Clinical Aspects of BRCA-Associated Breast and Ovarian Cancer

From a clinical perspective, it is important to determine whether or not BRCA-associated malignancies are distinct, either in appearance, biology or outcome. BRCA-associated breast cancers are usually infiltrating ductal carcinomas (NOS), with some series reporting a modest increase in medullary

These tumors are usually poorly-differentiated, although there may be subtle differences in appearance between BRCA1-and BRCA2-associated cancers. Difficulties in obtaining concordance among pathologists with respect to the components of histologic grade preclude using these differences to judge the probability of detecting a mutation in either BRCA1 or BRCA2.

Mucinous histologies and low-grade tumors are under-represented among BRCA-associated ovarian cancers. From a biologic standpoint, BRCA-associated breast cancers tend to be aneuploid with high proliferative rates (by mitotis counts, flow cytometry or Ki-67 staining). The proportion of BRCA1-associated breast tumors that are hormone-receptor negative appears to be greater than expected, even accounting for the young age at onset of these cancers.

The distribution of hormone-receptor status in BRCA2-associated cancers is less clearly defined, but may be more similar to that of nonhereditary cases of comparable age. Although few data are available regarding other biologic parameters, P53 overexpression (and somatic mutation) appears to be common in BRCA-associated breast and ovarian cancer. Interestingly, HER2/neu overexpression appears to be quite uncommon in BRCA-associated breast cancers.

The prognosis of BRCA-associated cancers is a matter of some controversy (reviewed in ref. 21). Most published series have failed to demonstrate inferior survival for breast cancer patients with germline BRCA1 mutations when compared to population controls or women without mutations from the same ascertainment (e.g., early-onset breast cancer). Two series, however, one from Canada and one from France, have suggested that the presence of a BRCA1 mutation may be an adverse prognostic factor for survival.

Most of the published series suffer from a systematic survival bias in that only living women were tested. This bias could obscure an adverse effect of BRCA mutations on survival. In addition, other prognostic features (e.g., nodal status, hormone-receptor status, age) are not routinely taken into account in any of these series.

It is important to note that few data are available specifically regarding the impact of BRCA2 mutations on outcome, and the impact of the two genes may not necessarily be the same. To date, then, there is no conclusive evidence that women with BRCA-associated breast cancer have an inferior outcome when compared to women without mutations with a similar distribution of traditional prognostic factors. The matter requires further study, however, preferably in large groups of unselected, incident cases. As regards ovarian cancer, an early report suggested that women with BRCA-associated ovarian cancer had a superior survival when compared to controls.