Differential responses to therapy in Hispanic NSCLC patients with EGFR, KRAS, or TP53 mutations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21027-e21027
Author(s):  
Fahmin Basher ◽  
Diana Saravia ◽  
Gilberto Lopes
Keyword(s):  
Checkpoint Inhibitors ◽  
Egfr Mutations ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Kras Mutations ◽  
Tp53 Mutations ◽  
Hispanic Patients ◽  
Tumor Mutational Burden ◽  
Receive Treatment ◽  
Nsclc Patients

e21027 Background: Hispanic (H) patients with non-small cell lung cancer (NSCLC) tend to have more advanced disease at time of diagnosis and less likely to receive treatment compared to non-Hispanic white (NHW) Americans. While survival outcomes do not differ greatly, Hispanic patients tend to have lower response rates to immunotherapy and to targeted therapy with known EGFR mutations. We sought to determine if Hispanic patients with other common mutations present in NSCLC also demonstrate suboptimal responses to therapy compared to NHW patients. Methods: We performed a retrospective review of 468 patients with advanced stage NSCLC at the University of Miami / Sylvester Comprehensive Cancer Center who underwent next-generation sequencing (NGS) for whom treatment outcomes could be identified. Genomic results were obtained from Guardant360 and Foundation One testing in blood or tissue, respectively. Results: In our cohort, 154 patients (33%) were of Hispanic ethnicity, while 279 patients (60%) were NHW. Median age at time of diagnosis was 59, and 50% were male. PD-L1 status was known for 217 patients, with 110 expressing some level of PD-L1. EGFR mutations were present in 25% of all patients, KRAS mutations in 25%, and TP53 mutations in 61%. Average tumor mutational burden was 4.0 in Hispanic patients and 3.6 in NHW patients. We compared outcomes in patients receiving any therapy as well as those specifically receiving immune checkpoint inhibitors (ICI). No differences in OS were observed in our overall patient cohort between H and NHW patients. However, when stratifying patients with EGFR or KRAS mutations, Hispanic patients exhibit significantly shorter OS than their NHW counterparts. In patients with TP53 mutations, we observed no differences between H and NHW outcomes considering all therapy, but Hispanic patients exhibited improved OS with the use of ICI. Conclusions: Our data suggest that the presence of certain mutations in Hispanic patients with advanced NSCLC may serve some prognostic value in predicting responses to therapy, specifically the use of ICI. Further investigation is indicated to determine mechanisms leading to inferior responses after ICI therapy in Hispanic patients.[Table: see text]

Evaluation of different MET genotypes as biomarkers for immunotherapy outcomes in NSCLC patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21032-e21032
Author(s):  
Xuanzong Li ◽  
Linlin Wang
Keyword(s):  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Rank Test ◽  
Wild Type ◽  
Exact Test ◽  
Entire Cohort ◽  
Kaplan Meier ◽  
Tumor Mutational Burden ◽  
The Difference ◽  
Nsclc Patients

