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

Abstract

Background: ERBB2 amplifications have been recently shown as a potential targetable alteration in metastatic colorectal cancer, 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 [EudraCT number 2005-003463-23] allowed us to evaluate the occurrence and the prognostic impact of ERBB2 alteration. Design(s): 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 panelbV2 and an algorithm previously validated. All cases were screened by immunohistochemistry (IHC) with PATHWAY anti-HER-2/neu (4B5) from Ventana and by FISH (zytolight SPEC ERBB2/CEN17 dual color) on TMAs. Result(s): Altogether, ERBB2 alterations were present in 64 pts (3.8%) and in 42 (5,6%) in the KRAS wild type group. We identified 17 mutations (1%), most frequent p.V842I (5 pts), p.V777L (3 pts), p.L755S (3 pts). No significant association with RAS or BRAF mutations nor mutual exclusivity. We identified NGS ERBB2 amplification in 49 pts (2.9%), 46 by FISH (including the 39 IHC 3+). Discordances were observed in the 0/1+ category, 4 being amplified by FISH and NGS. 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 embolies. Conclusion(s): ERBB2 alteration is a rare event found in approximately 4% of stage III CC pts. Its poor prognostic value supports the evaluation of anti-ERBB2 therapies in the adjuvant setting. Due to their low frequency, screening for those alterations by NGS should show to be more cost effective than IHC and FISH.