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Ignacio I. Wistuba



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    ES04 - Liquid Biopsies in Lung Cancer (ID 772)

    • Event: WCLC 2018
    • Type: Educational Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 203 BD
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      ES04.00 - Introduction with Poll Questions (ID 14931)

      15:15 - 15:20  |  Presenting Author(s): Ignacio I. Wistuba

      • Abstract
      • Slides

      Abstract not provided

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    ES08 - The Pathologist - An Essential Member of the Patient Care Team (ID 776)

    • Event: WCLC 2018
    • Type: Educational Session
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 206 AC
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      ES08.04 - Neoadjuvant Therapy (ID 12811)

      14:30 - 14:50  |  Presenting Author(s): Ignacio I. Wistuba

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA04 - Novel Approaches with IO (ID 900)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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      MA04.09 - Neoadjuvant Atezolizumab in Resectable Non-Small Cell Lung Cancer (NSCLC): Updated Results from a Multicenter Study (LCMC3) (ID 12941)

      14:30 - 14:35  |  Author(s): Ignacio I. Wistuba

      • Abstract
      • Presentation
      • Slides

      Background

      Cisplatin-based chemotherapy, before or after surgery, provides only a 5% benefit in 5yr. OS in resectable NSCLC. A 20 patient study (NEJM April 2018) showed that preoperative immune checkpoint inhibitor therapy yielded a clinically meaningful major pathologic response rate (MPR ≤10% residual viable tumor cells) and did not delay or complicate surgery. This large multicenter trial measures MPR and biomarkers of benefit using neoadjuvant atezolizumab (atezo) [NCT02927301].

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We planned 2 cycles of atezo (1200mg, days 1, 22) in patients with stages IB -selected IIIB resectable NSCLC prior to surgical resection (day 40 +/- 10). Chest CT, PET were planned pre-atezo and presurgery to assess response. Primary tumor +/- node biopsies and blood samples were obtained before atezo and presurgery for biomarker studies. The primary endpoint was MPR. Secondary endpoints included safety, response by PD-L1, OS, and DFS.

      4c3880bb027f159e801041b1021e88e8 Result

      For this updated efficacy and safety analysis (Feb’18 datacut), we report first 54 of 180 planned pts: 29 males, median age 65 yr, all ECOG 0-1; 17 current, 33 former smokers; 35 non-squamous NSCLC; clinical stages Ib/IIa/IIb/IIIa/IIIb = 5/11/13/20/5. Two pts received one dose of atezo due to treatment related AE (Gr 1 pyrexia, Gr 2 dyspnea) but underwent uncomplicated resection with MPR assessment. There was 1 unrelated Gr 5 AE (sudden cardiac death post surgical resection), 16 Gr 3-4 AEs (3 treatment related). Surgery was delayed in 1 pt due to Gr3 pneumonitis. By RECIST, 3 pts had PR, and 49 had SD. 50 pts underwent surgery and 47 pts had MPR assessment: 2 pts discontinued study preop due to radiographic PD and 2 discontinued due to other reasons; 3 pts had unresectable disease. MPR rate was 10/50 (20%, 95% CI 10-34%) including 3 pts who had pCR (no viable tumor cells) in the primary tumor. Excluding 5 pts who had known driver mutations (4 EGFR+, 1 ALK+), MPR rate was 10/45 (22%, 95% CI 11-37%). PD-L1 status was evaluable in 44/54 pts; 8/10 pts with MPR had PD-L1+ status and 2 had unknown PD-L1 status; 8/28 PDL-1 (+) patients had MPR (29%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In a multicenter study, neoadjuvant atezo was well tolerated. MPR rate is encouraging. Clinical and pathological responses are often discordant. Correlative analyses on pre- and post atezo tissues are ongoing. Preliminary correlative analyses in blood samples are included in a separate abstract.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA04.10 - Comprehensive Peripheral Blood Immunophenotyping and T-Cell Clonal Analysis During Neoadjuvant Immunotherapy with Atezolizumab in NSCLC (ID 13118)

