. The major technical platforms used in clinical practice include hybrid capture and amplicon sequencing, either of which can be applied to tumor or cell free DNA testing. Essential steps for any NGS assay include: 1) capture of some or all of the genome; 2) massively parallel sequencing; 3) alignment of the sequencing reads to a reference genome; 4) variant calling and 5) variant interpretation. Each of these steps has a major influence on the assay output, including breadth of coverage (how much of the genome to sequence?), depth of sequencing (how sensitive is the assay?), accuracy, and clinical relevance. In general, DNA hybrid capture assays are optimized for breadth, both in terms of overall genomic real estate (from 100s of genes to the entire genome) and for capturing complex changes such as copy alterations and structural variants. The drawback to the approach, however, is high cost, limited analytic sensitivity, and suboptimal capture and sequencing of highly repetitive regions, leading to poorly-covered or uncovered areas of the genome. Amplicon based sequencing, in contrast, requires a much more focused design. This approach uses PCR to capture the genomic regions of interest and then employs massively parallel sequencing to interrogate each individual PCR amplicon. This approach is lower cost, more sensitive, and faster than hybrid capture, but is best suited for small targeted panels (10s to 100s of genes), is less reliable for detection of copy number changes and rearrangements, and is prone to PCR-related errors. Many of the large academic and commercial NGS panels rely on hybrid capture technology to detect a range of mutations, losses and amplifications, and insertion-deletion/rearrangement events occurring across several hundred genes implicated in human tumorigenesis.1,2

      In addition to revealing the mutational status of characterized oncogenes and tumor suppressor genes, these panels can uncover a host of changes to the DNA representing underlying mutagenic processes or DNA repair defects. For example, mismatch repair deficiency/microsatellite instability is characterized by insertion-deletion events in association with repetitive stretches of DNA and/or certain patterns of nucleotide substitution (C>T changes with an adjacent 3' or 5' guanine). Many laboratories have leveraged existing panel sequencing assays to detect mismatch repair deficiency and are beginning to replace PCR and/or immunohistochemistry screening to identify patients at risk of Lynch syndrome and/or as a biomarker for response to PD-1 inhibition.1,3 Beyond detection of specific DNA damage signatures, the ability to quantify mutational changes on NGS platforms has given rise to the concept of tumor mutational burden (TMB) and the recognition that this may serve as a biomarker for response to immune checkpoint inhibitors. Attempts to compare TMB values across testing platforms has focused attention on the wide technical and informatic variation intrinsic to different NGS assays that may influence TMB calculation, including gene content, choice of tumor-only vs tumor/normal paired sequencing, germline filtration methods, and unrelated clonal processes (such as clonal hematopoeisis). 4 As a result, identification of a single cutpoint for predicting therapeutic response to immunotherapy is challenging and has driven efforts to standardize NGS panels for TMB detection. 5

      While most DNA-based NGS panels in use today are sufficiently sensitive for reliable detection of single nucleotide substitutions (e.g. KRAS G12D; EGFR L858R) or small insertion deletions (EGFR exon 19 deletion mutations), these panels often fall short in detection of large structural variants including rearrangements.6 Functional rearrangements typically result from gene breakages and fusions occurring within intronic (non-coding) sequences. On a per gene basis, introns tend to be significantly larger than coding exons, which means that an NGS assay designed with cost and sensitivity concerns in mind must have restricted overall intronic coverage. In addition, introns tend to contain a much higher proportion of repetitive elements, thus the tools used for rearrangement detection must be able to discern the presence of these variants despite low sequencing coverage and nonspecific sequence mismatches. In practice, these issues lead to reduced clinical sensitivity for detection of large deletions and rearrangement events. RNA-based NGS platforms, including targeted RNAseq and anchored multiplex PCR, detect the fusion transcript directly, eliminating the need to target introns. Labs may now employ workflows in which a DNA assay is used for mutation and copy changes and an RNA assay is used for rearrangement detection. A substantial minority of DNA sequencing-negative lung cancers may have a fusion detected by an RNA assay, leading some groups to advocate for sequential DNA then RNA testing protocols in driver negative lung adenocarcinomas.7

      NGS is a powerful tool to guide the diagnosis and treatment of patients with lung cancer. Improvements in assay design, chemistry, bioinformatics and variant interpretation will continue to increase its reliability and use across tumor and specimen types. Coordination with experts versed in the limitations of the technology is essential for appropriate implementation in clinical practice.

      References:

      1. Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 2017; 23(6): 703-13.

      2. Sholl LM, Do K, Shivdasani P, et al. Institutional implementation of clinical tumor profiling on an unselected cancer population. JCI Insight 2016; 1(19): e87062.

      3. Papke DJ, Jr., Nowak JA, Yurgelun MB, et al. Validation of a targeted next-generation sequencing approach to detect mismatch repair deficiency in colorectal adenocarcinoma. Mod Pathol 2018; 31(12): 1882-90.

      4. Garofalo A, Sholl L, Reardon B, et al. The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine. Genome Med 2016; 8(1): 79.

      5. Miao D, Margolis CA, Vokes NI, et al. Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. Nat Genet 2018; 50(9): 1271-81.

      6. Davies KD, Le AT, Sheren J, et al. Comparison of Molecular Testing Modalities for Detection of ROS1 Rearrangements in a Cohort of Positive Patient Samples. J Thorac Oncol 2018; 13(10): 1474-82.

      7. Benayed R, Offin M, Mullaney K, et al. High Yield of RNA Sequencing for Targetable Kinase Fusions in Lung Adenocarcinomas with No Mitogenic Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation Burden. Clin Cancer Res 2019.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

  • +

    IBS22 - JTO Workshop: How to Get Your Manuscript Published (Ticketed Session) (ID 53)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Young Investigators
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/10/2019, 07:00 - 08:00, Tokyo (1982)
    • +

      IBS22.01 - JTO Workshop: How to Get Your Manuscript Published (Now Available) (ID 3382)

      07:00 - 08:00  |  Presenting Author(s): Alex A Adjei

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      IBS22.02 - JTO Workshop: The Life Cycle of a Manuscript (Now Available) (ID 3383)

      07:00 - 08:00  |  Presenting Author(s): Mary S Todd

      • Abstract
      • Presentation
      • Slides

      Abstract

      This session will describe the process of a manuscript from initial submission to final publication. The session will focus on ways that submitting authors can ensure a seamless and timely handling of their manuscripts. Interactions between authors and editorial offices offer insight into common situations and themes. Participants will learn why editorial offices and publishers require what they require. Time will also be devoted to promotion of published work.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

  • +

    MA08 - Pawing the Way to Improve Outcomes in Stage III NSCLC (ID 127)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 12
    • Now Available
    • +

      MA08.01 - Analysis of PD-L1 Expression on Circulating Stromal and Tumor Cells in Lung Cancer Patients Treated with Chemoradiation Therapy and Atezolizumab (Now Available) (ID 2965)

      15:15 - 16:45  |  Presenting Author(s): Steven H Lin  |  Author(s): Alexander Augustyn, Jianzhong He, Yawei Qiao, Zhongxing Liao, Ashvathi Raghavakaimal, Kirby Gardner, John Victor Heymach, Anne Tsao, Daniel Adams

      • Abstract
      • Presentation
      • Slides

      Background

      We have previously shown dynamic changes to PD-L1 expression during chemoradiotherapy (CRT) could be tracked by evaluating PD-L1 expression on circulating cells. How these changes relate to immunotherapy response is unknown. We prospectively monitored PD-L1 expression in 2 cell types found in circulation (Circulating tumor cells [CTCs] and Cancer Associated Macrophage-like Cells [CAMLs]) in locally advanced non-small cell lung cancer (LA-NSCLC) patients (pts) treated with atezolizumab and CRT.

