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J. Zhang
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.07 - Impact of Major Co-Mutations on the Immune Contexture and Response of KRAS-Mutant Lung Adenocarcinoma to Immunotherapy (ID 6343)
16:42 - 16:48 | Author(s): J. Zhang
- Abstract
- Presentation
Background:
Activating mutations in the KRAS proto-oncogene define a prevalent and clinically heterogeneous molecular subset of lung adenocarcinoma (LUAC). We previously identified three major subgroups of KRAS-mutant LUAC on the basis of co-occurring genetic events in TP53 (KP), STK11/LKB1 (KL) and CDKN2A/B (KC) and reported that LKB1-deficient tumors exhibit a “cold” tumor immune microenvironment, with reduced expression of several immune checkpoint effector/mediator molecules, including PD-L1 (CD274). Here, we extend these findings and examine the clinical outcome of co-mutation defined KRAS subgroups to therapy with immune checkpoint inhibitors.
Methods:
We conducted a single-institution analysis of clinical and molecular data (PCR-based next generation sequencing of panels of 50, 134 or 409 genes) prospectively collected from patients enrolled into the MD Anderson Lung Cancer Moon Shot GEMINI database. KRAS-mutant LUAC were separated into KP, KL and K (wild-type for TP53 and STK11) groups. The log- rank test and Fisher’s exact test were used for comparison of progression-free survival (PFS) and objective response rate (ORR) respectively between the groups. In addition, automated IF-based enumeration of lymphocyte subsets was performed in 40 surgically resected LUAC (PROSPECT cohort) with available whole exome sequencing data.
Results:
Among 229 patients with KRAS-mutant LUAC who consented to the protocol we identified 35 patients with metastatic disease (17 KP, 6 KL, 12 K) that received immunotherapy with nivolumab (N=29), pembrolizumab (N=3), nivolumab/urelumab (N=1) and durvalumab/tremelimumab (N=2) and had robust clinical outcome data. There was no impact of different KRAS alleles (G12C/G12V/G12D) on PFS (P=0.6149, log-rank test) or ORR to immune checkpoint inhibitors (P=0.88, Fisher’s exact test, 2x3 contingency table). In contrast, co-mutation defined KRAS subgroups exhibited significantly different median PFS to immunotherapy (KP: 18 weeks, KL: 6 weeks, K: 16 weeks, P=0.0014, log-rank test). Objective responses were observed in 9/17 (52.9%) KP and 3/12 (25%) K tumors compared to 0/6 (0%) KL tumors (P=0.049, Fisher’s exact test, 2x3 contingency table). In the PROSPECT cohort of surgically resected LUACs with available whole exome sequencing data, somatic mutation in STK11 was associated with reduced intra-tumoral densities of CD3+ (P=0.0016), CD8+ (P=0.0125) and CD4+ (P=0.0036) lymphocytes.
Conclusion:
Mutations in STK11/LKB1 are associated with an inert tumor immune microenvironment and poor clinical response of KRAS-mutant LUAC to immune checkpoint blockade. The mechanism that underlies this phenotype and strategies to overcome it are under investigation. The impact of additional co-mutations on the immune profile and response of KRAS-mutant LUAC to immunotherapy is also being explored.
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MA14 - Immunotherapy in Advanced NSCLC: Biomarkers and Costs (ID 394)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:M. Reck, D.R. Spigel
- Coordinates: 12/06/2016, 16:00 - 17:30, Strauss 2
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MA14.03 - The Impact of Genomic Landscape of EGFR Mutant NSCLC on Response to Targeted and Immune Therapy (ID 6242)
16:12 - 16:18 | Author(s): J. Zhang
- Abstract
- Presentation
Background:
EGFR mutations define a distinct subset of NSCLC characterized by clinical benefit from tyrosine kinase inhibitors. The impact of genomic alterations that coexist with EGFR mutations is not fully understood. In addition, the responsiveness of EGFR mutant NSCLC to immune checkpoint blockade is not well defined.
