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

Many women with a mutation in BRCA1 or BRCA2 will undergo bilateral salpingo-oophorectomy to reduce their risks of ovarian, fallopian tube, and breast cancer.¹ Risks and benefits of oophorectomy should be weighed, including degree of protection against cancer and consequences of induced surgical menopause on health and quality of life.^2,3 We and others have shown that the risks of ovarian and breast cancers are reduced by preventive oophorectomy,^4–7 but the optimum age for oophorectomy has not been determined, and the impact of oophorectomy on mortality has not been well studied. The optimal age for oophorectomy should reflect age-specific cancer incidence rates and prevalence of occult ovarian cancer at different ages in BRCA1 and BRCA2 carriers.

In this extension of our earlier work,⁴ we have expanded our cohort of mutation carriers from 1,828 to 5,783 women and extended mean length of follow-up from 3.5 to 5.6 years. We estimate the probability of having an occult cancer by age at oophorectomy, magnitude of risk reduction from prophylactic oophorectomy on cancer incidence, and impact of oophorectomy on all-cause mortality by gene, age group, and history of breast cancer.

In this cohort, 5,783 women with a BRCA1 or BRCA2 mutation were observed prospectively for an average of 5.6 years (Table 1); 186 new ovarian, fallopian, and peritoneal cancers were diagnosed, including 108 women diagnosed clinically with intact ovaries (through symptoms or screening), 46 women with an occult cancer at the time of oophorectomy, and 32 women with peritoneal cancer after oophorectomy. Among women with intact ovaries, 98 cancers were diagnosed in BRCA1 mutation carriers (annual rate, 0.91%), and 10 cancers were diagnosed in BRCA2 mutation carriers (annual rate, 0.30%). The highest incidence rate for BRCA1 mutation carriers was observed between the ages of 50 and 59 years (annual risk, 1.7%); for BRCA2 mutation carriers, it was observed between the ages of 60 and 69 years (annual risk, 0.6%; Table 2).

Of the 46 occult cancers diagnosed at oophorectomy, 27 were classified as ovarian, 18 as primary fallopian tube carcinoma, and one as peritoneal. The earliest cancer discovered at prophylactic oophorectomy was in a BRCA1 carrier age 34 years; three of the 44 cancers in BRCA1 carriers were diagnosed at age ≤ 40 years, and 19 were diagnosed between ages 40 and 49 years. Only two BRCA2 mutation carriers were diagnosed with occult cancer, in both cases after age 60 years (Table 3).

Thirty-two women were diagnosed with primary peritoneal cancer after oophorectomy (mean age at diagnosis, 51.6 years; range, 36 to 69 years); 28 were BRCA1 mutation carriers, and four were BRCA2 mutation carriers. On average, 6.1 years had elapsed from preventive surgery to peritoneal cancer diagnosis (range, one to 20 years). Annual risk of peritoneal cancer after oophorectomy was 0.20% for BRCA1 mutation carriers; it was 0.10% for BRCA2 mutation carriers.

In women with occult ovarian cancer (ie, only detected at surgery), 5-year survival rate was much better than that in women with clinically detected ovarian cancer (91.6% v 54.4%; P < .01; Fig 1). In women with peritoneal cancer, 5-year survival rate was 38.4%.

To estimate the extent to which prophylactic oophorectomy reduced risk of ovarian, fallopian tube, or peritoneal cancer, a Cox proportional hazards model was employed. Crude HR associated with oophorectomy was 0.25 (95% CI, 0.17 to 0.38; P < .001); adjusted HR was 0.20 (95% CI, 0.13 to 0.30; P < .001 [BRCA1 and BRCA2 mutation carriers combined]).

Among all women in the cohort, 507 have died, including 329 as a result of breast cancer, 67 as a result of ovarian, fallopian, or peritoneal cancer, 49 as a result of other cancers, 44 as a result of other causes (not cancer), and 18 as a result of unknown causes. Among the 2,633 women in the cohort who had not been diagnosed with any cancer before completion of the baseline questionnaire, 69 have died, including 22 as a result of breast cancer, 22 as a result of ovarian, fallopian, or peritoneal cancer, four as a result of pancreatic cancer, two as a result of endometrial cancer, five as a result of other cancers, 11 as a result of other causes, and three as a result of unknown causes.