      Method

      Samples were taken from a completed phase II DETERRED trial (NCT02525757) where atezolizumab was added for one year after completing CRT (N=10) or concurrently and after CRT (N=30). Samples from 39 pts from the study were available for analysis. Baseline blood sample (7.5 ml) were drawn prior to start of CRT (T0), and a second sample was drawn ~1 month after completing CRT (T1), and a 3rd sample was drawn ~2 months after completing CRT (T2). Blood was processed by CellSieve™ microfilters; stained for cytokeratin/PDL1/CD45 to identify CTCs and CAMLs. PD-L1 intensity was measured and grouped by 4 scores: 0-negative, 1-low, 2-medium, & 3-high. Tumor IHC for PD-L1 levels from core biopsies was done with Dako 22c3 and was compared to T0 samples. PD-L1 levels from tumor and in circulating cells were used to evaluate PFS and OS. Significance was assessed by log-rank testing.

      Result

      PD-L1 IHC was available for 85% of pts, and there was at least one cytokeratin positive cell (CTC or CAML) found in 100% of T0 samples. CTCs were found in 33% of T0, 24% of T1 & 43% T2. CAMLs were found in 92% of T0, 97% of T1, & 97% of T2 samples. No correlation was seen comparing tumor PD-L1 expression percentage and the T0 PD-L1 staining intensity on CTCs/CAMLs. Tumor PD-L1>1% was found in 58% and >50% in 24% of IHC samples, yet there was no correlation between tumor PD-L1 expression and PFS or OS. At T0, PD-L1 expression in CTCs/CAMLs was low (0-1) in 18 pts and high (2-3) in 15, but no relationship to PFS (HR=0.6, 95%CI 0.2-1.7, p=0.48) or OS (HR=1.7, 95%CI 0.5-6.4, p=0.66) was found. However, pts with high PD-L1 at T1 or T2, regardless of levels at T0, had a trend towards improved PFS (HR 2.5, 95%CI 0.7-8.6, p=0.13), and a significantly better OS (HR 14.2, 95%CI 2.4-81.8, p=0.003). Interestingly, of the 15 pts who had low PD-L1 at T0, 7 had induced PD-L1 expression at T1 or T2. All samples with induced PD-L1 expression had better PFS (HR 8.3, 95%CI 1.4-50.2, p=0.02) and OS (HR 8.7, 95%CI 1.2-64.0, p=0.03) compared to those who remained low.

      Conclusion

      While baseline tumor or circulating cellular PD-L1 expression was not correlated with clinical outcomes, sequential monitoring of high PD-L1 expression in CTCs/CAMLs after CRT appeared to be associated with better clinical outcomes in pts who received consolidation atezolizumab after CRT, particularly in pts who had induced expression at follow up during the consolidation phase. Dynamic tracking of PD-L1 may serve as a predictive biomarker for immunotherapy effectiveness in LA-NSCLC after CRT.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA08.02 - Durvalumab Impact in the Treatment Strategy of Stage III Non-Small Cell Lung Cancer (NSCLC): An EORTC Young Investigator Lung Cancer Group Survey (Now Available) (ID 608)

      15:15 - 16:45  |  Presenting Author(s): Matteo Giaj Levra  |  Author(s): Justin Benet, Baktiar Hasan, Thierry Berghmans, Alessio Bruni, Anne Marie Clasina Dingemans, Niccolo' Giaj Levra, John G Edwards, Corinne Faivre-Finn, Nicolas Girard, Elisa Gobbini, Laurent Greillier, Lizza Hendriks, Sylvie Lantuejoul, Antonin Levy, Silvia Novello, Mary O'Brien, Martin Reck, Alessia Pochesci, Jessica Menis, Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      Stage III NSCLC represents a very heterogeneous population with extremely different treatment modalities including surgery, chemotherapy (CT) and radiotherapy (RT), mostly in combination. The results of the PACIFIC trial have now been reported in full including an overall survival (OS) benefit with durvalumab in addition to concomitant CT-RT. An electronic European survey was circulated to evaluate the impact of durvalumab in the staging and treatment strategy of stage III disease.

      Method

      A Young Investigator EORTC Lung Cancer Group survey containing 31 questions, was distributed between 31/01/18 and 31/03/19 to EORTC LCG and several European thoracic oncology societies’ members

      Result

      206 responses were analyzed (radiation oncologist: 50% [n=103], pulmonologist: 26.7% [n=55], medical oncologist: 22.3% [n=46]; 81.5% with >5 years experience in treating NSCLC). Italy (27.7%, n=57), Netherlands (22.8%, n=47), France (13.6%, n=28), and Spain (11.6%, n=24) contributed most. 83.5% (n=172) confirmed that they had access to durvalumab at the time of the survey. 97.6% (n=201) report that treatment decision is made by a multidisciplinary board. Regarding staging, 76.7% (n=158) support the need of a mediastinal pathological staging in case of suspect lymph-nodes, with a preference for EBUS/EUS (61.2%, n=126). 81.6% (n=168) treated more than half of patients with a concomitant CT-RT with the 1st cycle of chemotherapy in 39.7% (n=81). 95.1% consider durvalumab as practice changing, especially given the OS results (77.9%, n=152/195). 30% (n=119/395) will give patients concomitant CT-RT if PD-L1 >1%, and in borderline resectable cases 17.7% (n=70/395) will propose concomitant CT-RT instead of surgery. Durvalumab administration will be given regardless of PDL1 status in 13.1% (n=27) and 28.6% (n=59) would consider the possibility of a rebiopsy after CT-RT in case of negative PD-L1. 38.8% (n=80) foresee some problems with PD-L1 testing in this population due to availability of cytologic or small histologic samples. About 53.8% (n=105/195) normally will start durvalumab within 6 weeks after CT-RT and 48.5% (n=100) would also use durvalumab after sequential CT-RT

      Conclusion

      Durvalumab results are changing the treatment approach to stage III unresectable (and maybe resectable) NSCLC and planned strict adherence to the patient population as recruited to the PACIFIC study, was not demonstrated. This survey was released after the EMA approval of durvalumab and PD-L1 status seems to play a role in the treatment strategies, but surprisingly almost half of the clinicians will use durvalumab after sequential CT-RT without safety or efficacy data.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA08.03 - Adjuvant Pembrolizumab in N2 Positive NSCLC Treated with Concurrent Chemoradiotherapy Followed by Surgery: Phase II, Prospective Study (Now Available) (ID 1744)

      15:15 - 16:45  |  Presenting Author(s): Sehhoon Park  |  Author(s): Hyun Ae Jung, Jong Ho Cho, Jong-Mu Sun, Hong Kwan Kim, Se-Hoon Lee, Yong Soo Choi, Jin Seok Ahn, Jhingook Kim, Keunchil Park, Jae Ill Zo, Young Mog Shim, Myung-Ju Ahn

      • Abstract
      • Presentation
      • Slides

      Background

      The standard treatment option for stage IIIA-N2 subgroup is still under discussion with controversies. We hypothesize that immune checkpoint inhibitor consolidation therapy could have an additional role in prolongation of the disease-free survival (DFS) for stage IIIA-N2 NSCLC treated with tri-modalities therapy.

      Method

      This is a phase 2 study evaluating the clinical efficacy of pembrolizumab treatment after CCRT with curative resection in stage IIIA-N2 NSCLC pts (NCT03053856). Pathologically confirmed pts were treated with five cycles of CCRT, weekly paclitaxel (50mg/m2) and cisplatin (25mg/m2) combined with radiotherapy (total of 44Gy over 22 fractions) followed by curative resection. Adjuvant Pembrolizumab (200mg fixed dose) is applied every three weeks up to 2 years or until disease recurrence. The primary objective is disease-free survival of more than 20 months. The first patient was recruited in October 2017, and the data for this abstract was locked at 20th of January, 2019.