Methods:
We queried our prospectively collected MD Anderson Lung Cancer Moon Shot GEMINI Database to identify EGFR mutant NSCLC patients. We analyzed the genomic landscape of these tumors derived from next generation sequencing, performed as part of routine clinical care, to comprehensively describe the concurrent genomic aberrations in EGFR mutant NSCLC and their impact on clinical outcomes. We used log rank and Fisher’s exact tests to identify associations between co-concurrent mutations and clinical outcomes.
Results:
1958 non-squamous NSCLC patients were identified in the GEMINI database. The frequency of EGFR mutations was 14.1% (n=276). Among EGFR mutant patients, 188 underwent targeted next generation sequencing of a minimum of 46 cancer related genes. The majority of EGFR mutant patients (77.6%, n=146) had at least one coexisting mutation. The most frequent co-mutations identified were TP53 (47%, n=88), CTNNB1 (7.5%, n= 14) and PIK3CA (6.5%, n=12). ALK and ROS1 translocations were found to coexist with EGFR mutations in one patient each. Of patients treated with a first or second generation TKI, concurrent TP53 mutations were associated with a shorter progression free survival (HR= 1.81, P= 0.039). Eight patients with EGFR/CTNNB1 co-mutations developed acquired TKI resistance with T790M secondary mutation being the resistance mechanism in six (75%) of them suggesting that coexisting mutation can dictate emerging resistance mechanisms. Twenty patients were treated with anti PD1/PD-L1 agents (nivolumab n= 18, pembrolizumab n=2). Only two (10%) patients achieved confirmed radiological response, one lasting for 6 months and the second ongoing at 6 months. Both patients were never smokers, one with EGFR exon 20 insertion and no concurrent mutations, and the other with EGFR exon 19 deletion and TP53 mutation. Sixteen patients developed confirmed progressive disease. Finally, one patient with 17 pack-year smoking history, EGFR G719/S768I double mutation and concurrent PIK3CA mutation achieved stable disease lasting for four months. The median progression free survival for the cohort treated with immunotherapy was 2 months (range: 1-not reached).
Conclusion:
Concurrent genomic aberrations may predict response duration to TKIs and may be associated with particular emerging resistance mechanisms to TKIs in EGFR mutant NSCLC. Immunotherapy results in durable clinical benefit in a subset of EGFR mutant NSCLC patients.
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OA20 - Immunotherapy and Markers (ID 401)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 2
- Moderators:M. Früh, C.S. Baldotto
- Coordinates: 12/07/2016, 11:00 - 12:30, Stolz 2
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OA20.05 - The Influence of Neoadjuvant Chemotherapy, on Immune Response Profile in Non-Small Cell Lung Carcinomas (ID 5738)
11:35 - 11:45 | Author(s): J. Zhang
- Abstract
- Presentation
Background:
The clinical efficacy observed with PD-1/PD-L1 inhibitors in non-small cell lung carcinoma (NSCLC) has prompted to characterize the immune response in lung tumors treated with chemotherapy. Our goal was to determine the characteristics of immune microenvironment of localized, surgically resected, NSCLCs from patients who received and did not receive neo-adjuvant chemotherapy. Using multiplex immunofluorescence (mIF) and image analysis, we investigated PD-1/PD-L1 expression, and quantified tumor infiltrating lymphocytes (TILs) and tumor associated macrophages (TAMs).
Methods:
We studied formalin-fixed and paraffin embedded (FFPE) tumor tissues from 111 stage II and III resected NSCLC, including 61 chemonaïve (adenocarcinoma, ADC=33; squamous cell carcinoma, SCC=28) and 50 chemotherapy-treated (ADC=30; SCC=20) tumors. mIF was performed using the Opal 7-color fIHC Kit™ and analyzed using the Vectra™ multispectral microscope and inForm™ Cell Analysis software (Perkin Elmer, Waltham, MA). The markers studied were grouped in two 6-antibody panels: Panel 1, AE1/AE3 pancytokeratins, PD-L1 (clone E1L3N), CD3, CD4, CD8 and CD68; and Panel 2, AE1/AE3, PD1, Granzyme B, FOXP3, CD45RO and CD57.
