Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy responseReport as inadecuate

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Breast Cancer Research

, 17:134

First Online: 03 October 2015Received: 17 November 2014Accepted: 10 September 2015DOI: 10.1186-s13058-015-0642-8

Cite this article as: Lips, E.H., Michaut, M., Hoogstraat, M. et al. Breast Cancer Res 2015 17: 134. doi:10.1186-s13058-015-0642-8


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.

Abbreviationsbpbase pairs

CNAcopy number alteration

COSMICCatalogue of Somatic Mutations in Cancer

ddACdose dense cyclophosphamide, doxorubicin

DSBdouble strand break

EGFRepidermal growth factor receptor

ERestrogen receptor

HER2human epidermal growth factor receptor 2

KEGGKyoto Encyclopedia of Genes and Genomes

MLPAmultiplex ligation-dependent probe amplification

mTORmammalian target of rapamycin

NACneoadjuvant chemotherapy

NGSnext generation sequencing

pCRpathological complete remission


TGFtransforming growth factor

TNBCtriple negative breast cancer

VEGFvascular endothelial growth factor

Esther H. Lips and Magali Michaut contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s13058-015-0642-8 contains supplementary material, which is available to authorized users.

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Author: Esther H. Lips - Magali Michaut - Marlous Hoogstraat - Lennart Mulder - Nicolle JM Besselink - Marco J. Koudijs - Edwin 


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