      Result

      Total of 40 pts were screened, and 37 pts received treatment. Median age was 64 years (range 39-74), and twenty-three pts were male (62.2%). As a curative surgery, pts received lobectomy (n=34), bi-lobectomy (n=2), or pneumonectomy (n=1). Adenocarcinoma was predominant (n=27, 73.0%). After the neoadjuvant CCRT, down-staging were observed in nine pts (24.3%). The median follow-up duration was 10.6 months (range 3.1-17.2), and pts received a median of 11 cycles (range 1-22) of adjuvant pembrolizumab. DFS is not reached. Fourteen patients discontinued treatment due to disease progression (n=9), adverse events (n=4) and withdraw consent (n=1). There was a case of grade 4 pneumonitis and a case of grade 3 autoimmune hepatitis which lead to discontinuation of the treatment. Otherwise, grade 1-2 hypothyroidism (n=6), pneumonitis (n=5), skin rash (n=3) were observed. Patients with severe immune-related adverse event showed a significantly high percentage of Ki-67 + cells among CD8 T-cells in peripheral blood.

      Conclusion

      This study is the first study to demonstrate the feasibility of adjuvant pembrolizumab monotherapy in stage IIIA-N2 patients. Updated clinical outcome will be presented at the conference.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA08.04 - Discussant - MA08.01, MA08.02, MA08.03 (Now Available) (ID 3744)

      15:15 - 16:45  |  Presenting Author(s): Delvys Rodriguez-Abreu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA08.05 - A Multi-Center Analysis of Right vs Left-Sided Pneumonectomy Following Induction Therapy (Now Available) (ID 1178)

      15:15 - 16:45  |  Presenting Author(s): Chi-Fu Jeffrey Jeffrey Yang  |  Author(s): Nicholas R Mayne, Athar Battoo, Sai Yendamuri, Todd Demmy, Robert McKenna, Thomas A D’amico, Mark Berry

      • Abstract
      • Presentation
      • Slides

      Background

      Previous single-center studies of pneumonectomy following induction therapy for non-small-cell lung cancer (NSCLC) have found a significant perioperative risk associated with right-sided pneumonectomy. We examined the impact of laterality on long-term survival after induction therapy followed by pneumonectomy in a multi-institutional analysis.

      Method

      Perioperative and long-term outcomes of patients with NSCLC who underwent pneumonectomy following induction chemotherapy with or without radiation from 2000-2016 across 3 institutions were evaluated using multivariable logistic regression, Cox proportional hazards modeling and propensity score-matched analysis. Patients who underwent a completion pneumonectomy or who had M1 disease were excluded from the analysis.

      Result

      During the study period, 172 patients (right n = 78 [45%], left n = 94 [55%]) met inclusion criteria. Right-sided pneumonectomy was associated with a similar perioperative complication rate (38% [30/78] vs 27% [25/94], p=0.10), and 30-day (13% [10/78] vs 9% [8/94], p=0.36) and 90-day mortality (23% [18/78] vs 13% [12/94], p=0.08) when compared to left-sided pneumonectomy. In multivariable analysis, right-sided pneumonectomy was not found to be a predictor of higher perioperative complications (OR 0.85 [95% CI: 0.33-2.14], p=0.73) or 30-day (OR 2.06 [95% CI: 0.44-9.69], p=0.36) and 90-day mortality (OR 2.06 [95% CI: 0.54-7.88], p=0.29). Overall survival between right and left pneumonectomy was not significantly different in unadjusted (5-year survival 30% [95% CI: 19%-41%] vs 29% [95% CI: 20%-39%], log-rank p=0.77 [Figure]) or multivariable analysis (adjusted hazard ratio, 1.05 [95% CI: 0.63-1.76], p = 0.84). A propensity score-matched analysis of 108 patients balancing baseline characteristics—including pulmonary function, tumor size and stage—was also performed, and found no significant differences in perioperative complication rates (46% [25/54] vs 48% [26/54], p=0.85), 30-day (17% [9/54] vs 7% [4/54], p=0.14) and 90-day mortality (26% [14/54] vs 13% [7/54], p=0.09) between right versus left pneumonectomy, respectively. Overall survival was not significantly different between right- and left-sided pneumonectomy (5-year survival 33% [95% CI: 20%-47%] vs 28% [95% CI: 16%-41%], log-rank p=0.98).

      right vs left pneumonectomy figure.png

      Conclusion

      In this multi-center analysis, right-sided pneumonectomy after induction therapy was not associated with significantly higher perioperative mortality rates or worse long-term survival when compared to a left-sided pneumonectomy.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA08.06 - Perioperative Outcomes of Lung Cancer Patients with Interstitial Pneumonia (Now Available) (ID 1372)

      15:15 - 16:45  |  Presenting Author(s): Aki Katarina Kobayashi  |  Author(s): Yu Okubo, Masaya Yotsukura, Yukihiro Yoshida, Kazuo Nakagawa, Noriko Motoi, Shun-ichi Watanabe

      • Abstract
      • Presentation
      • Slides

      Background

      Interstitial lung disease is mostly found in elderly male smokers who also have relatively high risks of developing lung cancer. For these patients, modality to treat malignancy is limited to prevent acute exacerbation of interstitial pneumonia. We analyzed the perioperative outcomes of this group of patients with both interstitial pneumonitis and resectable lung cancer with curative intent.

      Method

      We retrieved the characteristics and medical courses of consecutive patients who had undergone pulmonary resections from medical records. In this analysis, usual interstitial pneumonia (UIP) was characterized by the presence of basal predominant, subpleural reticular abnormalities with traction bronchiectasis and honeycomb cysts detected in bilateral lung field on chest computed tomography preoperatively. Pathological findings on surgical specimen were used confirmation of diagnosis. The incidence and outcomes of acute exacerbation within 30 days from operation were analysed.

      Result

      From 2015 to 2017, there were 1,477 patients who underwent pulmonary resection for primary lung cancer at our institute. Among them there were 81 (5.5%) patients diagnosed as UIP by specific findings on chest computed tomography. Of 81 patients evaluated, 68 (84.0 %) were men, the median age was 73 years (range, 55-88). For Eastern Cooperative Oncology Group (ECOG) performance status, all 81 patients were categorized in status 0. Seventy-four patients (91.4%) underwent lobectomy, 1 (1.2%) bi-lobectomy, 2 (2.5%) segmentectomy and 4 (4.9%) wide wedge resections for primary lung cancer. The mean duration of surgery was 129 mins (range, 54-316), and mean value for blood loss was 36.5 ml (range, 0-396). A complete resection (R0) was achieved in 79 cases (97.5%). Postoperative complications were observed in 19 patients (23.5%) including prolonged air leakage (n=4, 4.9%), late onset of air leakage (n=3, 3.7%), surgical site infection, chylothorax and cerebral infarction. Nine patients (11.1%) manifested acute exacerbation of interstitial pneumonia within 30 days after surgery. There were 3 post-operative deaths (3.7%) within 30 days after surgery. Two deaths (2.5%) were due to acute exacerbation of interstitial pneumonia and 1 (1.2%) case of SAH on 1POD.

      Conclusion

      Pulmonary resection for patients with interstitial lung disease led to 9 (11.1%) cases of acute exacerbation within 30 days from surgery. Mortality related to acute exacerbation was found only 2 cases (2.5%) at our hospital, which was tolerable postoperative outcome for pulmonary resection for lung cancer with curative intent.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA08.07 - The Concordance Between Patient Reported Outcomes and Clinician Reported Outcomes During Radiotherapy in Lung Cancer Patients  (Now Available) (ID 2507)

      15:15 - 16:45  |  Presenting Author(s): Evalien Veldhuijzen  |  Author(s): Iris Walraven, Margriet Kwint, Laura Roose, José Belderbos, Tomas Janssen

      • Abstract
      • Presentation
      • Slides

      Background

      Capturing information on toxicity in (non-)small cell lung cancer patients receiving radiotherapy or chemoradiotherapy, is crucial for optimal symptom management. Patient Reported Outcomes (PROs) have the potential to improve toxicity detection by adding direct information from the patient perspective. The aim of this study is therefore to determine the predictive and additional value of PROs on prospectively scored clinician reported toxicity.