e21032 Background: Previous studies suggested that MET exon 14 ( METex14) mutation regarding as a distinct subset was sensitive to MET-inhibitors, but poorly response to immunotherapy. Conversly, MET non-exon-14 (non-ex14) mutations including those undetermined functions and affecting the kinase or extracellular domains were found to be associated with the resistance to MET-inhibitors. However, therapeutic strategies for MET-non-ex14 mutant cancer are still largely unknown, and the relationship between MET-non-ex14 mutations and the efficacy of immune checkpoint inhibitors (ICIs) has never been reported. Using two public ICIs-treated cohorts, we aimed to assess the role of MET mutations including both METex14 and MET-non-ex14 mutations in NSCLC patients undergoing ICIs therapy. Methods: A total of 385 ICIs-treated NSCLC patients were enrolled to our study. MET mutations were defined as any nonsynonymous mutations, and we divided them into METex14 and MET-non-ex14 mutation subsets according to the mutated-position on MET. Kruskal-Wallis test was used to analyze the difference of tumor mutational burden (TMB) score, and the Fisher’s exact test was applied to compare the rates of durable clinical benefit (DCB). Log-rank test was used to analyze the differences between Kaplan-Meier survival curves. Results: In the entire cohort, we found that 17 patients (17/385, 4.4%) had MET mutations, most of which were pure METex14 mutations (10/17, 58.8%). The median TMB of patients in the entire NSCLC cohort was 6.89 mut/Mb. MET-non-ex14 mutant patients (7/385, 1.8%) possessed a significantly higher TMB than METex14-mutant (10/385, 2.6%) and MET wild-type (368/385, 95.6%) sub-cohorts, respectively (median TMB, 17.92 mut/Mb versus 4.17 mut/Mb, p = 0.008; 17.92 mut/Mb versus 6.96 mut/Mb, p = 0.01, respectively). DCB was more common in patients harbored MET-non-ex14 mutations than patients with METex14 mutations and MET wild-type (66.7% versus 14.3%, p = 0.103; 66.7% versus 29.9%, p = 0.075, respectively). We found that patients with MET-non-ex14 mutations had a numerically longer progression free survival (PFS) than those with METex14 mutations and MET wild-type (p = 0.169). Moreover, the PFS was significantly longer in MET-non-ex14-mutant subgroup than patients with METex14 mutations (median PFS, 9.1 versus 2.1 months, p = 0.025). Correspondingly, the overall survival (OS) was significantly longer in MET-non-ex14-mutant subgroup than their wild-type counterparts (median OS, not reached versus 11 months, p = 0.039). Additionally, patients with MET-non-ex14 mutations exhibited relatively better OS versus METex14-mutant patients (median OS, not reached versus 18 months, p = 0.175). Conclusions: MET-non-ex14 mutations were associated with higher TMB, improved DCB rate, and could act as a favorable prognostic biomarker in ICIs-treated NSCLC patients.

Usefulness of cytological samples (CS) for the assessment of ALK rearrangements in non-small cell lung cancer (NSCLC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18008-e18008 ◽  
Author(s):  
Maria D. Lozano ◽  
Tania Labiano ◽  
Maria I. Zudaire ◽  
Alfonso Gurpide ◽  
Javier Zulueta ◽  
...  
Keyword(s):  
Molecular Subtype ◽  
Egfr Mutations ◽  
Fish Analysis ◽  
Gene Rearrangements ◽  
Cell Block ◽  
Alk Rearrangement ◽  
Kras Mutations ◽  
Inhibitor Analysis ◽  
Dual Colour ◽  
Nsclc Patients

e18008 Background: ALK gene rearrangements define a new molecular subtype of NSCLC with response to Crizotinib, a dual MET and ALK inhibitor. Analysis of ALK rearrangements has been performed in biopsies or surgical specimens. However, advanced NSCLC is often diagnosed by FNA cytology obtained through minimally invasive techniques, and frequently CS are the only tumour sample available. We assessed the feasibility of determining ALK rearrangements in CS. Methods: We studied prospectively ALK rearrangements in 53 CS from 53 NSCLC patients (30 M/23 F) by FISH (Vysis dual colour break apart probe). We considered positive for ALK rearrangement when > 15% of cells show splits signals. Tumor samples were obtained by bronchoscopy -FNA in 26 cases (49.1%), EBUS-FNA in 7 (13.2%), EUS-FNA in 3 cases (5.7%), CT-FNA in 3 (5.7%), and direct FNA in 6 cases (11.3%). Two cavity fluids (3.8%), 4 imprints (7.5%), and 2 cellblocks received for consultation (3.8%) were also studied. FISH was performed on non-stained ThinPrep in 28 cases (52.8%), Papanicolau stained smears in 15 cases (28.3%), cell block in 9 cases (17%), and 1 stained ThinPrep. All cases were tested for EGFR and KRAS mutations. Correlation cytological/paraffin embedded samples was performed in 4 paired cases. Results: Thirty-seven samples(69.8%) were adequate for FISH analysis. Three cases (8.1%) had ALK rearrangements: non-smoker women with adenocarcinoma, two of them with signet ring cells. One case had a concurrent EGFR mutation in exon 21. FISH study was unsuccessful in 16 cases (30.2%):10 Papanicolau stained smears (62.5%), 5 unstained ThinPrep (31.3%), and 1 cell block. Nineteen ThinPrep slides were adequate for FISH analysis (86.4%) as well as 8 out of 9 cell blocks. Concordance rate in paired cases were 100%. Conclusions: Determination of ALK gene rearrangements in CS is feasible. It is mandatory an exquisite management and care of the samples to preserve quality. ThinPrep and cell blocks are the most suitable samples for FISH analysis, while Papanicolau stained smears provide poor results. Coexistence of ALK gene rearrangements and EGFR mutations was observed in one case, indicating that such alterations are not necessarily mutually exclusive.