We estimated the impact of oophorectomy on death resulting from any cause until age 70 years. Adjusted HR for all-cause mortality to age 70 years associated with oophorectomy was 0.31 (95% CI, 0.26 to 0.38; P < .001). Among women with both ovaries intact at baseline, HR for all-cause mortality to age 70 years associated with oophorectomy was 0.25 (95% CI, 0.18 to 0.35; P < .001). HRs by mutation, age at study entry, and history of breast cancer are listed in Table 4. Among women who had been previously treated for breast cancer, HR for all-cause mortality to age 70 years was 0.39 (95% CI, 0.30 to 0.50; P < .001) for women who underwent oophorectomy before or within 3 years of breast cancer diagnosis; it was 0.24 (95% CI, 0.17 to 0.32; P < .001) for women who underwent oophorectomy ≥ 3 years after diagnosis.

The striking finding in this study of BRCA1 or BRCA2 mutation carriers was the effect of oophorectomy on all-cause mortality. Among women who were unaffected with cancer at study entry, risk of death in the follow-up period fell by 77% after oophorectomy. Impact of oophorectomy on mortality results in large part from reduction in the incidence of ovarian, tubal, and peritoneal cancers—but there is an important component from reducing breast cancer incidence and mortality as well. We have previously shown that oophorectomy reduces risk of breast cancer by 48% in women with a BRCA1 mutation,⁶ and once the cancer is diagnosed, it reduces patient case fatality by 70%.⁸ Average age at cohort entry was 46.0 years, and women were observed until a mean age of 51.6 years. It is expected that in young women, noncancer causes of death will be rare, and reduction in all-cause mortality associated with oophorectomy may attenuate as the women age and other causes of death emerge. Prolonged follow-up of this cohort will allow us to estimate mortality over the lifespans of the women.

We identified 46 invasive cancers in 1,390 women at the time of prophylactic oophorectomy, representing a prevalence of 4.2% among BRCA1 mutation carriers and 0.6% among BRCA2 mutation carriers undergoing surgery. Of the 46 occult cancers, 18 were classified as primary fallopian tube; this observation supports the position that standard of care should include removal of tubes with the ovaries at the time of preventive surgery. Assignment of cancer site was conducted by review of pathology reports and medical records; centralized pathology review was not performed. Distinction between primary cancers of the ovary and fallopian tube is difficult, especially with regard to advanced-stage cancers. However, the current recommendation is for bilateral salpingo-oophorectomy. This study was initiated in 1995, before the recommendation for removal and detailed pathologic evaluation of the fallopian tubes, and therefore, there was no standard procedure across centers regarding salpingectomy. We did not systematically evaluate or record presence of preinvasive fallopian lesions, such as tubal intraepithelial cancers, and 5-year survival of 92% reflects the course of invasive cancers only. Prevalence of occult carcinomas in previous studies of oophorectomy patients varied widely,^9–12 but the numbers of women studied were much smaller. Prevalence was 1.5% for BRCA1 mutation carriers who underwent oophorectomy at age < 40 years and was 3.8% for women who underwent surgery between age 40 and 49 years. The data presented here support the recommendation for a BRCA1 mutation carrier to undergo oophorectomy at age 35 years; if a woman with a BRCA1 mutation chooses to delay salpingo-oophorectomy until age 40 years, we estimate that she will have a 4.0% chance of being diagnosed with ovarian cancer, either clinically before or at the time of salpingo-oophorectomy. If she chooses to wait until age 50 years, the probability rises to 14.2%. Only one case of ovarian cancer was diagnosed at age < 50 years in our cohort of BRCA2 mutation carriers. Among 245 BRCA1 mutation carriers who were cancer free at baseline and underwent oophorectomy at age < 40 years, there were three deaths: one resulting from breast cancer, one resulting from occult ovarian cancer, and one resulting from primary peritoneal cancer. Among 567 BRCA1 mutation carriers who were cancer free at baseline and underwent oophorectomy between ages 40 and 49 years, there were 11 deaths: four resulting from breast cancer, three resulting from primary peritoneal cancer, one resulting from gastric cancer, one resulting from hepatic cancer, one resulting from pancreatic cancer, and one resulting from a noncancer cause.

There were 108 clinically detected ovarian cancers, but it was not possible to distinguish those that were symptomatic and those that were detected because of screening. Nevertheless, all women in the cohort were aware of their mutation status, and for most, ovarian screening had been recommended. In women with clinically detected ovarian cancer, 10-year survival rate was 35%, similar to that in mutation carriers diagnosed with ovarian cancer in a separate cohort who did not know their mutation status at time of diagnosis.¹³ Survival of women with occult ovarian cancer was much better. Together, these observations suggest that the benefit of awareness of mutation status regarding ovarian cancer mortality is attributable to oophorectomy, through prevention and earlier detection.