      Method

      An observational study was performed in lung cancer patients (n=111) treated with (chemo)radiation with curative intent. The EORTC QLQ-C30 and the EORTC LC-13 questionnaires were used to score PROs on a scale of 0-100 for a selection of commonly occurring toxicities (i.e. dysphagia, dyspnea, anorexia, fatigue, cough and nausea). Clinicians prospectively scored the maximum toxicity during, and at the end of treatment using the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. Receiver operating characteristic (ROC) curves were constructed to evaluate the performance (i.e. discrimination) of PROs on predicting clinician scored CTCAE toxicity (grade ≥2). Furthermore, cut-off points were determined from the ROC-curve on the basis of the best trade‐off values between sensitivity and specificity (0,5). Validity of the model was assessed with the ability to predict the number of grade ≥2 toxicities (calibration).

      Result

      roc-curve for predictive ability of six pro toxicities for ctcae based toxicity.png

      Assessment of predictive performance in our cohort demonstrated a good fit for anorexia (AUC: 0,810 95% CI 0,699 to 0,921) and dysphagia (AUC: 0,828 95% CI 0,743 to 0,914) with sensitivity scores of 85,7%, 67,4% and specificity scores of 74,0% and 92,6% respectively. Both dyspnoea (AUC: 0,765 95% CI 0,60 to 0,910) and nausea (AUC: 0,745, 95% CI 0,548 to 0,942) showed a fair fit with sensitivity score of 74,1% for both toxicities and specificity of 69,1% and 68,3% respectively. A poor fit was found for cough (AUC: 0,667 95% CI 0,495-0,839) with a sensitivity of 55,6% and specificity of 30,4%. The model failed to discriminate for fatigue (AUC: 0,507 95% CI 0,368-0,645). Calibration showed that clinician based CTCAE toxicities substantially underestimated all PRO-based toxicities.

      Conclusion

      This study has identified that patient reported toxicities and clinician reported toxicities do not always concord. Only anorexia and dysphagia showed good agreement, while for the other toxicities, the agreement was only fair to poor. Furthermore, we showed that clinicians substancially underreport the existence of toxicities. This study adds to the growing body of evidence indicating the potential beneficial role of using PRO-based toxicity reporting in clinical cancer care for lung cancer.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA08.08 - Discussant - MA08.05, MA08.06, MA08.07 (Now Available) (ID 3745)

      15:15 - 16:45  |  Presenting Author(s): Norihiko Ikeda

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA08.09 - Results of Trimodality Therapy for Patients with cN2 Lung Cancer Diagnosed by Video-Assisted Mediastinoscopic Lymphadenectomy (VAMLA) (Now Available) (ID 1295)

      15:15 - 16:45  |  Presenting Author(s): Sergi Call  |  Author(s): Carme Obiols, Ramon Rami-Porta, Silvia Catot, Miriam Nuñez, Marc Campayo, Francisco Perez Ochoa, Mireia Serra-Mitjans, Jose Belda-Sanchis

      • Abstract
      • Presentation
      • Slides

      Background

      After a properly performed transcervical lymphadenectomy, invasive restaging of the mediastinum is unnecessary because 
there is no material left for a new biopsy. Therefore, when video-assisted mediastinoscopic lymphadenectomy (VAMLA) is used at primary staging, the only parameters to select patients for lung resection after induction therapy are: the stability of the primary tumor and the absence of extrathoracic disease assessed by PET-CT. The aim of this study is to analyze the results of those patients with cN2 NSCLC diagnosed by VAMLA who underwent trimodality treatment in terms of feasibility and survival.

      Method

      Prospective observational single-center study of 250 patients (206 men; median age, 65.7; range, 42-86) with NSCLC cN0-1 (by PET-CT) who underwent VAMLA from 01-2010 to 12-2017. Patients with cN2 diagnosed by VAMLA who underwent trimodality treatment (cisplatin-based chemotherapy concomitant with radical radiotherapy [mean 54Gy, range 40-70Gy] plus lung resection) were analyzed. Follow-up was completed in March 2019. Median follow-up for surviving patients was 39.5 months (range, 8-108). Survival analysis was performed by the Kaplan-Meier method; the log-rank test was used for comparisons. Patients who died within 90 days after resection were excluded from survival analyses. A p-value of less than 0.05 was considered significant. The IBM SPSS Statistics for Mac, version 20.0 was used.

      Result

      The rate of unsuspected N2-3 disease in the whole series was 14.5% (35 patients). 28 patients out of 35 were considered for trimodality treatment. The results of restaging based on the PET-CT were: disease progression in 8 (28.5%) (mostly distant metastases), and stability of the primary tumor or partial response in 20 patients (71.5%). Of 20 patients without progression, 13 (46.5%) underwent lung resection; the remaining 7 were considered unfit for surgery. Three- and 5-year survival rates for those candidates for chemoradiotherapy (n=28) were: 91.7% and 80.2%, respectively, for patients in whom complete lung resection was achieved; 34.3% and 0%, respectively, for those considered unfit for surgery; and 19% and 0%, respectively, for those with progression after chemoradiotherapy (p < 0.0001)(Figure 1).

      figure1.jpg

      Conclusion

      The use of VAMLA to select patients for trimodality treatment is feasible. Based on the results obtained (high rate of unsuspected cN2 diagnosed by VAMLA and prolonged survival of those patients in whom the trimodality treatment was accomplished), VAMLA should be included in the current staging algorithms, especially for those tumors with intermediate risk of N2 and normal mediastinum by PET-CT.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA08.10 - Early and Late Outcomes After Surgery for pT4 NSCLC Reclassified by AJCC 8<sup>th</sup> Edition Criteria (Now Available) (ID 2941)

      15:15 - 16:45  |  Presenting Author(s): Jack G Mouhanna  |  Author(s): Amit Katz, Pierre O Fiset, Roni F Rayes, Aya Siblini, Emma Lee, Andrew Seely, Christian Sirois, David Mulder, Jonathan Cools-Lartigue, Lorenzo E. Ferri, Jonathan D. Spicer

      • Abstract
      • Presentation
      • Slides

      Background

      Classically, T4 non-small cell lung cancers (NSCLC) are tumors of any size that have features of local extension often precluding surgical resection or necessitating complex extended pulmonary surgery. However, the new AJCC 8thedition includes tumors greater than 7cm regardless of adjacent organ extension. The early perioperative outcomes from T4 resections must be contextualized to the increasingly heterogeneous classification offered by the new staging system. Our goal was to examine perioperative and long-term outcomes from pT4 resections based on the AJCC 7thedition versus those of the expanded criteria of the 8thedition.

      Method

      This is a retrospective study of pT4 surgical resections at the Montreal General Hospital from 2011-2018. Data was analyzed using GraphPad Prism and SPSS.

