Evaluation and Management of Women With BRCA1/2 Mutations
Evaluation and Management of Women With BRCA1/2 Mutations
The review by Beth Peshkin and
Claudine Isaacs in this issue of
ONCOLOGY is an excellent
overview of the recognition, evaluation,
and clinical management of
women with BRCA1 and BRCA2
mutations. It is comprehensive and
practical, and emphasizes the approach
that a risk assessment and clinical
genetics program might take to
the evaluation of an individual concerned
about the possibility that
hereditary breast/ovarian cancer predisposition
might be present in her
kindred. The authors clearly and concisely
present the risks of breast, ovarian,
and other cancers associated with
BRCA1 and BRCA2 mutation carrier
status, as well as some of the issues that
have arisen in the estimation of those
risks. They provide a review of factors
that may modify gene penetrance
(cancer risks), and devote the final
segment of their article to a clear and
rational discussion of the surveillance
and preventive options available for
the management of the associated
breast and ovarian cancer risks.
Managing Mutation Carriers With
a New Breast Cancer Diagnosis
Since it would be difficult to improve upon this manuscript, we will use this opportunity to consider the implications of the data summarized by Peshkin and Isaacs for the use of genetic information in the management of women with a breast cancer diagnosis. The authors note the 3% per year risk of second breast cancer and the significant risk of ovarian cancer in surviving carriers. They were part of a team that conducted a prospective study of women offered genetic testing at breast cancer diagnosis, and found that women who tested positive for a BRCA1/2 mutation were more likely to elect bilateral mastectomy at diagnosis than women testing negative or who declined testing. Our group previously developed a model, which showed that prophylactic contralateral mastectomy could improve survival in mutation carriers with a good prognosis from their initial breast cancer. Still, young women who are aware of their mutation status may prefer breast-conserving therapy, and can reduce their risk of a second breast cancer by exploiting the remarkable effect of hormonal modulation on the development of BRCA1- and BRCA2-associated breast cancers. In a case-control study, Narod et al showed that BRCA1/2 mutation carriers taking tamoxifen after primary breast cancer reduced their risk of contralateral breast cancer by 50% irrespective of the estrogen-receptor (ER) status of the primary tumor. Chemotherapy was associated with a 60% reduction in risk of contralateral breast cancer, as was oophorectomy in premenopausal patients. These observations have been confirmed, despite the fact that more than 80% of BRCA1-associated breast cancers are ER-negative (as well as PR-negative and HER2-negative), raising obvious questions about mechanism. A recent report showed a trend of increasing frequency of ER positivity with advancing age in BRCA1 carriers, as with noncarriers, but different from BRCA2 carriers, whose tumors are much more often ER-positive in general. Premenopausal women with mutations and ER-positive tumors can still participate in the Tamoxifen and Exemestane Trial (TEXT), in which they would undergo salpingo-oophorectomy plus adjuvant tamoxifen or exemestane (Aromasin) after chemotherapy. The gynecologic surgery is important for women who have completed childbearing and have at least a reasonable prognosis from their breast cancer because of the high risk of lethal second ovarian cancer in carriers. BRCA1-Associated Breast Tumors
Of course, women must survive their index breast cancer to really be concerned about second primary tumors. BRCA2-associated breast tumors and their prognoses appear similar to sporadic breast cancers. However, Foulkes et al can be credited with the observation that BRCA1- related breast tumors have a characteristic phenotype. They are usually high-grade ductal carcinoma (10% are medullary) and very frequently (90%) negative for ER, PR, and HER2, positive for cytokeratins 5, 6, and 14 (associated with the basal-like group), and overexpress cyclin E, p53, and epidermal growth factor receptor (EGFR).[7-9] Several pieces of evidence demonstrate that women with BRCA1 breast cancer have a worse outcome than women with sporadic tumors. Many groups are working to exploit unique features of BRCA1 tumors (including defects in DNA repair associated with the genetic defect itself) using rational therapies that might prove more effective than standard chemotherapeutic strategies. The special case of breast cancer patients with BRCA1/2 mutations serves to highlight the ways in which our increasing understanding of the hereditary breast/ovarian cancer syndrome presents opportunities to improve treatment and prevention options, and potentially survival, for these very high-risk individuals.
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