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© 1999 American Society for Clinical Oncology
Breast Cancer in Carriers of BRCA1 and BRCA2 Mutations: Tackling a Molecular and Clinical ConundrumMassachusetts General Hospital Cancer Center, Boston, MA THE IDENTIFICATION OF BRCA1 and BRCA21,2 marked the first time that highly penetrant cancer predisposition genes were linked to the development of a common cancer, raising the possibility that many women might be carriers of a deleterious germline mutation and hence at increased risk for developing breast and ovarian cancer. As a result, studies of the two BRCA genes have been at the forefront of efforts aimed at integrating molecular genetics and clinical oncology. Epidemiologic studies have focused on the frequency of genetic variations within the population and their associated risk for developing breast and ovarian cancer. At the same time in the clinic, new cancer genetics programs have evolved to provide complex and often highly charged genetic information, while preserving genetic privacy and facing uncertainty about clinical recommendations for mutation carriers. The study of the BRCA genes raises the possibility that diagnostic screening recommendations and even therapeutic options may eventually be based on germline genotype. As an initial step in this direction, a number of reports have examined whether breast cancers arising in carriers of BRCA1 or BRCA2 mutations are characterized by distinct molecular markers and have a different prognosis from the more common sporadic forms. This issue of the Journal of Clinical Oncology contains two articles addressing the potential prognostic significance of BRCA1 and BRCA2 mutations in breast cancer. Verhoog et al3 compared disease-free and overall survival between 28 patients with breast cancer arising in members of known BRCA2-linked pedigrees and controls matched for age and year of diagnosis. No statistically significant differences were observed. Phillips et al4 undertook an extensive and critical review of the literature addressing prognostic markers and clinical outcome in breast cancers in known carriers of BRCA1 or BRCA2 mutations. They point out important problems in the design and interpretation of such studies, including small sample size and ascertainment bias. Breast cancers arising in carriers of BRCA1 mutations tend to have some favorable and unfavorable molecular markers, although the most consistent findings are the high frequency of tumors that are negative for estrogen and progesterone receptors and a moderately increased frequency of tumors with p53 gene mutations. BRCA2-associated tumors do not show consistent histologic features. No reliable conclusions can be made about prognosis for BRCA1- or BRCA2-associated tumors, compared with sporadic breast cancers. Although the analysis does not extend to ovarian cancer arising in carriers of these mutations, many of the same design problems are likely to exist. Clearly, a definitive comparison of prognosis between sporadic and BRCA-associated cancers will have to await large, population-based analyses. So what have we learned to date about the role of the BRCA genes in the development of breast cancer and how might this eventually be translated into clinical recommendations for known mutation carriers? Germline mutations in BRCA1 and BRCA2 account for a small fraction of breast cancer cases. Based on epidemiologic predictions, some form of genetic predisposition is commonly cited for 5% to 10% of all cases of breast cancer, but direct mutational analyses have demonstrated BRCA gene mutations in far smaller numbers. As predicted, the proportion of cases with a clear genetic predisposition depends upon the age of onset of breast cancer. About 7% to 10% of women with early-onset breast cancer (younger than age 40) have mutations in either BRCA1 or BRCA2,5-7 a fraction that declines rapidly with advancing age, as the incidence of sporadic breast cancer increases. Among women with breast cancer at any age presenting to a high-risk oncology clinic with a strong family history of breast cancer, about 16% harbor a germline mutation in BRCA1, a frequency that is increased to 30% to 40% in the subset of women who have both familial breast and ovarian cancer or who belong to a population in which founder mutations may be prevalent, such as Ashkenazi Jews.8 In striking contrast to other tumor suppressor genes, BRCA1 and BRCA2 mutations seem to be restricted to breast cancers arising in individuals who have inherited one mutant germline allele, and they are not observed in sporadic breast cancer. This has led to the suggestion that BRCA-associated breast cancers may be fundamentally different in their molecular origin from the more common sporadic forms. This difference might also reflect a critical requirement for the timing of BRCA gene inactivation within stem cells of the developing breast. For instance, women who have inherited one mutant BRCA allele may be more likely to harbor breast stem cells in which the remaining allele has been lost before the estrogen-driven cellular proliferation that accompanies puberty. Recent mouse models have shown that specific inactivation of BRCA1 in mammary tissue leads to the development of mammary tumors9 and may shed light on the potential interactions between BRCA1 inactivation and estrogen-induced cell proliferation.10 What do we know about the functional properties of the proteins encoded by BRCA1 and BRCA2? Current studies have linked these two gene products to a common pathway involved in the maintenance of chromosomal integrity, possibly resulting from direct participation in the repair of DNA breaks, as well as in the regulation of gene expression.11-16 Mice completely lacking either BRCA1 or BRCA2 in all their cells fail to develop past an early embryonic stage, and cells from mice with a partial loss of gene function show evidence of chromosomal instability.17-20 Cells that lack either BRCA1 or BRCA2 gene function seem to be more sensitive than normal cells to ionizing radiation, and even in the absence of DNA damage, they exhibit a profound proliferation defect. Inactivation of p53 in these cells allows their renewed proliferation, a striking observation implying that loss of BRCA gene function itself activates a p53-dependent cellular response.21,22 This has led to the suggestion that mutation of p53 may be required before inactivation of either BRCA1 or BRCA2 may lead to the development of breast cancer. Analyses of BRCA1-associated breast cancers have not shown p53 mutations in all cases but do suggest an increased frequency compared with sporadic cases.4 As noted, the significance of such molecular genotyping studies must be interpreted with caution because of the small number of tumors analyzed. In addition, it is increasingly evident that mutations in human cancer commonly