The risk of skin cancer in women who carry BRCA1 or BRCA2 mutations.

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.

An appraisal of genetic testing for prostate cancer susceptibility.

Most criteria for genetic testing for prostate cancer susceptibility require a prior diagnosis of prostate cancer, in particular cases with metastatic disease are selected. Advances in the field are expected to improve outcomes through tailored treatments for men with advanced prostate cancer with germline pathogenic variants, although these are not currently offered in the curative setting. A better understanding of the value of genetic testing for prostate cancer susceptibility in screening, for early detection and prevention is necessary. We review and summarize the literature describing germline pathogenic variants in genes associated with increased prostate cancer risk and aggressivity. Important questions include: what is our ability to screen for and prevent prostate cancer in a man with a germline pathogenic variant and how does knowledge of a germline pathogenic variant influence treatment of men with nonmetastatic disease, with hormone-resistant disease and with metastatic disease? The frequency of germline pathogenic variants in prostate cancer is well described, according to personal and family history of cancer and by stage and grade of disease. The role of these genes in aggressive prostate cancer is also discussed. It is timely to consider whether or not genetic testing should be offered to all men with prostate cancer. The goals of testing are to facilitate screening for early cancers in unaffected high-risk men and to prevent advanced disease in men with cancer.

Genetic Testing for All: Overcoming Disparities in Ovarian Cancer Genetic Testing.

Nearly 3% of the population carries genetic variants that lead to conditions that include hereditary breast and ovarian cancer and Lynch syndrome. These pathogenic variants account for approximately 20% of ovarian cancer cases, and those with germline pathogenic variants have an odds ratio between 4 and 40 for developing ovarian cancer compared with noncarriers. Given the high prevalence of genetic variants, multiple organizations, including ASCO, recommend universal genetic counseling and testing for women diagnosed with epithelial ovarian cancer. Unfortunately, most individuals with a hereditary ovarian cancer syndrome are unaware of their underlying mutation, and racial and ethnic minority individuals as well as patients of low socioeconomic status experience disproportionate rates of underrecognition, leading to late and missed diagnoses. In this article, we review the current understanding of disparities in genetic testing for people with ovarian cancer, the role of population-based genetic testing, and innovative strategies to overcome the critical inequities present in current cancer genetic medicine. Underuse and disparities related to accessing recommended genetic services are complex and multifactorial, requiring improvements in processes related to provider identification, genetic counseling and testing referral, and patient uptake/adherence. Through the expansion of remote genetic counseling, offering online strategies for genetic testing, and reaching at-risk relatives through direct relative contact cascade testing and population-based genetic testing, there are a growing number of innovations in the field of genetic medicine, many of which emphasize health equity and offer promising alternatives to the current paradigm of genetic testing.

The risks of breast and ovarian cancer associated with the Ashkenazi Jewish founder allele BRCA2 6174delT.

Approximately 1% of the Ashkenazi Jewish population carries the BRCA2 6174delT (c.5946del) pathogenic variant. It is important to have accurate knowledge of the risks of breast and ovarian cancer associated with this specific variant so that women may be counseled accordingly. In this prospective study, we estimated the risks of breast and ovarian cancer associated with the 6174delT variant compared with the risks for other pathogenic variants in the BRCA2 gene. The annual risk for developing breast cancer was significantly lower in 246 women who carried the 6174delT variant compared with 721 non-Jewish women who carried a variant at any other locus in BRCA2 (1.2% per year vs. 2.4% per year, p = 0.003). We estimated the cumulative risk of breast cancer from age 30 to 70 to be 39% for carriers of the BRCA2 6174delT variant and 61% for carriers of other BRCA2 variants. The annual risk for ovarian or fallopian tube cancer was 0.51% per year for the 233 women who carried the 6174delT variant compared to 0.22% per year for the 1128 carriers of other BRCA2 variants; the difference was not significant. Lower risks for breast cancer associated with 6174delT may not impact screening and prevention choices, however, the discussion should be based on accurate risk assessment.

Changes in Bone Mineral Density After Prophylactic Bilateral Salpingo-Oophorectomy in Carriers of a BRCA Mutation.

