Ovarian cancer: Identifying and managing high-risk patients
Two cases illustrate when to refer for genetic counseling and what to advise women concerned about prevention.
In 1989, the observation that Swedish women had both a high risk of ovarian cancer and the highest per capita dairy consumption in the world led some investigators to postulate a relationship between lactose consumption and ovarian cancer. The reason: When compared with matched controls, women with ovarian cancer were more likely to have high levels of galactose, a component sugar of the disaccharide lactose and a known oocyte toxin.11
This observation, however, has been inconsistent. Therefore, no specific dietary strategy can be recommended to reduce the risk of ovarian cancer.
Recommendation. I would advise this patient to maintain a normal body mass index. Data are insufficient to support more specific diet recommendations.
Talc exposure
When talc is placed on the perineum, it may enter the vagina and ascend to the upper genital tract. Because talc is structurally similar to asbestos, it may theoretically increase the ovarian cancer risk. The observation that women who undergo tubal sterilization procedures or hysterectomy have a lower risk of ovarian cancer supports the ascending-carcinogen hypothesis.
Multiple case-control studies have shown a small but consistent increased risk with perineal application of talc (odds ratio 1.3, 95% confidence interval [CI], 1.1–1.6).12 The risk appears to be time- and dose-dependent, with greater risk associated with more frequent application of perineal talc over a long duration.
Recommendation. The practice of applying genuine talc to the perineum should be discouraged. Cornstarch-based dusting powders are widely available.
Infertility drugs
One of the most difficult issues to study is the relationship between infertility drugs and ovarian cancer, although we know that unexplained infertility is an independent risk factor for ovarian cancer.
A retrospective study that claimed an association between prolonged clomiphene exposure and ovarian cancer13 was not restricted to invasive epithelial ovarian cancers, but included granulosa cell tumors. These estrogen-secreting neoplasms of stromal origin may directly contribute to infertility by disrupting normal follicular maturation and the menstrual cycle.
A number of studies—including a large collaborative analysis of 12 case-control studies—have reported an association between fertility drugs and invasive epithelial ovarian cancer.14 In addition, many of the theoretical models of epithelial ovarian cancer pathogenesis implicate both incessant ovulation and high gonadotropin levels as important steps in malignant transformation of ovarian epithelium.
Oral contraceptives (OCs), which reduce ovulatory events, and moderate gonadotropin levels are associated with a consistent and significant protective effect.
Recommendation. It seems prudent, in the absence of convincing data, to use fertility medication only when absolutely indicated, at the lowest effective dose, and for the shortest duration possible without compromising treatment success.
However, prior exposure to these agents should not be considered an indication for increased surveillance or prophylactic surgery.
Estrogen replacement therapy
Women on estrogen replacement therapy appear to have an increased risk of ovarian cancer. When compared to nonusers, “ever-users” had a relative risk of ovarian cancer of 2.2 (95% CI, 1.53–3.17), and the risk increased with the duration of use.15 Long-term users, defined as women who used estrogen replacement therapy for at least 20 years, had a relative risk of 3.2 (95% CI, 1.7–5.7).16
Although some studies suggest a protective effect of combination hormone replacement regimens that include both estrogen and progesterone, this observation has not been confirmed. Thus, long-term estrogen users should consider an increased risk of developing ovarian cancer when deciding whether to initiate or continue estrogen replacement therapy.
Recommendation. I would advise the Case 2 patient to stop HRT.
Primary prevention
Oral contraceptives
OCs reduce the risk of ovarian cancer significantly. A number of studies have demonstrated a 10% risk reduction per year for up to 5 to 7 years of use.17 This effect appears to persist for at least 10 years after OCs are discontinued. It also has been observed in patients known to be BRCA1 and BRCA2 carriers and is the basis for recommending OCs as a chemoprophylactic method in known carriers who wish to retain fertility.18
Long-term estrogen users should consider increased risk of ovarian cancer. Ovarian cancer: High-risk patients.
However, use of OCs by BRCA carriers is not without some controversy. An Israeli population-based study19 of ovarian cancer and OC use demonstrated a protective effect of pregnancy but not use of OCs. It is unclear why the Israeli data is inconsistent with prior published reports.
Recommendation. In Case 1, the patient has taken OCs for 9 years. Her risk has been substantially reduced, and I would advise her to continue OC pills when not attempting to get pregnant, until she is near menopause.
Prophylactic surgery
In high-risk women, preventive surgery may substantially reduce but not completely eliminate the risk of ovarian cancer. For example, bilateral salpingo-oophorectomy in BRCA carriers reduces the risk of ovarian cancer by more than 90% and the risk of breast cancer by more than 50%.20,21
