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Geoffrey Liu
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MA18 - Advances in Diagnosis of Common Types of NSCLC (ID 145)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Pathology
- Presentations: 1
- Now Available
- Moderators:Yuko Minami, Mary Beth Beasley
- Coordinates: 9/10/2019, 11:30 - 13:00, Tokyo (1982)
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MA18.07 - Identification of Neuroendocrine Transformation in Anaplastic Lymphoma Kinase Rearranged (ALK+) Tumors After Tyrosine Kinase Inhibitors (Now Available) (ID 1137)
11:30 - 13:00 | Author(s): Geoffrey Liu
- Abstract
- Presentation
Background
Acquired resistance after ALK tyrosine kinase inhibitors treatment has multiple known mechanisms: new mutations or gene amplifications, bypass signaling and rarely neuroendocrine histological transformation. Here we describe results of a program utilizing routine biopsy post-progression in ALK+ patients for clinical and research purposes.
Method
Since 2014, ALK+ lung cancer patients treated at the Princess Margaret Cancer Centre have undergone routine biopsies at disease progression time points upon failure of an ALK-tyrosine kinase inhibitor (TKI) for both clinical purposes and research purposes, in particular to obtain tissue for primary derived xenograft (PDX) engraftment.
Result
All 9/9 patients consented for research sampling during clinical biopsy procedures (median 2 extra cores/passes); 2 patients were biopsied more than once; 3 PDX models from 2 patients have engrafted; 3 additional models are too early to assess engraftment. Engraftment occurred in patients with clinically aggressive tumors and poor survival outcomes. In this process, we identified 2 patients with neuroendocrine transformation post-second generation ALK TKI: (a) a 59 yo Asian female, never smoker, diagnosed six years prior with metastatic disease, heavily pretreated with crizotinib (12 months), pemetrexed (16 months), ceritinib (25 months), alectinib (6 months) and brigatinib (3 months); post-alectinib biopsy showed no transformation, while post-brigatinib liver biopsy demonstrated transformation to large cell neuroendocrine carcinoma; (b) a 75 yo Caucasian female, never smoker, diagnosed eight months prior and started on alectinib with a partial response, progressed in a single site; endobronchial biopsy demonstrated high grade neuroendocrine transformation. Both biopsies were positive for neuroendocrine markers (chromogranin and synaptophysin), TTF-1 and diffusely co-expressed ALK on immunohistochemistry. Assessment of PDX engraftment of these models is ongoing.
Conclusion
Routine combined clinical and research biopsy of ALK+ patients at time of TKI failure helped to identify these recent cases of neuroendocrine transformation as a possible mode of resistance and provide tissue for model development. This is the first time that ALK+ transformation to large cell neuroendocrine carcinoma is reported in the literature. (PP, AFF, SNMF, LN contributed equally).
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OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)
- Event: WCLC 2019
- Type: Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Luis M Montuenga, Julie George
- Coordinates: 9/09/2019, 11:00 - 12:30, Interlaken (1988)
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OA08.01 - Organoid Cultures as Novel Preclinical Models of Non-Small Cell Lung Cancer (Now Available) (ID 2115)
11:00 - 12:30 | Author(s): Geoffrey Liu
- Abstract
- Presentation
Background
There is an unmet need to develop novel clinically relevant models of NSCLC to accelerate identification of drug targets and our understanding of the disease. Organoids, which are cells grown in three-dimensional environments in Matrigel, have emerged as novel preclinical models of cancer. Recently protocols for generating NSCLC organoids have been reported, but the growth, and molecular features of organoids as compared to their matching primary patient tumor or patient-derived xenografts (PDX) remain vague.
Method
Thirty surgically resected NSCLC patient tumor and 35 PDX tissue of lung adenocarcinoma and squamous cell carcinoma subtypes were processed for organoid establishment. Organoids and matching tumor tissues were characterized by histology and immunohistochemistry, and molecularly profiled by whole exome and RNA-sequencing. Subcutaneous injection of organoids in vivo was performed to confirm tumorgenicity. Organoids were subjected to drug testing and drug response was verified in the matched PDX.
