Synapse - Genetic predictors of response to systemic therapy in esophagogastric cancer

Genetic predictors of response to systemic therapy in esophagogastric cancer Journal Article

Authors:	Janjigian, Y. Y.; Sanchez-Vega, F.; Jonsson, P.; Chatila, W. K.; Hechtman, J. F.; Ku, G. Y.; Riches, J. C.; Tuvy, Y.; Kundra, R.; Bouvier, N.; Vakiani, E.; Gao, J.; Heins, Z. J.; Gross, B. E.; Kelsen, D. P.; Zhang, L.; Strong, V. E.; Schattner, M.; Gerdes, H.; Coit, D. G.; Bains, M.; Stadler, Z. K.; Rusch, V. W.; Jones, D. R.; Molena, D.; Shia, J.; Robson, M. E.; Capanu, M.; Middha, S.; Zehir, A.; Hyman, D. M.; Scaltriti, M.; Ladanyi, M.; Rosen, N.; Ilson, D. H.; Berger, M. F.; Tang, L.; Taylor, B. S.; Solit, D. B.; Schultz, N.
Article Title:	Genetic predictors of response to systemic therapy in esophagogastric cancer
Abstract:	The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability– high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein–Barr virus–positive patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance. SIGnIFICAnCE: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. © 2017 American Association for Cancer Research.
Keywords:	protein expression; major clinical study; systemic therapy; biological marker; ipilimumab; ticilimumab; epidermal growth factor receptor 2; protein p53; in situ hybridization; cyclin dependent kinase inhibitor 2a; epidermal growth factor receptor 3; k ras protein; esophagus cancer; fibroblast growth factor receptor 2; scatter factor receptor; esophagogastric cancer; n methyl dextro aspartic acid receptor 2a; nivolumab; human; article; pembrolizumab; durvalumab
Journal Title:	Cancer Discovery
Volume:	8
Issue:	1
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2018-01-01
Start Page:	49
End Page:	58
Language:	English
DOI:	10.1158/2159-8290.cd-17-0787
PROVIDER:	scopus
PMCID:	PMC5813492
PUBMED:	29122777
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85042561938&doi=10.1158%2f2159-8290.CD-17-0787&partnerID=40&md5=a5a2a5d1ef90219b3b6fb463e3e5498a
Notes:	Article -- Export Date: 2 April 2018 -- Source: Scopus