Oncotarget

Research Papers:

Pathological complete response after cisplatin neoadjuvant therapy is associated with the downregulation of DNA repair genes in BRCA1-associated triple-negative breast cancers

Pawel Domagala _, Jolanta Hybiak, Janusz Rys, Tomasz Byrski, Cezary Cybulski, Jan Lubinski

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Oncotarget. 2016; 7:68662-68673. https://doi.org/10.18632/oncotarget.11900

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Abstract

Pawel Domagala1, Jolanta Hybiak1, Janusz Rys2, Tomasz Byrski3, Cezary Cybulski4, Jan Lubinski4

1Department of Pathology, Pomeranian Medical University, Szczecin, Poland

2Department of Tumor Pathology, Maria Sklodowska-Curie Memorial Cancer Centre & Institute of Oncology, Krakow Branch, Krakow, Poland

3Department of Oncology, Pomeranian Medical University, Szczecin, Poland

4Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland

Correspondence to:

Pawel Domagala, email: paweldom@pum.edu.pl

Keywords: breast cancer, triple-negative, DNA repair, cisplatin, BRCA1

Received: June 11, 2016     Accepted: August 26, 2016     Published: September 8, 2016

ABSTRACT

Pathologic complete response (pCR) after neoadjuvant chemotherapy is considered a suitable surrogate marker of treatment efficacy in patients with triple-negative breast cancers (TNBCs). However, the molecular mechanisms underlying pCR as a result of such treatment remain obscure. Using real-time PCR arrays we compared the expression levels of 120 genes involved in the main mechanisms of DNA repair in 43 pretreatment biopsies of BRCA1-associated TNBCs exhibiting pCR and no pathological complete response (non-pCR) after neoadjuvant chemotherapy with cisplatin. Altogether, 25 genes were significantly differentially expressed between tumors exhibiting pCR and non-pCR, and these genes were downregulated in the pCR group compared to the non-pCR group. A difference in expression level greater than 1.5-fold was detected for nine genes: MGMT, ERCC4, FANCB, UBA1, XRCC5, XPA, XPC, PARP3, and RPA1. The non-homologous end joining and nucleotide excision repair pathways of DNA repair showed the most significant relevance. Expression profile of DNA repair genes associated with pCR was different in the node-positive (20 genes with fold change >1.5) and node-negative (only 3 genes) subgroups. Although BRCA1 germline mutations are the principal defects in BRCA1-associated TNBC, our results indicate that the additional downregulation of other genes engaged in major pathways of DNA repair may play a decisive role in the pathological response of these tumors to cisplatin neoadjuvant chemotherapy. The results suggest that patients with node-positive BRCA1-associated TNBCs that do not exhibit pCR after cisplatin neoadjuvant chemotherapy may be candidates for subsequent therapy with PARP inhibitors, whereas UBA1 may be a potential therapeutic target in node-negative subgroup.


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