Title
Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response
Author
Lips, Esther H. (Netherlands Cancer Institute)
Michaut, Magali (Netherlands Cancer Institute)
Hoogstraat, Marlous (Netherlands Cancer Institute; University Medical Center Utrecht)
Mulder, Lennart (Netherlands Cancer Institute)
Besselink, Nicole J.M. (University Medical Center Utrecht)
Koudijs, Marco J. (University Medical Center Utrecht)
Cuppen, Edwin (University Medical Center Utrecht)
Voest, Emile E. (University Medical Center Utrecht; Netherlands Cancer Institute)
Bernards, Rene (Netherlands Cancer Institute)
Nederlof, Petra M. (Netherlands Cancer Institute)
Wesseling, Jelle (Netherlands Cancer Institute)
Rodenhuis, Sjoerd (Netherlands Cancer Institute)
Wessels, L.F.A. (TU Delft Pattern Recognition and Bioinformatics) 
Date
2015-10-03
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 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.
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.
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http://resolver.tudelft.nl/uuid:a01a711a-5fff-4d19-8986-03b9fed372a4
DOI
https://doi.org/10.1186/s13058-015-0642-8
ISSN
1465-5411
Source
Breast Cancer Research, 17 (1), 1-9
Part of collection
Institutional Repository
Document type
journal article
Rights
© 2015 Esther H. Lips, Magali Michaut, Marlous Hoogstraat, Lennart Mulder, Nicole J.M. Besselink, Marco J. Koudijs, Edwin Cuppen, Emile E. Voest, Rene Bernards, Petra M. Nederlof, Jelle Wesseling, Sjoerd Rodenhuis, L.F.A. Wessels