Clinical Considerations in the Management of Individuals at Risk for Hereditary Breast and Ovarian Cancer

Mark E. Robson, MD


Cancer Control. 2002;9(6) 

In This Article

Clinical aspects of BRCA-Associated Breast and Ovarian Cancer

The most striking clinical feature of BRCA-associated breast cancer is its propensity to strike younger women. In the BCLC dataset, the risk of breast cancer by age 50 was 49% for BRCA1 mutation carriers and 28% for BRCA2 mutation carriers.[8] Among unselected Ashkenazi female breast cancer patients with one of the specific BRCA founder mutations that are common in that population, 27 (79%) of 34 of patients with BRCA1-associated breast cancer were diagnosed before the age of 50, as were 10 (67%) of 15 of patients with BRCA2-associated disease.[29] A similar but less dramatic predilection for early-onset disease is noted in women with BRCA-associated ovarian cancer. In the BCLC families, the BRCA1-associated ovarian cancer risk was 23% to 29% by age 50 compared with 0.4% to 3.3% by the same age among women with a BRCA2 mutation.[8,36] In a population-based series of women with ovarian cancer, 24 (61%) of 39 affected BRCA1 mutation carriers were diagnosed before the age of 50, as were 5 (24%) of 21 women with BRCA2-associated disease.[37] Similarly, in a study of Ashkenazi women with ovarian cancer, 31 (54%) of 57 affected BRCA1 carriers and 3 (10%) of 29 affected BRCA2 carriers were diagnosed before age 50.[27]

BRCA-associated breast cancers are usually infiltrating ductal carcinomas, with some authors reporting an increased frequency of medullary and atypical medullary types. The tumors are often poorly differentiated, although there may be subtle differences between BRCA1 and BRCA2-associated disease in this regard. BRCA-associated cancers are often aneuploid, with high proliferative rates by flow cytometry or Ki-67 staining. BRCA1-associated cancers are usually, but not always, hormone receptor-negative, as opposed to BRCA2-associated tumors, which often express these receptors. HER-2/neu overexpression appears to be uncommon, particularly in BRCA1, but p53 mutations are common and may be directly relevant to the pathogenesis of BRCA-associated cancer.[38,39,40]

BRCA-associated ovarian cancers have not been as thoroughly studied as breast cancers. High-grade disease appears to predominate, and serous or endometrioid histologies are most common. Mucinous tumors are distinctly underrepresented, as are tumors of borderline malignant potential.[27,37] As for breast cancer, somatic p53 mutations are frequently observed.

The prognosis of BRCA-associated cancer has been a matter of some controversy. Despite the adverse histopathologic features associated with BRCA-associated breast cancer, most series have not shown that breast cancer patients with germline mutations have a worse survival than those who do not.[41,42,43,44,45] However, most of the published reports may have been subject to a systematic survival bias in that only living women were tested, which could have obscured a clinically relevant effect of mutation status on outcome. In support of this hypothesis are studies of unselected Ashkenazi women with breast cancer performed with an anonymized design that allowed linkage of clinical data to genotype without regard to survival. In these series, women with mutations experienced a worse survival than women without mutations.[28,46,47] A similar design has been applied to the study of Ashkenazi women with ovarian cancer. In contrast to breast cancer patients, women with BRCA-associated ovarian cancer had an improved survival compared to those without mutations.[48]

Based on the above data, there is no clear indication that systemic adjuvant therapy should be modified on the basis of germline BRCA status, although the threshold for treatment may be lowered for women with BRCA-associated breast disease. However, questions have arisen as to whether women with BRCA mutations should be offered breast-conserving therapy. One study has demonstrated an apparent increased risk of metachronous ipsilateral disease among mutation carriers surviving for a prolonged period after their initial breast cancer, apparently related to an increased risk of new primary lesions within the treated breast.[49,50] Studies with generally shorter follow-up, however, have not clearly identified a dramatically elevated risk when the influence of young age is taken into account.[28,51] The apparent contradiction may be resolved by a model wherein a breast lesion is as likely to be controlled by radiotherapy in women with BRCA mutations as in those without such mutations, but that the breast tissue of mutation carriers remains at risk for the development of new primary malignancies, which may not manifest until many years later. This hypothesis is consistent with the observation of a significant risk of metachronous contralateral breast cancer in women with mutations. This risk has been reported to be between 25% and 30% at 10 years after the first breast cancer, with some suggestion that the risk may decrease with increasing age at the initial diagnosis.[28,51,52] Whether scattered radiation from adjuvant radiotherapy increases contralateral breast cancer risk is currently unknown, but there has been no indication as yet of a substantial increase in contralateral risk among women receiving breast conserving treatment compared to those undergoing mastectomy of the affected breast. Thus, while women with germline BRCA mutations should not be precluded from undergoing breast-conserving therapy, those who would consider bilateral risk-reducing mastectomy should be made aware that their future reconstruction options may be affected by adjuvant radiotherapy.


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