      14:35 - 14:40  |  Author(s): Ignacio I. Wistuba

      • Abstract
      • Presentation
      • Slides

      Background

      Immune-checkpoint blockade targeting PD-L1/PD-1 to activate anti-tumor immunity is associated with improved response rates and survival compared to chemotherapy in selected metastatic NSCLC patients. Evaluation of the pre-therapeutic immune profile and its treatment-related evolution associated with clinical benefit will guide future immunotherapy development and support clinical decision-making. Here, we present an analysis of peripheral blood (PB) immunophenotyping and T-cell-receptor (TCR) clonality before and after immunotherapy from an ongoing 180-patient phase II study of atezolizumab as neoadjuvant therapy with stage IB-IIIB resectable NSCLC (NCT02927301; LCMC3).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      As of February 5th datacut, the first 54 enrolled and dosed patients are presented. The biomarker evaluable population (BEP) further subset to patients with paired PB samples analyzed within 72 hours after collection and a major pathological response (MPR) assessment. Comprehensive immune cell phenotyping (10-color flow cytometry, IMMUNOME) and TCR-Vß-analysis by flow cytometry were performed. Immunoprofile analyses were correlated with atezolizumab treatment, pathological response and PD-L1 expression.

      4c3880bb027f159e801041b1021e88e8 Result

      In this ongoing analysis, BEP included 31 patients. 5 patients (16%, 95% CI (5%, 34%)) had a MPR; all of which stained positive for PD-L1 by IHC using 22C3 (TPS≥1%) and SP142 (PD-L1 expression on ≥1% tumor cells (TC) and/or tumor infiltrating immune cells (IC)) at baseline. We observed significant increases in natural killer (NK) cells (p=0.005) and CD8+ T-cells (p=0.031) and a Th1-response related dendritic cell (DC) subpopulation (p=0.031) and significant decreases in B-cells (p=0.015) after treatment.

      Patients who achieved MPR show lower baseline levels of degranulated CD8+ T-cells (p=0.015), late-activated NK-cells (p=0.043), memory CD4+ (p=0.048) and memory CD8+ T-cells (p=0.032); changes in PB NK-cells (p=0.041), a decrease in M-MDSCs and a Th-2 and Th-17-response related DC subpopulation (p=0.043) in response to treatment were noted in patients with MPR versus non-MPR.

      Among the 16 patients with TC/IC 1/2/3 (> 1% PD-L1 expression) the following significant differences were observed compared to TC0/IC0 (7 patients): higher levels of late-activated CD4+ T-cells (p=0.025) and mid-activated CD8+ T-cells (p=0.044) at baseline, decrease of senescent T-cells (p=0.041), monocytic myeloid-suppressor cell subpopulations (M-MDSCs) and an increase in a Th1-response related DC subpopulation (p=0.026) after treatment.

      TCR clonality analysis showed expansions in Vß-subtypes after atezolizumab treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Immunophenotyping and TCR-Vß-repertoire analysis in peripheral blood samples from NSCLC patients treated with neoadjuvant atezolizumab show differences in immune cell subsets in baseline samples and changes after treatment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA06 - PDL1, TMB and DNA Repair (ID 903)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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      MA06.02 - Prospective Immunogenomic Profiling of Non-Small Cell Lung Cancer: Genomic and Immune Profiling Updates from Project ICON (ID 13523)

      13:35 - 13:40  |  Author(s): Ignacio I. Wistuba

      • Abstract
      • Presentation
      • Slides

      Background

      Our previous work has demonstrated that higher level of genomic complexity is associated with more heterogeneous neoantigen repertoire, suppressed T cell repertoire and postsurgical relapse in localized non-small cell lung cancers (NSCLC) highlighting the complex interaction of tumor molecular and immune landscape and their impact on cancer biology and patient survival. We launched the ICON Project (Immune Genomic Profiling of NSCLC) to prospectively delineate the molecular and immune landscape of early stage NSCLC and their impact on patient survival through a multidisciplinary approach. Here we report the updated genomic and immune analyses.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Surgical specimens from stage I-III NSCLC were subjected to whole-exome and RNA sequencing for mutational analysis, in silico neoantigen prediction and gene expression analysis as well as T cell receptor sequencing, cytometry by time-of-flight and multiplex immunofluorescence staining.

