RT Journal Article
SR Electronic
T1 Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer
JF Cancer Discovery
JO Cancer Discov
FD American Association for Cancer Research
SP 49
OP 58
DO 10.1158/2159-8290.CD-17-0787
VO 8
IS 1
A1 Janjigian, Yelena Y.
A1 Sanchez-Vega, Francisco
A1 Jonsson, Philip
A1 Chatila, Walid K.
A1 Hechtman, Jaclyn F.
A1 Ku, Geoffrey Y.
A1 Riches, Jamie C.
A1 Tuvy, Yaelle
A1 Kundra, Ritika
A1 Bouvier, Nancy
A1 Vakiani, Efsevia
A1 Gao, Jianjiong
A1 Heins, Zachary J.
A1 Gross, Benjamin E.
A1 Kelsen, David P.
A1 Zhang, Liying
A1 Strong, Vivian E.
A1 Schattner, Mark
A1 Gerdes, Hans
A1 Coit, Daniel G.
A1 Bains, Manjit
A1 Stadler, Zsofia K.
A1 Rusch, Valerie W.
A1 Jones, David R.
A1 Molena, Daniela
A1 Shia, Jinru
A1 Robson, Mark E.
A1 Capanu, Marinela
A1 Middha, Sumit
A1 Zehir, Ahmet
A1 Hyman, David M.
A1 Scaltriti, Maurizio
A1 Ladanyi, Marc
A1 Rosen, Neal
A1 Ilson, David H.
A1 Berger, Michael F.
A1 Tang, Laura
A1 Taylor, Barry S.
A1 Solit, David B.
A1 Schultz, Nikolaus
YR 2018
UL http://cancerdiscovery.aacrjournals.org/content/8/1/49.abstract
AB 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. Cancer Discov; 8(1); 49–58. ©2017 AACR.See related commentary by Sundar and Tan, p. 14.See related article by Pectasides et al., p. 37.This article is highlighted in the In This Issue feature, p. 1