Patient attitudes toward oncofertility care in male cancer patients receiving targeted and immune therapies.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21593-e21593
Author(s):  
Katy K. Tsai ◽  
Puneet Kamal ◽  
Joris Ramstein ◽  
Alain Patrick Algazi ◽  
Adil Daud ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Checkpoint Inhibitors ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Patient Attitudes ◽  
Durable Response ◽  
Care Plans ◽  
Future Fertility ◽  
Long Term Treatment ◽  
The Impact

e21593 Background: Tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) have resulted in durable response for many cancer patients. The impact of these agents on future fertility are not well described, and patients are often committed to long-term treatment without adequate oncofertility counseling. We sought to better characterize patient attitudes toward oncofertility and challenges faced by male cancer patients undergoing treatment with TKI or ICI. Methods: Men receiving TKI/ICI at the UCSF Helen Diller Family Comprehensive Cancer Center were retrospectively identified. Eligible men had received at least one dose of TKI/ICI. Detailed questionnaires addressing cancer history, possible effects of treatment on fertility, and obstacles to fertility preservation were completed. Results: Between January 2013 to September 2016, 51 men with a mean age of 46 years (SD 12, range 21-72), 65% white, completed questionnaires. Most (61%) were CML patients, with 12% RCC, 10% GIST, 6% melanoma, and NET, oligodendroglioma, and HCC comprising remaining histologies. 96% were treated with TKI, and 4% with ICI. At the time of diagnosis, 35% of patients indicated a desire to father future children, and 53% believed that cancer treatment might affect their fertility. Despite this, 45% were not asked whether having children was important to them, and 47% did not receive information from any provider on their oncology care team about the possible risks of TKI/ICI to future fertility. The majority of patients felt there was inadequate discussion of how treatment might affect testosterone levels (73%) and their ability to father a child (53%), yet only 14% recalled adequate referrals to a fertility specialist. Conclusions: These data demonstrate that male cancer patients perceive treatment-related infertility risks as important, yet have few opportunities to discuss these concerns with providers. Care plans to address oncofertility needs, especially as TKI/ICI are increasingly used in multiple cancer types, are needed as part of the diagnosis, treatment, and follow up of these patients. Larger retrospective and prospective studies are ongoing to further characterize this patient cohort.

KRAS amplification and mutation as independent events in gastroesophageal adenocarcinomas (GEA).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15565-e15565
Author(s):  
Joseph Chao ◽  
Russell Madison ◽  
Jeffrey S. Ross ◽  
Vincent A. Miller ◽  
Siraj Mahamed Ali ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Older Patient ◽  
Kras Mutations ◽  
Independent Events ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Tissue Specimens ◽  
Kras Codon