      4c3880bb027f159e801041b1021e88e8 Result

      From 2016-2018, 127 patients were accrued and 50 surgical samples have undergone WES, RNAseq, TCR sequencing and immune phenotyping. Median age is 66 yrs (range: 39-86), 52% (26/50) were female and 76% (38/50) former smokers. 76% (38/50) are non-squamous carcinomas and 24% (12/50) squamous cell carcinomas. 34% have stage I disease (17/50), 30% stage II (15/50), 34% stage III (17/50) and 2% stage IV (1/50). The majority of patients had upfront surgery (45/50; 90%). With median follow-up of 19 months, 15 patients have relapsed. Median tumor mutational burden is 7.8mut/Mb and predicted neoantigen burden was 10/sample (range: 0-250). Predicted neoantigen burden is significantly correlated with tumor mutational burden (r=0.41, p=0.002). The most commonly mutated genes are TP53, KRAS, CDKN2A, PIK3CA, EGFR, BRAF, GRIN2A and ATM. C->A transversions and C->T transitions were the most common mutational subtypes. PD-1 expression and regulatory T-cell (CD4+/FoxP3+) infiltration are significantly increased in tumor tissue compared to normal tissue (p=0.003 and p=0.02 respectively), while CD3, CD8, granzyme B and CD45RO are decreased in tumor tissue compared to normal lung.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NSCLC tumors have an immunosuppressive microenvironment compared to tumor adjacent normal lung tissues. Clinical data will be adequate to conduct genomic and immune profiling comparisons across different clinical subgroups. Mutational and neoantigen profiling are consistent with previously reported studies and correlations between molecular and immune landscapes and its impact on patient survival are ongoing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA03 - Advances in Lung Cancer Pathology (ID 897)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 BD
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      OA03.03 - Phase 2B of Blueprint PD-L1 Immunohistochemistry Assay Comparability Study (ID 14530)

      10:50 - 11:00  |  Author(s): Ignacio I. Wistuba

      • Abstract
      • Presentation
      • Slides

      Background
      PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each developed as predictive biomarker for specific anti PD1/PD-L1 immunotherapies. The Blueprint (BP) phase 1 comparability study demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells (TPS), while the SP-142 PD-L1 assay appeared to stain a lower percentage of tumor cells when compared to the other assays. The first part of BP phase 2 (BP2A) re-affirmed these findings in a larger cohort of ‘real life’ specimens scored by 24 experienced pulmonary pathologists, and also showed that the 73-10 assay developed for avelumab showed greater sensitivity than all other assays to detect PD-L1 on tumour cells. BP2A also demonstrated generally excellent inter-observer agreement for tumor cell PD-L1 scoring using both glass slides and digital images, with slightly lesser agreement for the cytology samples included in the study cohort. Inter-observer agreement for immune cell scoring on glass or digital slides was poor. Phase 2B of Blueprint (BP2B) aimed to compare PD-L1 scoring on triplet samples representing large tumor resection blocks, small biopsy samples and fine needle aspirate cell blocks prepared from the same tumor. a9ded1e5ce5d75814730bb4caaf49419 Method
      Triplet samples of large resected tumor block, small biopsy sample and fine needle aspirate cell block (the latter two taken from the resected tumour specimen) were gathered from 31 resected primary lung cancers (17 adenocarcinomas, 12 squamous cell carcinomas, and 2 large cell carcinomas). Sections from all 93 blocks were stained with the pharmDx 28-8 and 22C3, the FDA-approved SP142 and SP263, or clinical trial associated 73-10 PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. All H&E and PD-L1 IHC slides were scanned and digital images were used to score all cases by the same 24 pathologists involved in BP2A. As before, tumor cells PD-L1 staining were scored as continuous variable and into 7 cut-off-defined categories, as used in various immune checkpoint inhibitor trials. Immune cells were not scored. 4c3880bb027f159e801041b1021e88e8 Result
      The data reaffirm the relative comparability of 28-8, 22C3 and SP263 assays across the range of scores; SP142 assay scores were lower, those for 73-10 higher. Inter-observer agreement between readers ranged from moderate to near perfect (Kappa-Fleiss (K-F) scores generally >0.7); best overall agreement was on aspirates. Overall, the agreement between scores on the different sample types from the same tumor was good (most K-F scores >0.7); aspirates showed no significant difference from biopsy samples or whole surgical blocks. In contrast to biopsies and surgical blocks, scores could, however, not be rendered in about 14% of aspirate sections. 8eea62084ca7e541d918e823422bd82e Conclusion
      The results of BP2B confirms earlier results and also demonstrate comparable performance for fine needle aspirates in those cases where TPS scores were possible. 6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA03.05 - Characterization of the Immunologic Intra-Tumor Heterogeneity in Early Stages of Non-Small Cell Lung Cancer by Multiplex Immunofluorescence (ID 13334)

