Objective

Bilateral salpingo-oophorectomy (oophorectomy) is recommended to women with a germline BRCA1 or BRCA2 mutation before natural menopause to prevent ovarian and fallopian tube cancer. The adverse effects of early surgical menopause are well established. Although many of the side effects can be ameliorated by the use of hormone therapy (HT); use of HT in this group of predominantly young patients remains suboptimal. The goal of this study was to identify the frequency of HT use, as well as predictors of HT uptake in BRCA mutation carriers who underwent preventive oophorectomy before natural menopause.

Methods

Eligible participants were identified from a longitudinal study of BRCA mutation carriers. We included premenopausal women with no personal history of cancer who underwent oophorectomy before age 50 and who had a minimum of 2 years of follow-up. Detailed information on HT use and other important variables was collected by a research questionnaire every 2 years. Descriptive statistics were used to evaluate the use of HT in various subgroups.

Results

A total of 793 women with a BRCA1 or BRCA2 mutation were included in this analysis. The mean age at oophorectomy was 42 years (range 28-49). Sixty-one percent of the women reported using HT after oophorectomy. Factors associated with HT use included young age at surgery, a high level of education and preventive mastectomy.

Conclusions

The uptake of HT after oophorectomy in women with a BRCA1 or BRCA2 mutation varies by age, education, and surgical history. Clinician and patient awareness may lead to better utilization of HT in women who undergo oophorectomy at an early age to help mitigate the adverse effects associated with surgical menopause.

Introduction

Preventive bilateral salpingo-oophorectomy is the most effective means of reducing the risk of ovarian cancer among women with an inherited BRCA1 or BRCA2 mutation. Some women are diagnosed with an invasive cancer (ovarian or fallopian tube) at the time of preventive surgery, referred to as an 'occult' cancer. The survival experience of these women is not known.

Methods

We estimated the 10-year survival for 52 BRCA mutation carriers diagnosed with an occult ovarian or fallopian tube cancer at the time of preventive bilateral salpingo-oophorectomy.

Results

The mean age at diagnosis was 51.6 (range 33-69) years. All were serous cancers (although 14 were missing information on histologic subtype). Of the 20 cases with information available on stage at diagnosis, 10 were stage I, 1 was stage II, and 9 were stage III (n=32 missing). After a mean of 6.8 years, 12 women died (23%). The 10-year all-cause survival was 74%.

Conclusion

Although based on only 52 cases, these findings suggest a more favorable prognosis for BRCA mutation carriers diagnosed with an occult rather than incident disease.

BACKGROUND: It has not been clearly established if skin cancer or melanoma are manifestations of BRCA1 or BRCA2 mutation carrier status. Estimating the risk of skin cancer is an important step towards developing screening recommendations. METHODS: We report the findings of a prospective cohort study of 6,207 women from North America who carry BRCA1 or BRCA2 mutations. Women were followed from the date of baseline questionnaire to the diagnosis of skin cancer, to age 80 years, death from any cause, or the date of last follow-up. RESULTS: During the mean follow-up period of eight years, 3.7% of women with a BRCA1 mutation (133 of 3,623) and 3.8% of women with a BRCA2 mutation (99 of 2,584) reported a diagnosis of skin cancer (including both keratinocyte carcinomas and melanoma). The cumulative risk of all types of skin cancer from age 20 to 80 years was 14.1% for BRCA1 carriers and 10.7% for BRCA2 carriers. The cumulative risk of melanoma was 2.5% for BRCA1 carriers and 2.3% for BRCA2 carriers, compared to 1.5% for women in the general population in the United States. The strongest risk factor for skin cancer was a prior diagnosis of skin cancer. CONCLUSION: The risk of non-melanoma skin cancer in women who carry a mutation in BRCA1 or BRCA2 is similar to that of non-carrier women. The risk of melanoma appears to be slightly elevated. We suggest that a referral to a dermatologist or primary care provider for BRCA mutation carriers for annual skin examination and counselling regarding limiting UV exposure, the use of sunscreen and recognizing the early signs of melanoma might be warranted, but further studies are necessary.

Objective

Preventive breast surgery and MRI screening are offered to unaffected BRCA mutation carriers. The clinical benefit of these two modalities has not been evaluated among mutation carriers with a history of ovarian cancer. Thus, we sought to determine whether or not BRCA mutation carriers with ovarian cancer would benefit from preventive mastectomy or from MRI screening.

