Familial Ovarian Cancer: A Case Study
By Karen Eanet, MS, CGC

Ann was referred for genetic counseling because she was considering prophylactic oophorectomy due to a family history of ovarian cancer. She is 38 years old and has one daughter, age 2. Her mother was diagnosed with ovarian cancer at age 48 and died from the disease at 52. Her maternal grandmother died from ovarian cancer in her early 50s. She is of Ashkenazi Jewish descent.

While most ovarian cancer cases are sporadic, about 5-10% are thought to be inherited. Families like Ann's with site-specific ovarian cancer have an increased risk of carrying mutations in BRCA1 and BRCA2. One study found that 5% of women with ovarian cancer diagnosed before age 70, regardless of family history, had mutations in BRCA1.1 In families with 2 or more cases of ovarian cancer, regardless of the presence of breast cancer, 37% of families had a mutation in BRCA1 and 9% had a mutation in BRCA2.2 Up to 10% of all ovarian cancer patients may be BRCA1/2 mutation carriers. A significant proportion of families, however, have no detectable mutation in either gene, suggesting the presence of additional, as yet unidentified, heritable mutations linked to ovarian cancer.

In general, a woman with 1 first-degree relative (mother, sister) with ovarian cancer, has a 3-4 fold increased risk to develop the condition herself.3 With multiple affected family members, her risk is further increased. Ashkenazi Jewish women with an affected first-degree relative have up to a 10% risk for developing ovarian cancer, and the chance that a detectable mutation may be found in their families is between 10-30%.4

In Ann's family, there appears to be a dominant inheritance pattern of ovarian cancer, and her own risk to develop ovarian cancer is related to the chance that there is a mutation in her family. Her family fits most closely into the classification of a site-specific ovarian cancer, and, therefore, BRCA1/2 testing was discussed. According to the BRCAPRO risk assessment model, her risk of carrying a mutation is approximately 24%. While the risks, benefits, and limitations of genetic testing for BRCA1/2 mutations are similar for both breast and ovarian cancer, there are some distinct issues.

In Ashkenazi Jewish individuals, there are three common mutations (two in BRCA1 and one in BRCA2) associated with hereditary breast and ovarian cancer. These mutations are thought to occur in about 2% of the Ashkenazi Jewish population.5 While it is generally preferable to start gene testing in an affected individual, in Ashkenazi Jewish families it may be appropriate to test someone without cancer for these specific mutations because of their increased frequency. If Ann is tested and no mutation found, her risk of having a mutation could be reduced by 90%.

An issue for Ann in her decision over prophylactic oophorectomy is her desire for additional children. Gene testing may provide additional information about her risk for ovarian cancer that may help her decide. A mutation-positive result would be the most informative. Should a mutation be found, Ann may not want to delay having another child, or she may decide to have the surgery and forgo having more children. A mutation-negative result would reduce her risk for a known mutation but does not eliminate the chance that there is still an inherited form of ovarian cancer in her family.

Options for women at increased risk for ovarian cancer include increased surveillance and prophylactic surgery. Screening methods include clinical examination, transvaginal ultrasound with color Doppler, and tumor markers (CA125). However, none of these is completely reliable. Other options include long-term use of oral contraceptives and prophylactic oophrectomy, although the efficacy of the latter procedure is still unclear. In addition, very little data exist on outcomes of prophylactic surgery in mutation carriers. As BRCA1/2 mutation carriers are also at increased risk for breast cancer, clinical breast exams, mammography, chemoprevention, and prophylactic mastectomy should also be considered.

Genetic counseling for women concerned about ovarian cancer is a complex process that requires a detailed medical history, careful analysis of family history, and confirmation of diagnoses in affected relatives. In addition, risk assessment and genetic testing options must be discussed sensitively. Because ovarian cancer is often fatal and screening and prevention options are limited, it is important to provide anticipatory guidance for women considering genetic testing. There is still much to learn about the genetic factors influencing the development of ovarian cancer and, unfortunately, many of our patients' questions remain unanswered.

References:
1. Stratton J et al. (1997). Contribution of BRCA1 mutations to ovarian cancer. New Eng J of Med, 336(16): 1125-1130.
2. Gayther SA et al. (1996). High frequency of germline BRCA1 and BRCA2 mutations in familial ovarian cancer. Am J Hum Genet, 59: 173.
3. Stratton J et al. (1998) A systematic review and meta-analysis of family history and risk of ovarian cancer. Brit J of Obstet Gynecol, 105(5): 493-9.
4. Steinberg K et al. (1998) Increased risk for familial ovarian cancer among Jewish women: A population-based case-control study. Genet Epi, 15:51-59.
5. Tonin P et al. (1996) Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med, 2(11): 1179-1183.
Vogelstein, B & Kinzler, K (Eds) (1998). The Genetic Basis of Human Cancer. New York, NY: McGraw-Hill.
Offit, K (1998) Clinical Cancer Genetics: Risk Counseling and Management. New York, NY: Wiley-Liss, Inc.