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

Abstract

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 pre-and 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 in TP53 or PIK3CA were identified in 24.8% of the pre-NCT tumor samples but in only 12.1% of the post-NCT tumor samples (P < 0.001). Patients with initial TP53 and PIK3CA mutations who became negative for the mutations after NCT had a higher Miller-Payne score (P ¼ 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 PIK3CA may 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. Ó2014 AACR.

1976 Significance of PIK3CA mutations in patients with early breast cancer treated with adjuvant chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) study

“…Our PIK3CA mutation rate (23.3%) was consistent with the literature, as well as our rate of different hotspot mutations [3,14,19,[22][23][24][25][26][27][28][29][30][31][32][33][34]. Also, we confirmed significant associations of different types of PIK3CA mutations with clinicopathological and molecular characteristics.…”

“…One important question is the possible effect of PIK3CA status on cancer outcome and treatment efficacy. Notably, many studies examining the prognostic significance of PIK3CA mutations in breast cancer [35] have been published, however very few included a large enough number of patients [3,14,19,[22][23][24][25][26][27][28][29][30][31][32][33][34]. Also, less than half of them [22,24,26,28,30,31,33] used data from clinical trials, thus excluding the effect of treatment heterogeneity when evaluating prognostic factors.…”

Transcriptome Analysis of Triple-Negative Breast Cancer Reveals an Integrated mRNA-lncRNA Signature with Predictive and Prognostic Value

“…We performed macrodissection of tumor tissues to ensure that the percentage of tumor cells was 80% or more in all breast cancer specimens (18). Total RNA was isolated from 275 adjuvant TNBC samples, 33 paired adjacent normal breast tissues, and 82 CNB TNBC tissues using the Rneasy Plus Mini Kit (Qiagen).…”

Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer

“…3B) [74,76]. Several studies showed that appearance of new mutations, undetectable in the primary tumor, can arise after neoadjuvant chemotherapy (PTEN and TP53), HER2-targeted therapies (PIK3CA), and during endocrine therapy (ESR1) for metastatic breast cancer [50][51][52][53][54][77][78][79]. Even though the relative proportion of drug-resistant subclones is generally higher in the post-treatment specimens, retreating cancers with drugs on which they previously progressed often continues to produce tumor response.…”