EGFR and MET amplifications determine response to HER2 inhibition in ERBB2-amplified esophagogastric cancer Journal Article

Authors: Sanchez-Vega, F.; Hechtman, J. F.; Castel, P.; Ku, G. Y.; Tuvy, Y.; Won, H.; Fong, C. J.; Bouvier, N.; Nanjangud, G. J.; Soong, J.; Vakiani, E.; Schattner, M.; Kelsen, D. P.; Lefkowitz, R. A.; Brown, K.; Lacouture, M. E.; Capanu, M.; Mattar, M.; Qeriqi, B.; Cecchi, F.; Tian, Y.; Hembrough, T.; Nagy, R. J.; Lanman, R. B.; Larson, S. M.; Pandit-Taskar, N.; Schöder, H.; Iacobuzio-Donahue, C. A.; Ilson, D. H.; Weber, W. A.; Berger, M. F.; de Stanchina, E.; Taylor, B. S.; Lewis, J. S.; Solit, D. B.; Carrasquillo, J. A.; Scaltriti, M.; Schultz, N.; Janjigian, Y. Y.
Article Title: EGFR and MET amplifications determine response to HER2 inhibition in ERBB2-amplified esophagogastric cancer
Abstract: The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with ERBB2 (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplification of EGFR and ERBB2. Heterogeneous 89Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking EGFR amplification or with acquisition of MET amplification, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in ERBB2 and MET coamplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in ERBB2-amplified EG cancer. SIGNIFICANCE: Analysis of patients with ERBB2-amplified, trastuzumab-resistant EG cancer who were treated with the HER kinase inhibitor afatinib revealed that sensitivity and resistance to therapy were associated with EGFR/ERBB2 coamplification and MET amplification, respectively. HER2-directed PET imaging and cell-free DNA sequencing could help guide strategies to overcome the emergence of resistant clones.See related commentary by Klempner and Catenacci, p. 166.This article is highlighted in the In This Issue feature, p. 151. ©2018 American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 9
Issue: 2
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2019-02-01
Start Page: 199
End Page: 209
Language: English
DOI: 10.1158/2159-8290.Cd-18-0598
PUBMED: 30463996
PROVIDER: scopus
PMCID: PMC6368868
Notes: Source: Scopus
Citation Impact
MSK Authors
  1. Mario E Lacouture
    319 Lacouture
  2. David Solit
    537 Solit
  3. Geoffrey Yuyat Ku
    119 Ku
  4. Heiko Schoder
    327 Schoder
  5. Marinela Capanu
    256 Capanu
  6. Yelena Yuriy Janjigian
    189 Janjigian
  7. Karen T Brown
    171 Brown
  8. David H Ilson
    321 Ilson
  9. Nancy Bouvier
    37 Bouvier
  10. Jason S Lewis
    302 Lewis
  11. Michael Forman Berger
    495 Berger
  12. Steven M Larson
    877 Larson
  13. Mark Schattner
    114 Schattner
  14. Efsevia Vakiani
    195 Vakiani
  15. David P Kelsen
    427 Kelsen
  16. Barry Stephen Taylor
    186 Taylor
  17. Nikolaus D Schultz
    258 Schultz
  18. Helen Hyeong-Eun Won
    90 Won
  19. Pau Castel
    23 Castel
  20. Wolfgang Andreas Weber
    165 Weber
  21. Maurizio Scaltriti
    123 Scaltriti
  22. Jaclyn Frances Hechtman
    160 Hechtman
  23. Marissa   Mattar
    17 Mattar
  24. Joanne Soong
    3 Soong
  25. Yaelle Tuvy
    8 Tuvy
  26. Besnik Qeriqi
    6 Qeriqi
  27. Christopher Joseph Fong
    3 Fong