Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Lips, Esther; Michaut, Magali; Hoogstraat, Marlous; Mulder, Lennart; Besselink, Nicolle; Koudijs, Marco; Cuppen, Edwin; Voest, Emile; Bernards, Rene; Nederlof, Petra; Wesseling, Jelle; Rodenhuis, Sjoerd; Wessels, Lodewyk
• Is Part Of: Breast cancer research. Volume 17:Issue 1(2015)
• Page Start: 1
• Page End: 10
• Publication Date: 2015-12
• Subjects: Breast -- Cancer -- Periodicals; 616.99449
• DOI: 10.1186/s13058-015-0642-8
• Languages: English
• ISSNs: 1465-542X

Abstract

Abstract Introduction In 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. Methods Next 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. Results The mutations observed were diverse and few recurrent mutations were detected. Most mutations were inTP53, TTN, andPIK3CA (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 forBRCA1 . Samples with a relapse had a higher copy number alteration rate, and amplifications ofTTK andTP53BP2 were associated with a poor chemotherapy response. Conclusions In 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.