Purpose The purposes of this study were to estimate the reduction in risk of ovarian, fallopian tube, or peritoneal cancer in women with a BRCA1 or BRCA2 mutation after oophorectomy, by age of oophorectomy; to estimate the impact of prophylactic oophorectomy on all-cause mortality; and to estimate 5-year survival associated with clinically detected ovarian, occult, and peritoneal cancers diagnosed in the cohort. Patients and Methods Women with a BRCA1 or BRCA2 mutation were identified from an international registry; 5,783 women completed a baseline questionnaire and ≥ one follow-up questionnaires. Women were observed until either diagnosis of ovarian, fallopian tube, or peritoneal cancer, death, or date of most recent follow-up. Hazard ratios (HRs) for cancer incidence and all-cause mortality associated with oophorectomy were evaluated using time-dependent survival analyses. Results After an average follow-up period of 5.6 years, 186 women developed either ovarian (n = 132), fallopian (n = 22), or periton...

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Impact of Oophorectomy on Cancer Incidence and Mortality in Women With a BRCA1 or BRCA2 Mutation

The cloning of the breast cancer susceptibility genes BRCA1 and BRCA2 nearly two decades ago helped set in motion an avalanche of research exploring how genomic information can be optimally applied to identify and clinically care for individuals with a high risk of developing cancer. Genetic testing for mutations in BRCA1, BRCA2, and other breast cancer susceptibility genes has since proved to be a valuable tool for determining eligibility for enhanced screening and prevention strategies, as well as for identifying patients most likely to benefit from a targeted therapy. Here, we discuss the landscape of inherited mutations and sequence variants in BRCA1 and BRCA2, the complexities of determining disease risk when the pathogenicity of sequence variants is uncertain, and current strategies for clinical management of women who carry BRCA1/2 mutations.

https://science.sciencemag.org/content/sci/343/6178/1466.full.pdf

Two decades after BRCA: setting paradigms in personalized cancer care and prevention.

Women with adverse mutations in the BRCA1 or BRCA2 gene are at an increased lifetime risk of ovarian cancer, and these mutations also increase vulnerability to cancers of the fallopian tube and peritoneum. Risk levels were examined in a prospective study based on data from an international registry comprising 32 centers in Canada, the United States, Europe, and Israel. The 1828 women identified as carrying a BRCA1 or BRCA2 mutation were followed up for a mean of 3.5 years. Participants had a mean age at entry of 47 years. Approximately three-fourths of the women carried a BRCA1 mutation and about one-fourth, a BRCA2 mutation; eight individuals carried both. Nearly one-third of women in the study (30.4%) had undergone bilateral salpingo-oophorectomy before entering the study, and another 38.5% had an oophorectomy during follow-up. Fifty incident cancers were discovered during follow-up. Thirty-two of these cancers developed in women with intact ovaries. Eleven cancers were identified at the time of prophylactic oophorectomy, and 7 others after this procedure. The cumulative incidence of peritoneal cancer was estimated at 4.3% two decades after oophorectomy. The overall adjusted reduction in cancer risk associated with bilateral oophorectomy was 80%, with a multivariate hazard ratio of 0.2 and a 95% confidence interval of 0.07-0.58 (Fig. 1). The risk of ovarian, tubal, and primary peritoneal cancers in women with intact ovaries was highest for those 60-70 years of age who carried the BRCA1 mutation. Based on estimated incidence rates for women having both ovaries intact, the estimated penetrance of ovarian cancer was 62% up to age 75 years for carriers of the BRCA1 mutation, and 18% up to age 75 for those carrying the BRCA2 mutation. The investigators conclude that the risk of ovarian, tubal, and peritoneal cancer is lowered by 80% for carriers of the BRCA1 or BRCA2 mutation who undergo prophylactic oophorectomy. The findings support prophylactic surgery as a very effective risk reduction measure. Both the ovaries and the fallopian tubes should be removed. The residual risk of peritoneal cancer is not high enough to recommend against prophylactic surgery.