      11:15 - 11:25  |  Author(s): Ignacio I. Wistuba

      • Abstract
      • Presentation
      • Slides

      Background

      Recurrence of non-small cell lung carcinoma (NSCLC) is associated with genetic and epigenetic intra-tumor heterogeneity (ITH). The interaction between malignant cells, stromal cells, and tumor-associated immune-cells (TAICs), such as T-cell lymphocytes (TCLs) and tumor-associated macrophages (TAMs), is important for progression of NSCLC and the characterization of the immunologic ITH might be relevant to predict recurrence in surgically treated patients at early stages of NSCLC. The aim of this study was to characterize the immunologic ITH of primary NSCLC tumors at early stages using image analysis and multiplex immunofluorescence (mIF) approaches.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eight cases of stage IA and 8 cases of stage IB surgically resected NSCLC (11 adenocarcinomas, ADCs; and 5 squamous-cell carcinomas, SCCs) with a history of early recurrence were selected for this preliminary analysis. FFPE blocks were obtained and consecutive sections were stained with two panels of mIF for immune profiling, panel 1: pan-cytokeratin (AE1/AE3), PD-L1, PD-1, CD3, CD8, and CD68; panel 2: AE1/AE3, CD3, CD8, granzyme-B (GB), CD45RO, and FOXP3. Three not adjacent, intra-tumor regions (3mm2 each) per case were randomly selected after gridding the whole tumor section. A total of 41 intra-tumor regions were scanned by Vectra multispectral-microscope and analyzed using InForm-software. TAICs were quantified in epithelial and stromal compartments from each intra-tumor region. G-Cross AUC (area under the curve) was computed for specific intervals of distances between TAICs and malignant cells. Median distance between TAICs and malignant cells within each region was calculated.

      4c3880bb027f159e801041b1021e88e8 Result

      The median density of TCLs and TAMs were 1527 cells/mm2 and 635 cells/mm2, respectively, without significant differences between histologic subtypes. TCLs were predominantly concentered in stromal compartment (median, 2222 cells/mm2) compared with epithelial compartment (median, 332 cells/mm2). Percentage and density of TCLs and TAMs varied 4 and 8 times, respectively, between cases and regions. Non-cytotoxic T-cells and inactive cytotoxic T-cells were the most prevalent phenotypes. Higher density of TAMs and antigen-experienced TCLs were observed in stage IB than stage IA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Characterization of immunologic ITH of NSCLC is able by mIF and image analysis with FFPE tumor tissue. There is variability of TAICs densities between regions from the same tumor and different subpopulations were observed. TAMs and exhausted T-cells were more prominent in stage IB (tumor >3cm) suggesting these cells may play an important role in recurrence. Ongoing studies with a larger cohort and comparison with non-recurrent surgically treated patients are warranted. Supported by CPRITRP160668 and UTLungSPORE grants

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.03 - Biology (Not CME Accredited Session) (ID 935)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.03-12 - PD-L1 Expression is Predominant in CD68+ Tumor-Associated Macrophages in Stage I-III Non-Small Cell Lung Cancers (ID 13340)

      16:45 - 18:00  |  Author(s): Ignacio I. Wistuba

      • Abstract
      • Slides

      Background

      PD-L1 tumor expression is a leading biomarker in metastatic non-small lung cancer (NSCLC). Its role and expression in surgically resectable lung cancers is not yet defined. The association between PD-L1 expression on tumor and CD68+ tumor-associated macrophages (TAMs) and the inflammatory cells within the tumor microenvironment continues to be studied. We analyzed 97 surgically resected lung cancers utilizing immunofluorescence profiling and flow cytometry (n=47) with the aim of defining PD-L1 expression and its association with tumor inflammatory cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Multiplex immunofluorescence profiling of lung cancers was performed with the focus on malignant cells (MC), MC PD-L1%, CD3+, CD8+, PD-1+ cells, CD68+, CD68+ PD-L1%, and CD20+ cells. Data on cell populations were expressed as the number of cells per mm2, PD-L1 expression as percentage. Flow cytometry was performed on freshly disaggregated tumor samples. The associations of cell populations with clinical and pathologic characteristics were assessed using Spearman's rank correlation coefficient and Wilcoxon rank-sum test.