      Result

      We identified 158 patients with pT4 tumors based on AJCC-8: 40 by AJCC-7 criteria (Group1) and 118 with tumors >7cm considered pT4 in AJCC-8 (Group2). Demographics and clinical characteristics are detailed in Table 1. The incidence of major complications (grade 3 or 4) was similar in both cohorts (17.5% in Group1 and 13.6% in Group2; p=0.37), with 3.8% in-hospital mortality (7.5% in Group1 and 2.5% in Group2; p=0.16). Overall survival was 76% at 1 year, 44% at 3 years and 34% at 5 years. Median overall survival was 27 months and was similar between Group1 and Group2 (25.8 and 27.4 months, respectively p=0.7). Nevertheless, Group2 had better peri-operative survival than Group1: 99% vs 92% 90-day mortality (p=0.02) and 95% vs 83% 6-month mortality (p<0.01). Finally, Kaplan-Meier curves adjusted for predictors of survival with Cox regression analysis show early mortality in Group 1 with equalization of the curves at 1 year (Figure 1).

      table 1.jpg

      figure 1.png

      Conclusion

      While long-term oncological outcomes are similar for pT4 >7cm to those of AJCC-7 pT4 patients, differences in perioperative outcomes point to the heterogeneity of the new AJCC-8 classification with regards to surgical management.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA08.11 - SLCG SCAT Trial: Surgical Audit to Lymph Node Assessment Based on IASLC Recommendations (Now Available) (ID 2252)

      15:15 - 16:45  |  Presenting Author(s): Jose Ramon Jarabo Sarceda  |  Author(s): SERGIO Bolufer, Roberto Mongil, Pedro Lopez De Castro, RAMON Moreno, JUAN CARLOS PeÑalver, Raúl Embún, Joaquín Pac, Francisco Javier Algar, Pablo Gámez, Marcelo Jiménez, Gabriel Sales, Eva Pereira, Bartomeu Massuti, Mariano Provencio, Florentino Hernando-Trancho

      • Abstract
      • Presentation
      • Slides

      Background

      The Spanish Lung Cancer Group (SLCG) developed a multicenter trial in which completely resected pathological N positive NSCLC patients received different schemes of adjuvance based on level of tumoral BRCA expression (SCAT trial). We assess here surgical topics, with an in-depth analysis of quality of lymphadenectomy based on IASLC recommendations, evaluating their effect on survival.

      Method

      Phase-III SLCG-SCAT trial included patients with completely resected (R0) NSCLC with pathological hilar and/or ipsilateral mediastinal lymph node (LN) involvement. Patients from SLCG-SCAT trial in which complete pathologic report with information about mediastinal lymph node dissection was available (including number of lymph nodes assessed and involved by tumor in each hilar and mediastinal region), were included for our study. We also analyzed data about estimated overall survival (OS) and disease-free survival (DFS). All patients underwent surgical resection in high-volume departments of thoracic surgery.

      Result

      Lymph node assessment

      From the whole series (451 patients), in 33.7%, 17.7% and 49.9% of cases, regions 7, 10 and 11 respectively were not assessed. No lymph nodes were biopsied from region 8, 9 and 12 in 80%, 61.9% and 91.1% of cases, respectively. Region 10 was that with the higher number of lymph nodes resected (medium 4.64). From them, 27.9% were involved by tumor. Median assessed mediastinal regions was 4. In 21.1% of patients, lymph nodes from only one or two regions were obtained. In most of the patients (91.8%), one or two N1 regions were assessed. From 272 patients with N1 (no N2) involvement, 15.4% had no N2 regions biopsied, 20.2% had one N2 region evaluated and only 39.7% had three or more N2 regions assessed. On the other hand, from 179 patients with positive N2, 8.9% had no N1 regions biopsied and 54.7% had one. From 409 patients with at least one N2 lymph node resected, 120 (29.3%) shown the highest region involved. Number of mediastinal regions assessed and affected, and number of lymph nodes resected and affected were significantly higher in patients with N1 plus N2 disease than those with isolated N1 or N2 involvement.

      Survival

      Median follow-up was 52.3 months. Five-year OS was 55.7% (CI95% 50.8%-60.3%). Differences were found on OS regarding type of lymph node involvement (N1, N2 or both) (p=0.002). Five-year OS was 61.7% (CI95%:55.4%-67.4%), 51.5% (CI95%:39.2%-62.4%) and 42.3% (CI95%:32.1-52.2%) for patients with N1, N2 and N1+N2 disease, respectively. No differences were found in survival regarding total number of N1 or N2 regions evaluated. Both number of regions involved and number of lymph nodes with tumor were significantly related to worse prognosis.

      Conclusion

      International recommendations for surgical lymph node assessment in NSCLC were not deemed for the design of the trial and were not followed in a high proportion of cases. Patterns of N1 and N2 involvement shown to impact prognosis. The design of trials assessing surgical series of patients undergoing complete resection requires the control of surgical procedures in order to avoid recruitment biases.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA08.12 - Discussant - MA08.09, MA08.010, MA08.11 (Now Available) (ID 3746)

      15:15 - 16:45  |  Presenting Author(s): Leah Backhus

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

  • +

    MA15 - Usage of Computer and Molecular Analysis in Treatment Selection and Disease Prognostication (ID 141)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Pathology
    • Presentations: 12
    • Now Available
    • +

      MA15.01 - Cellular Prion Protein Transcriptionally Regulated by NFIL3 Enhances Lung Cancer Cell Lamellipodium Formation and Migration (Now Available) (ID 151)

      15:45 - 17:15  |  Presenting Author(s): Shin-Chih vincent Lin  |  Author(s): Chia-Hung Lin, Nien-Chu Shih, Hsin-Ling Liu, Wen-Chao Wang, Kun-Yang Lin, Yi-Cheng Lin, Yi-Chen Yeh, Hiroshi Minato, Takeshi Fujii, Yu-Chung Wu, Mei-Yu Chen, Teh-Ying Chou

      • Abstract
      • Presentation
      • Slides

      Background

      Tumor invasion and metastasis are the major causes of treatment failure and mortality in lung cancer patients. However, the precise molecular targets responsible for tumor invasion remain unclear.

      Method

      In this study, we identified a group of genes with differential expression in in situ and invasive lung adenocarcinoma tissues by cDNA microarray analysis; among these genes we further characterized the association of the upregulation of PRNP, the gene encoding cellular Prion protein (PrPc), with lung adenocarcinoma invasiveness through immunohistochemistry and in situ hybridization analysis on clinical tissues. The roles of PrPc in lung cancer cell lines were also verified by using immunofluorescence staining, in vitro transwell assay and in vivo metastasis mouse model. In addition, the impact of PrPc on the activation of the JNK signaling pathway was investigated by Western blot analysis. Finally, luciferase reporter assay and chromatin immunoprecipitation assay were used to identify the transcriptional activators of PRNP.

      Result

      Immunohistochemistry on clinical specimens showed association of PrPc expression with invasive but not in situ lung adenocarcinoma. Consistently, the expression of PrPc was higher in the highly invasive than in the lowly invasive lung adenocarcinoma cell lines. Knockdown of PrPc expression in cultured lung adenocarcinoma cells decreased their lamellipodium formation, in vitro migration and invasion, and in vivo experimental lung metastasis. Phosphorylation of JNKs was found to correlate with PrPc expression and the inhibition of JNKs suppressed the PrPc-induced up-regulation of lamellipodium formation, cell migration, and invasion. Moreover, we identified the nuclear factor, interleukin 3 regulated (NFIL3) protein as a transcriptional activator of the PRNP promoter. Accordingly, NFIL3 promoted lung cancer cell migration and invasion in a PrPc-dependent manner. High NFIL3 expression in clinical specimens of lung adenocarcinoma was also associated with tumor invasiveness and poor survival of patients.

      Conclusion

      Our observations suggest that PRNP expression is associated with the invasiveness of lung adenocarcinoma, and cell line model demonstrated that PrPc serves as a critical factor for lung cancer cell lamellipodia formation, migration and invasion via JNK signaling. A novel transcription factor, NFIL3, was identified to upregulate PRNP expression in lung cancer cells; further characterizations showed that NFIL3 promotes lung cancer cell migration through PrPc-dependent manner. Moreover, high NFIL3 expression was found to be associated with lung cancer invasiveness in clinical tissues. Overall, NFIL3/PrPc axis plays a critical role in lung cancer invasiveness and metastasis, and may be the potential therapeutic targets in the future.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA15.02 - Deep Learning Approach for Automated Tumor Cells Detection and Estimation of PD-L1 22C3 Assay Expression in Lung Adenocarcinoma (Now Available) (ID 577)

      15:45 - 17:15  |  Presenting Author(s): Jianghua Wu  |  Author(s): Dongmei Lin, Wei Sun, Changling Liu, Xiaoqing Liu, Yajun Zhang, Junjie Zhang, Haiyue Wang, Xinying Liu, Xin Yang, Shaoping Ling

      • Abstract
      • Presentation
      • Slides

      Background

      It is vital and challenging to assess an accurate PD-L1 expression status on tumor cells for immunotherapy in lung cancer. The purpose of this study was to set up an automated system to detect the tumor cells and estimate the tumor proportion score (TPS) of PD-L1 immunohistochemistry (IHC) expression for lung adenocarcinoma based on deep learning, and provide a potential Artificial Intelligences (AI) assistive diagnostic tool in the quantification of PD-L1 interpretation.

