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Women with gene mutation may respond to chemotherapy differently

BMJ 2001; 322 doi: (Published 07 April 2001) Cite this as: BMJ 2001;322:818
  1. Deborah Josefson
  1. San Francisco

    Women who harbour mutations in BRCA1, a gene implicated in some types of hereditary breast cancer, may respond differently to chemotherapy from those lacking such mutations, a new study has found.

    Researchers from Thomas Jefferson University Medical Center in Philadelphia, Pennsylvania, and the Burnham Institute in LaJolla, California, presented these findings recently at the annual meeting of the American Association for Cancer Research in New Orleans, Louisiana.

    The work highlights the heterogeneity of cancers and the emergence of pharmacogenomics, foretelling a time when chemotherapeutic regimens will be tailor made according to the individual genetic profiles of patients and their tumours. The BRCA1 gene is located on chromosome 17 and is believed to function normally as a tumour suppressor and transcriptional regulator (regulates the “reading” of DNA to RNA). As such, it is intimately involved in the cell cycle.

    Moreover, it encodes a protein involved in the cellular response to DNA damage. Mutations in BRCA1 increase the susceptibility to breast, ovarian, and prostate cancers. The frequency of BRCA1 mutations in the general population is 1 in 833, and in Jewish women of eastern European descent 1 in 107. Women with BRCA1 mutations face a 50-80% lifetime risk of developing breast cancer and tend to develop it at an earlier age than those without such mutations.

    Dr Bruce Turner and colleagues of Jefferson Medical College and John Reed, director of the Burnham Institute, found that human breast cancer cell lines with BRCA1 mutations demonstrated a twofold to fourfold increase in apoptosis (programmed cell death) after treatment with ionising radiation, cisplatinum, and doxyrubicin, compared with cell lines lacking BRCA1 mutations.

    Moreover, they found that the BRCA1 tumour cell lines were resistant to other agents, such as paclitaxel and docetaxel, treatments used commonly in ovarian cancer and in advanced stage breast cancers. The investigators additionally showed that these differences in drug sensitivity could be traced to the levels of another protein, Bcl2, which is implicated in apoptosis. Loss of Bcl2 results in higher levels of cell death after DNA damage. Dr Turner found that normal BRCA1 regulates the gene expression of Bcl2. Breast tumours expressing BRCA1 mutations lacked or had reduced levels of the Bcl2 protein and were resistant to chemotherapy with taxols, which induce cell death through a Bcl2 pathway. They remained susceptible to traditional chemotherapies which interact directly with DNA, independent of Bcl2.

    Commenting on the work, Dr Turner said: “The finding has important clinical applications. This suggests that women with BRCA1 mutations would not be good candidates for certain types of chemotherapy agents like Taxol [paclitaxel] and may suggest that they are better candidates for drugs such as Adriamycin [doxorubicin], cisplatin, and other newly discovered agents. It also explains the lack of response in cells that have been treated with taxanes.” In the future, genetic profiling of both the tumours and patients will likely occur that will be matched to the most appropriate or optimal therapy according to susceptibility and tolerance studies.

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