Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response

Abstract

IntroductionIn triple negative breast cancers (TNBC) the initial response to chemotherapy is often favorable, but relapse and chemotherapy resistance frequently occur in advanced disease. Hence there is an urgent need for targeted treatments in this breast cancer subtype. In the current study we deep sequenced DNA of tumors prior to chemotherapy to search for predictors of response or resistance.MethodsNext generation sequencing (NGS) was performed for 1,977 genes involved in tumorigenesis. DNA from 56 pre-treatment TNBC-biopsies was sequenced, as well as matched normal DNA. Following their tumor biopsy, patients started neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. We studied associations between genetic alterations and three clinical variables: chemotherapy response, relapse-free survival and BRCA proficiency.ResultsThe mutations observed were diverse and few recurrent mutations were detected. Most mutations were in TP53, TTN, and PIK3CA (55 %, 14 %, and 9 %, respectively). The mutation rates were similar between responders and non-responders (average mutation rate 9 vs 8 mutations). No recurrent mutations were associated with chemotherapy response or relapse. Interestingly, PIK3CA mutations were exclusively observed in patients proficient for BRCA1. Samples with a relapse had a higher copy number alteration rate, and amplifications of TTK and TP53BP2 were associated with a poor chemotherapy response.ConclusionsIn this homogenous cohort of TNBCs few recurrent mutations were found. However, PIK3CA mutations were associated with BRCA proficiency, which can have clinical consequences in the near future.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0642-8) contains supplementary material, which is available to authorized users.

PIK3CA mutations and their response to neoadjuvant treatment in early breast cancer: A systematic review and meta‐analysis

“…As shown in Table , 20 studies including 4392 patients were included in our meta‐analysis . Overall, PIK3CA mutation incidence in our meta‐analysis was 22.4% (range 7.7–39.0%).…”

Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis

“…A few studies have evaluated whether predictability can be improved by considering a tumor’s somatic genetic aberrations alone [11,12] or in combination with gene expression [13]. Recent next-generation sequencing efforts have identified genes recurrently mutated in TNBC, including TP53 and PIK3CA , but unfortunately have not yielded any new predictive or prognostic clues [12,14].…”

“…A few studies have evaluated whether predictability can be improved by considering a tumor’s somatic genetic aberrations alone [11,12] or in combination with gene expression [13]. Recent next-generation sequencing efforts have identified genes recurrently mutated in TNBC, including TP53 and PIK3CA , but unfortunately have not yielded any new predictive or prognostic clues [12,14]. Among existing markers of chemosensitivity, BRCA germline mutation carriers are known to receive greater benefit from platinum-based chemotherapy [15] and poly(ADP-ribose) polymerase (PARP) inhibitors in TNBC and ovarian cancers [16–18], but it is unclear whether patients with these tumors also benefit from ACT chemotherapy.…”

News on the medical treatment of young women with early-stage HER2-negative breast cancer

“…high expression of stem cell markers) implicated in endocrine resistance that could render them more aggressive [10,11]. Young patients have a higher risk of developing triple-negative breast cancer (TNBC) [12], the most aggressive subtype characterized by poor prognostic and molecular features [13] and the worst survival [9]. The majority of TNBC shows BRCAness features (i.e.…”