      Method

      Fifty PD-L1 22C3 IHC slides of lung adenocarcinoma samples on digitized whole-slide images (WSI) database was employed. We first designed a model with a fully convolutional neural network (FCNN) based on U-ResNet architecture to obtain the cancer segmentation. Representative regions were selected from each slide, and 100 regions were collected for manual annotations as a training set for cancer detection. Another 50 regions were used to validate the performance of automated cancer detection and TPS estimation as a test set. After the quality control, a whole model of automated cancer cell segmentation and membrane positive estimation was set up on standard PD-L1 22C3 IHC staining. TPS could be automatically predicted by AI tool and then compared with the interpretations of pathologists.

      Result

      The results of automated lung adenocarcinoma cells segmentation on the test set of 22C3 IHC staining showed a moderate sensitivity (71.46%) with a high specificity (95.94%) which was much more crucial for TPS counting. In rest 43 out of 50 regions after a quality control, TPS estimated by the automated PD-L1 analysis based on cancer segmentation showed a significant correlation with the average scores (r=0.9609, p<0.001) and the median scores (r=0.9523, p<0.001) of pathologists' interpretations.

      results.png

      Conclusion

      We provide an automated tumor cells detection and TPS estimation model for lung adenocarcinoma and demonstrate the potential of using machine learning methods to access PD-L1 IHC status conveniently. A further validation of AI tool for automated scoring PD-L1 in diagnostic routine is highly recommended in the future.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA15.03 - Exploring Digital Pathology-Based Morphological Biomarkers for a Better Patients’ Selection to the Immune Checkpoint Inhibitor of Lung Cancer (Now Available) (ID 1777)

      15:45 - 17:15  |  Presenting Author(s): Noriko Motoi  |  Author(s): Hiroshi Yoshida, Tomoharu Kiyuna, Hidehito Horinouchi, Takashi Kohno, Shun-ichi Watanabe, Yuichiro Ohe, Atsushi Ochiai

      • Abstract
      • Presentation
      • Slides

      Background

      For eligible patients’ selection for immune checkpoint inhibitor therapy (ICI), it is important to establish more accurate predicting biomarkers, in addition to PD-L1 IHC and MSI-high. We hypothesized that morphological characteristics should reflect genetic alteration, thus could predict ICI responsiveness. In this study, we examined the predictive potential of morphological characteristics using digital whole-slide images as a new biomarker for ICI-treatment on non-small cell lung cancer (NSCLC) and their relationship to PD-L1 IHC and genetic alterations.

      Method

      71 NSCLC who received ICI therapy were recruited. Digital images of H&E and PD-L1 (22C3) IHC stained slides of pre-treatment biopsied or resected materials were examined by previously reported image analysis techniques using e-Pathologist ® (NEC, Japan). Morphological characteristics of cancer cells (three and six parameters of nuclear shape and chromatin texture) were extracted as MC-scores. Of 11 cases (pilot cohort), PD-L1 IHC (22C3) and tumor mutation burden (TMB) by the NGS-based target sequence (NCC oncopanel ®) were examined. Correlation between MC-score, PD-L1 IHC, TMB status, and clinical outcome was calculated. A p-value of less than 0.05 was defined as statistically significant.

      Decision tree analysis for evaluating predicting ICI-responsiveness was built using statistically significant MC-scores. We also tested the predictive value of a deep learning analysis (AI model) with 5-fold cross-validation. AUC (area under the curve) of ROC analysis was calculated.

      Result

      Of the responders, the MC-score of cancer cell were statistically different from those of the non-responders; nuclear texture contour complexity (11.8 vs. 8.25, median value of responder vs. non-responders; p<0.01), homogeneity (0.396 vs. 0.421; p<0.01), angular second moment (ASM) (0.0203 vs. 0.0214; p=0.049) and nuclear circularity (0.878 vs. 0.885, p=0.026). Circularity (p=0.011) and texture homogeneity (p=0.048) correlated with TMB. ASM texture correlated with PD-L1 expression (p=0.018). The decision tree model for predictive and screening purposes resulted in 0.83 and 0.62 accuracies, respectively. AUC of AI-model for ICI responsiveness resulted in fair (0.74 on average, range 0.55-0.81).

      Conclusion

      Our results indicate the substantial value of the morphological feature as a biomarker for ICI therapy. Morphological characteristics are eligible from archived FFPE samples, showed good correlation to the underlying genetic alteration. Digital pathology can serve useful predictive morphological biomarkers for precision medicine of lung cancer patients, and promising the power of AI-assisted pathology.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA15.04 - Discussant - MA15.01, MA15.02, MA15.03 (Now Available) (ID 3780)

      15:45 - 17:15  |  Presenting Author(s): Anja C. Roden

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA15.05 - Computerized Measurements of Cellular Diversity on H&amp;E Tissue Are Prognostic of OS and Associated with Mutational Status in NSCLC (Now Available) (ID 1975)

      15:45 - 17:15  |  Presenting Author(s): Vamsidhar Velcheti  |  Author(s): Cheng Lu, Kaustav Bera, Xiangxue Wang, Pingfu Fu, Michael Yang, David Rimm, Kurt A Schalper, Anant Madabhushi

      • Abstract
      • Presentation
      • Slides

      Background

      Tumor heterogeneity is known to be implicated in chemotherapeutic resistance and poor prognosis for non-small cell lung cancer (NSCLC). In this study we sought to evaluate the role of computer extracted features reflecting the intrinsic cellular morphological diversity (ICMD) of tumors from digitized H&E stained images of early-stage NSCLC patients. Additionally, we sought to evaluate the association of these ICMD features in adenocarcinomas with the ALK and EGFR mutational status.

      Method

      Two cohorts, D1 and D2, of digitized H&E stained tissue microarray images (TMA) of NSCLC, n=395 and n=91, respectively, were used for modeling the ICMD predictor. A pretrained deep learning model was used for segmentation of nuclei, and clusters of proximally located nuclei were identified. The ICMD features were then extracted as the variations in shape, size, and texture measurements of nuclei within the clusters. A Cox proportional hazard model using the ICMD features was then trained for lung adenocarcinomas (LUAD, n=270), and squamous cell carcinomas (LUSC, n=216), separately, and was validated on independent cohort from (D3) The Cancer Genome Atlas (TCGA) (n=473) to predict Overall Survival (OS). Univariate and multivariate analyses were performed on (D3).

      Result

      In (D3), high risk patients predicted by the ICMD features had significantly poorer survival (HR (95% CI) = 1.48 (1.06-2.06), p=0.021 for LUSC, HR (95% CI) = 1.59 (1.11-2.29), p=0.006 for LUAD) in univariate analysis. In multivariate analysis, controlling for major clinical variables, ICMD was independently associated with 5-year OS (p<0.016). (See Table 1) We also found that ICMD features were associated with driver mutations ALK (p=0.0204) and EGFR (p=0.0017) in LUAD.

      Table 1| Multivariate analysis for overall survival on the validation set D3.