Result
Using a novel culture condition that our laboratory developed, we have collected tumor samples from 16 primary and 13 PDX samples of adenocarcinoma (n=29) and 14 primary and 22 PDX samples of squamous cell carcinoma (n=36). Over 85% (57/65) of our patient and PDX tumor tissues formed organoids that exhibited a wide range of short-term (<3 months) and long-term (>3 months) growth. Specifically, the success rate of establishing short-term and long-term models are 74% (48/65) and 14% (9/65), respectively. The long-term propagable organoids recapitulated the histology of the patient and PDX tumor. They also retained the ability to form xenograft in NOD-SCID mice. The organoids preserved mutation, copy number aberrations and global gene expression profile of the parental tumors. We additionally showed the utility of short-term and long-term organoids for identifying biomarkers of sensitivity to drugs and combinational targeted therapies.
Conclusion
NSCLC organoids are novel patient-derived ex-vivo tumor models for anti-cancer drug screening and biomarker discovery, thus could be incorporated into novel drug discovery pipelines. Further efforts are ongoing to increase the success rate of establishing long-term organoid lines.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-30 - Non-Small Cell Lung Cancer (NSCLC) Next Generation Sequencing (NGS): Integrating Genomic Sequencing into a Publicly Funded Health Care Model (Now Available) (ID 2588)
09:45 - 18:00 | Author(s): Geoffrey Liu
- Abstract
Background
Standard of care (SOC) molecular diagnostics for stage IV NSCLC patients in Ontario, Canada includes publicly reimbursed EGFR/ALK, and BRAF/ ROS-1 testing in selected cases. Other genomic alterations are not tested routinely at all institutions; however, enhanced molecular testing may broaden treatment options for patients by identifying actionable targets. This study evaluated costs, identified actionable targets, and determined clinical trial eligibility as a result of using the Oncomine Comprehensive Assay v3 (OCA v3, ThermoFisher) NGS in stage IV NSCLC patients at a single institution.
Method
This prospective study of stage IV NSCLC out-patients at Princess Margaret Cancer Centre (Toronto) began in February 2018 and recruitment is ongoing (NCT03558165). NSCLC patients without EGFR/ALK/KRAS/BRAF alteration (unless failure of prior targeted therapy and tissue rebiopsy), had diagnostic samples tested by OCAv3 (ThermoFisher; 161 genes: hotspots, fusions, and copy number variations). Primary endpoints were identification of incremental actionable targets and clinical trial opportunities as a result of broader OCAv3 testing. Secondary endpoints include feasibility and cost from the Canadian public healthcare perspective.
Result
From Feb 2018- Jan 2019 65 patients were enrolled [62% (N=40) completed/ 21% (N=14) screen fail/ 17% (N=11) pending], median age of completed cohort was 65, 60% (N=24) female, never/light smokers 68% (N=27), Asian 38% (N=15), previously treated 33% (N=13). Actionable targets beyond SOC were identified in 33% (N=13): ERBB2 (N=8), BRAFV600 (N=3), NRG fusion (N=1), MET exon 14 (N=1). Failure of NGS was secondary to insufficient tissue. 91% (N=10) of screen failures was secondary to tissue exhaustion from prior sequential SOC molecular testing. New clinical trial options were identified in 70% as a result of OCA v3 testing. Incremental costs per case beyond EGFR/ALK are estimated at $540 CAD. If ROS-1 and BRAF testing were publicly reimbursed at current rates, the incremental profiling cost with OCAv3 would be $90 CAD per case.
Conclusion
The OCAv3 consolidates genomic testing, identifies additional actionable targets, and substantially increases clinical trial eligibility for patients at a small incremental cost. Sample failures are reflective of exhausted diagnostic tissue as a result of prior sequential genomic testing. The key barrier to implementation of NGS remains funding in the Canadian health care system.
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P1.01-70 - Dominant Circulating Myeloid Populations Are Associated with Poor Response in NSCLC Treated with 1st Line PD-1 Monotherapy (Now Available) (ID 2295)
09:45 - 18:00 | Author(s): Geoffrey Liu
- Abstract
Background
Immune subpopulations within the tumor microenvironment (TME) play a central role in determining response to checkpoint inhibitors. Myeloid derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have a predominantly immunosuppressive role by stimulating T regulatory cells. We hypothesize that elevated myeloid-to-lymphocyte measures in the peripheral blood predict for greater numbers of myeloid derived suppressor cells in the TME and worse outcomes.
