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BRCA-1 methylation and TP53 mutation in triple-negative breast cancer patients without pathological complete response to taxane-based neoadjuvant chemotherapy

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Abstract

Introduction

Triple-negative breast cancer (TNBC) patients without pathological complete response (pCR) to neoadjuvant chemotherapy have an unfavourable prognosis. TNBC harbouring BRCA-1 germline mutations may be less responsive to taxanes, while sensitivity to DNA-damaging agents is retained. A similar effect was seen in tumours with epigenetic BRCA-1 silencing. Patients without pCR to neoadjuvant chemotherapy consisting of epirubicin plus docetaxel routinely received post-operative CMF at our centre. Here, we investigated the effect of adjuvant CMF in patients with or without BRCA-1 methylation or TP53 mutation.

Methods

DNA was extracted from formalin-fixed paraffin-embedded tissue. For determining BRCA-1 methylation status, quantitative methylation-specific PCR was performed. For the investigation of TP53 mutation status, DNA was PCR amplified and sequenced by Sanger sequencing.

Results

Twenty-four patients were included; BRCA-1 methylation was present in 41.7 %, while TP53 mutations were observed in 66.7 %. At a median follow-up of 27.5 months, 20 % of patients with BRCA-1 methylation had a disease-free survival (DFS) event, as compared to 64.3 % in the non-methylated group (p = 0.0472). Median DFS in the non-methylated group was 16 months and was not reached in the methylated group (n.s.). No association TP53 mutation status with clinical outcome was observed.

Conclusions

Adjuvant CMF is of limited activity in TNBC refractory to taxane-based neoadjuvant chemotherapy. In this population, BRCA-1 methylation was associated with a significant decrease in DFS events suggesting a better prognosis and potentially retained activity of DNA-damaging agents.

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Acknowledgments

This work was supported by the medical research budget of the Medical University of Vienna.

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Authors and Affiliations

  1. Department of Medicine 1, Academic Teaching Hospital Elisabethinen Linz, Linz, Austria

    Mathilde Foedermayr, Miriam Sebesta, Ansgar Weltermann & Otto Zach

  2. Comprehensive Cancer Centre Vienna, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Margaretha Rudas, Anna S. Berghoff, Regina Promberger, Matthias Preusser, Peter Dubsky, Florian Fitzal, Michael Gnant, Guenther G. Steger, Christoph C. Zielinski & Rupert Bartsch

  3. Department of Pathology, Medical University of Vienna, Vienna, Austria

    Margaretha Rudas

  4. Institute for Neurology, Medical University of Vienna, Vienna, Austria

    Anna S. Berghoff

  5. Clinical Division of Oncology, Department of Medicine 1, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Matthias Preusser, Guenther G. Steger, Christoph C. Zielinski & Rupert Bartsch

  6. Department of Surgery, Medical University of Vienna, Vienna, Austria

    Regina Promberger, Peter Dubsky, Florian Fitzal & Michael Gnant

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  1. Mathilde Foedermayr
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Corresponding author

Correspondence to Rupert Bartsch.

Additional information

Mathilde Foedermayr and Rupert Bartsch contributed equally to this study.

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Foedermayr, M., Sebesta, M., Rudas, M. et al. BRCA-1 methylation and TP53 mutation in triple-negative breast cancer patients without pathological complete response to taxane-based neoadjuvant chemotherapy. Cancer Chemother Pharmacol 73, 771–778 (2014). https://doi.org/10.1007/s00280-014-2404-1

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  • DOI: https://doi.org/10.1007/s00280-014-2404-1

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