Results:
Positive PD-L1 expression (>5%) in malignant cells (MCs) was detected in 48% (n=53/111) of NSCLCs. Overall, chemotherapy-treated tumors showed significantly higher percentages of MCs expressing PD-L1 (median, 18.2%) than chemo-naïve cases (median, 1.8%; P=0.033). Higher densities of inflammatory cells expressing granzyme B (P=0.036), CD57 (P=0.001) and PD-1 (P=0.016) were detected in chemotherapy-treated NSCLCs compared with chemo-naïve tumors. In contrast, lower densities of FOXP3-positive regulatory T cells were detected in chemotherapy-treated tumors when compared with chemo-naïve cases (P=0.032). Following chemotherapy ADCs exhibited significantly higher levels of CD57-positive cells (P<0.0001) and lower density of FOXP3-positive cells (P=0.002) than chemo-naïve tumors. Chemotherapy-treated SCCs demonstrated higher density of PD-1-positive cells than chemo-naïve tumors (P=0.004). In chemotherapy-treated cancers, lower levels of CD4 helper T positive cells and tumor associated macrophages (TAMs) CD68-positive cells were associated with worse overall survival (OS; P=0.04 and P=0.005, respectively) in univariate analysis. In chemotherapy-treated ADC patients, lower levels of CD68-positive (P=0.010) and higher levels of FOXP3-positive cells correlated with worse OS (P=0.044).
Conclusion:
We developed a robust mIF panel of 10 markers to study inflammatory cells infiltrates in FFPE NSCLC tumor tissues. Chemotherapy-treated NSCLCs exhibited higher levels of PD-L1 expression and T cell subsets compared to chemo-naïve tumors, suggesting that chemotherapy activates specific immune response mechanisms in lung cancer. (Supported by CPRIT MIRA and UT Lung SPORE grants, and MD Anderson Moon Shot Program).
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OA20.06 - Prospective ImmunogenomiC PrOfiling of Non-Small Cell Lung Cancer - The ICON Project (ID 5560)
11:45 - 11:55 | Author(s): J. Zhang
- Abstract
- Presentation
Background:
Previous attempts to define tumor and stromal immunologic environment in non-small cell lung cancer (NSCLC) utilized archival tissue. We established prospective comprehensive immonogenomic profiling protocol in NSCLC (ICON Project). The goal is to integrate immunomic, genomic, transcriptomic, proteomic, demographic, clinical, pathologic, and outcome data from 100 surgically resected early stage NSCLC.
Methods:
Tumor and normal lung tissue are collected at the time of surgery, blood samples before and after surgery. Tumor samples are processed for tumor infiltrating lymphocyte (TILs) isolation and expansion; development of patient derived xenografts (PDX), immunohistochemical immune markers, and immunopeptidome profiling. Blood samples are analyzed with flow cytometry.
Results:
57 patients with median age of 65 years (27 males) have been enrolled within 5 months, of which 33 (66%) contributed samples to the study. Four were never smokers, with others being former or current smokers. Majority (N=27) had adenocarcinoma, 4 squamous cell carcinoma, and 2 pleomorphic carcinoma. 15 patients had stage I, 11 stage II, and 7 stage III disease; 5 patients received induction chemotherapy. Median tumor size was 3.5 cm and 29 underwent R0 and 4 R1 resection. Pre-REP TIL expansion was successful in the majority of samples (68.2%, n=22). Twelve PDX models with a take rate of 40% have been generated. Interim analysis of tumor samples by IHC demonstrated higher median distribution of all cell types: CD3+ T cells, cytotoxic T cells CD8+, PD1+ cells, tumor associated macrophages (TAM) CD68+, TAM CD68+PD-L1+, CD20+B cells, memory T cells CD45R0, natural killer cells CD57+, regulatory FOXP3+ T cells, and cytotoxic granzyme B cells (cells/mm[2]) in the stroma as compared to the tumor compartment. Intra-tumoral regulatory FOXP3+T cells were more abundant in squamous cell carcinomas compared to adenocarcinomas (median 312 vs 51 cells/mm[2], p = 0.05). Higher concentration of intra-tumoral CD68+PD-L1+ expressing cells was observed following neoadjuvant chemotherapy (median 97 vs 60 cells/mm[2] no chemo; p= 0.077), as was the concentration of memory T cells CD45R0 (median 129 vs 30 cells/mm[2], no chemo; p = 0.077). Mass spectrometry-based immunopeptidome analysis identified several thousand peptides, of which 4 promising antigens have been chosen for further development as immunotherapeutic T-cell targets.