target a functional pathway, not just a single gene within that pathway. For instance, the p53 pathway may be disrupted in tumors by a mutation within the p53 gene itself, as well as by overexpression of the MDM2 gene or deletion of the p14ARF gene, both of which result in increased degradation of p53 protein.23 Components of other pathways involved in monitoring DNA damage, including the so-called mitotic checkpoint, may also be disrupted in tumors with BRCA gene mutations, allowing cells to ignore the chromosomal instability that results from loss of BRCA gene function.24 More information about the precise function of BRCA1 and BRCA2, and about whether related pathways are disrupted in sporadic breast cancer, will be required before we can conclude that BRCA-associated tumors are truly distinct in their molecular derivation. How then to apply molecular insights about BRCA1 or BRCA2 genes to the clinic? Beyond the prognostic implications of BRCA-associated breast cancer are questions about whether it should be treated differently from sporadic breast cancer. Are breast cancers that lack BRCA gene function more sensitive to radio- or chemotherapeutic regimens than sporadic tumors, or are mutation carriers themselves at increased risk for delayed toxicity from DNA-damaging agents? Should the surgical treatment of known carriers with either breast cancer or ductal carcinoma-in-situ be altered to reflect the possible risk for developing an ipsilateral second tumor? At present, there is no evidence to indicate that treatment of breast cancer in a known carrier of a BRCA gene mutation should differ from that of a sporadic tumor of comparable stage and grade. The primary clinical implication of BRCA1 or BRCA2 mutations in women who have breast cancer remains their risk for developing a second contralateral breast tumor (estimated at approximately 30%25) or ovarian cancer, as well as the risk for their unaffected family members. Approaches to the prevention of breast cancer in a healthy BRCA1 and BRCA2 mutation carrier depend upon the penetrance of these mutations, ie, how likely is a carrier of a BRCA gene mutation to develop breast cancer and at what age? Early studies based on cancer pedigrees suggested an 80% to 90% lifetime risk of breast cancer, but these studies are subject to selection bias because these kindreds were specifically identified by the presence of many affected members within a large family.26 More recent population-based studies have used recurrent founder mutations in the Ashkenazi Jewish population, which facilitate mutation detection, to calculate a predicted lifetime risk of developing breast cancer in mutation carriers as 50% to 60%.27 Much of this discrepancy results from differences in ascertainment and in methods used to calculate breast cancer risk. However, they do raise the possibility that alleles of so-called "modifier" genes might be coinherited along with the mutant BRCA allele in some families, thereby enhancing or reducing the risk for developing either breast or ovarian cancer. At present, this remains a theoretical concept and there is no definite evidence that a woman who carries a BRCA gene mutation and has a family history of breast cancer is more at risk for developing breast cancer than a carrier identified within the general population who does not have such a strong family history. Of note, the great majority of mutations in BRCA1 lead to premature protein termination, and no differences in penetrance have been documented for different mutations. BRCA2 mutations also seem to be equivalent, with the possible exception of those resulting in truncation within the central domain of the protein, which may be associated with an increased relative risk for ovarian compared with breast cancer, and stop codons at the extreme C-terminus which seem not be clinically significant. Given an elevated risk for developing breast cancer, what are we then to recommend to carriers of BRCA1 or BRCA2 mutations? Sadly, we know little more now than we did a few years ago, when the prevalence of these mutations was first established, due in part to the small numbers of affected women, the long time for clinical end points in intervention studies, and the difficult and highly personal nature of the treatment decisions being considered.28 What is the optimal frequency for mammographic screening, do newer techniques, such as magnetic resonance imaging, offer an advantage, and when is it appropriate to consider prophylactic mastectomy? Mathematical models weighing risk and benefit as a function of age and estimated penetrance of these mutations suggest some benefit to surgical prophylaxis,29 as does retrospective analysis of familial breast cancer kindreds,30 but strong recommendations cannot be made and decisions are usually individualized. Prophylactic oophorectomy is often considered after child-bearing years and may reduce the risk of subsequent breast cancer as well as ovarian cancer, although these benefits may need to be balanced with the likelihood of increased osteoporosis and the risk of extraovarian peritoneal cancer arising from Müllerian remnants rather than from the ovary itself. The potential efficacy of antiestrogens, including tamoxifen and raloxifene, in suppressing or delaying the development of breast cancer in women at increased risk for breast cancer remains the most promising area of clinical investigation.31-34 However, the risk-benefit analysis derived from large cohorts of women with moderate risk factors for breast cancer may differ when applied to a subset with germline mutations in BRCA1 or BRCA2. The effectiveness of hormonal chemoprevention in carriers of a BRCA1 mutation, who seem to be at risk for primarily estrogen and progesterone receptor–negative breast cancer, remains to be determined, as does the timing and duration of such treatments, given the high lifetime risk of developing breast cancer.35 In summary, we are witnessing an evolving story, from both a clinical and laboratory perspective, that is likely to repeat itself as additional germline variations in the population are linked to susceptibility for other forms of cancer. Few topics in medicine are likely to be as scrutinized by the public, who are concerned both about the risk for common cancers and about the application of genetics, with its apparent power to predict the future and discriminate between individuals based on their genotype. Large-scale clinical trials designed to address key medical issues are the only way to define the optimal treatment for carriers of germline mutations in cancer predisposition genes and to design new diagnostic, preventive, and therapeutic measures in individuals at high risk for developing cancer. That will be the challenge. REFERENCES
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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