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
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MSK Authors
  1. Hans Gerdes
    122 Gerdes
  2. Valerie W Rusch
    638 Rusch
  3. Neal Rosen
    351 Rosen
  4. Mark E Robson
    358 Robson
  5. David Solit
    420 Solit
  6. Geoffrey Yuyat Ku
    82 Ku
  7. Liying Zhang
    86 Zhang
  8. Zsofia Kinga Stadler
    139 Stadler
  9. Marinela Capanu
    189 Capanu
  10. Yelena Yuriy Janjigian
    133 Janjigian
  11. Marc Ladanyi
    848 Ladanyi
  12. Jinru Shia
    445 Shia
  13. David Hyman
    176 Hyman
  14. Laura Hong Tang
    308 Tang
  15. Vivian Strong
    141 Strong
  16. Ahmet Zehir
    145 Zehir
  17. Daniel Coit
    407 Coit
  18. David H Ilson
    258 Ilson
  19. Nancy Bouvier
    28 Bouvier
  20. Michael Forman Berger
    373 Berger
  21. Efsevia Vakiani
    161 Vakiani
  22. Manjit S Bains
    220 Bains
  23. David P Kelsen
    309 Kelsen
  24. Jianjiong Gao
    62 Gao
  25. Barry Stephen Taylor
    135 Taylor
  26. Nikolaus D Schultz
    193 Schultz
  27. Benjamin E Gross
    26 Gross
  28. Jamie C Riches
    15 Riches
  29. David Randolph Jones
    150 Jones
  30. Daniela   Molena
    35 Molena
  31. Sumit   Middha
    51 Middha
  32. Karl Philip Jonsson
    19 Jonsson
  33. Zachary Joseph Heins
    6 Heins
  34. Ritika   Kundra
    15 Kundra
  35. Yaelle Tuvy
    2 Tuvy