Importance: Preventive surgery is strongly recommended for individuals with a BRCA mutation at a young age to prevent ovarian cancer and improve overall survival. The overall effect of early surgical menopause on various health outcomes, including bone health, has not been clearly elucidated. Objective: To evaluate the association of prophylactic bilateral salpingo-oophorectomy with bone mineral density (BMD) loss among individuals with a BRCA mutation. Design, Setting, and Participants: This retrospective cohort study of participants with a BRCA mutation who underwent oophorectomy through the University Health Network, Toronto, Ontario, Canada, recruited participants from January 2000 to May 2013. Eligibility criteria included having a BRCA mutation, at least 1 ovary intact prior to surgery, and no history of any cancer other than breast cancer. Bone mineral density was measured using dual-energy x-ray absorptiometry before and after surgery. Data analysis began in December 2018 and finished in January 2019. Main Outcomes and Measures: The annual change in BMD from baseline to follow-up was calculated for the following 3 anatomical locations: (1) lumbar spine, (2) femoral neck, and (3) total hip. Results: A total of 95 women had both a baseline and postsurgery BMD measurement with a mean (SD) follow-up period of 22.0 (12.7) months. The mean (SD) age at oophorectomy was 48.0 (7.4) years. Among women who were premenopausal at time of surgery (50 [53%]), there was a decrease in BMD from baseline to follow-up across the lumbar spine (annual change, -3.45%; 95% CI, -4.61% to -2.29%), femoral neck (annual change, -2.85%; 95% CI, -3.79% to -1.91%), and total hip (annual change, -2.24%; 95% CI, -3.11% to -1.38%). Self-reported hormone therapy use was associated with significantly less bone loss at the lumbar spine (-2.00% vs -4.69%; P = .02) and total hip (-1.38% vs -3.21; P = .04) compared with no hormone therapy use. Among postmenopausal women at time of surgery (45 [47%]), there was also a significant decrease in BMD across the lumbar spine (annual change, -0.82%; 95% CI, -1.42% to -0.23%) and femoral neck (annual change, -0.68%; 95% CI, -1.33% to -0.04%) but not total hip (annual change, -0.18%; 95% CI, -0.82% to 0.46%). Conclusions and Relevance: This study found that oophorectomy was associated with postoperative bone loss, especially among women who were premenopausal at the time of surgery. Targeted management strategies should include routine BMD assessment and hormone therapy use to improve management of bone health in this population.

Effects of bilateral salpingo-oophorectomy on menopausal symptoms and sexual functioning among women with a BRCA1 or BRCA2 mutation.

INTRODUCTION: Prophylactic bilateral salpingo-oophorectomy (BSO) is recommended at an early age to BRCA mutation carriers to prevent ovarian cancer. It is critical to evaluate the impact of BSO on non-cancer outcomes, including quality of life (QOL), menopausal symptoms and sexual functioning. METHODS: BRCA mutation carriers who elected to undergo a BSO completed three questionnaires prior to surgery and then again approximately one and three years following surgery which included: 1) medical history questionnaire, 2) Menopause-Specific Quality of Life Intervention questionnaire and 3) Sexual Activity Questionnaire. The change in quality of life, menopausal symptoms and sexual functioning before and after oophorectomy was determined using a paired t-test and stratified by menopausal status at surgery. RESULTS: We included 140 BRCA mutation carriers with an average follow-up of 3.5 years following BSO. Among 93 women who were premenopausal, oophorectomy was associated with an increase in menopausal symptoms (vasomotor, physical) (P < 0.001) and a decline in sexual functioning (discomfort, pleasure) (P ≤ 0.0001), but had no impact on overall QOL (P = 0.31). HRT mitigated, but did not eliminate the adverse effects. Women who were postmenopausal at surgery (n = 47) experienced an increase in physical symptoms (P = 0.03) and a decline in sexual functioning (discomfort) (P = 0.004) and in overall QOL (P = 0.04). CONCLUSIONS: This study demonstrates that 3.5 years after oophorectomy, BRCA mutation carriers experience a significant worsening of menopausal symptoms and a decline in sexual functioning, particularly among those who underwent surgery prior to natural menopause. The use of HRT mitigated some but not all the effects. Overall, women who were premenopausal at surgery did not experience a decline in their QOL.

Analogs of human genetic skin disease in domesticated animals.