e15565 Background: KRAS mutations are common oncogenic events across cancers, but effective RAS-directed therapies are lacking. However, recent studies support use of PD-1 blockade in most subsets of lung cancer with KRAS short variant mutations (KRASSV) (PMID: 28039262), and preclinical data supports combined MEK and SHP2 inhibition in KRAS amplified ( KRASa) GEA (PMID: 30093730). We sought to explore the landscape of KRAS altered GEA and compare genomic profiles of KRAS-altered and KRAS wild-type (WT) cases for biomarkers of response to targeted therapies and immune checkpoint inhibitors. Methods: 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based comprehensive genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Descriptive statistics were used to compare among subgroups. Results: KRASSV and KRASa were identified in 11% and 5.8% of gastric adenocarcinoma (GA), respectively, and in 7.2% and 17% of esophageal adenocarcinoma (EA), respectively. KRASa and KRASSV were nearly mutually exclusive, co-occurring in only 4.4% of KRAS altered cases. ERBB2 alterations were less common in KRASSV and KRASa GEA (both 9%) as compared with KRAS WT GEA (19%) (p = 1.9E-16). EGFRa was less common in KRASSV vs KRASa GEA (1.9% vs 9.3%, p = 2.6E-8), whereas PIK3CASV was more common in KRASSV vs KRASa (16% vs 5.0%, p = 1.5E-11). Median TMB for all groups was similar; however, KRASSV GEA had a higher mean TMB (9.7 mut/Mb) as compared to KRASa (5.1 mut/Mb, p = 5.0E-12) and KRAS WT cases (5.8 mut/Mb, p = 2.2E-07). KRAS codon 12/13 accounted for > 80% of predicted pathogenic mutations. MSI-high was also more prevalent in KRASSV (11.3%) vs KRASa (0.9%, p = 4.8E-15) and KRAS WT GEA (2.4%, p = 1.8E-25). MSI-high KRASSV GEA was associated with older patient age (median 72 years) and with high TMB (median 40.9 mut/mb). Conclusions: GA was enriched for KRAS mutation whereas EA was enriched for KRAS amplification. KRAS WT vs KRASSV vs KRASa each presented distinct genomic profiles. KRASa in the absence of KRAS mutation exists in 11% of GEA and warrants further exploration to inform combination treatment strategies.

scholarly journals Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2 Trial

2019 ◽  
Vol 104 (12) ◽  
pp. 6193-6200 ◽  
Author(s):  
Benedito A Carneiro ◽  
Bhavana Konda ◽  
Rubens B Costa ◽  
Ricardo L B Costa ◽  
Vinay Sagar ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Median Number ◽  
Preliminary Evidence ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Phase 2 ◽  
Platinum Based Chemotherapy

Abstract Context Systemic treatment of metastatic adrenocortical carcinoma (ACC) remains limited to chemotherapy and mitotane. Preliminary evidence suggesting that antitumor immune responses can be elicited in ACC has fostered interest in checkpoint inhibitors such as anti–PD-1 nivolumab. Objective The primary endpoint was objective response rate according to the response evaluation criteria in solid tumors. Secondary endpoints were progression-free survival (PFS), overall survival, and safety. Design Single-arm, multicenter, phase 2 clinical trial with two-stage design. Setting Comprehensive cancer center. Patients Ten adult patients with metastatic ACC previously treated with platinum-based chemotherapy and/or mitotane as well as patients who declined front-line chemotherapy. Intervention Nivolumab (240 mg) IV every 2 weeks. Results Ten patients with metastatic ACC were enrolled between March and December 2016. The median number of doses of nivolumab administered was two. Three patients only received one treatment [one died of disease progression, one discontinued due to adverse events (AEs), one withdrew after beginning treatment]. The median PFS was 1.8 months. The median follow-up was 4.5 months (range, 0.1 to 25.6 months). Two patients had stable disease for a duration of 48 and 11 weeks, respectively. One patient had an unconfirmed partial response but discontinued the study due to an AE. Most AEs were grade 1/2. The most common grade 3/4 treatment-related AEs were aspartate aminotransferase and alanine aminotransferase elevations, mucositis, and odynophagia. Conclusion Nivolumab demonstrated modest antitumor activity in patients with advanced ACC. The nivolumab safety profile was consistent with previous clinical experience without any unexpected AEs in this population.

Ethnic difference of driver mutation frequencies and correlations between driver mutations and histologic subtypes in lung adenocarcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1552-1552
Author(s):  
Yuki Yamane ◽  
Koichi Goto ◽  
Akikazu Kawase ◽  
Katsuya Tsuchihara ◽  
Sachiyo Mimaki ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Ethnic Difference ◽  
The United States ◽  
Driver Mutation ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Cancer Center ◽  
Histological Subtypes ◽  
Kras Mutations ◽  
Met Amplification