      4c3880bb027f159e801041b1021e88e8 Result

      97 patients, 55 (57%) female and 42 (43%) male, with median tumor size 4.0 cm underwent surgical resection for pathologic stage I (N=39), stage II (N=34), and stage III (N=24) NSCLC. 85 (88%) were former smokers, 12 (12%) never smokers. 62 (65%) had adenocarcinoma, 25 (25%) squamous cell carcinoma, 10 (10%) other histology. Neoadjuvant chemotherapy was administered in 16 (16%) patients. R0 resection was achieved in 89 (92%) patients. At the median follow-up duration of 16 months, 18 patients experienced recurrence.

      CD68+ cells were less abundant than MC within tumor environment (median 120 cell/mm2 vs 4699, p<0.0001). However, PD-L1% expression was significantly higher on CD68+ vs MC within the tumor (median 33% vs 0.02%, p<0.0001); this was true for all stages. CD68+ PD-L1% in SCC was higher compared to adenocarcinoma (median 55% vs 30%, p=0.26). Induction chemotherapy increased CD68+ PD-L1% (median 31% no chemo vs 58%, p=0.05) without affecting the proportion of effector CD8+ TIL expressing its receptor, PD-1 (p=0.757). Tumors with > median CD68+ PD-L1% expression were associated with higher CD3+ (p=0.006), CD8+ (p=0.06), and CD68+ (p=0.004) cell numbers within the tumor.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In early NSCLC PD-L1% expression appears to be predominant in CD68+ TAMs rather than in malignant cells. Higher than median PD-L1% expression on CD68+ is associated with increased in CD3+ and CD8+ T cells. Further studies are required to understand the role of CD68+PD-L1 cells within tumor microenvironment, the influence of neoadjuvant chemotherapy or immunotherapy regimens on these cells, and their effect on outcomes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.03-24 - TMPRSS4: A Novel Prognostic Biomarker and Therapeutic Target in NSCLC (ID 11988)

      16:45 - 18:00  |  Author(s): Ignacio I. Wistuba

      • Abstract
      • Slides

      Background

      Genomic analyses are identifying novel genes involved in the pathogenesis of non-small cell lung cancer (NSCLC). TMPRSS4, a membrane-anchored serine protease, was previously found as highly overexpressed in NSCLC. Since proteases have been functionally related to cancer growth and metastasis, we sought to study the prognostic value and role of TMPRSS4 in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      TMPRSS4 expression was evaluated by immunohistochemistry and H-score calculation in TMAs containing a total number of 455 cases. Kaplan-Meier, log-rank and Cox analyses were used to study the prognostic value. In addition, functional assays using NSCLC cell lines and in vivo models were used to assess the possible role of this protease in NSCLC.

      4c3880bb027f159e801041b1021e88e8 Result

      High expression of TMPRSS4 was associated with reduced relapse-free survival (RFS, p=0.003) and overall survival (OS, p=0.007) in NSCLC patients. The prognostic value was also found in patients with stages I-II. Multivariant Cox regression analysis identified TMPRSS4 as an independent prognostic factor in NSCLC for both RFS (HR 1.61 [1.16-2.23], p<0.004) and OS (HR 1.52 [1.14-2.03], p<0.005). In functional studies we developed genetic systems to overexpress or reduce TMPRSS4 levels in lung cancer cells lines. Overexpression in LKR13 cells led to increased clonogenicity, migration and multiorganic metastasis in liver, bone and suprarenal gland. Abrogation of TMPRSS4 in H358 and H2170 cell lines caused a very strong reduction in proliferation (>70%, 96h after plating), clonocenicity (>90%, after 15 days in culture) and subcutaneous tumor growth. Reduction in S and G2/M phases of the cell cycle, increased apoptosis, and changes in gene expression of cell replication- and migration-promoting genes (i.e. MCM6, TYMS and CDKN1A(p21)) were also found. Cells lacking TMPRSS4 were highly sensitized to chemotherapy, including cisplatin, paclitaxel and gemcitabine, which significantly enhanced the antiproliferative, antitumor and proapoptotic effect of these drugs.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results show that TMPRSS4 is a biomarker of poor prognosis in NSCLC and plays an important role in tumor growth and metastasis, and suggest that its blockade may enhance sensitivity to chemotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.04-22 - CD73 Immunohistochemical Expression in Malignant Cells and Correlation with Immune Infiltrate in Non-Small Cell Lung Carcinoma (NSCLC). (ID 11859)

