Late Toxicity Is Not Increased in BRCA1/BRCA2 Mutation Carriers Undergoing Breast Radiotherapy in the United Kingdom

Abstract

Purpose:To undertake the first substantial clinical study of breast radiotherapy toxicity in BRCA1 and BRCA2 mutation carriers in the United Kingdom. Experimental Design: Acute and late radiation effects were evaluated in a retrospective study of 55 BRCA1 and BRCA2 mutation carriers treated with radiotherapy for breast cancer at four centers between 1983 and 2002. Individual matching with controls who had sporadic breast cancer was undertaken for age at diagnosis, time since completion of radiation, and treatment variables. Detailed assessments were undertaken by one examiner. Median follow-up was 6.75 years for carriers and 7.75 years for controls. Rates of late events (rib fractures, lung fibrosis, necrosis of soft tissue/bone, and pericarditis) as well as LENT-SOMA scores and clinical photography scores of breast size, shape, and skin telangiectasia were the primary end points. Results: No increase in clinically significant late toxicity was seen in the mutation carriers. Conclusions:These data add substantial weight to the evidence that the outcomes in the treated breast from radiotherapy in women with BRCA1 or BRCA2 mutations are comparable with those in women with sporadic breast cancer.Because BRCA1 and BRCA2 were identified as high-risk breast-ovarian cancer susceptibility genes in the last decade, much effort has gone into addressing issues of how best to treat women who develop familial breast cancer. Given that these genes are integral to the DNA repair pathways, an important issue is whether ionizing radiation therapy induces excessive normal tissue reaction and/or the formation of second cancers in BRCA mutation carriers. Thus far, epidemiologic data suggests that there is no effect, but there are limitations in the data set which have made it difficult to exclude a difference. Early studies of radiotoxicity were limited by their use of a loosely defined family history as a surrogate for mutation status (1, 2). Similarly, reports on outcomes in known mutation carriers have had limitations. Gaffney et al. (3) evaluated acute (not chronic) radiotherapy reactions in 30 BRCA1 and 20 BRCA2 carriers, but did not have a control group. The most comprehensive and recent review of the issues of radiation effect is that of Pierce et al. (4), who assessed the reactions of 71 carriers and 213 matched controls. However, this was a multicenter analysis which was undertaken by chart review only, at nine different hospitals in North America. Data on acute and chronic toxicity were collected following conservative surgery and radiotherapy. No differences in toxicity were seen in the carriers versus controls with a median follow-up of 5.3 years for carriers and 4.6 years for controls.In the absence of data from prospective studies on outcomes, the current study was based on that of Pierce et al. (4), to be able to compare data sets, but was designed in more detail to minimize interobserver variation by having a single clinician perform all studies. Furthermore, in order to detect smaller differences than migh...

Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation

“…Germline BRCA1 mutation carriers indeed exhibit a higher recurrence rate of another primary tumor in the contralateral breast (Verhoog et al, 1998;Haffty et al, 2002) and ovary (Metcalfe et al, 2005); however, this is more likely due to the underlying genetic defect than the DNA damage by previous regimens. A recent report demonstrated that late toxicity is not increased in 37 Brca1 mutation carriers undergoing breast radiotherapy after a medium follow-up of 6.75 years (Shanley et al, 2006). Since the case number is small and radiation-induced cancers often have a long latency (Kirova et al, 2005), a large-scale epidemiological study should be done to clarify this issue.…”

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.…”

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

“…Case participants were women treated for breast cancer with chemotherapy and/or radiotherapy who were known to carry a mutation in the BRCA1 or BRCA2 genes. They were recruited from three genetics centers as part of the study detailed in the associated article, ''Late toxicity is not increased in BRCA1/2 mutation carriers undergoing breast radiotherapy in the United Kingdom (17).'' Of the 55 mutation carriers described in that article, 34 received chemotherapy and are included in this study.…”

“…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?…”