Acute Chemotherapy–Related Toxicity Is Not Increased in BRCA1 and BRCA2 Mutation Carriers Treated for Breast Cancer in the United Kingdom

Abstract

Purpose:To evaluate acute toxicity induced by chemotherapy for breast cancer in a retrospective study of 62 BRCA1/2 mutation carriers matched 1:1with women who had treatment for sporadic disease in the United Kingdom between 1983 and 2003. Experimental Design: All participants were interviewed by one of two researchers using standardized questionnaires, and their medical records were reviewed by one research nurse.The two main regimens received were cyclophosphamide, methotrexate, and fluorouracil and fluorouracil, epirubicin, and cyclophosphamide. The proportion of cases and controls receiving anthracyclinebased treatment was equivalent, but fewer BRCA1 cases received this treatment than did BRCA2 mutation carriers. Toxicity was documented using the Eastern Cooperative Oncology Group Common Toxicity Criteria for hematologic, infective, and gastrointestinal toxicities. No increase in toxicity was seen in BRCA1/2 mutation carriers. Results: The only significant difference was that neutropenia was less evident in BRCA2 mutation carriers than in either BRCA1 mutation carriers or controls. As a result, there was no requirement for dose reduction among BRCA2 mutation carriers, in contrast to 10 of 39 BRCA1 carriers and 16 of 62 controls (P = 0.02). Conclusions:This result has implications for therapy and indicates that women with mutations in BRCA1 and BRCA2 may be given the same doses of chemotherapy as noncarriers.BRCA1 and BRCA2 mutation carriers face a high risk of both breast and ovarian cancer due to mutations in these DNA double-strand break repair genes. Adjuvant breast cancer treatments of chemotherapy and radiotherapy rely on killing cells by mechanisms which include inducing DNA damage, affecting cell cycle checkpoints, or cell division, as reviewed by Kennedy et al. (1). The BRCA1 and BRCA2 genes have been shown to be integrally involved in these pathways, particularly in the repair of DNA double-strand breaks by homologous recombination. It is important to examine the effects of radiation and chemotherapeutic agents in BRCA1 and BRCA2 carriers as one would expect that they could have a greater incidence of normal tissue toxicity from both modalities compared with women with sporadic disease. The accompanying report evaluates the late effects of radiation in a case-control study of BRCA1/2 mutation carriers and sporadic controls in the United Kingdom (17). In conjunction with that study, the toxicity of chemotherapy was also examined to address the following questions: are BRCA1/2 mutation carriers more at risk of acute toxicity from chemotherapy? Do such individuals experience more severe decreases in blood counts and chemotherapy cycle delays, and would this result in a requirement for

The late radiotherapy normal tissue injury phenotypes of telangiectasia, fibrosis and atrophy in breast cancer patients have distinct genotype-dependent causes

“…Chemotherapy may increase late effects (Fiets et al, 2003;Shanley et al, 2006) especially anthracycline containing regimens but the number of patients that received anthracyline and non-anthracyline-based chemotherapy in this study is too small for any meaningful statistical analysis to compare the two chemotherapies (Table 1).…”

BRCA1 185delAG truncation protein, BRAt, amplifies caspase-mediated apoptosis in ovarian cells

“…While our data does demonstrate that BRAt protein increases cell death following STS treatment in both normal and ovarian cancer cells in our in vitro tissue culture model, we are unaware of any clinical reports that indicate a decreased tolerance or increase in overall side effect profiles for ovarian cancer patients with germline BRCA1 founder mutations as compared to those with sporadic disease. Rather, it has been reported that acute chemotherapy-related toxicity is not increased in BRCA1 mutation carriers (Shanley et al 2006). Thus, we speculate that in vivo, the presence of the BRCA1 185delAG truncation protein increases chemosensitivity in ovarian cancer cells; however, normal somatic cells are not adversely affected due to their non-proliferative nature.…”

Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers

“…In fact, contradictory results have been achieved about the response to DNA-damaging agents by dermal fibroblasts and lymphocytes derived from BRCA1 mutation carriers, which prevent a definitive assessment on whether the expression of only one allele affects cell behavior (30,31). Moreover, two in vivo studies ruled out an increased toxicity for BRCA1 mutation carriers following either chemotherapy or radiotherapy (32,33). Thus, whether a cellular "BRCA1 heterozygous phenotype" actually exists and whether it is recapitulated by the T47DpS-BR clone selectively under MMC challenge (but not under CDDP challenge or by the MCF7pS-BR2 clone under any stress condition) remains an open question.…”