Genetic skin diseases encompass a vast, complex, and ever expanding field. Recognition of the features of these diseases is important to ascertain a correct diagnosis, initiate treatment, consider genetic counseling, and refer patients to specialists when the disease may impact other areas. Because genodermatoses may present with a vast array of features, it can be bewildering to memorize them. This manuscript will explain and depict some genetic skin diseases that occur in both humans and domestic animals and offer a connection and memorization aid for physicians. In addition, we will explore how animal diseases serve as a model to uncover the mechanisms of human disease. The genetic skin diseases we will review are pigmentary mosaicism, piebaldism, albinism, Griscelli syndrome, ectodermal dysplasias, Waardenburg syndrome, and mucinosis in both humans and domesticated animals.

Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation.

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 peritoneal (n = 32) cancer, of whom 68 have died. HR for ovarian, fallopian, or peritoneal cancer associated with bilateral oophorectomy was 0.20 (95% CI, 0.13 to 0.30; P < .001). Among women who had no history of cancer at baseline, HR for all-cause mortality to age 70 years associated with an oophorectomy was 0.23 (95% CI, 0.13 to 0.39; P < .001). CONCLUSION: Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.

Chemotherapy-induced amenorrhea in patients with breast cancer with a BRCA1 or BRCA2 mutation.

PURPOSE: To determine the likelihood of long-term amenorrhea after treatment with chemotherapy in women with breast cancer who carry a BRCA1 or BRCA2 mutation. PATIENTS AND METHODS: We conducted a multicenter survey of 1,954 young women with a BRCA1 or BRCA2 mutation who were treated for breast cancer. We included premenopausal women who were diagnosed with invasive breast cancer between 26 and 47 years of age. We determined the age of onset of amenorrhea after breast cancer for women who were and were not treated with chemotherapy, alone or with tamoxifen. We considered chemotherapy-induced amenorrhea to have occurred when the patient experienced ≥ 2 years of amenorrhea, commencing within 2 years of initiating chemotherapy, with no resumption of menses. RESULTS: Of the 1,426 women who received chemotherapy, 35% experienced long-term amenorrhea. Of the 528 women who did not receive chemotherapy, 5.3% developed long-term amenorrhea. The probabilities of chemotherapy-induced amenorrhea were 7.2% for women diagnosed before age 30 years, 33% for women age 31 to 44 years, and 79% for women diagnosed after age 45 years (P trend < .001). The probability of induced amenorrhea was higher for women who received tamoxifen than for those who did not (52% v 29%; P < .001). CONCLUSION: Age at treatment and use of tamoxifen are important predictors of chemotherapy-induced amenorrhea in women who carry a BRCA1 or BRCA2 mutation. The risk of induced long-term amenorrhea does not seem to be greater among mutation carriers than among women who do not carry a mutation.

Frequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation.

OBJECTIVE: To evaluate the impact of carrying a BRCA1 or BRCA2 mutation on the probability of experiencing premature natural menopause. DESIGN: Observational study. SETTING: Patients in an academic research environment. PATIENT(S): Women who carry a BRCA1 or BRCA2 mutation (case subjects) and women who do not carry a mutation (control subjects). INTERVENTION(S): Survey about reproductive history administered on study entry and every 2 years thereafter. MAIN OUTCOME MEASURE(S): The impact of carrying a BRCA mutation on age at menopause and other factors, including parity, age at first birth, age at last birth, and self-reported fertility. RESULT(S): A total of 908 matched pairs were identified. The mean age at natural menopause was 48.8 years for BRCA1 carriers, 49.2 years for BRCA2 carriers, and 50.3 years for control subjects. Women who carried a BRCA mutation had parity similar to noncarriers and were as likely as noncarriers to have a child after age 35 years. Similar proportions reported a history of fertility problems (12.5% vs. 13.7%) and use of fertility medication (6.0% vs. 7.0%). CONCLUSION(S): Women who carry a BRCA mutation experience menopause earlier, on average, than women who do not have a mutation, but the difference is small and does not appear to affect fertility.

The impact of prophylactic salpingo-oophorectomy on quality of life and psychological distress in women with a BRCA mutation.