Conclusion:
The ICON is an ongoing, ambitious prospective project that aims to define the baseline immunologic characteristics of surgically resectable NSCLC. The rapid enrollment illustrates the enthusiasm for tumor immunoprofiling amongst patients and physicians alike. Data from this patient cohort will serve as a baseline comparison for upcoming neoadjuvant immunotherapy trials.
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P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.05-028 - Phenotypic and Functional Profiling of Tumor-Infiltrating Lymphocytes (TIL) in Early Stage Non-Small Cell Lung Cancer (NSCLC) (ID 6044)
14:30 - 14:30 | Author(s): J. Zhang
- Abstract
Background:
The ICON study aims to perform a comprehensive immunogenomic characterization of early stage localized non-small cell lung cancer (NSCLC) and lay the foundation for the identification of barriers to tumor immunity that may be targeted in future trials. Earlier work has demonstrated the prognostic significance of TIL in localized NSCLC. This work evaluates the functional status of T cells infiltrating the NSCLC tumors and their capacity to expand ex-vivo and perform effector function in the first 22 patients enrolled.
Methods:
Patients enrolled on the ICON study underwent surgery. Fresh tumor samples were mechanically disaggregated and immediately stained for flow cytometry. Panels consisted of markers of T cell subsets, differentiation status, T cell function, activation and exhaustion. PD-L1 expression was assessed on malignant cells as well as CD68+ tumor-associated macrophages (TAMs) by IHC. Fragments from the tumor tissue were also placed in culture in media containing IL-2 for ex-vivo TIL expansion. TIL cultures were maintained for 3-5 weeks and subsequently underwent phenotypical and functional characterization.
Results:
Analysis of freshly disaggregated tumor tissue (n=22) from NSCLC tumor or adjacent normal tissue by flow cytometry demonstrated that effector CD8[+] T cells found in the tumor were less functional than T cells infiltrating normal tissue, revealed by a decrease in the co-expression of the cytotoxic effector molecules perforin and granzyme B (p=0.0004) together with an enhanced expression of the inhibitory receptor PD-1 (p<0.0001). Immunohistochemistry analysis showed PD-L1 expression on malignant cells and/or CD68+ TAMs on all tumor samples except one, strongly suggesting that the PD-1/PD-L1 inhibitory axis was engaged contributing to decreased T cell functionality. TIL could be expanded from the majority of samples (68.2%, n=22). The degree of infiltration predicted the ability to grow TIL ex-vivo (median CD3+ infiltrate of 15.25% of live cells in disaggregated tumor tissue for samples from which TIL could be grown versus 2.9% when TIL could not grow p = 0.015). Immunophenotyping following expansion showed an enrichment in CD8+ aβTCR+ T-cells expressing both perforin and granzyme B indicating that TILs propagated with IL-2 regained functionality (p=0.016). Lastly, NSCLC TIL were rapidly expanded using anti-CD3 antibody, feeder cells and IL-2 over two weeks (n=6) and reached clinically relevant numbers for TIL ACT (range 381-1282 fold expansion).
