OVARIAN CANCER

Genetic Epidemiology

Approximately 15% to 20% of all women with invasive ovarian cancer carry a BRCA1 or BRCA2 mutation, and several national groups suggest offering genetic testing to all woman diagnosed with invasive epithelial ovarian cancer (with the exception of mucinous cancers). In the event of a positive genetic test, testing is extended to unaffected female relatives. However, if there is no living affected relative, then testing may begin with an unaffected woman.

The frequency of BRCA mutations among ovarian cancer patients is not the same for all ethnic groups. In some populations, there are recurrent (founder) mutations. In these populations, the overall frequency of BRCA mutations tends to be high and one, or a small number, of specific mutations, will account for a large proportion of mutations. For example, approximately 30% to 40% of Jewish women with ovarian cancer carry one of the three founder mutations (two in BRCA1 and one in BRCA2). The frequency of BRCA mutations has been estimated at 1 in 12 cases of ovarian cancer in French-Canadians and 1 in 6 cases in Pakistan. In these populations, it may be possible to offer testing for a limited number of mutations. The excess risk of ovarian cancer in Jewish families with multiple cases of breast or ovarian cancer appears to be almost entirely due to the three Jewish founder mutations. Among women with a BRCA mutation, the ovarian cancer incidence is much greater than expected. If a founder mutation is not identified through screening of a Jewish family, a different (nonfounder) mutation will be found in approximately 2% to 4%.

In the ethnically mixed populations of North America, approximately 15% to 20% of all patients with invasive ovarian cancer carry a mutation in BRCA1 or BRCA2. However, the range of mutations is wide, and genetic testing must be comprehensive (full genomic screening with rearrangement testing). Among BRCA1 carriers, the risk of ovarian cancer is significant in women above the age of 35 (approximately 1% per year) and preventive measures must be initiated early. Women who carry a pathogenic mutation in the BRCA1 gene have a lifetime risk of approximately 40% for developing invasive ovarian cancer. Among BRCA2 carriers, the risk is lower and is less likely to occur below age 50. A meta-analysis estimated the risk of ovarian cancer to be 16%. Also, among BRCA2 carriers, the risk of ovarian cancer may vary with the position of the mutation. Other genes that have been implicated in breast cancer risk may increase the risk of ovarian cancer; these include CHEK2, PALB2, BARD1, BRIP1, RAD50, RAD51C, NBN, and MRE11. Though germline mutations in these genes can be identified in up to 5% of women with ovarian cancer, the actual increase in ovarian cancer risk associated with these genes is unknown at present. These preliminary research findings have led some experts to suggest multigene panel testing in women who do not have mutations in BRCA1 or BRCA2.

Pathology and Surgical Presentation of Hereditary Ovarian Cancer

Ovarian cancers that occur in women with a BRCA mutation appear to be similar to their sporadic counterparts with the exception that mucinous tumors and tumors of low malignant potential (or “borderline” tumors) are rarely observed in women with a BRCA mutation. The great majority of BRCA-linked ovarian cancers show moderate to poor differentiation. In most of the studies to date, the proportion of endometrioid and clear cell carcinomas associated with BRCA mutations may be overrepresented due to inaccurate historical diagnoses. Most hereditary ovarian tumors present at an advanced surgical stage, but stage I or stage II tumors are now being discovered in the context of high-risk screening programs, or as an incidental finding associated with a risk-reducing salpingo-oophorectomy (RRSO) in an asymptomatic woman. Several studies have reported on the presence of early ovarian cancers among pathology specimens obtained at the time of risk-reducing surgery. The frequency of occult malignancy ranges between 2% and 10%. Some of these early tumors are identified in the distal fallopian tube, supporting the hypothesis that this may be a site of origin for most ovarian/fallopian tube cancers in high-risk women. It is necessary that the fallopian tube be completely removed and serially sectioned when a RRSO is performed.

Clinical Outcome and Treatment Effects

A number of studies have reported that the survival of patients with BRCA-associated ovarian cancer is improved, compared to women with sporadic ovarian cancer. A study of consecutive cases of ovarian cancers that compared BRCA-associated cancer to sporadic ovarian cancers from the same institution found that BRCA mutation status was a favorable and independent predictor of survival for women with advanced disease. It is clear that improved survival rate is most likely the result of a better response of BRCA-associated tumors to current DNA damaging therapies and less likely a factor of improved surgical outcomes as a result of different patterns of tumor invasion.

Risk-Reducing Bilateral Salpingo-Oophorectomy

In 1995, a consensus panel of the NIH recommended RRSO for high-risk women at age 35 years, or after childbearing is complete. It seems logical that this procedure should eliminate the incidence of ovarian cancer, but there are two reasons for the potential failure of RRSO. First, it is possible that the removed ovaries or fallopian tubes contain foci of occult carcinoma and that the cancer had spread locally to the peritoneum at the time of the resection. Secondly, it is possible that de novo cancer arises in the peritoneum after salpingo-oophorectomy. The peritoneum is derived from coelomic epithelium, of the same embryologic origin as the surface epithelium of the ovary. Despite the recent understanding that high-grade serous ovarian cancer likely originates in the distal fallopian tube, it is becoming increasingly difficult to justify a de novo origin for high-grade serous carcinoma in the peritoneum.

It is difficult to measure the risk of peritoneal cancer in women with intact ovaries. Peritoneal, fallopian, and serous ovarian cancers are histologically indistinguishable, and symptomatic women often present with multiple foci of cancer involving the peritoneum, tubes, omentum, and ovary. Tubal cancer is also difficult to discriminate from ovarian cancer and may be classified as ovarian cancer. New serous cancers that arise in the abdominal peritoneum, following a salpingo-oophorectomy, are considered primary peritoneal cancers, even though they may have a biologic relationship to the distal fallopian tube.

Piver et al. reported that 6 of 324 women who underwent RRSO experienced primary peritoneal cancer. The mutation status of these women was unknown, and there was no standard period of follow-up. Kauff et al. followed 170 BRCA carriers for an average of 2 years. They observed 1 peritoneal cancer among 98 women who chose RRSO, versus 5 ovarian/peritoneal cancers in 72 women with intact ovaries. In a historical cohort study of 551 BRCA1 and BRCA2 carriers, Rebbeck et al. reported that the incidence of ovarian or peritoneal cancer was diminished by 96% (95% confidence interval [CI]: 84% to 99%) in women who underwent risk-reducing oophorectomy, compared to those with intact ovaries.

Finch et al. followed 1,045 women with a mutation who underwent a bilateral RRSO and compared the cancer risk with that in 783 women who did not undergo the procedure. The overall reduction in cancer risk associated with bilateral salpingo-oophorectomy was 80% (hazard ratio = 0.20; 95% CI: 0.07 to 0.58; p = 0.003). The estimated cumulative incidence of peritoneal cancer was 4.3% at 20 years after salpingo-oophorectomy.

An additional benefit of risk-reducing oophorectomy is a marked reduction in the risk of breast cancer. Oophorectomy performed at a relatively early age (<40) is associated with a greater degree of protection than is surgery performed near the age of menopause, and the protective effect is evident for 15 years post-oophorectomy. Eisen et al. found that oophorectomy was associated with a significant reduction in breast cancer risk: 56% for BRCA1 carriers and of 46% for BRCA2

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