OBJECTIVES: The objective of this study was to measure the impact of prophylactic salpingo-oophorectomy on health-related quality of life and psychological distress in women. METHODS: Women who underwent prophylactic salpingo-oophorectomy between August 20, 2003 and June 26, 2008 because of a BRCA1 or BRCA2 mutation were invited to participate. Participants completed three questionnaires (SF-12(®) Health Survey, Brief Symptom Inventory and the Impact of Events Scale) before prophylactic surgery and again 1 year after surgery. Measures of health-related quality of life, of general psychological distress and of ovarian cancer worry before and after surgery were compared. RESULTS: Few women who underwent salpingo-oophorectomy experienced a worsening in physical or mental health functioning after salpingo-oophorectomy. On average, women experienced less ovarian cancer-specific worry after surgery; 34.3% experienced moderate to severe ovarian cancer-specific distress before surgery, compared with 18.6% after surgery. CONCLUSIONS: For most women, physical and mental health-related quality of life did not deteriorate after prophylactic salpingo-oophorectomy, and they were less worried about ovarian cancer. A subset of women continued to experience moderate to severe cancer-specific distress. Identification of these women is important in order to provide continued counseling and support.

BRCA carriers, prophylactic salpingo-oophorectomy and menopause: clinical management considerations and recommendations.

Women who inherit a mutation in either the BRCA1 or BRCA2 gene have greatly elevated lifetime risks of ovarian cancer, fallopian tube cancer and breast cancer. Preventive surgical removal of the ovaries and fallopian tubes (salpingo-oophorectomy) is recommended to these women, often prior to natural menopause, to prevent cancer. The ensuing hormone deprivation may impact on health and quality of life. Most of these women experience menopausal symptoms shortly after surgery; however, there may also be longer term consequences that are less well understood. In this review, we highlight recent studies that examine the implications of salpingo-oophorectomy on health and quality of life in BRCA-positive women and we discuss the care of women following prophylactic surgery.

Quality of life and health status after prophylactic salpingo-oophorectomy in women who carry a BRCA mutation: A review.

Prophylactic salpingo-oophorectomy is recommended to women who carry a BRCA1 or BRCA2 mutation at age 35 or after childbearing is complete. This procedure is the mainstay of ovarian and fallopian tube cancer prevention in these women. Therefore an understanding of the short and long-term impact of the surgery is essential. Salpingo-oophorectomy, particularly when done prior to natural menopause, may impact on several aspects of quality of life and health. The health benefits of this surgery (cancer prevention) should outweigh the costs of the procedure in terms of quality of life and long term health. In this review, the impact of this surgery on quality of life and health in women who carry a BRCA mutation is discussed. Preliminary studies have focused on short-term effects, such as quality of life. In the short term, overall quality of life appears to be similar before and after surgery, however vasomotor symptoms related to surgical menopause and changes in sexual functioning are common. HRT appears to mitigate some but not all of these symptoms. Women report high levels of satisfaction with their decision to have the surgery despite the impact of prophylactic salpingo-oophorectomy. Studies of the long term health and quality of life after salpingo-oophorectomy in women who carry a BRCA mutation have not yet been published.

Risk factors for non-invasive lesions of the fallopian tube in BRCA mutation carriers.

OBJECTIVE: To identify risk factors for the presence of a non-invasive lesion of the fallopian tube in women with a BRCA1 or BRCA2 mutation. METHODS: 173 BRCA mutation carriers underwent a prophylactic salpingo-oophorectomy at the University Health Network, Toronto between 2000 and 2008 and were evaluated for the presence of a non-invasive lesion of the fallopian tube. Patients were classified as having p53 overexpression ("p53-signature"), a tubal intra-epithelial carcinoma (TIC) or normal tubal epithelium. We obtained a risk factor questionnaire from all patients. We calculated odds ratios for several risk factors, comparing patients with a tubal abnormality to those with normal histology. RESULTS: Of the 173 patients, 43 (25%) were found to have a tubal lesion, including 23% of the BRCA1 mutation carriers and 27% of the BRCA2 mutation carriers. The prevalence of a non-invasive tubal lesion increased with age; an abnormality was present in 5% of women who had surgery before the age of 40 (1 of 12) and in 56% of women who underwent surgery at age 60 or above (6 of 13; p=0.004). A non-invasive lesion of either type was found in 31.2% of women with a BMI > 25 kg/m2) compared to 18.0% of patients with a BMI < 25 kg/m2 at the time of surgery (p=0.05). The average duration of oral contraceptive use among women with normal tubes was 6.0 years, compared to an average duration of 4.0 years for women with a p53 signature (p=0.09) and was 2.7 years for women with a TIC (p=0.0003). CONCLUSION: The prevalence of tubal p53 signature and TIC increases with age at salpingectomy and with BMI. Oral contraceptive use is associated with a decrease in the prevalence of TICs.

