HER3 is a tyrosine kinase receptor and involved in cell proliferation and carcinogenesis. Preclinical data suggest that HER3 plays a critical role in the escape mechanism from anti-EGFR directed treatment in metastatic colorectal cancer (mCRC) patients. Additionally, HER3 downstream signaling has shown to stimulate angiogenesis. We therefore hypothesize that variations in genes involved in the HER3 signaling pathway may predict outcome in patients with mCRC treated with first-line FOLFIRI and bevacizumab (bev) or FOLFIRI and cetuximab (cet).
The impact of 4 functional SNPs within the HER3, NRG1, NEDD4 and BTC genes on outcome was evaluated in 585 pts with mCRC treated with either first-line FOLFIRI/bev (n = 293) or FOLFIRI/cet (n = 292) in the randomized phase III FIRE-3 trial. Genomic DNA was extracted from FFPE and the SNPs were analyzed by PCR-based direct sequencing.
Baseline characteristics in the FOLFIRI/bev and FOLFIRI/cet cohorts were as follows: female:male ratio=1/3:2/3 in both arms; age >65y (48% and 47%) and median PFS/OS=10.1/23.7 and 9.6/26.5 months. The HER3 rs2271189 SNP showed significant association with PFS. A/A genotype carriers treated with FOLFIRI/bev had a shorter median PFS compared to those harboring any G allele (7.0 vs 10.3 months) in both univariate (HR 1.60, 95% CI 1.09-2.36, p = 0.014) and multivariate analysis (HR 1.64, 95% CI 1.09-2.46, p = 0.018). The same effect on PFS could be seen in patients receiving FOLFIRI/cet. Here again, A/A carriers showed a shorter median PFS than those having any G allele (7.9 vs 10.0 months) in both univariate (HR 1.56, 95% CI 1.13-2.15, p = 0.005) and multivariate analysis (HR 1.40, 95% CI 1.00-1.96, p = 0.05).
Our results provide the first evidence that the HER3 polymorphism rs2271189 might serve as a predictive/prognostic marker in pts with mCRC treated with FOLFIRI/bev and FOLFIRI/cet in the first line setting. Targeting HER3 might be a promising approach to further improve treatment options against mCRC and to overcome resistance to both anti-EGFR and anti-angiogenic therapy.
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This work was supported by the National Institute of Health P30CA014089, the Gloria Borges Wunderglo Project, and the Daniel Butler Research Fund. Martin D. Berger received a grant from the Werner and Hedy Berger-Janser foundation for cancer research. Yuji Miyamoto received a grant from the Japan Society for the Promotion of Science (S2606). Ryuma Tokunaga received a grant from the Uehara Memorial Foundation.
S. Stintzing: Advisory board member: Amgen, Bayer, Lilly, Merck KgaA, Nordic Pharma, Roche, Sanofi V. Heinemann: Advisory board member: Amgen, Baxalta, Boehringer Ingelheim, Lilly, Merck KgaA, Merrimack, Roche AG, Sanofi, Servier, Sirtex, Taiho. H-J. Lenz: Advisory board member: Merck Serono, Roche. All other authors have declared no conflicts of interest.