Commentary (Masciari/Garber): Evaluation and Management of Women With BRCA1/2 Mutations

OncologyONCOLOGY Vol 19 No 11
Volume 19
Issue 11

The review by Beth Peshkin andClaudine Isaacs in this issue ofONCOLOGY is an excellentoverview of the recognition, evaluation,and clinical management ofwomen with BRCA1 and BRCA2mutations. It is comprehensive andpractical, and emphasizes the approachthat a risk assessment and clinicalgenetics program might take tothe evaluation of an individual concernedabout the possibility thathereditary breast/ovarian cancer predispositionmight be present in herkindred. The authors clearly and conciselypresent the risks of breast, ovarian,and other cancers associated withBRCA1 and BRCA2 mutation carrierstatus, as well as some of the issues thathave arisen in the estimation of thoserisks. They provide a review of factorsthat may modify gene penetrance(cancer risks), and devote the finalsegment of their article to a clear andrational discussion of the surveillanceand preventive options available forthe management of the associatedbreast and ovarian cancer risks.

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.[1] 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.[2] 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.[3] 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.[4] Chemotherapy was associated with a 60% reduction in risk of contralateral breast cancer, as was oophorectomy in premenopausal patients.[4] 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.[5] 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.[6] 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.[10] 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.[11] 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.


The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


1. Metcalfe, K, Lynch, HT, Ghadirian, P, et al: Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 22:2328-2335, 2004.
2. Schwartz MD, Lerman C, Brogan B, et al: Impact of BRCA1/BRCA2 counseling and testing on newly diagnosed breast cancer patients. J Clin Oncol 22:1823-1829, 2004.
3. Schrag D, Kuntz KM, Garber JE, et al: Benefit of prophylactic mastectomy for women with BRCA1 or BRCA2 mutations. JAMA 283:3070-3072, 2000.
4. Narod SA, Brunet JS, Ghadirian P, et al: Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Hereditary Breast Cancer Clinical Study Group. Lancet 356:1876-1881, 2000.
5. Foulkes WD, Metcalfe K, Sun P, et al: Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: The influence of age, grade, and histological type. Clin Cancer Res 10:2029-2034, 2004.
6. Metcalfe KA, Lynch HT, Ghadirian P, et al: The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers. Gynecol Oncol 96:222-226, 2005.
7. Foulkes WD, Stefansson IM, Chappuis PO, et al: Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95:1482-1485, 2003.
8. van der Groep P, Bouter A, van der Zanden R, et al: Re: Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 96:712-713, 2004.
9. Lakhani SR, Jacquemier J, Sloane JP, et al: Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90:1138-1145, 1998.
10. Robson ME, Chappuis PO, Satagopan J, et al: A combined analysis of outcome following breast cancer: Differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res 6:R8-R17, 2004.
11. Farmer H, McCabe N, Lord CJ, et al: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917-921, 2005.

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