      Multivariate Cox Proportional Hazard Model Analysis Controlling for Other Variables

      TCGA-LUSC

      TCGA-LUAD

      Variable

      HR (95% CI)

      p value

      HR (95% CI)

      p value

      Age (>65 vs <=65)

      1.14(0.81-1.61)

      0.451

      0.89(0.63-1.28)

      0.540

      Smoking status

      1.36(0.83-2.23)

      0.221

      1.14(0.64-2.01)

      0.661

      Overall Stage (Stage II vs I)

      1.13(0.66-1.94)

      0.651

      1.86(1.04-3.32)

      0.037

      T-Stage (T2,3 vs T1)

      1.26(0.85-1.87)

      0.244

      1.25(0.85-1.85)

      0.263

      N-Stage (N1 vs N0)

      1.36(0.77-2.41)

      0.292

      3.11(1.55-6.23)

      0.001

      Developed Model

      High risk vs. Low risk

      1.52(1.08-2.13)

      0.016

      1.55(1.09-2.22)

      0.015

      CI = 95% confidence interval; HR = Mantel-Haenszel Hazard ratio. Values in bold are statistically significant, p<=0.05.

      Conclusion

      Computer extracted image features of cellular diversity were able to predict OS in NSCLC and were also associated with the ALK and EGFR mutational status. Future work will entail evaluating ICMD features in predicting added benefit of adjuvant therapy in early stage NSCLCs as well as correlating with gene expression data.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA15.06 - Stage I Lung Adenocarcinoma Gene Expression Associated with Aggressive Histologic Features for Guiding Precision Surgery and Therapy (Now Available) (ID 1124)

      15:45 - 17:15  |  Presenting Author(s): Jiarui Zhang  |  Author(s): Eric Burks, Travis Sullivan, Jacob Sands, Shawn Regis, Brady McKee, Andrea McKee, Sherry Zhang, Hanqiao Liu, Gang Liu, Steven Dubinett, Avrum Spira, Jennifer Beane, Kimberly Christ, Marc Lenburg

      • Abstract
      • Presentation
      • Slides

      Background

      Stage I lung adenocarcinomas (LUADs) show heterogeneity in histologic patterns which correlate with malignant behavior. Solid, micropapillary and cribriform patterns are associated with worse survival whereas lepidic (in situ) predominance has the best prognosis. In this study, we sought to characterize histologic pattern specific gene expression in resected clinical stage I LUADs. We also aimed to train and validate a genomic biomarker predictive of histologic aggressive patterns with the ultimate goal of being able to impact surgical and therapeutic decision making for post-biopsy management.

      Method

      A training cohort of 56 tumors from patients meeting NCCN high-risk screening criteria with stage I LUAD was included for pathologic annotation and whole exome RNA sequencing. Histologic pattern subtyping in 5% increments including all diagnostic slides was performed. A single representative FFPE block was chosen for RNA library-prep with Illumina TruSeq Access Kit and sequencing. Negative binomial models were used to identify gene expression differences associated with percent solid, cribriform, or micropapillary histology, and EnrichR was used for gene pathway enrichment analysis. Ss-GSEA was used to predict tumor infiltration of 20 immune cell types. A random-forest classifier for predicting aggressive histologic patterns was trained using 5-fold cross validation. A set of tumors from 16 independent patients with ≤2.0 cm clinical stage I LUAD was macro-dissected into 32 paired components (lepidic + non-lepidic regions) and subjected to RNAseq. Six tumors were defined as non-aggressive (lepidic + acinar/papillary) and ten tumors were defined as aggressive (lepidic + solid/micropapillary/cribriform). Four aggressive tumors were upstaged after surgical resection.

      Result

      In the training cohort, we identified 1322 genes associated with tumor histologic composition(FDR q <0.05 and fold-change > 2). Genes whose expression differs with solid histology% are enriched for involvement in DNA replication, cell cycle regulation and inflammation (FDR q<0.001). Genes whose expression is associated with micropapillary% are enriched for involvement in tRNA-aminoacylation and decrease of T-cell activity (FDR q<0.001). The functional enrichment of genes whose expression is associated with cribiform% was less informative. LUADs with micropapillary patterns exhibited gene expression consistent with decreased antigen presentation and low T-cell infiltration, and solid patterns exhibited gene expression consistent with increased infiltration of T-regulatory and Th2 cells (FDR q<0.05).

      A gene expression classifier was trained to predict the presence of aggressive histologic patterns. We validated this classifier on a set of 16 tumor specimens from which we macro-dissected and analyzed tissue from the most aggressive histologic pattern (AUC = 1.00). We also found that this classifier could differentiate lepidic regions isolated from aggressive tumors from lepidic regions isolated from non-aggressive tumors (AUC = 0.74).

      Conclusion

      We identified solid-, micropapillary- and cribriform-specific gene expression and associated immune response among clinical stage I LUADs, and developed a classifier predictive of aggressive histologic features using either lepidic (in situ) or non-lepidic components. As such, this biomarker has the potential to predict histologic aggressiveness even from pre-surgical tumor biopsies where all histologic patterns may not be represented. Such a biomarker may be useful in guiding clinical decision making including extent of surgical resection.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA15.07 - Circulating miRNA: A Biomarker for Classification of Lung Cancer and Benign Lung Disease (Now Available) (ID 2218)

      15:45 - 17:15  |  Presenting Author(s): Alvida Qvick  |  Author(s): Anders Wirén, Maria Rönnqvist, Gisela Helenius

      • Abstract
      • Presentation
      • Slides

      Background

      Circulating biomarkers for cancer have great potential for diagnosis as well as follow up of treatment. MicroRNAs (miRNA) are involved in the expression of a majority of proteins with different cell types having different miRNA expression. The aim of this study was to create a circulating miRNA-based model to discriminate patients with lung cancer from patients with benign lung disease.

      Method

      Samples were collected from patients under investigation for lung cancer at Örebro University hospital. Patients were then divided into groups based on diagnosis, which resulted in NSCLC adenocarcinoma (n=24), NSCLC squamous cell carcinoma (n=13), SCLC (n=4) and a heterogeneous group consisting of different benign lung diseases (n=19). Healthy controls were collected separately (n=17).

      Circulating miRNA was processed using the extraction-free library preparation miRNA Whole Transcriptome Assay with probes for 2083 human mature miRNAs and analyzed with massive parallel sequencing.

      Differential expression between groups was estimated using edgeR. MiRNAs that had the highest impact on patient grouping were used in a sPLS discriminant analysis. The resulting classification model was validated using the leave-one-out method.

      Result

      The final model for comparison between patients with benign lung disease and patients with lung cancer contained 19 miRNAs. The model had an error rate of 15 % with errors distributed evenly between groups. A sub-analysis of patients with mutations in EGFR (n=5) and KRAS (n=6) was performed showing two distinct patterns in miRNA expression.classifyer.png

      Conclusion

      MiRNA shows promise as a circulating biomarker for lung cancer but may not be sufficient as an independent classifier. The predictive power may be improved by using several biomarkers in combination. The difference in expression between tumors with different mutations may be derived from alternate driving processes in these tumors.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA15.08 - Discussant - MA15.05, MA15.06, MA15.07 (Now Available) (ID 3781)

      15:45 - 17:15  |  Presenting Author(s): John Longshore

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA15.09 - PD-L1 Status in Relation with Non-Small Cell Lung Cancer Major Subtypes, Differentiation, Molecular Profiling and Smoking History (Now Available) (ID 2874)

      15:45 - 17:15  |  Presenting Author(s): Zhaolin Xu  |  Author(s): Alexi Surette, Mathieu Castonguay, Drew Bethune, Arik Drucker, Daniel French, Harry Henteleff, Mary Macneil, Wojciech Morzycki, Madelaine Plourde, Stephanie Snow

      • Abstract
      • Presentation
      • Slides

      Background

      Continued advances in lung cancer precision medicine have allowed targeted therapies based on an individual tumor’s genetic makeup. Recent advances in immune therapy based on immune checkpoint inhibitors have provided additional promising results. Currently, the majority of lung cancer mutational data available in the literature are from advanced stage non-small cell lung cancer. Mutational data from early stage lung cancer patients is limited. There is also limited data on PD-L1 tumor status is relation to mutational status along with other pathological and clinical characteristics. In this study, we evaluated these issues in 871 cases of surgically resected lung cancer.