Methods

First, the annual mortality rate for ovarian cancer patients was estimated for a cohort of 178 BRCA mutation carriers from Ontario, Canada. Next, the actuarial risk of developing breast cancer was estimated using an international registry of 509 BRCA mutation carriers with ovarian cancer. A series of simulations was conducted to evaluate the reduction in the probability of death (from all causes) associated with mastectomy and with MRI-based breast surveillance. Cox proportional hazards models were used to evaluate the impacts of mastectomy and MRI screening on breast cancer incidence as well as on all-cause mortality.

Results

Twenty (3.9%) of the 509 patients developed breast cancer within ten years following ovarian cancer diagnosis. The actuarial risk of developing breast cancer at ten years post-diagnosis, conditional on survival from ovarian cancer and other causes of mortality was 7.8%. Based on our simulation results, among all BRCA mutation-carrying patients diagnosed with stage III/IV ovarian cancer at age 50, the chance of dying before age 80 was reduced by less than 1% with MRI and by less than 2% with mastectomy. Greater improvements in survival with MRI or mastectomy were observed for women who had already survived 10years after ovarian cancer, and for women with stage I or II ovarian cancer.

Conclusions

Among BRCA mutation-carrying ovarian cancer patients without a personal history of breast cancer, neither preventive mastectomy nor MRI screening is warranted, except for those who have survived ovarian cancer without recurrence for ten years and for those with early stage ovarian cancer.

Importance

Prophylactic bilateral salpingo-oophorectomy is recommended for BRCA1 mutation carriers to prevent ovarian cancer. Whether or not hormone replacement therapy (HRT) initiated after oophorectomy is associated with an increased risk of breast cancer has not been evaluated in a prospective study.

Objective

To determine the association between HRT use and BRCA1-associated breast cancer.

Design, setting, and participants

A prospective, longitudinal cohort study of BRCA1 and BRCA2 mutation carriers from 80 participating centers in 17 countries was conducted between 1995 and 2017 with a mean follow-up of 7.6 years. Participants had sought genetic testing for a BRCA1 or BRCA2 mutation because of a personal or family history of breast and/or ovarian cancer. Carriers of BRCA1 mutation with no personal medical history of cancer who underwent bilateral oophorectomy following enrollment were eligible for the cohort study.

Exposures

A follow-up questionnaire was administered every 2 years to obtain detailed information on HRT use. A left-truncated Cox proportional hazard analysis was used to estimate the hazard ratios (HRs) and 95% CIs associated with the initiation of HRT use postoophorectomy.

Main outcomes and measures

Incident breast cancer.

Results

A total of 872 BRCA1 mutation carriers with a mean postoophorectomy follow-up period of 7.6 years (range, 0.4-22.1) were included in this study. Mean (SD) age of participants was 43.4 (8.5) years. Among these, 92 (10.6%) incident breast cancers were diagnosed. Overall, HRT use after oophorectomy was not associated with an increased risk of breast cancer. The HR was 0.97 (95% CI, 0.62-1.52; P = .89) for ever use of any type of HRT vs no use; however, the effects of estrogen alone and combination hormonal therapy were different. After 10 years of follow-up, the cumulative incidence of breast cancer among women who used estrogen-alone HRT was 12% compared with 22% among women who used estrogen plus progesterone HRT (absolute difference, 10%; log rank P = .04).

Conclusions and relevance

These findings suggest that use of estrogen after oophorectomy does not increase the risk of breast cancer among women with a BRCA1 mutation and should reassure BRCA1 mutation carriers considering preventive surgery that HRT is safe. The possible adverse effect of progesterone-containing HRT warrants further study.

Background

Risk-reducing mastectomy (RRM) is offered to women with a BRCA1 or BRCA2 pathogenic variant, however, there are limited data on the impact on breast cancer mortality.

Methods

Participants were identified from a registry of women with BRCA1/2 pathogenic variants. We used a pseudo-randomised trial design and matched one woman with a RRM to one woman without a RRM on year of birth, gene, and country. We estimated the hazard ratio (HR) and 95% confidence intervals (CI) for dying of breast cancer in the follow-up period.

Results

There were 1654 women included; 827 assigned to the RRM arm and 827 assigned to the control arm. After a mean follow-up of 6.3 years, there were 20 incident breast cancers (including 15 occult cancers) and two breast cancer deaths in the RRM arm, and 100 incident breast cancers and 7 breast cancer deaths in the control arm (HR = 0.26; 95% CI 0.05-1.35; p = 0.11). The probability of dying of breast cancer within 15 years after RRM was 0.95%.

Conclusions

In women with a BRCA1 or BRCA2 pathogenic variant, RRM reduces the risk of breast cancer, and the probability of dying of breast cancer is low.

