Tubal Ligation Shown to Reduce Incidence of Ovarian Cancer for BRCA1 Carriers

ABSTRACT & COMMENTARY

Synopsis: Ovarian cancer occurs frequently in women who carry the BRCA1 and BRCA2 gene mutations. In this multinational, retrospective, case-control study, a prior tubal ligation was shown to provide significant protection against subsequent ovarian cancer development. Thus, tubal ligation is a feasible option to reduce risk of ovarian cancer in women with BRCA1 mutations who have completed childbearing.

Source: Narod SA, et al. Lancet. 2001;357:1467-1470.

The lifetime risk for ovarian cancer in women who carry mutations in the BRCA1 or BRCA2 genes is high; estimated to be 40%1 and 25%2 respectively. About 10% of all new cases of ovarian cancer in North America are associated with mutations in these genes.3 In several case control and prospective studies, tubal ligation has been associated with decreased risk of invasive epithelial ovarian cancer, but risk reduction had not previously been demonstrated for those genetically predisposed, such as with BRCA1 or BRCA2 mutations. Thus, the Hereditary Ovarian Cancer Clinical Study Group performed a matched case control study among women who had undergone genetic testing and who carried a pathogenic mutation in BRCA1 or BRCA2. Cases were 232 women with a history of invasive ovarian cancer and controls were 232 women without ovarian cancer. Cases and controls were matched for year of birth, country of residence, and mutation (BRCA1 or BRCA2).

The median age at which ovarian cancer was diagnosed was 51 years (range, 24-81) and the study was performed at a median of 5 years after diagnosis. Tubal ligation was reported by 39 of the ovarian cancer patients compared to 69 of the controls. Of the participants with BRCA1 mutations, significantly fewer patients than controls had ever had tubal ligation. This association remained significant after adjustment for oral contraceptive (OC) use, parity, personal history of breast cancer, and ethnic group. Among BRCA2 carriers, tubal ligation was not found to reduce risk significantly.

Also demonstrable in this study was a strong protective effect of OCs, and this was evident for carriers of either BRCA1 or BRCA2 mutations. The combination of OC use and tubal ligation offered the greater protection than either method alone. Among BRCA1 mutation carriers, tubal ligation and a history of OC use, compared with neither exposure, was associated with an odds ratio of 0.28 (0.15-0.52; P < .0001).

COMMENT by William B. Ershler, MD

Tubal ligation has been associated with a decreased risk of ovarian cancer. For example, after 12 years of follow-up in the Nurses Health Study,4 a strong inverse relation between tubal ligation and ovarian cancer was seen. There have been several case control studies that were reviewed in a meta-analysis,5 and again, there appeared to be decreased risk of ovarian cancer in those that had received tubal ligation. The current study adds the important information that the protective effect is evident in those with high risk, those with BRCA1 mutations. The study did not show a significant effect for those carrying BRCA2 mutations, most likely because of the smaller number of participants with this mutation (59 of the 232 cases), and the later onset of ovarian cancer in those with this mutation. The age at tubal ligation was important, with the greatest effect observed in those who had this procedure at a younger age. However, a significant protection was observed even in those who had the procedure at a later age.

This report also confirmed the strong protective effect of prior use of OCs. In fact, the risk reduction for those who had used OCs and had a tubal ligation was 72% when compared to those who had neither interventions.

The mechanism whereby tubal ligation protects against ovarian cancer development is a matter of conjecture at present. A variety of hypotheses have been proposed that implicate an altered hormonal microenvironment or reduced inflammation, but a definitive explanation awaits experimental demonstration.

Methods of preventing ovarian cancer in women with or without these genetic predispositions include prophylactic oophorectomy, chemoprevention with OCs, or regular screening (eg, by ultrasound and serum CA-125). OCs alone have been shown to reduce risk by approximately 50%,6 but some physicians and patients are concerned about the potential increased risk of breast cancer by such an approach.

Currently, and as clearly supported by this report, tubal ligation offers protection for women at high risk of developing ovarian cancer (particularly those with BRCA1 mutations). In such women who have completed childbearing, tubal ligation with or without continued OCs would seem a logical recommendation.

References

1. Ford D, et al. Lancet. 1994;343:692-695.

2. Ford D, et al. Am J Hum Genet. 1998;62:676-689.

3. Risch HA, et al. Am J Hum Genet. 2001;68:700-711.

4. Hankinson SE, et al. JAMA. 1993;270:2813-2818.

5. Whittemore AS, et al. Am J Epidemiol. 1992;136:
1184-1203.

6. Narod SA, et al. N Engl J Med. 1998;339:424-428.