      Method

      Multiplexed molecular profiling in 871 surgically resected lung cancer specimens was performed. A panel of genes including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK was tested. Tumor PD-L1 status was also evaluated by immunohistochemistry using pharmDx22C3. PD-L1 status was measured by tumor proportional score (TPS): <1%, 1-49% and ≥50% tumor cell positivity. Correlations between PD-L1 and gene mutation status, smoking history, histological grade, gender and age of paraffin embedded blocks were analyzed.

      Result

      This cohort includes adenocarcinoma (68%), squamous cell carcinoma (SCC) (22%) and other subtypes (10%). The average age is 67. Females account for 52%. A positive smoking history was present in 93%. Well differentiated tumors (G1) account for 11%, moderately differentiated (G2) 37% and poorly and undifferentiated (G3) 52%. EGFR mutations were identified in 7.4% and KRAS mutations in 31.7%. TPS <1% accounted for 48.8%, 1-49% for 34.6% and ≥50% for 16.5%.

      There was no statistically significant difference in PD-L1 TPS between histological subtypes or gender. Significantly more G1 tumors had a TPS <1% (76.7%) compared to G2 (57.4%, p=0.0013) and G3 tumors (41.8%, p<0.0001). Fewer G1 tumors had a TPS 1-49% (20.9%) than G2 (34.1%, p=0.015) and G3 (35.2%, p=0.01) tumors. G3 tumors were more likely to have a TPS ≥50% (24.6%) than G1 (2.3%, p<0.0001) and G2 (7.63%, p<0.0001) tumors. Never smokers were more likely to have a TPS <1% (71.1% vs 50.6%, p=0.04) and less likely to have a TPS ≥50% (5.8% vs 16.5%, p=0.04). Tumors with EGFR mutation were more likely to have a TPS <1% than those without EGFR mutation (70.7% vs 47.3%, p=0.0003) and less likely to have a TPS 1-49% (20.0 vs 35.5%, p=0.011). Tumors with KRAS mutations were less likely to have a TPS <1% (36.6% vs 54.9%, p<0.0001) and more likely to have a TPS 1-49% (40.6% vs 31.5%, p=0.0086) and ≥50% (22.8% vs 13.6%, p=0.0007). PD-L1 IHC performed on blocks stored for 2 years or longer had a statistically significant higher rate of TPS <1% compared to blocks stored for less than 2 years.

      Conclusion

      This study provides information relating to the relationship between PD-L1 levels and tumor molecular profile, histological grade and patient demographics. Additionally, we raise the possibility of false negatives on IHC performed for PD-L1 on paraffin embedded blocks stored for 2 years or more.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA15.10 - Stromal Markers of Activated Tumor Associated Fibroblasts Predict Poor Survival and Are Associated with Necrosis in Non-Small Cell Lung Cancer (Now Available) (ID 2212)

      15:45 - 17:15  |  Presenting Author(s): Jordi Alcaraz  |  Author(s): Josep Lluís Carrasco, Millares Laura, Anabel Martínez-Romero, Julio Sánchez De Cos, Ramon Rami-Porta, Luis M Seijo, Jose Ramirez, Noemi Reguart, Esther Barreiro, Eduard Monsó

      • Abstract
      • Presentation
      • Slides

      Background

      Tumor associated fibroblasts (TAFs) are essential contributors of the progression of non-small cell lung cancer (NSCLC). Most lung TAFs exhibit an activated phenotype characterized by the expression of α-SMA and fibrillar collagens. However, the prognostic value of these activation markers in NSCLC remains unclear.

      Method

      We conducted a retrospective multicentric study of the prognostic value of the standard markers of activated fibroblasts. For this purpose, we conducted a quantitative image analysis of α-SMA immunostaining and picrosirius red staining of fibrillar collagens imaged by bright-field and polarized microscopy, respectively, using tissue microarrays with samples from 220 surgical patients, which elicited a percentage of positive staining area for each marker and patient.

      Result

      Kaplan-Meier curves showed that all TAF activation markers were significantly associated with poor survival, and their prognostic value was independent of TNM staging as revealed by multivariate analysis, which elicited an adjusted increased risk of death after 3 years of 129% and 94% for fibrillar collagens imaged with bright-field (p = 0.004) and polarized light (p = 0.003), respectively, and of 89% for α-SMA (p = 0.009). We also found a significant association between all TAF activation markers and tumor necrosis, which is often indicative of hypoxia, supporting a pathologic link between tumor desmoplasia and necrosis/hypoxia.

      Conclusion

      Our findings identify patients with large histologic coverage of fibrillar collagens and α-SMA+ TAFs to be at higher risk of recurrence and death, supporting that they could be considered for adjuvant therapy. Moreover it supports that antifibrotic drugs aiming to target tumor fibrosis may be an effective therapeutic approach to improve survival in NSCLC.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA15.11 - Establishing a Cell Sociology Platform for the Assessment of Targetable Interactions to Predict Lung Cancer Outcome (Now Available) (ID 2652)

      15:45 - 17:15  |  Presenting Author(s): Erin A Marshall  |  Author(s): Katey SS Enfield, Paul Gallagher, Martial Guillaud, Calum Macaulay, Wan Lam

      • Abstract
      • Presentation
      • Slides

      Background

      The tumor microenvironment (TME) is a complex mixture of tumor epithelium, stroma and immune cells. The immune component of the TME is highly prognostic for tumor progression and patient outcome. Immune functionality, however, is often dictated by direct cell-to-cell contacts and cannot be resolved by simple metrics of cell density (for example, number of cells per mm2 or flow cytometry). For example, direct contact between CD8+ T cells and target cells is necessary for CD8+ T cell activity, and direct contact between PD1+ and PD-L1+ cells is necessary for the efficacy of immune checkpoint inhibitors. Current immunohistochemistry (IHC) techniques identify immune cell numbers and densities, but lack assessment of spatial relationships (or “cell sociology”). Here, we develop a platform to examine these direct interactions within the TME, and assess their relationship with patient outcome in two independent non-small cell lung cancer (NSCLC) cohorts.

      Method

      Tissue sections of primary tumors from lung adenocarcinoma (LUAD) patients with known clinical outcome were stained using 2 multiplex IHC panels: CD3/CD8/CD79a (Panel 1) and PD1/PDL1/CD8 (Panel 2). Hyperspectral image analysis determined the phenotype of all cells. Using the same IHC panels, these observations were assessed in a secondary NSCLC dataset (n=674). Deconvolution of these images was used to identify cell types, and cellular ‘neighborhoods’ were assessed using a Voronoi approach. This cohort was also profiled by for gene expression to validate immune subset fractions. We further identified other tumor features, including the presence of tertiary lymphoid organs (TLOs; transient immune structures necessary for antibody production from B cells).

      Result

      High density of intra-tumoral CD8+ T cells was associated with non-recurrence of tumors. However, we find that a non-random cell sociology pattern of CD8+ T cells directly surrounded by tumor cells was more significantly associated with non-recurrence compared to density alone. Monte Carlo re‐sampling analysis determined that these cell sociology patterns were non-random.

      Conclusion

      Hyperspectral cell sociology expands our understanding of the complex interplay between tumor cells and immune infiltrate. This technology improves our understanding of the tumour microenvironment and allows us to directly quantify interactions that dictate immune responses to cancers. Consequently, the implementation of this platform could improve predictions of responses to immunotherapy and lead to a deeper understanding of anti-tumor immunity.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

    • +

      MA15.12 - Discussant - MA15.09, MA15.10, MA15.11 (Now Available) (ID 3782)

      15:45 - 17:15  |  Presenting Author(s): David Hwang

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.