Frequency of PIK 3CA Mutations in Chinese HER2+ Metastatic Breast Cancer Patients and Association with Clinical Benefit to Lapatinib and Capecitabine Treatment.

Abstract Background: Activating mutations in PIK3CA are frequent in breast cancer (Campbell et al. Cancer Res 2004;64:7678-7681). Previous analyses suggest that the presence of PIK3CA activating mutations were associated with poor clinical outcome (Li et al. Breast Can Res Treat 2006;96:91-95) and could confer resistance to treatment with trastuzumab (T) (Berns et al. Cancer Cell 2007;12:395-402). Lapatinib (L) is an oral tyrosine kinase inhibitor targeting EGFR and HER2 pathways. L plus capecitabine (C) has demonstrated efficacy in women with HER2+ metastatic breast cancer (MBC) previously treated with T (Geyer et al. N Engl J Med 2006;355(26):2733-2743). EGF109491 evaluated the efficacy of L+C in 52 Chinese HER2+ MBC patients. The clinical benefit rate (CBR) was 57.7% (PR 44% and SD 44%) and median progression free survival (PFS) was 6.3 months. The purpose of this analysis was to establish the frequency of PIK3CA mutations in this small cohort of Chinese patients and to determine if the presence of a PIK3CA mutation has any impact on clinical benefit to L+C.Methods: 38/52 patients provided tumor samples for biomarker analysis. Briefly, DNA was extracted from these tumor samples, amplified by PCR and sequenced by Pyrosequencing methods to identify the presence of frequent activating mutations in exons 9 and 20 in PIK3CA. Mutation status was tested for association with CBR and PFS using contingency table analysis and proportional hazards analysis respectively.Results:11/38 (29%) patients harbored a mutation in the PIK3CA gene, consistent with published frequencies. 9/11 mutations reside in the catalytic domain and 2/11 mutations reside in the accessory domain of the gene. There was no statistical association with CBR (p=0.639) or PFS (HR=1.01, p=0.989) in PIK3CA wildtype patients vs. PIK3CA mutant patients. PIK3CA wildtype n=27 (%)PIK3CA Mutation n=11 (%)CR0 (0)0 (0)PR12 (44%)4 (36%)SD13 (48%)5 (45%)PD1 (4%)1 (9%)Unknown1 (4%)1 (9%)HR1.01 (p=0.989) Conclusion: The frequency of PIK3CA mutations in this small cohort of Chinese HER2+ MBC patients is consistent with published frequencies. There was no statistically significant association between the presence of a PIK3CA mutation and clinical benefit to L+C in these patients. These results are in agreement with previous reports that mutations in PIK3CA do not seem to impact clinical outcome following L-containing treatment regimens. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1140.