1552 Background: The frequencies of known driver mutation in lung adenocarcinoma from patients in the United States have been reported by the NCI’s Lung Cancer Mutation Consortium (LCMC), indicating driver mutations were detected in 54% (280/516) of tumors. In this report, mutations found: EGFR 17%, KRAS 22%, HER2 0.6%, PIK3CA 1.2%, BRAF 2%, MET amplification 0.6%, MAP2K1 0.4%, NRAS 0.4%, AKT 0%, ALK rearrangements 7%. However little is known about ethnic difference of driver mutation frequencies and correlations between driver mutations and histological subtypes in lung adenocarcinoma. Methods: Known driver mutations in tumors from 97 Japanese patients with lung adenocarcinoma who underwent surgical resection between 1999 and 2003 in National Cancer Center Hospital East were analyzed by next-generation sequencing and confirmed by Sanger sequencing. Correlations between driver mutations and histological subtypes were also assessed. Results: Driver mutations were detected in 72% of tumors. Mutations found: EGFR 57%, KRAS9%, HER2 2%, PIK3CA 2%, BRAF 1%, MET amplification 1%, MAP2K1 0%, NRAS 0%, AKT 0%. Due to the limitation of rearrangement detection by exon-sequencing, ALK rearrangements were not analyzed. Compared with the report by LCMC, the frequency of EGFR mutations was high and that of KRAS mutations was low in the present study. All mutations were mutually exclusive. The number of predominant histological subtypes of tumors harbored EGFR mutations were papillary 28, acinar 3, solid 5, lepidic 19. That with KRAS mutations showed papillary 2, acinar 2, solid 2, lepidic 3, and HER2 mutations showed papillary 1 and acinar 1. Two tumors harbored PIK3CA mutations showed both histological acinar pattern. Each of BRAF mutation and MET amplification showed lepidic and papillary pattern, respectively. Conclusions: It was suggested that there should be ethnic difference of driver mutation frequencies in lung adenocarcinoma between Asian and non-Asian patients, although the details of ethnic distribution included in LCMC study has not been opened. In addition, each driver mutations did not correspond to specific histological subtypes of lung adenocarcinoma.

Effective use of electronic medical record (EMR) data in analysis of association between KRAS mutations and depression in colorectal cancer patients.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 861-861
Author(s):  
Jenny Jing Li ◽  
Jessica Harper ◽  
Hong Zhu ◽  
Nizar Bhulani ◽  
Chad Michael Guenther ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Kras Mutation ◽  
Screening Test ◽  
Data Exchange ◽  
Missing Values ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Wild Type ◽  
Distress Screening ◽  
Kras Mutations

861 Background: Previous studies have demonstrated that KRAS mutations were associated with higher rates of depression in patients with metastatic colorectal cancer (CRC). The objective of this study was to evaluate the feasibility of extracting EMR data to examine the association between KRAS mutations and positive screening test for depression in CRC patients. Methods: Retrospective review of stage I to IV CRC patients seen between 2011 and 2015 at an academic, NCI-Designated Comprehensive Cancer Center was performed. At each clinic visit, depression was assessed using the Patient Health Questionnaire-2 (PHQ-2), which is part of the institution’s universal Distress Screening tool. PHQ-2 score of 2 and above was considered positive screening test for depression. PHQ-2 and KRAS mutation data were extracted from the EMR via the Clinical Data Exchange Network bioinformatics tool and confirmed by retrospective chart review. Chi-square test was used to assess the association between KRAS mutation and depression. Multiple imputation was used to impute the missing values. Results: Of the 484 CRC patients, KRAS status was known in 45 cases: 22 (49%) were KRAS mutated and 23 (51%) were KRAS wild type. PHQ-2 score was 0 in 42 cases (93.3%), 1 in 2 cases (4.4%), and ≥2 in 1 case (2.3%). The rate of positive PHQ-2 for KRAS mutated vs wild type was 4% vs 0% (p = 0.36). The result based on 50 imputed datasets suggests a trend towards an association between KRAS mutation and depression (p = 0.09). Conclusions: This study did not demonstrate an association between KRAS mutation and depression in patients with colorectal cancer, probably due to a high proportion of missing data. Bioinformatics studies that extract and analyze EMR data are a feasible and effective platform to assess the association of genomic data with clinical outcomes. Additional validated algorithms and data are needed to further optimize such studies.

