ERBB2 alterations emerged as a new prognostic, albeit rare, biomarker from an adjuvant PETACC8 trial in patients with stage III colon cancer investigators reported at the ESMO 2016 Congress in Copenhagen, Denmark on 10 October. Although ERBB2 alterations occured at a low frequency, their presence associated with a markedly poorer prognosis, making both screening for ERBB2 alterations and the testing of anti-ERBB2 therapies a consideration in adjuvant colon cancer setting.
Pierre Laurent-Puig, Department of Biology, Hôpital Européen Georges Pompidou; INSERM UMR-S1147, Paris Descartes University in Paris, France, explained that ERBB2 amplifications have recently been shown to be a targetable alteration in metastatic colorectal cancer (mCRC). Lending further impetus to this study was the response seen in the HERACLES trial with dual-targeted therapy comprising trastuzumab and lapatinib in patients with HER2-positive mCRC. Prof. Laurent-Puig emphasised that defining the occurrence and prognostic role of ERBB2 alterations in stage III colon cancer could lead to additional adjuvant strategies, which are sorely needed in colon cancer.
Overall, 2559 patients with resected, histologically proven stage III colon adenocarcinoma participated in the PETACC8 trial; 2043 patients signed the informed consent for the translational research programme. Of these, 1795 patients had tissue samples for screening by next generation sequencing (NGS), and 1804 patients had samples for immunochemistry and FISH analyses.
The investigators searched for amplification of the ERBB2 gene and for mutation in exons 19 to 21 using the colon/lung cancer panel V2 and an algorithm that had been previously validated. All samples were screened for ERBB2 staining with polyclonal antibody HER2 clone 4B5 from Ventana Roche and by FISH using kit zytolight SPEC ERBB2/CEN17 dual colour.
ERBB2 alterations associate with poorer prognosis in colon cancer
Using these methods, ERBB2 alterations were detected in 64 (3.8%) patients; of these 17 (1%) samples contained ERBB2 mutations. The most frequently detected mutations were p.V842I in 5 patients, and 3 samples each harboured p.V777L and p.L755S mutations. Neither a significant association with RAS or BRAF mutations nor mutual exclusivity was determined. ERBB2 amplification was detected in 49 (2.9%) patient samples by NGS that were confirmed in 28 cases by FISH.
The prognostic value of ERBB2 alterations was evaluated by univariate analysis of pooled data from all patients showing either ERBB2 mutations or amplifications.
ERBB2 alterations signalled a poorer prognosis and were associated with both shorter time to recurrence (TTR), hazard ratio (HR) 1.55; 95% confidence interval (CI) 1.02, 2.36 (p = 0.04), and shorter overall survival, HR 1.57; 95% CI 0.99, 2.5 (p = 0.05). The prognostic value in TTR remained following adjustments for confounders, including treatment, the presence of RAS mutation, histological grade, tumour location, pT and pN status, and the presence of bowel obstruction or perforation, and venous or lymphatic embolism.
Although ERBB2 alteration is a relatively rare event that occurs in approximately 4% of patients with stage III colon cancer, ERBB2 alteration has been found to associate with decreased time to recurrence and shorter overall survival. Since its presence signals a poor prognosis, the authors concluded that the use of anti-ERBB2 therapies in the adjuvant setting is supported for testing in a clinical trial context.
ERBB2 alterations a new prognostic biomarker in stage III colon cancer from a FOLFOX based adjuvant trial (PETACC8)
P. Laurent-Puig, R. Balogoun, A. Cayre, K. Le Malicot, J. Tabernero, E. Mini, G. Folprecht, J.-L. van Laethem, J. Thaler, L. Nørgård Petersen, E. Sanchez, J. Bridgewater, S. Ellis, C. Locher, C. Lagorce, J.-F. Ramé, C. Lepage, F. Penault-Llorca, J. Taieb
This study was funded by Merck and Sanofi.