Conclusion:
Overall, while TILs present in NSCLC are functionally inhibited, they can be expanded ex-vivo from most tumor samples and regain a functional phenotype for potential use in adoptive T-cell therapy.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-024 - EGFR Mutations in Small Cell Lung Cancer (SCLC): Genetic Heterogeneity and Prognostic Impact (ID 4154)
14:30 - 14:30 | Author(s): J. Zhang
- Abstract
Background:
EGFR mutations in SCLC were first reported in cases of lung adenocarcinoma which transformed to SCLC after TKI treatment and such mutation was speculated to be a TKI resistance mechanism. Recently case reports and high throughput sequencing in a small number of samples suggested that EGFR mutations do exist in de novo SCLC. But the genetic and clinical characteristics have not been studied in large number of samples. This study aims to conduct a large scale survey of the EGFR mutations among Chinese SCLC patients, and to analyze the genetic and clinical characteristics of such mutations.
Methods:
Mutation status in exon 18-21 of EGFR was assessed by dideoxy-sequencing in 565 SCLC tumors treated in Zhejiang Cancer Hospital, Hangzhou, China from 2009 to 2014 and correlated with clinical parameters. Chi-square test were used to show the correlation of clinic variables with EGFR mutation. Survival analysis was performed using the Kaplan-Meier method.
Results:
40 instances of EGFR mutation are detected in 565 clinical samples. The mutation rate is 7.1%. Besides classic mutations E19 deletion（n=3）and E21 L858R(n=3), the rest of the mutations detected are atypical including E18 (G719D/S, G696R, S695N/D, N700D, I715F, L688F, P694L), E19(K757N, A755V, V742I, E736K, N756Y, E749K, P753L, A755T), E20 (T790M, H773R, S768R/N, R776H/C, G796D, D807N, R803W/Q, Y813C, G810S, A763T, G779D, Q791R, C781Y, N771S), E21(L858V, G874R, K867E). Among the EGFR mutation positive patients, 27.5% (11/40) are non-smokers, higher than the EGFR negative group (16.4%, 86/525). But it is not statistically significant (p=0.129). And EGFR mutation is not correlated with sex (female vs male), age (≥65y vs <65y) or clinical stages (limited stage vs extensive stage). After matching the treatment history of the EGFR mutation positive and negative patients (excluding patients who were not treated ,only treated by traditional Chinese medicine or one cycle chemotherapy or biological therapy , treatment unkown ), univariate analysis shows that the EGFR mutation positive patients have better overall survival than the EGFR negative group, with medium OS of 24.433m±4.864m vs 14.00m±0.838m respectively (p=0.018). COX regression analysis suggests that limited stage (HR=2.610), <65 years (HR=1.476) and EGFR mutation (HR=0.587, p=0. 0.039) were independently predictive of better OS.
Conclusion:
Among the de novo SCLC patients diagnosed, there exists a group harboring EGFR mutations, most of which are non-classic mutations. After matching the treatment history of patients, analysis reveals that EGFR mutations are predictive of better OS.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-061 - Image Analysis-Based Expression of Nine Immune Checkpoints Identifies Distinct Immunoprofiling Patterns in Non-Small Cell Lung Carcinomas (ID 5548)
14:30 - 14:30 | Author(s): J. Zhang
- Abstract
Background:
The understanding of the co-expression of immune checkpoints in non-small cell lung carcinoma (NSCLC) is important to potentially design combinatorial immunotherapy approaches in this disease. We examined the expression of a panel of immune checkpoints markers by immunohistochemistry (IHC) and quantitative image analysis in a large cohort of surgically resected NSCLCs, and correlated those findings with patients’ clinicopathological features and tumors’ inflammatory cells infiltrate and molecular characteristics.
Methods:
We studied 225 formalin fixed and paraffin embedded (FFPE) tumor tissues from stage I-III NSCLCs, including 123 adenocarcinomas (ADC) and 83 squamous cell carcinomas (SCC), placed in tissue microarrays (TMAs). Nine immune checkpoints markers, 4 (PD-L1, B7-H3, B7-H4, IDO1) expressed predominantly in malignant cells (MCs), and 5 (ICOS, VISTA, TIM3, LAG3 and OX40) expressed mostly in stromal tumor associated inflammatory cells (TAICs). All IHC markers were examined using quantitative image analysis system (Aperio).