Method
We identified all advanced NSCLC patients treated with immunotherapy between 2010-2019 at the Princess Margaret Cancer Center. Patients who received first line monotherapy with a PD-1 inhibitor were reviewed for clinical information including age, sex, histology, stage, smoking status, ethnicity, PD-L1 expression and tumor genotype. Myeloid cells lines analyzed included neutrophils, monocytes and platelets, expressed as ratios to peripheral lymphocytes. Multivariate analyses were conducted using the cox and logistic regression models to adjust for confounders.
Result
We identified 75 patients who were eligible for analysis. Disproportionate increases in the different myeloid cell types were highly correlated with each other (all Pearson’s rho>0.8) and the neutrophil to lymphocyte ratio (NLR) was selected as representative. A high NLR (>5) was associated with shorter time-to-treatment-failure (median TTF 9.7 vs 29.4 months) that remained significant after adjusting for confounders including PD-L1 and presence of liver metastases (p=0.004). High NLR was also an independent predictor of poor OS (median 11.3 vs 56.8 months, HR 3.02, p=0.04). Although NLR was not predictive of radiographic response, there was a trend to association with a rapidly progressive phenotype defined by primary progressive disease and a duration of therapy ≤2 months (p=0.06). Other predictive factors included the presence of liver metastases, which was associated with a worse OS (HR3.37 p=0.05) but not TTF (p=0.14). An association was also seen between NLR and liver metastases (mean NLR 6.6 vs 25.2 in the absence and presence of liver metastases respectively, p<0.001).
Conclusion
A disproportionate increase in peripheral immune myeloid populations may represent a systemic, myeloid-driven, immunosuppressive state that is significantly associated with primary refractory disease, rapid progression, and poor survival. A subset of about 50 patients with biobanked tissue are presently being analyzed using multiplex immunofluorescence to assess for MDSCs in the TME to correlate with peripheral blood findings.
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P1.07 - Nursing and Allied Professionals (ID 171)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Nursing and Allied Professionals
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.07-15 - Screening for Long Term Ototoxicity in Lung and Upper Aerodigestive Cancer Survivors Treated with Platinum Chemotherapy (ID 2011)
09:45 - 18:00 | Author(s): Geoffrey Liu
- Abstract
Background
Platinum-induced ototoxicity (PIO) is the hearing disorder that results from the temporary or permanent inner ear dysfunction after treatment with platinum based chemotherapy. Debilitating symptoms can include hearing loss, tinnitus and ear pain, affecting 40-80% of adults treated with platinum chemotherapies (up to 50% of lung cancer patients). There is no cure for PIO and the focus should be on early detection and lifestyle management. Ototoxicity negatively impacts quality of life in survivorship impacted by difficulty in speech recognition, safety concerns, social isolation and depression. At most cancer centres, hearing tests are not routinely performed in adults receiving cisplatin.
This study aims to implement screening audiometry initially through formal audiometry testing, and later through a mobile electronic tablet-based platform. Our study goals are: i) to confirm the high prevalence of ototoxicity; and ii) the feasibility of implementing an in-clinic tablet based hearing test as part of routine care for lung cancer patients.
Method
Using the CIHR Knowledge-to-Action framework, we formally assessed the clinic readiness, barriers to implementation, identification of facilitators, and initiated a pilot outpatient clinic-based study in our lung and head and neck cancer patients to determine viability and sustainability within the clinic.
Result
Prevalence of hearing loss ranged between 22-58% of cisplatin-treated patients. Barriers to implementation included: (i) difficulty contacting some survivors; (ii) coordinating testing across broad geographic areas; (iii) missing test results; (iv) allocation of physician versus nursing responsibilities in a multidisciplinary setting; (v) health care provider education; and (vii) long-term transition plan to primary care follow-up. Nursing/clinic champions improved uptake substantially. New procedures were necessary to ensure that tests are performed, results checked, and patients were triaged accordingly.
