Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in patients with HER2-positive operable breast cancer

Body: Introduction: In vitro studies have shown that lapatinib enhances the immune-mediated cytotoxicity (ADCC) of trastuzumab. FcgR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in patients with HER2-positive metastatic breast cancer. There are no data on the relationship between these polymorphisms and the combination of trastuzumab plus lapatinib in the early stage setting. We performed a pharmacogenomics analysis of CHER-LOB, a randomized phase II trial of preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B), or both (arm C) in HER2-positive operable breast cancer. Methods: FcgRIIa-H131R and FcgRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Pathologic complete response (pCR) of genotyped cases was evaluated by FcgR polymorphism and treatment arm. Results: Genotyping was successfully performed in 73/121 (60%) patients. No deviation from the Hardy-Weinberg equilibrium was observed. Similarly to the overall results of the CHER-LOB study, in the subset of patients genotyped in this analysis, a significant improvement in pCR rate was observed in favor of the combination of lapatinib plus trastuzumab (arm C) compared to arm A (OR=3.66, P=0.037), and B (OR=3.03, P=0.049). Such improvement was restricted to carriers of FcgRIIIa V allele (C vs. A, OR=5.33, P=0.043; C vs. B, OR=6.50, P=0.012), while it was not observed in patients with FcgRIIIa F/F genotype (C vs. A, OR=2.14, P=0.642; C vs. B, OR=0.71, P=0.737). Disease free survival (DFS) was not different by treatment arm in all genotyped cases, but a trend toward significance for an interaction between FcgRIIIa V allele and better DFS with the combination of lapatinib plus trastuzumab was detected (P=0.058). No significant associations were observed by FcgRIIa polymorphism. Conclusions: Host-related immune signatures may mediate lapatinib enhanced trastuzumab-dependent ADCC. FcgRIIIa genotypes may help predict different outcomes to lapatinib plus trastuzumab in HER2-Positive Early Breast Cancer.