Results:
Using > median value of the immune checkpoint expressions as positive expression we observed that MCs H-score expressing PD-L1, B7-H3, B7-H4 and IDO1was higher in SCC than ADC, with 3 out of 4 markers showing statistically significant (P<0.05) differences. In contrast, density of TAICs expressing ICOS, VISTA, OX40, LAG3 and TIM3 was higher in ADC than SCC, with 3 out of 5 markers demonstrating significant (P<0.05) differences. Furthermore, we identified frequent co-expression of markers: a) 11% ADC (13/123) and 10% SCC (8/83) co-expressed 8 to 9 markers; b) 45% ADC (55/123) and 32% SCC (27/83) co-expressed 6 to 7 markers, c) 28% ADC (35/123) and 40% SCC (33/83) co-expressed 4 to 5 markers, and d) 16% ADC (20/123) and 18% SCC (15/83) co-expressed 2 to 3 markers. In ADC, higher number of TAICs expressing OX40 and lower levels of MCs expressing B7-H4 were detected in tumors with EGFR (median, 7.49 vs. 1.16, P=0.021) and KRAS (median, 6.88 vs. 0.67, P=0.033) mutation compared with wild-type tumors, respectively. Univariate analysis demonstrated that high B7-H4 and low OX40 expression in MCs and in TAICs respectively correlated with worse overall survival (OS; P=0.016 and P=0.037, respectively) in ADC patients.
Conclusion:
We detected different patterns of immune checkpoints expression in NSCLC with higher level of markers found in malignant cells of SCC and in stromal inflammatory cells of ADC. Immune checkpoints expression correlated with the outcome of NSCLC patients. Importantly, co-expression of several immune checkpoints is a frequent event in NSCLC (Supported by CPRIT MIRA and UT Lung SPORE grants).
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-023 - Circulating Tumor DNA (ctDNA)-Based Genomic Profiling of Known Cancer Genes in Lung Squamous Cell Carcinoma (LUSC) (ID 5393)
14:30 - 14:30 | Author(s): J. Zhang
- Abstract
Background:
Next-generation sequencing (NGS) of ctDNA is increasingly used for non-invasive genomic profiling of human cancers. However, studies to date have not detailed the ctDNA genomic landscape in LUSC.
Methods:
From June 2014 to June 2016, ctDNA from 467 patients with stage 3 or 4 (AJCC 7[th] edition) LUSC (60% male, 40% female; median age of 69 [range 27-96]) were tested with Guardant 360[TM], a ctDNA NGS assay that detects single nucleotide variants (SNVs) of 54-70 cancer genes and certain copy number amplifications (CNAs), indels, and fusions. The median time between diagnosis and ctDNA testing was 238 days. Somatic alterations were compared with those in the 2016 LUSC TCGA dataset.
Results:
426 patients (92.2%) had at least one somatic alteration detected. The most commonly observed SNVs (> 5% frequency) were TP53 (64.8%), PIK3CA (7.8%), CDKN2A (6.1%), and KRAS (5.9%). Frequencies of SNVs known to be significant in LUSC correlated well between our cohort and the TCGA (Spearman r = 0.93) but were generally lower in our cohort (Table 1). Several of our most frequently observed CNAs are strongly associated with LUSC (EGFR, CDK6, MYC, ERBB2, PDGFRA, KIT, CCND1). In addition, MET exon 14 skipping (1.3%), EGFR exon 19 deletion (1.9%), EGFR exon 20 insertion (0.5%), ERBB2 exon 20 insertion (0.3%) and EML4-ALK fusion (0.7%) were detected. These alterations have rarely been reported in LUSC.
Conclusion:
Patterns of SNVs and CNAs in LUSC obtained by ctDNA profiling are largely consistent with those from TCGA tissue profiling, although the frequency of key SNVs is lower. The presence of actionable alterations atypical for LUSC in 4.7% of this clinical cohort may represent underappreciated treatment options. Further investigation is warranted to evaluate whether these findings reflect a distinct mutational landscape in heavily treated advanced disease (which is under-represented in the TCGA) and/or challenges in histopathological classification. Figure 1
