Clinical Studies Favorable Prognostic Impact in Loss of TP53 and PIK3CA Mutations after Neoadjuvant Chemotherapy in Breast Cancer

We investigated the loss of somatic mutations in TP53 and PIK3CA in breast cancer tissue after neoadjuvant chemotherapy (NCT) and the clinical relevance of the observed mutation profiles. Samples were derived from three cohorts: Cohort 1 consisting of 206 patients undergoing NCT with matched preand postchemotherapy tumor tissues; Cohort 2 consisting of 158 additional patients undergoing NCT; and Cohort 3, consisting of 81 patients undergoing chemotherapy with prechemotherapy tumor tissues. In the first cohort, somatic mutations inTP53 orPIK3CAwere identified in 24.8%of the pre-NCT tumor samples but in only 12.1% of the post-NCT tumor samples (P< 0.001). Patientswith initialTP53 and PIK3CAmutationswho becamenegative for themutations after NCT had a higher Miller–Payne score (P 1⁄4 0.008), improved disease-free survival, and improved overall survival than those with no change or the opposite change. The association of loss of mutations in TP53 and PIK3CA and improved survival was successfully validated in the second cohort. In addition, 28.4% of the tumors showed intratumoral heterogeneity of somatic mutations in TP53 or PIK3CA, whereas 71.6% were homogeneous, either with or without the mutations. Our data reveal the novel concept that chemotherapy may reduce mutation frequency in patients with breast cancer. Furthermore, the loss of somatic mutations in TP53 and PIK3CAmay be translated to biomarkers for prognosis via further verification, which may optimize the choice of sequential therapy and improve patient survival. Cancer Res; 74(13); 3399–407. 2014 AACR.