Comparison of HER2 overexpression with total Her2 mutation on resistance of EGFR-targeted therapy in Ras wild-type mCRC patients.

Abstract

3594 Background: Cetuximab has shown clinical benefit in patients with metastatic colorectal cancer (mCRC) harboring wild-type Ras, however, only partial patients respond to cetuximab treatment. The effect of human epidermal growth factor receptor 2 (HER2) protein overexpression and Her2 gene mutant on the efficacy of cetuximab treatment was not well elucidated in patients with Ras wild-type unresectable mCRC. Methods: From June 2008 to December 2014, we identified 216 patients with Ras wild-type unresectable liver-limited mCRC base on our previous study (ClinicalTrials: NCT01564810.), whose Her2 gene mutation was analyzed by next-generation sequencing for single nucleotide polymorphism (SNP) of Her2 gene and HER2 protein overexpression was determined by immunohistochemistry and fluorescence in situ hybridization (FISH). Results: Of these 216 patients, 103 were received cetuximab plus chemotherapy (cetuxima group) and 113 were received chemotherapy alone (chemotherapy group). The total rate of HER2 overexpression was 8.8%, including 9.7% in cetuximab group and 7.9% in chemotherapy group. HER2 overexpression caused impaired survival compared with HER2 non-overexpression patients in cetuxima group, with a median progression-free survival (PFS) of 4 months (95% CI 2.482-5.518) versus 10 months (95% CI 8.963-11.037; P< 0.0001), and a median overall survival (OS) of 15 months (95% CI 7.5-22.2) versus 36 months (95% CI 31.4-40.5) ( P< 0.0001). While, HER2 overexpression had no effect on treatment efficacy in chemotherapy group, when compared with HER2 non-overexpression paitents, with a median PFS of 5 months (95% CI 2.228-7.772) versus 5 months (95% CI 4.004-5.996; P= 0.615), and a median OS of 21 months (95% CI 6.975-35.025) versus 21 months (95% CI 17.772-24.228; P= 0.629). Meanwhile, we observed 25.5% of total Her2 mutant (24.2% in cetuximab group and 26.5% in cetuximab group), among of them 5 patients are HER2 overexpression. Total Her2 mutation has no impact on survival compared with Her2 wild-type ones in neither cetuximab group nor chemotherapy group. In further bioinformatics analysis is underdoing, and which subgroup or type of Her2 mutant potential affect cetuximab treatment need confirm. Conclusions: We show HER2 overexpression rather than total Her2 mutant contribute to resistance of cetuximab treatment in patients with mCRC harboring wild-type Ras. Next, the subgroup mutant in total Her2 mutant needs further analysis to confirm their roles in survival after cetuximab treatment.