Conclusion
Substantial barriers were identified for clinical implementation of the routine post-platinum audiometry screening for ototoxicity in lung cancer survivors, but a list of potential solutions has led to good uptake of this process in the clinic. In a future follow-up pilot, we will test the potential benefits (time- and labour-savings; more efficient use of resources) of an in-clinic, portable, brief, tablet-based hearing test screening program, in place of formal audiometry testing.
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P1.10 - Prevention and Tobacco Control (ID 175)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.10-05 - Tobacco Retail Availability and Tobacco Cessation Among Lung Cancer Survivors (ID 1089)
09:45 - 18:00 | Presenting Author(s): Geoffrey Liu
- Abstract
Background
Continued smoking after a lung cancer diagnosis is associated with poorer outcomes. Tobacco retail availability is negatively associated with cessation in non-cancer patients but this has not been explored in cancer survivors. We evaluated the impact of tobacco retail availability on tobacco cessation in lung cancer survivors.
Method
Lung cancer survivors from Princess Margaret Cancer Centre (Toronto, Canada) completed questionnaires at diagnosis and follow-up evaluating changes in tobacco use with a median of 26 months apart. Validated tobacco retail location data were obtained from Ministry of Health and patient home addresses were geocoded using ArcGIS 10.6.1, which calculated walking time/distance to nearest vendor, and vendor density within 250 meters (m) and 500m from patient residences. Multivariable logistic regression and Cox proportional hazard models evaluated the impact of vendor availability on cessation and time to quitting after diagnosis respectively, adjusting for significant clinico-demographic and tobacco covariates.
Result
242/721 lung cancer survivors smoked at diagnosis; subsequent overall quit rate after diagnosis was 66%. Mean distance and walking time to a vendor was 0.8 km (range 0-13) and 10 min (range 0-157). On average, there was one vendor (range 0-19) within 250m and five vendors (range 0-36) within 500m from pts; 40% and 64% of pts lived within 250m and 500m from at least one vendor respectively. Greater distance (aOR 1.28 per 1000m [95% CI 0.97-1.70] p = 0.08) and increased walking time (aOR 1.02 per minute [1.00-1.05] p = 0.08) to a tobacco vendor had a non-significant trend towards increased chances of quitting at one year. Living within 250m (aOR 0.43 [0.25-0.74] p = 0.003) or 500m (aOR 0.50 [0.28-0.88] p = 0.02) to at least one vendor reduced quitting at one year. Living near more vendors within 500m had a non-significant trend towards having an increasing dose effect on reducing cessation rates at one year (aOR 0.97 per vendor [0.94-1.00] p = 0.08). Living within 500m to a vendor reduced chance of quitting at any time (aHR 0.70 [0.50-1.00] p = 0.05).
Conclusion
Close proximity to tobacco retail outlets is associated with reduced cessation rates for lung cancer survivors. Reducing density of tobacco vendors is a cessation strategy that could positively impact lung cancer patient outcomes.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-07 - Genomic Profiling of Liquid Biopsies During 2nd/3rd Generation ALK Inhibitor Therapy to Identify Novel Mechanisms of Resistance (ID 804)
09:45 - 18:00 | Author(s): Geoffrey Liu
- Abstract
Background
Second- and third-generation ALK inhibitors each have diverse mechanisms of resistance. Only a fraction of resistance is due to secondary mutations of the ALK gene. Altered bypass tracts are likely the case in some other instances. Genomic alterations of other genes and pathways may be a third mechanism of resistance. Repeat liquid biopsies during the course of patients’ treatments can provide a minimally invasive method for sampling cancer-specific genomic information that leads to improved treatment selection.
Method
In the Lung Cancer Clinic of the Princess Margaret Cancer Centre, serial plasma samples were collected from six lung cancer patients with ALK rearrangement at multiple serial clinic visits pre- and post- progression on next-generation ALK inhibitors. We focused on next generation agents, as there has been previous focus on crizotinib resistance mechanisms already. Cell-free DNA (cfDNA) was extracted (median: 50 ng; range: 20-2760 ng) and profiled using a next-generation sequencing (NGS) platform with Geneseeq Prime 425-gene panel at a mean coverage depth of 4747X (and a deduplicated mean coverage depth of 2160X).