Tumor mutational burden assessed by a targeted NGS assay to predict clinical benefit from immune checkpoint inhibitors in non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14266-e14266 ◽  
Author(s):  
Sacha Rothschild ◽  
Ilaria Alborelli ◽  
Katharina Leonards ◽  
Laura P Leuenberger ◽  
Spasenija Savic Prince ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Predictive Power ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Nsclc Patients

e14266 Background: In non-small cell lung cancer (NSCLC) immune checkpoint inhibitors (ICIs) significantly improve overall survival (OS). Tumor mutational burden (TMB) has emerged as a predictive biomarker for patients treated with ICIs. Here we evaluated the predictive power of TMB measured through / by the Oncomine Tumor Mutational Load (TML - Thermo Fisher Scientific) targeted sequencing assay in 71 NSCLC patients treated with ICIs. Methods: TMB was assessed retrospectively in 71 metastatic NSCLC patients receiving ICI therapy. Clinical data (RECIST 1.1) were collected and patients were characterized as either having durable clinical benefit (DCB) or no durable benefit (NDB). Additionally, genetic alterations and PD-L1 expression were assessed and compared with TMB and response rate. Results: TMB was significantly higher in patients with DCB compared to patients with NDB (median TMB = 9.2 versus 5.3 mutations/Mb, Mann-Whitney p = 0.014). 70% of patients with high TMB (cutoff = 3rd tertile, TMB ≥ 9.2) were responders (DCB) compared to 29% of patients with low TMB (cutoff = 1st tertile, TMB ≤ 4.5). TMB-high patients showed significantly longer progression-free survival (PFS) and OS (log rank test, p = .0030 for PFS and 0 .0375 for OS, respectively). Combining PD-L1 expression and TMB value increased the predictive power of TMB. Conclusions: Our results show that the TML panel is an effective tool to stratify patients for ICI treatment. We believe that a combination of biomarkers will maximize the precision of patient selection.

KRAS amplification and mutation are independent events in gastroesophageal adenocarcinomas (GEA).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 70-70
Author(s):  
Russell Madison ◽  
Joseph Chao ◽  
Jeffrey S. Ross ◽  
Vincent A. Miller ◽  
Siraj Mahamed Ali ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Older Patient ◽  
Kras Mutations ◽  
Independent Events ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Tissue Specimens ◽  
Kras Codon

70 Background: KRAS mutations are common oncogenic events across cancers, but effective RAS-directed therapies are lacking. However, recent studies support use of PD-1 blockade in most subsets of lung cancer with KRAS short variant mutations (KRASSV) (PMID: 28039262), and preclinical data supports combined MEK and SHP2 inhibition in KRAS amplified ( KRASa) GEA (PMID: 30093730). We sought to explore the landscape of KRAS altered GEA and compare genomic profiles of KRAS-altered and KRAS wild-type (WT) cases for biomarkers of response to targeted therapies and immune checkpoint inhibitors. Methods: 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based comprehensive genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Descriptive statistics were used to compare among subgroups. Results: KRASSV and KRASa were identified in 11% and 5.8% of gastric adenocarcinoma (GA), respectively, and in 7.2% and 17% of esophageal adenocarcinoma (EA), respectively. KRASa and KRASSV were nearly mutually exclusive, co-occurring in only 4.4% of KRAS altered cases. ERBB2 alterations were less common in KRASSV and KRASa GEA (both 9%) as compared with KRAS WT GEA (19%) (p = 1.9E-16). EGFRa was less common in KRASSV versus KRASa GEA (1.9% vs. 9.3%, p = 2.6E-8), whereas PIK3CASV was more common in KRASSV versus KRASa (16% vs 5.0%, p = 1.5E-11). Median TMB for all groups was similar; however, KRASSV GEA had a higher mean TMB (9.7 mut/Mb) as compared to KRASa (5.1 mut/Mb, p = 5.0E-12) and KRAS WT cases (5.8 mut/Mb, p = 2.2E-07). KRAS codon 12/13 accounted for > 80% of predicted pathogenic mutations. MSI-high was also more prevalent in KRASSV (11.4%) versus KRASa (0.9%, p = 4.8E-15) and KRAS WT GEA (3.0%, p = 1.8E-25). MSI-high KRASSV GEA was associated with older patient age (median 72 years) and with high TMB (median 40.9 mut/mb). Conclusions: GA was enriched for KRAS mutation whereas EA was enriched for KRAS amplification. KRAS WT versus KRASSV versus KRASa each presented distinct genomic profiles. KRASa in the absence of KRAS mutation exists in 11% of GEA and warrants further exploration to inform combination treatment strategies.

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