      16:45 - 18:00  |  Presenting Author(s): Ignacio I. Wistuba

      • Abstract
      • Slides

      Background

      CD73 is potential novel target for lung cancer immunotherapy involved in the adenosine pathway that induces tumor microenvironment immunosuppression. We investigated the immunohistochemical (IHC) expression of CD73 in a large cohort of NSCLC and correlated with tumor’s clinical, pathological, molecular and immune cells infiltration data.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We examined 175 surgically resected stages I-III formalin-fixed and paraffin-embedded NSCLC tumors tissue microarrays, including 107 adenocarcinomas (ADC) and 68 squamous cell carcinomas (SqCC). For IHC, we used the anti-CD73 antibody (clone D7F9A, Cell Signaling Technology) and evaluated membrane (basolateral and luminal) expression in malignant cells. In a subset of cases, CD73 IHC expression was correlated with data available on: a) CD73 gene mRNA expression (Illumina arrays; n=91); b) EGFR and KRAS mutation status and mutational load (whole exome sequencing; n=104); and, c) density of tumor associated immune cells infiltration (CD3, CD4, CD8, CD68, CD45RO, CD57, FOXP3, and granzyme B) and immune checkpoints expression (PD-L1, PD-1, ICOS, TIM-3, IDO-1, B7-H3, B7-H4, VISTA and OX40) assessed by IHC and image analysis (n=172).

      4c3880bb027f159e801041b1021e88e8 Result

      ADC showed higher CD73 IHC expression than SqCC (P<0.0001). Pathological stage I ADCs showed higher CD73 expression than higher tumor stages (P=0.0419). Using any level of CD73 expression (>1%) CD73 was expressed in 73% and 40% of ADCs and SqCs, respectively. High expression (>50% of malignant cells) was detected in 35% of ADCs and 20% of SqCC. No other significant correlations with clinical-pathological variables, including patients’ outcome were found. Interestingly, ADCs with EGFR (P=0.04) and KRAS (P=0.02) mutation expressed higher CD73 levels than wild-type tumors. In ADC, CD73 IHC expression correlated significantly with the density of immune T CD3+, CD4+, CD8+, CD45RO+ and FOXP3+ cells, as well as macrophages CD68+ cells in tumors (r values range: 0.22-0.45; P values range: 0.001-0.02). Overall, we did not find significant correlations between CD73 immunostaining and the IHC expression of the immune checkpoints examined. CD73 IHC expression correlated positively with mRNA CD73 gene expression levels in all NSCLCs (r=0.6; P<0.0001), ADCs (r=0.6; P<0.0001), and SqCCs (r=0.49, P<0.0001) histology

      8eea62084ca7e541d918e823422bd82e Conclusion

      We identified that CD73 protein expresses in a subset of resected NSCLCs, being significantly higher in adenocarcinoma histology. In this histology type, CD73 correlates with immune T cells and macrophages infiltration, and notably, with tumor’s EGFR and KRAS mutation. Our data suggest that CD73 is a potential target for NSCLC, particularly for adenocarcinoma histology (Supported by grants CPRIT RP160668 and UT Lung SPORE).

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.09 - Pathology (Not CME Accredited Session) (ID 975)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.09-27 - Histopathologic Parameters Define Features of Treatment Response to Neoadjuvant Chemotherapy in Non-Small Cell Lung Cancer (ID 14257)

      12:00 - 13:30  |  Author(s): Ignacio I. Wistuba

      • Abstract

      Background

      Previous studies indicate that neoadjuvant chemotherapy improves survival in patients with loco-regionally advanced non-small cell lung cancer (NSCLC). The amount of residual viable tumor has been associated with long-term overall survival. This histopathologic measure has potential to become a standard method for evaluation of the effectiveness of neoadjuvant therapy regimens. However, adequate comparison of chemotherapy-treated and untreated lung cancers is lacking. We analyzed histopathologic characteristics of resected NSCLC with and without prior neoadjuvant chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Histopathologic assessment was performed of specimens obtained from patients enrolled on the immunogenomic lung cancer study (ICON), which integrates clinical, pathologic, immune, genomic and outcome data from surgically resected NSCLC. Cases included material from 10 patients who underwent neoadjuvant chemotherapy and 10 patients treated with primary surgery (adenocarcinoma, n=5; squamous cell carcinoma, n=5; for each cohort). Hematoxylin and eosin-stained tumor sections (mean, 6; range, 3-10) were evaluated and semiquantitatively scored for parameters commonly attributed to treatment response. The percentage of viable tumor was estimated by comparison to the proportion of fibrosis and necrosis on each slide. Additional parameters analyzed included the presence of inflammation, tertiary lymphoid structures (TLS), macrophages, lymphovascular invasion (LVI), cholesterol clefts, giant cells and neovascularization (score 0-3). For each patient, the results for all slides were averaged to determine a mean value. P values were calculated using the Mann-Whitney test.

