ERBB2 alterations a new prognostic biomarker in stage III colon cancer from a FOLFOX based adjuvant trial (PETACC8)

Date

10 Oct 2016

Session

Gastrointestinal tumours, colorectal 2

Presenters

Pierre Laurent-Puig

Citation

Annals of Oncology (2016) 27 (6): 149-206. 10.1093/annonc/mdw370

Authors

P. Laurent-Puig1, R. Balogoun1, A. Cayre2, K. Le Malicot3, J. Tabernero4, E. Mini5, G. Folprecht6, J. van Laethem7, J. Thaler8, L. Nørgård Petersen9, E. Sanchez10, J. Bridgewater11, S. Ellis12, C. Locher13, C. Lagorce14, J. Ramé15, C. Lepage16, F. Penault-Llorca17, J. Taieb18

Author affiliations

  • 1 Department Of Biology, Hôpital Européen Georges Pompidou; Inserm Umr-s1147, Paris Descartes University, 75006 - Paris/FR
  • 2 Department Of Pathology, Centre Jean Perrin, 63011 Clermont-Ferrand - Clermont-Ferrand/FR
  • 3 Biostatistics, Fédération Francophone de Cancérologie Digestive (FFCD), 21079 - Dijon/FR
  • 4 Oncologia Médica, Vall d`Hebron University Hospital Institut d'Oncologia, 08035 - Barcelona/ES
  • 5 Experimental And Clinical Medicine, University of Florence, Section of Internal Medicine, Florence/IT
  • 6 Medical Department I, University Hospital Carl Gustav Carus, 1307 - Dresden/DE
  • 7 Dept. Of Gastroenterology, Erasme University Hospital-(Universite Libre de Bruxelles), 1070 - Brussels/BE
  • 8 Dept. Internal Medicine Iv, Klinikum Wels - Grieskirchen, 4600 - Wels/AT
  • 9 Department Of Oncology, Roskilde Hospital, Roskilde/DK
  • 10 Instituto Português De Oncologia Do Porto Francisco Gentil, Instituto Portugues de Oncologia Centro do Porto(IPO-Porto), Porto/PT
  • 11 University College London, UCL - University College London, WC1E 6DD - London/GB
  • 12 Department Of Medical Oncology, Centre Catalan d'Oncologie Clinique St. Pierre, Perpignan/FR
  • 13 Service Gastroentérologie, CH de Meaux, 77100 - Meaux/FR
  • 14 Department Of Gastroenterology And Gi Oncology, Hopital European George Pompidou, Paris/FR
  • 15 Department Of Oncology, Centre Catherine de Sienne, Nantes/FR
  • 16 Hepato-gastroenterology Department, Dijon University Hospital And Inserm U866, Fédération Francophone de Cancérologie Digestive (FFCD), 21079 - Dijon/FR
  • 17 Department Of Pathology, Centre Jean Perrin, 63011 - Clermont-Ferrand/FR
  • 18 Department Of Gastroenterology And Digestive Oncology, Hopital European George Pompidou, 75015 - Paris/FR
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Background

ERBB2 amplifications have been recently shown as a potential targetable alteration in metastatic colorectal cancer (mCRC). Indeed, dual-targeted therapy with trastuzumab and lapatinib, has been shown to be of potential interest in HER2-positive mCRC patients (pts) in the HERACLES trial. This discovery reinforces the interest to study the occurrence and the prognostic role of ERBB2 alterations in stage III colon cancer (CC) where we need to improve adjuvant strategies. Prospective collection of PETACC8 study allowed us to evaluate the occurrence and the prognostic impact of ERBB2 alteration.

Methods

From the 2559 pts of PETACC8 trial, 2043 signed the translational research informed consent. Among them, tissues samples were available in 1795 pts for NGS screening, and 1804 were available for immunochemistry and FISH analysis. We searched for ERBB2 mutation in exon 19 to 21 and for amplification, using the colon lung cancer panel V2 and an algorithm previously validated. All cases were screened for ERBB2 staining using the polyclonal antibody HER2 clone 4B5 from Ventana Roche and by FISH using kit zytolight SPEC ERBB2/CEN17 dual color.

Results

Altogether, ERBB2 alterations were present in 64 pts (3.8%). We identified 17 mutations (1%), the most frequent were p.V842I (5 pts), p.V777L (3 pts), p.L755S (3 pts). There was no significant association with RAS or BRAF mutations nor mutual exclusivity. We identified NGS ERBB2 amplification in 49 pts (2.9%), 39 were confirmed by immunochemistry (FISH results will be shown at the meeting). We evaluated the prognostic impact of ERBB2 alterations by pooling pts mutated or amplified. In univariate analysis, ERBB2 alterations were associated with shorter time to recurrence (HR: 1.55 [95%CI: 1.02; 2.36] p = 0.04) and shorter overall survival (HR: 1.57 [0.99; 2.5] p =0.05). This prognostic value was maintained after adjustment for treatment, RAS mutation, histological grade, tumor location, pT and pN status, bowel obstruction or perforation and venous or lymphatic embolism.

Conclusions

ERBB2 alteration is a rare event found in approximately 4% of stage III CC pts. Its poor prognostic value supports the testing of anti-ERBB2 therapies in the adjuvant setting.

Clinical trial identification

EudraCT number 2005-003463-23

Legal entity responsible for the study

N/A

Funding

Merck and Sanofi

Disclosure

P. Laurent-Puig: Consulting or advisory role: Sanofi Merck Serono Amgen Genomic Health Myriad Genetics Integragen Prizer Roche Glycart. J. Tabernero: Consultant/Advisory role from Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Roche, Sanofi, Symphogen, Takeda and Taiho. G. Folprecht: Honoraries from Merck, Roche/Genentech, Lilly, Bayer, Sanofi-Aventis, Baxalta, Servier, Boehringer. Study grant from Merck. J. Thaler: Honoraria and research funding from Sanofi and Merck. L. Nørgård Petersen: Consulting or advisory role: Bayer Roche Glycart. J. Bridgewater: Consulting or advisory role for: Merck Serono Travel, accommodations, expenses: MSD Onoclogy Merck Serono Honoraria: Merck Serono. C. Lepage: Travel, accommodations, expenses: Ipsen. F. Penault-Llorca: Research grants and honoraria from Roche. J. Taieb: honoraria from: Merck Amgen Lilly Sanofi Celgene Roche Glycart. All other authors have declared no conflicts of interest.

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