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A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer
  1. P O Chappuis1,*,
  2. J Goffin2,
  3. N Wong3,
  4. C Perret4,
  5. P Ghadirian4,
  6. P N Tonin5,
  7. W D Foulkes5
  1. 1Division of Medical Genetics, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
  2. 2Department of Oncology, McGill University, Montreal, Quebec, Canada
  3. 3Cancer Prevention Research Unit and Department of Medicine, Sir M B Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada
  4. 4Epidemiology Research Unit, Research Centre, CHUM-Hôtel-Dieu, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
  5. 5Program in Cancer Genetics, Departments of Oncology and Human Genetics, Research Institute of the McGill University Health Centre and Department of Medicine, McGill University, Montreal, Quebec, Canada
  1. Correspondence to:
 Dr W D Foulkes, Montreal General Hospital/Room L10-120, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada;

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Neoadjuvant (preoperative) chemotherapy was initially developed as a first line treatment for locally advanced breast cancer. More recently, it has been used to treat earlier stage operable disease, with the hope that not only could the treatment be used as an in vivo assessment of tumour response, but also that it might more readily eradicate occult distant micrometastases. Many studies have shown a small but significant increase in breast conservation when neoadjuvant chemotherapy was used but, overall, most randomised studies have not shown any survival advantage following this treatment.1,2 Despite this, it has been noted that women receiving neoadjuvant chemotherapy who experience either a clinical complete response (cCR) (≤40% of all those treated) or, more clearly, a pathological complete response (pCR) (≤10%) have a better long term outcome than women who achieve less than a complete response.1,2

Germline mutations in the BRCA1 and BRCA2 genes are the major genetic predisposition to breast cancer. Some of the functions of BRCA1 and BRCA2 proteins could be directly involved in response to cytotoxic agents, such as the role of BRCA1/2 in DNA repair3 or apoptosis.4,5 Distinct pathological features6 and gene expression profiles7 suggest that there are differences in hereditary breast cancer compared to sporadic cases, which might lead to differences in treatment response. In vitro data suggest that cells without functional BRCA1 or BRCA2 protein are particularly sensitive to several chemotherapeutic drugs4 or ionising radiation.8 Mouse and human cell lines deficient in BRCA1 or BRCA2 display an increased sensitivity to agents causing double strand DNA breaks.9,10 This hypersensitivity has been shown for mitoxantrone, amsacrine, etoposide, doxorubicin, and cisplatin with a subsequent increased level of apoptosis.9,11–13 Differences in drug sensitivity might be explained by interaction of BRCA1/2 proteins …

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  • * Present address: Divisions of Oncology and Medical Genetics, University Hospital, Geneva, Switzerland.