      4c3880bb027f159e801041b1021e88e8 Result

      All histopathologic parameters typically associated with treatment response could also be identified in untreated specimens, albeit in different proportions. Compared to the untreated cohort, samples after chemotherapy were characterized by lower proportion of viable tumor (42.4% vs 67.7%, p=0.04) and higher degrees of fibrosis (46.6% vs 26.6%, p=0.08), and necrosis (11.0 % vs 5.6%, p=0.35). Among the additional parameters, similar scores were seen for inflammation (1.54 vs 1.46, p=0.60), TLS (1.00 vs 0.80, p=0.47), LVI (0.16 vs 0.23, p=0.62), and neovascularization (both 0) while macrophages (0.94 vs 0.12, p=0.20), cholesterol clefts (0.92 vs 0.13, p= 0.03) and giant cells (0.80 vs 0.40, p=0.17) were more common among the neoadjuvant cohort.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Histopathologic variables commonly associated with chemotherapy treatment response can also be identified in treatment naïve lung cancers. However, the amount of viable tumor, fibrosis and cholesterol clefts are parameters strongly associated with neoadjuvant therapy. These results highlight the importance of assessing the type and extent of treatment response. Analysis of larger patient cohorts will reveal potential prognostic value in primary tumors, chemotherapy-treated, and eventually immunotherapy-treated tumors.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 978)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.12-06 - SLFN11 Expression and Efficacy of PARP Inhibitor Therapy in Extensive Stage Small Cell Lung Cancer: ECOG-ACRIN 2511 Study (ID 14113)

      12:00 - 13:30  |  Author(s): Ignacio I. Wistuba

      • Abstract

      Background

      Veliparib (V),an oral small molecule inhibitor of poly (ADP) ribose polymerase (PARP) enhanced cytotoxic chemotherapy in preclinical models of small cell lung cancer (SCLC). The combination of V with cisplatin/etoposide (CE) doublet showed efficacy improvement as first-line therapy of extensive stage SCLC (ES-SCLC) with adjusted PFS HR: 0.63 1-sided p=0.01. There was differential treatment effect by strata (adjusted treatment HR comparing CE+V: CE: 0.34; 80% CI: 0.22 - 0.51; 1-sided p<0.001 for male patients with high tumor burden versus adjusted HR: 0.81 80% CI: 0.60 - 1.09; 1-sided p=0.18 for other patients subsets) highlighting the need to identify patient subset most likely to benefit. SLFN11 expression was previously shown to be associated with benefit of V when combined with temozolomide in relapsed SCLC and also predicted benefit of CE in preclinical models. We assessed the utility of SLFN11 as a predictive biomarker in the context of E2511 frontline clinical trial.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Archival tissue samples collected from patients with ES-SCLC enrolled and treated on E2511 study was employed for biomarker analysis looking at SLFN11 expression by immunohistochemistry. The study has 88% power to detect a PFS hazard ratio of 0.5 comparing SLFN11 (+) and (-) patients using a one-sided 0.025 level logrank test.

      4c3880bb027f159e801041b1021e88e8 Result

      There was an imbalance between control and experimental arms in the Male/abnormal LDH stratum (in strata) with respect to Age: p=0.006; malignant pleural effusion: p=0.095 and T stage: p=0.02. Median PFS was 5.1 mos on CE (95% CI 4.1-6.1) vs. 6.2 mos on CE+V (95% CI 5.9-8.8); HR=0.32, p=0.002 (unadjusted); median OS on CE was 8.8 mos (95% CI 6.6-11.1) vs. 9.5 mos on CE+V (95% CI 7.8-12.8); HR=0.76, p=0.39. Clinical outcome differences based on SLFN11 expression is ongoing and will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pending ongoing analysis of correaltion of biomarker with clinical outcomes

      6f8b794f3246b0c1e1780bb4d4d5dc53