Background

The lack of consensus on whether bilateral oophorectomy impacts risk of developing breast cancer among BRCA1 mutation carriers might be attributed to various biases, specifically, cancer-induced testing bias due to inclusion of prevalent cases. We conducted two complementary matched case-control analyses to evaluate the association of oophorectomy and BRCA1 breast cancer.

Methods

A research questionnaire was administered every two years to collect information on exposures and disease. In the first analysis, we limited the study to prevalent breast cancer cases (diagnosed prior to study entry; n = 2,962) who were matched to controls on year of birth and country of residence (n = 4,358). In the second approach, we limited to 330 incident cases (diagnosed in the follow-up period) and 1,548 matched controls. Conditional logistic regression was used to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) of invasive breast cancer.

Results

In the first approach, there was a significant inverse association between oophorectomy and the risk of developing breast cancer [OR = 0.43; 95% confidence interval (CI), 0.34-0.55; P < 00001]. In the second approach, there was no association between oophorectomy and risk (OR = 1.21; 95% CI, 0.87-1.70; P = 0.26).

Conclusions

The inclusion of women with a personal history of breast cancer prior to ascertainment likely impacts upon the association of oophorectomy and BRCA1 breast cancer risk.

Impact

Oophorectomy is unlikely a determinant of breast cancer risk in BRCA1 mutation carriers but should be offered at age 35 to reduce the risk of ovarian and fallopian tube cancer.

Purpose

Chemoprevention with a selective estrogen receptor modulator (tamoxifen or raloxifene) is a non-surgical option offered to high-risk women to reduce the risk of breast cancer. The evidence for tamoxifen benefit is based on trials conducted among predominantly postmenopausal women from the general population and on studies of contralateral breast cancer in women with a pathogenic variant (mutation hereafter) in BRCA1 or BRCA2. Tamoxifen has not been assessed as a primary prevention agent in women with an inherited BRCA mutation.

Methods

We conducted a prospective analysis of tamoxifen chemoprevention and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation. Data on tamoxifen (and raloxifene) use was collected by questionnaire and updated biennially. Information on incident cancers was collected by self-report and was confirmed by medical record review. In a matched analysis, we estimated the hazard ratio (HR) and 95% confidence intervals (CI) for developing a first primary breast cancer associated with tamoxifen or raloxifene use, using Cox proportional hazards analysis.

Results

There were 4578 unaffected women in the cohort, of whom 137 reported tamoxifen use (3%), 83 reported raloxifene use (2%) and 12 used both drugs (0.3%). Women who used tamoxifen or raloxifene were matched 1:3 with women who used neither drug on year of birth, country of residence, year of study entry and gene (BRCA1 or BRCA2). We generated 202 matched pairs. After a mean follow-up of 6.8 years, there were 22 incident breast cancers diagnosed among tamoxifen/raloxifene users (10.9% of users) and 71 cases diagnosed among non-users (14.3% of non-users; HR = 0.64; 95% CI 0.40-1.03; P = 0.07).

Conclusion

Chemoprevention may be an effective risk-reduction option for BRCA mutation carriers, but further studies with longer follow-up are necessary.

Background

Weight gain and other anthropometric measures on the risk of ovarian cancer for women with BRCA mutations are not known. We conducted a prospective analysis of weight change since age 18, height, body mass index (BMI) at age 18, and current BMI and the risk of developing ovarian cancer among BRCA1 and BRCA2 mutation carriers.

Methods

In this prospective cohort study, height, weight, and weight at age 18 were collected at study enrollment. Weight was updated biennially. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for ovarian cancer.

Results

This study followed 4,340 women prospectively. There were 121 incident cases of ovarian cancer. Weight gain of more than 20 kg since age 18 was associated with a 2-fold increased risk of ovarian cancer, compared with women who maintained a stable weight (HR, 2.00; 95% CI, 1.13-3.54; P = 0.02). Current BMI of 26.5 kg/m² or greater was associated with an increased risk of ovarian cancer in BRCA1 mutation carriers, compared with those with a BMI less than 20.8 kg/m² (Q4 vs. Q1 HR, 2.13; 95% CI, 1.04-4.36; P = 0.04). There were no significant associations between height or BMI at age 18 and risk of ovarian cancer.

Conclusions

Adult weight gain is a risk factor for ovarian cancer in women with a BRCA1 or BRCA2 mutation.

Impact

These findings emphasize the importance of maintaining a healthy body weight throughout adulthood in women at high risk for ovarian cancer.