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Salpingo -oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutation

Purpose Women with BRCA1/2 mutations inherit high risks of breast and ovarian cancer; options to reduce cancer mortality include prophylactic surgery or breast screening, but their efficacy has never been empirically compared. We used decision analysis to simulate risk-reducing strategies in BRCA1/2 mutation carriers and to compare resulting survival probability and causes of death. Methods We developed a Monte Carlo model of breast screening with annual mammography plus magnetic resonance imaging (MRI) from ages 25 to 69 years, prophylactic mastectomy (PM) at various ages, and/or prophylactic oophorectomy (PO) at ages 40 or 50 years in 25-year-old BRCA1/2 mutation carriers. Results With no intervention, survival probability by age 70 is 53% for BRCA1 and 71% for BRCA2 mutation carriers. The most effective single intervention for BRCA1 mutation carriers is PO at age 40, yielding a 15% absolute survival gain; for BRCA2 mutation carriers, the most effective single intervention is PM, yielding a 7% survival gain if performed at age 40 years. The combination of PM and PO at age 40 improves survival more than any single intervention, yielding 24% survival gain for BRCA1 and 11% for BRCA2 mutation carriers. PM at age 25 instead of age 40 offers minimal incremental benefit (1% to 2%); substituting screening for PM yields a similarly minimal decrement in survival (2% to 3%).

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Survival Analysis of Cancer Risk Reduction Strategies for BRCA1/2 Mutation Carriers

About one in 300 women will be diagnosed with breast cancer before the age of 40. Advances in screening have not had an impact on mortality in women who are too young to be candidates for screening. Risk factors for early breast cancer include a lean body habitus and recent use of an oral contraceptive. Breast cancers in very young women are typically aggressive, in part owing to the over-representation of high-grade, triple-negative tumours, but young age is an independent negative predictor of cancer-specific survival. Very early age-of-onset also correlates strongly with the risk of local recurrence and with the odds of contralateral breast cancer. Given the high risks of local and distant recurrence in young women with invasive breast cancer, most (if not all) young patients are candidates for chemotherapy. It is hoped that by increasing breast cancer awareness, the proportion of invasive breast cancers that are diagnosed at 2.0 cm or smaller will increase and that this will lead to a reduction in mortality.

Breast cancer in young women.

Several options for cancer prevention are available for women with a BRCA1 or BRCA2 mutation, including prophylactic surgery, chemoprevention and screening. The authors report on preventive practices in women with mutations from 9 countries and examine differences in uptake according to country. Women with a BRCA1 or BRCA2 mutation were contacted after receiving their genetic test result and were questioned regarding their preventive practices. Information was recorded on prophylactic mastectomy, prophylactic oophorectomy, use of tamoxifen and screening (MRI and mammography). Two thousand six hundred seventy-seven women with a BRCA1 or BRCA2 mutation from 9 countries were included. The follow-up questionnaire was completed a mean of 3.9 years (range 1.5-10.3 years) after genetic testing. One thousand five hundred thirty-one women (57.2%) had a bilateral prophylactic oophorectomy. Of the 1,383 women without breast cancer, 248 (18.0%) had had a prophylactic bilateral mastectomy. Among those who did not have a prophylactic mastectomy, only 76 women (5.5%) took tamoxifen and 40 women (2.9%) took raloxifene for breast cancer prevention. Approximately one-half of the women at risk for breast cancer had taken no preventive option, relying solely on screening. There were large differences in the uptake of the different preventive options by country of residence. Prophylactic oophorectomy is now generally accepted by women and their physicians as a cancer preventive measure. However, only the minority of women with a BRCA1 or BRCA2 mutation opt for prophylactic mastectomy or take tamoxifen for the prevention of hereditary breast cancer. Approximately one-half of women at risk for breast cancer rely on screening alone.

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A. Eisen

Papers

International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers.