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:
Notes: Article -- Export Date: 2 April 2018 -- Source: Scopus
Altmetric
Citation Impact
MSK Authors
  1. Hans Gerdes
    149 Gerdes
  2. Valerie W Rusch
    735 Rusch
  3. Neal Rosen
    381 Rosen
  4. Mark E Robson
    457 Robson
  5. David Solit
    547 Solit
  6. Geoffrey Yuyat Ku
    121 Ku
  7. Liying Zhang
    108 Zhang
  8. Zsofia Kinga Stadler
    203 Stadler
  9. Marinela Capanu
    258 Capanu
  10. Yelena Yuriy Janjigian
    190 Janjigian
  11. Marc Ladanyi
    1044 Ladanyi
  12. Jinru Shia
    530 Shia
  13. David Hyman
    302 Hyman
  14. Laura Hong Tang
    353 Tang
  15. Vivian Strong
    168 Strong
  16. Ahmet Zehir
    215 Zehir
  17. Daniel Coit
    472 Coit
  18. David H Ilson
    324 Ilson
  19. Nancy Bouvier
    38 Bouvier
  20. Michael Forman Berger
    497 Berger
  21. Mark Schattner
    114 Schattner
  22. Efsevia Vakiani
    196 Vakiani
  23. Manjit S Bains
    265 Bains
  24. David P Kelsen
    430 Kelsen
  25. Jianjiong Gao
    81 Gao
  26. Barry Stephen Taylor
    193 Taylor
  27. Nikolaus D Schultz
    263 Schultz
  28. Benjamin E Gross
    31 Gross
  29. Jamie C Riches
    23 Riches
  30. Maurizio Scaltriti
    126 Scaltriti
  31. Jaclyn Frances Hechtman
    163 Hechtman
  32. David Randolph Jones
    200 Jones
  33. Daniela   Molena
    80 Molena
  34. Sumit   Middha
    78 Middha
  35. Karl Philip Jonsson
    43 Jonsson
  36. Zachary Joseph Heins
    11 Heins
  37. Ritika   Kundra
    31 Kundra
  38. Yaelle Tuvy
    8 Tuvy
  39. Walid Khaled Chatila
    24 Chatila