There is conflicting evidence as to the residual familial risk among women who test negative for the BRCA1/BRCA2 mutation segregating in the family. Based on prospective evaluation of 353 women who tested negative for the BRCA1 mutation segregating in the family, five incident breast cancers occurred during more than 6,000 person-years of observation, for a lifetime risk of 6.8%. A report that the risk may be as high as fivefold in women who tested negative for the BRCA1 or BRCA2 mutation in the family  was followed by numerous letters to the editor suggesting that ascertainment biases account for much of this observed excess risk.[169,170,171,172,173,174] Three additional analyses have suggested an approximate 1.5-fold to 2-fold excess risk.[173,175,176] Several studies have involved retrospective analyses; all studies have been based on small observed numbers of cases and have been of uncertain statistical and clinical significance. No cases of ovarian cancer have been reported in these studies. Results from a prospective study of 375 women who tested negative for a known family mutation in BRCA1 or BRCA2 reported two invasive breast cancers, two in situ breast cancers, and no ovarian cancers diagnosed with a mean follow-up of 4.9 years. Four invasive breast cancers were expected, whereas two were observed. A second study of similar size but longer follow-up (395 women and 7,008 person-years of follow-up) also found no statistically significant overall increase in breast cancer risk among mutation-negative women (observed/expected [O/E] 0.82, 95% CI 0.39-1.51), although women who had at least one first-degree relative with breast cancer had a nonsignificant increased risk (O/E 1.33, 95% CI 0.41-2.91). On the basis of the currently available data, it appears that women testing negative for known familial BRCA1/BRCA2 mutations can adhere to general population screening guidelines unless they have sufficient additional risk factors, such as a personal history of atypical hyperplasia of the breast or family history of breast cancer, that are not accounted for by the familial mutation.
Breast and ovarian cancer risk in breast cancer families without detectable BRCA1/BRCA2 mutations
The majority of families with site-specific breast cancer test negative for BRCA1/BRCA2 and have no features consistent with Cowden syndrome or Li-Fraumeni syndrome. Three studies using population-based and clinic-based approaches have demonstrated no increased risk of ovarian cancer in such families. Although ovarian cancer risk was not increased, breast cancer risk remained elevated.[118,179,180]
Role of BRCA1 and BRCA2 in Sporadic Cancer
Given that germline mutations in BRCA1 or BRCA2 lead to a very high probability of developing breast and/or ovarian cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease. Although somatic mutations in BRCA1 and BRCA2 are not common in sporadic breast and ovarian cancer tumors,[181,182,183,184] there is increasing evidence that downregulation of BRCA1 protein expression may play a role in these tumor types. Compared with normal breast epithelium, many breast cancers have low levels of the BRCA1 mRNA, which may result from hypermethylation of the gene promoter.[185,186,187] Similar findings have not been reported for BRCA2 mutations, although the BRCA2 locus on chromosome 13q is the target of frequent loss of heterozygosity (LOH) in breast cancer.[188,189] Approximately 10% to 15% of sporadic breast cancers appear to have BRCA1 promoter hypermethylation, and even more have downregulation of BRCA1 by other mechanisms. Basal-type breast cancers (ER negative, progesterone receptor negative, human epidermal growth factor receptor 2 [HER2] negative, cytokeratin 5/6 positive), more commonly have BRCA1 dysregulation than other tumor types.[190,191,192] Loss of BRCA1 or BRCA2 protein expression is more common in ovarian cancer than in breast cancer, and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease.[194,195] Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.