We estimate the risk of peritoneal cancer in the 20 years after oophorectomy to be 3.9% for BRCA1 mutation carriers and 1.9% for BRCA2 mutation carriers, based on 32 incident cases of peritoneal cancer after oophorectomy. It is possible that some of these were actually metastases of subclinical disease present at time of surgery; if so, these might have been prevented if oophorectomy had been performed earlier. There were two cases of peritoneal cancer diagnosed among 646 women who underwent oophorectomy at age < 40 years (0.3%) versus 12 cases among 1,632 women who underwent oophorectomy between ages 40 and 50 years (0.7%).

In a large historical cohort study similar to ours, Domchek et al⁵ observed 2,482 BRCA1 and BRCA2 mutation carriers for a mean of 5.0 years. They estimated that risk reduction in all-cause mortality was significant for BRCA1 mutation carriers (HR, 0.38; 95% CI, 0.24 to 0.62) but not for BRCA2 mutation carriers (HR, 0.52; 95% CI, 0.22 to 1.23). We confirm here the impact of oophorectomy on mortality in our study of 5,783 carriers, and we report that the effect of oophorectomy on all-cause mortality is equally strong for BRCA1 (HR, 0.30; 95% CI, 0.24 to 0.38) and BRCA2 mutation carriers (HR, 0.33; 95% CI, 0.22 to 0.50). The observation that oophorectomy has a profound protective effect on all-cause mortality has several important implications. Age distribution of ovarian cancers should not be the sole criterion for determining the optimum age for surgery, because some of the benefit of oophorectomy may derive through means other than preventing ovarian cancer (particularly for breast cancer risk). After early oophorectomy, women have reported an increase in vasomotor symptoms, loss of libido, and a modest diminution of overall quality of life.^2,3 It is difficult to compare formally the decline in quality of life with an increase in life expectancy, and it is unlikely that any study can resolve this. Women without a history of breast cancer may be administered hormone replacement therapy for the relief of the acute symptoms of menopause without increasing their risk of breast cancer.^14,15 It is important that we ascertain the long-term effects of salpingo-oophorectomy and design effective treatments and preventive strategies for these.

Management of healthy women with a BRCA1 or BRCA2 mutation is a multidisciplinary effort, and options include chemoprevention, screening, oophorectomy, preventive mastectomy, and breast reconstruction. We have previously shown that preventive salpingo-oophorectomy is acceptable by the majority of women with a BRCA1 or BRCA2 mutation,¹⁶ that oophorectomy rates among healthy mutation carriers are high worldwide,¹⁷ and that patients report a high degree of satisfaction after surgery.³ In our study, we show that among unaffected women with a BRCA1 or BRCA2 mutation, all-cause mortality to age 70 years is reduced by 77% with oophorectomy. Among women with a history of breast cancer, the reduction in mortality is similar. This implies that genetic testing is likely to be beneficial in countries where patients who test positive for a mutation have access to salpingo-oophorectomy, even if limited resources are available for other aspects of care, such as magnetic resonance imaging, tamoxifen treatment, or breast reconstruction.

We thank Alejanda Ragone, Marcia Llacuachaqui, and Linda Steele for study enrollment and data collection.

The author(s) indicated no potential conflicts of interest.

Other members of the Hereditary Breast Cancer Clinical Study Group include: Ophira Ginsburg, André Robidoux, Charis Eng, Kevin Sweet, Dawna Gilchrist, Olufunmilayo Olopade, Fergus Couch, Claudine Isaacs, Jeffrey N. Weitzel, Mary B. Daly, Judy E. Garber, Dana Zakalik, Carey A. Cullinane, Carey Snider, Dominique Stoppa-Lyonnet, Howard Saal, Wendy Meschino, Wendy McKinnon, Marie Wood, Taya Fallen, Raluca Kurz, Siranoush Manoukian, Susan Armel, Rochelle Demsky, Jeanna McCuaig, Edmond Lemire, Jane McLennan, Seema Panchal, Louse Bordeleau, Albert E. Chudley, Susan T. Vadaparampil, Tuya Pal, Daniel Rayson, Susan Friedman (on behalf of FORCE [Facing Our Risk of Cancer Empowered]), Jacek Gronwald, and Tomasz Byrski.