Result
Somatic alterations from plasma cfDNA were detected in all six patients at various time points with three patients having detectable ALK alterations. Systemic progression (2/2 patients) correlated well with the ability of liquid biopsies to detect somatic mutations, while central nervous system (CNS)-predominant progression did not (4/4 patients). One patient, after disease progression on ceritinib, alectinib and brigatinib, exhibited variable allele fractions (AFs) of ALK G1202R mutation in cfDNA. The levels of G1202R decreased and ultimately became undetectable, corresponding to the patient’s clinical response to lorlatinib. In a patient who exhibited significant systemic progression, a massive increase in mutation AFs and many newly acquired mutations were detected in the cfDNA, including NOTCH1, DICER1, BRCA2, TP53, CDKN2A, ERBB3, and FAT1mutations. However, the increase in the number of co-mutations was not related to increases in the amount of extracted cfDNA.
Conclusion
Broad panel-based NGS of plasma cfDNA enabled noninvasive detection of systemic (but not CNS-predominant) progression during second and subsequent generation ALK inhibitor treatment, and can identify known and putative mechanisms of resistance for treatment decision-making.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-11 - Impact of Ethnicity on Outcome in Never Smokers with EGFR and ALK Wildtype (EGFR/ALK-Wildtype) Lung Adenocarcinomas (ID 2035)
10:15 - 18:15 | Author(s): Geoffrey Liu
- Abstract
Background
EGFR-mutations and ALK-rearrangements are frequent in lung adenocarcinoma (LUAD) samples from never smoker patients. Nevertheless, up to a quarter of all LUAD cases in never smokers are EGFR/ALK-wildtype: these patients have limited therapeutic options and few well-established clinical and molecular predictors of outcome. Our main objectives here were to investigate the prognostic impact of ethnicity in never smoker patients with EGFR/ALK-wildtype LUAD and seek for specific somatic events correlated to ethnical background in these patients.
Method
We included 85 samples from lifetime never-smoker patients with EGFR/ALK-wildtype LUAD collected from surgical resection with curative intent. Stages 1/2/3 were identified in 56 (66%)/15 (18%)/14 (16%) samples. A subset of those samples (n=46), with similar stage distribution, had snap-frozen tumor and paired-adjacent tissue available and were submitted to paired-end whole-exome sequencing. Fisher’s exact and Chi-squared tests were used to compare specific mutations between Asians vs non-Asians. Recurrence-free-survival (RFS) was calculated based on the Kaplan-Meier method; Cox modeling was used to generate hazard ratios (HR), adjusted for key clinical features.
Result
Most patients in the cohort were female (63/85, 74%); the median age was 68 years; median follow-up was 51 months. According to self-reports, 19/85 (22%) and 66/85 (78%) patients identified as Asians and non-Asians, respectively; no major clinical and pathologic differences were identified between these populations. Five-year recurrence free survival was significantly lower for Asians compared to non-Asians (50% vs. 78%, adjusted HR = 2.9; CI = 1.1-7.8, p=0.02), Figure 1. Among somatic events, in-frame deletions in CNPY3 (Toll-like receptor-specific co-chaperone for HSP90B1) were more frequent in Asians (30%) compared to non-Asians (18%). In contrast, DDX11 missense mutations (21% vs 0%; nucleic acid binding protein involved in genome stability), NOTCH2 multi-hits and frame-shift deletions (7% vs 1%), and KRAS missense mutations (7% vs 0%) were more frequently altered in non-Asians than in Asians.
Conclusion
In our cohort of never-smoker patients with EGFR/ALK-wildtype LUAD, Asian patients showed higher relapse rates than non-Asians. We identified differentially mutated genes by ethnicity that may partly account for these differences in outcome. (SNMF and AFF contributed equally)
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P2.03-37 - Genomic Landscape of EGFR/ALK Wild-Type Lung Adenocarcinomas in Never-Smokers and Importance of Epithelial-Mesenchymal-Transition (ID 1283)
10:15 - 18:15 | Author(s): Geoffrey Liu
- Abstract
Background
The molecular landscape of EGFR/ALK wild-type Lung Adenocarcinomas in never-smokers is poorly understood. Never-smokers usually have low PD-L1 expression and low Tumor Mutation Burden, challenging treatment strategies when no known driver-mutations are found. To identify putative driver mutations, we compared whole exome sequencing (WES) results in the EGFR/ALK wild-type Lung Adenocarcinoma in the never smokers Toronto cohort with a corresponding EGFR/ALK wild-type Lung Adenocarcinoma group of smokers from TCGA.
Method
For never-smokers with resected EGFR/ALK wild-type Lung Adenocarcinomas, frozen tumor and paired-normal-lung were evaluated by WES at a mean coverage of 238x. The paired-end reads were aligned using BWA and were further processed using the standard GATK pipeline. Somatic mutations and indels were identified using MuTect and VarScan, respectively. We compared mutations from our cohort to the TCGA smokers who had EGFR/ALK wild-type Lung Adenocarcinomas from publicly available data (TCGA) to identify genes at least 10% more frequently mutated in never smokers compared to the TCGA cohort.
Result
In our cohort with 45 never-smoker patients, 80% were females; median age was 70y; 29% were Asians; Stage I/II/III+ were 71%/15%/13%; after a median follow-up of 69 months, 24% had recurred. Median non-synonymous Tumor Mutation Burden was 1.3mut/Mb in never-smokers. We identified 39 genes that were more frequently mutated in never-smokers vs smokers, including some known tumor suppressor genes. The most prevalent genes included ADAM21 missense mutations (21% vs 1%; adj p=0.003), NOTCH2 frame-shift deletions and multi-hit mutations (40% vs 17%; adj p=0.04), MST1 missense mutations and in-frame deletions (13% vs 0%; adj p=0.008), ZMIZ2 frame-shift insertions (13% vs 0%; adj p=0.008) and FOXD4 missense mutations (10% vs 0%; adj p=0.02). Many of these differentially mutated genes have been previously associated to epithelial-mesenchymal-transition signaling pathways. Conversely and as expected, KRAS, TP53, STK11 and KEAP1 were more frequently mutated in the TCGA smokers EGFR/ALK wild-type Lung Adenocarcinomas cohort.
Conclusion
We identified multiple genes, particularly involved in the epithelial-mesenchymal-transition signaling pathways that are over-represented in never-smokers with EGFR/ALK wild-type Lung Adenocarcinomas, when compared to smokers with EGFR/ALK wild-type Lung Adenocarcinomas. This is a novel finding with potential clinical importance. Validation studies, analyzing epithelial-mesenchymal-transition signaling activation pathways on the EGFR/ALK wild-type Lung Adenocarcinomas never smokers population are needed to best identify the actual role in carcinogenesis and metastasis, guiding future treatment strategies. (AFF and SNMF contributed equally).
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-40 - Tumor-Stromal Microenvironment Interactions in a PDX Model of EGFR TKI Drug Tolerance (ID 509)
10:15 - 18:15 | Author(s): Geoffrey Liu
- Abstract
Background
Sixty to eighty percent of advanced stage lung adenocarcinoma patients with sensitizing epidermal growth factor receptor (EGFR) mutated tumors respond to EGFR tyrosine kinase inhibitors (TKIs). However, the vast majority of patients eventually progress due to acquired resistance. In vitro evidence suggests that minor populations of drug tolerant cells (DTCs) may be important for tumors surviving TKI. These studies cannot investigate changes in non-cancerous cell populations found within tumors. Yet, stromal cells have been implicated in protecting cancer cells from treatment-induced death and early stage lung adenocarcinomas responding to neoadjuvant EGFR TKI exhibited DTCs within large areas of fibrosis (NCT00188617). We hypothesize that molecularly characterizing DTCs in vivo in comparison to an untreated tumor in a patient-derived xenograft (PDX) model may delineate stromal changes that sustain DTCs, and potentially mimic clinical events.
