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Clinical next generation sequencing (NGS) of esophagogastric (EG) adenocarcinomas identifies distinct molecular signatures of response to HER2 inhibition, first-line 5FU/platinum and PD1/CTLA4 blockade

Date

09 Oct 2016

Session

Gastrointestinal tumours, non-colorectal 2

Presenters

Yelena Janjigian

Citation

Annals of Oncology (2016) 27 (6): 207-242. 10.1093/annonc/mdw371

Authors

Y.Y. Janjigian1, F. Sanchez-Vega2, P. Jonsson3, Y. Tuvy1, N. Bouvier4, J. Riches1, R. Kundra3, G. Ku2, J.F. Hechtman5, D. Kelsen1, L. Tang5, D. Ilson1, E. Vakiani5, Z. Stadler1, M. Callahan1, D.B. Solit1, M.F. Berger4, B.S. Taylor3, N. Schultz3

Author affiliations

  • 1 Medicine, Memorial Sloan-Kettering Cancer Center, 10065 - New York/US
  • 2 Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 3 Bioinformatics, Memorial Sloan-Kettering Cancer Center, 10065 - New York/US
  • 4 Cmo, Memorial Sloan-Kettering Cancer Center, 10065 - New York/US
  • 5 Pathology, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
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Background

TCGA identified potential therapeutic targets unique to subtypes of EG adenocarcinoma including RTK alterations in CIN tumors and immunotherapy in EBV and MSI tumors.

Methods

Patients with Stage IV EG adenocarcinoma were analyzed using a NGS assay (MSK-IMPACT) capable of detecting somatic mutations (MUT), deletions and amplifications (AMP) with results correlated with clinical outcomes.

Results

We analyzed 429 tumors from 319 pts with Stage IV EG adenocarcinoma (33% esophagus, 52% gastric, 15% GEJ). 80 of 319 (25%) pts had HER2+ (IHC 3 + , IHC2 + /FISH+) tumors: 71 collected pre-trastuzumab (T), 38 post-T, and 28 with paired pre/post samples. In the paired samples, we observed post-therapeutic loss of HER2 amplification (16%); gain of new AMP of MET (7%), EGFR (4%), and IGF1R (4%); MUT in ERBB4 (14%), KRAS (11%), PIK3CA (7%), MTOR (7%). Co-occurring EGFR/HER2 AMP were detected in the post-T tumors of 4 of 20 pts treated with afatinib with 3 achieving a PR. 20 of 319 pts (6%) pts had deleterious somatic (n = 15) or germline (n = 5) BRCA1/2 MUT; 4 of 5 BRCA1/2 germline pts had loss of the wild type allele and exhibited dramatic tumor regression on 5FU/platinum, with CR achieved in 2 pts (TTP 15 - 22 mos; OS 18 - 35 mos). The one germline BRCA1 pt without LOH experienced rapid disease progression with OS of 9 months; while analysis of somatic BRCA cases is ongoing, 1 pt with an inactivating somatic BRCA1 MUT (germline wt) and LOH achieved CR to 5FU/platinum ongoing at 28 mos. 12 of 319 pts (4%) had MSI tumors, of which 3 were treated with anti-PD1 inhibitor: 1 pt achieving a CR durable at 14 mos, 1 PR and 1 SD after 3 mos of ongoing therapy; 1 pt with MSS/EBV+ tumor achieved a CR ongoing at 17 mos with PD1/CTLA4 blockade.

Conclusions

We identified loss of ERBB2 AMP and secondary alterations in the RTK/RAS/PI3K pathway in pts with acquired trastuzumab resistance. Testing of EG patients for germline and somatic BRCA1 and BRCA2 may identify those most likely to respond to platinum-based chemotherapy. Promising activity was observed with immunotherapy in EG patients with MSI and EBV+ tumors.

Clinical trial identification

NCT01775072

Legal entity responsible for the study

Yelena Y. Janjigian, MD

Funding

This work was funded in part by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology and the National Cancer Institute Cancer Center Core Grant No. P30-CA008748. 2013 Conquer Cancer Foundation ASCO Career Development Award; 2014 and 2016 Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center.

Disclosure

Y.Y. Janjigian: Grants or patents: Boehringer Ingelheim, Bayer, Genentech, Eli Lilly, Pfizer, Merck. All other authors have declared no conflicts of interest.

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