Lynch syndrome (HNPCC), which includes multiple adenocarcinomas, involves a combination of colon cancer and endometrial or ovarian cancer and other malignancies of the gastrointestinal and genitourinary systems (71). The mutations that are associated with this syndrome are MSH2, MLH1, PMS1, and PMS2. The risk that a woman who is a member of one of these families will develop epithelial ovarian cancer depends on the frequency of this disease in first-and second-degree relatives, although these women appear to have at least three times the relative risk of the general population. A full pedigree analysis of such families should be performed by a geneticist to more accurately determine the risk.
Management of Women at High Risk for Ovarian Cancer
The management of a woman with a strong family history of epithelial ovarian cancer must be individualized and depends on her age, her reproductive plans, and the extent of risk.
In all of these syndromes, women at risk benefit from a thorough pedigree analysis. A geneticist should evaluate the family pedigree for at least three generations. Decisions about management are best made after careful study and, whenever possible, verification of the histologic diagnosis of the family members’ ovarian cancer.
The value of testing for BRCA1 and BRCA2 is established, and there are guidelines for testing (62,70,72). The importance of genetic counseling cannot be overemphasized because the decision is complex. The American Society of Clinical Oncology offered guidelines that emphasize careful evaluation by geneticists, careful maintenance of medical records, and an understanding in a genetic screening clinic of how to effectively counsel and manage these patients. Concerns remain over the use of the information, the impact on insurability, the interpretation of the results, and how the information will be used within a specific family (e.g., to counsel children).
Although there are some conﬂicting data, the behavior of breast cancers arising in women with germline mutations in BRCA1 or BRCA2 is comparable to the behavior of sporadic tumors (61,73). Women with breast cancer who carry these mutations are at a greatly increased risk of ovarian cancer and a second breast cancer: the lifetime risk of ovarian cancer is 54% for women who have a BRCA1 mutation and 23% for those with a BRCA2 mutation, and for the two groups together, there is an 82% lifetime risk of breast cancer (73).
Despite recommendation by the National Institutes of Health Consensus Conference on Ovarian Cancer, the value of screening with transvaginal ultrasonography, CA125 levels, or other procedures is not established in women at high risk (74). Bourne and coworkers showed that, using this approach, tumors can be detected approximately 10 times more often than in the general population, and they recommend screening in high-risk women, but other groups have not confirmed these findings, and bilateral salpingo-oophorectomy remains the most effective way to reduce risk (57,75).
Data derived from a multicenter consortium of genetic screening centers indicate that the use of the oral contraceptive pill is associated with a lower risk for development of ovarian cancer in women who have a mutation in either BRCA1 or BRCA2 (76). The risk reduction is significant: in women who take oral contraceptives for 5 or more years, the relative risk of ovarian cancer is 0.4, or a 60% reduction in the incidence of the disease.