Method
DTCs were harvested after one month of chronic erlotinib exposure in a lung adenocarcinoma PDX model harboring an exon 19 deletion; an untreated baseline (BL) tumor was also harvested. Histological characterization and single-cell RNA-sequencing (scRNA-seq) of DTCs and BL tumors were compared. ScRNAseq cell-types were assigned using reference component analysis. RNA expression levels of receptor/ligands were explored in cell populations.
Result
Post-erlotinib treatment, cell-type proportions within the tumor shifted dramatically, with substantially fewer cancer cells and more fibroblasts, mesenchymal stem cells (MSCs), and natural killer cells (NKCs). Two antigen presenting cell transcriptomic states (APC1 and APC2) were identified in both DTC and BL tumors: APC1s exhibited translation-related gene expression profiles while APC2s exhibited immune-response profiles. BL tumors contained mostly APC1s, whereas DTC tumors exhibited more equal proportions of both APC types. Expression profiles for some cell-types also shifted after treatment. Fibroblasts and NKCs exhibited shifts toward more inflammatory and immune-responsive expression profiles post-treatment. Fibroblasts and endothelial cells demonstrated gene expression shifts towards decreased angiogenesis and vasculature development. Paired ligand-receptor interactions between cancer-stromal cells were increased or decreased congruently post-treatment. Specifically, fibroblasts exhibited a shift from alpha-SMA+ myofibroblastic to more IL6+ inflammatory phenotypes, by mRNA and equivalent immunohistochemistry, post-treatment. Cancer cells exhibited a reciprocal increase in IL6R receptor expression post-treatment.
Conclusion
Using an EGFR mutant PDX model sensitive to EGFR TKIs, we see substantial post-treatment changes after chronic TKI exposure in non-cancerous (stromal) cell population composition involving their proportions, expression profiles, and their inferred communication with cancer cells. Understanding these potentially protective shifts in non-cancerous cell populations post-TKI-treatment may help identify clinically-relevant mechanisms of drug tolerance.
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P2.14-62 - Early, Subclinical SCLC Transformation in Patients with EGFR Mutant Lung Cancer Receiving Osimertinib, Detected Through Cell-Free DNA (ID 812)
10:15 - 18:15 | Author(s): Geoffrey Liu
- Abstract
Background
Liquid biopsies provide a convenient approachfor serial sampling and real-time disease monitoring, leading to the early detection of treatment response, disease progression and drug-resistance. Here,we present genomic profiling of serial liquid biopsies from seven lung cancer patients with activatingEGFRmutations receiving osimertinib in clinical practice.
Method
At Princess Margaret Cancer Centre, in the Lung Cancer Outpatient Clinics, plasma samples were obtained from each patient at defined clinical visits (between ~1–5 months in-between visits). Cell-free DNA (cfDNA; with a median of 57 ng; range: 3.5 to 3806 ng) was extracted from plasma samples and profiled using targeted capture next-generation sequencing with the Geneseeq Prime 425-gene panel, at a mean coverage depth of 4892X (with a deduplicated mean coverage depth of 2108X).
Result
Systemic tumour burden correlated with the detection of genomic alterations in cfDNA: Four of four of the patients with low tumour burden, despite minor disease progression, exhibited minimal EGFR and co-mutation allele frequencies (AFs). Conversely, significant increases in systemic (but not central nervous system) tumour burden led to increases in driver and co-mutation AFs (two our of three patients). EGFR C797S mutation and inactivating mutations in RB1 and TP53 were detected in the cfDNA of one patient nearly four months prior to the development of small cell lung cancer (SCLC) transformation confirmed on tissue biopsy with distinct transformed and untransformed areas. Both of the specific RB1 and TP53 mutations found in cfDNA have been previously associated with SCLC. Subsequent combination cisplatin-etoposide chemoradiation resulted in temporary complete remission of the transformed SCLC, corresponding to loss of RB1 mutation detection by cfDNA testing.
Conclusion
Profiling of plasma cfDNA using hybrid capture deep sequencing of a large gene panel can detect early subclinical transformation of EGFR-mutated lung cancer into small cell lung cancer (i.e., neuroendocrine transformation), leading to earlier diagnosis and management of the transformed disease. Serial liquid biopsy profiling can also be used to monitor disease progression. However, detection sensitivity of tumour cfDNA largely depends on systemic tumour burden.
