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Breast Cancer Res. 2015 Oct 3;17(1):134. doi: 10.1186/s13058-015-0642-8.

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

Author information

1
Department of Molecular Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. e.lips@nki.nl.
2
Department of Pathology, Amsterdam, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. e.lips@nki.nl.
3
Department of Molecular Carcinogenesis, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. m.michaut@nki.nl.
4
Department of Molecular Carcinogenesis, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. m.hoogstraat@nki.nl.
5
Department of Medical Oncology, UMC Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. m.hoogstraat@nki.nl.
6
Department of Molecular Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. l.mulder@nki.nl.
7
Department of Medical Oncology, UMC Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. n.besselink-2@umcutrecht.nl.
8
Department of Medical Oncology, UMC Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. m.j.koudijs@umcutrecht.nl.
9
Department of Medical Genetics, UMC Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. e.cuppen@hubrecht.eu.
10
Department of Medical Oncology, UMC Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. e.voest@nki.nl.
11
Department of Medical Oncology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. e.voest@nki.nl.
12
Department of Molecular Carcinogenesis, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. r.bernards@nki.nl.
13
Department of Pathology, Amsterdam, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. p.nederlof@nki.nl.
14
Department of Molecular Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. j.wesseling@nki.nl.
15
Department of Pathology, Amsterdam, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. j.wesseling@nki.nl.
16
Department of Medical Oncology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. s.rodenhuis@nki.nl.
17
Department of Molecular Carcinogenesis, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. l.wessels@nki.nl.
18
Department of EEMCS, Delft University of Technology, Mekelweg 4, 2628 CD, Delft, The Netherlands. l.wessels@nki.nl.

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.

PMID:
26433948
PMCID:
PMC4592753
DOI:
10.1186/s13058-015-0642-8
[Indexed for MEDLINE]
Free PMC Article

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