Prevalence of BRCA1 and BRCA2 germ line mutations among women with carcinoma of the fallopian tube.

OBJECTIVES: The purpose of this study is to determine the prevalence of BRCA1 and BRCA2 mutations among a large series of women with carcinoma of the fallopian tube. METHODS: Two series of women diagnosed with carcinoma of the fallopian tube were studied. Women identified from the Ontario Cancer Registry who were diagnosed with fallopian tube cancer between 1990 and 1998 and between 2002 and 2004. A second, hospital-based series was identified at Cedars Sinai Medical Centre, Los Angeles, California. These women were diagnosed between 1991 and 2007. Each subject was approached to provide her family history and ethnic background and to provide a blood sample for genetic testing for mutations in the BRCA1 and BRCA2 genes. RESULTS: In total, 108 patients with fallopian tube cancer were recruited (70 from Ontario and 38 from Los Angeles). Thirty-three patients (30.6%) were found to have a deleterious mutation; 23 in BRCA1 (21.3%) and 10 in BRCA2 (9.3%). The prevalence of mutations was 55.6% in Jewish women and was 26.4% in non-Jewish women. A family history of ovarian or breast cancer was positive for 24 women (23.3%); of these, 14 had a mutation (58.3%). Fourteen (14.4%) of the patients had a previous history of breast cancer; of these, 10 (71.4%) had a mutation. 40.3% of the women who were diagnosed with fallopian tube cancer before age 60 had a mutation, compared with 17.4% of the women diagnosed at age 60 and above. CONCLUSIONS: Approximately 30% of women with fallopian tube cancer have a mutation in BRCA1 or BRCA2. The highest frequencies of BRCA mutations were seen in women with fallopian tube cancer diagnosed under age 60, in Jewish women, in women with a family history of breast or ovarian cancer, and in women with a personal history of breast cancer. All patients diagnosed with invasive fallopian tube cancer should be considered candidates for genetic testing.

Risk factors for carcinoma of the fallopian tube in women with and without a germline BRCA mutation.

OBJECTIVE: The purpose of this study was to identify risk factors for fallopian tube cancer in women with and without a BRCA mutation. METHODS: Subjects with fallopian tube cancer were identified from two sources: 1) a large international registry of women who carry a BRCA1 or BRCA2 mutation (n=56), and; 2) a population-based study of ovarian and fallopian tube cancer conducted in Ontario, Canada (n=66). BRCA mutation status was established for all subjects. Each subject was matched to one or more unaffected controls, for date of birth (within four years), for BRCA mutation status (negative, BRCA1, and BRCA2), for country of residence and for past history of breast cancer (yes/no). All subjects completed a questionnaire about medical history and lifestyle factors. Odds ratios and 95% confidence intervals were calculated for parity, oral contraceptive use, tubal ligation, hormone replacement therapy and body mass index, using conditional logistic regression. RESULTS: We studied 103 women with fallopian tube cancer (48 with a BRCA1 mutation, 12 with a BRCA2 mutation and 43 with no identified BRCA mutation) and 980 matched controls. Increasing parity was associated with a decreased risk of fallopian tube cancer in non-carriers (trend per birth odds ratio 0.71 (95% CI 0.52-0.97), p=0.03), in BRCA1 carriers (OR=0.79 (0.62-1.02) p=0.07) and in BRCA2 carriers (OR=0.62 (0.34-1.15), p=0.13), but was statistically significant only for non-carriers. Oral contraceptive use was associated with a reduced risk in BRCA1 carriers (trend per year of use odds ratio=0.91 (0.83-0.99), p=0.03) but not for non-carriers (OR=0.97 (0.87-1.09), p=0.64) or for BRCA2 carriers (OR=0.94 (0.80-1.11), p=0.47). Hormone replacement therapy was associated with an increased risk for fallopian tube cancer in all subjects (OR=1.07 (1.01-1.13), p=0.03), and in the subgroups stratified by mutation, however the association was not significant in the subgroups. Tubal ligation was associated with a decreased risk of fallopian tube cancer for all subjects (OR=0.64 (0.31-1.28), p=0.21), however the reduction was not significant. CONCLUSIONS: Parity and oral contraceptive use are associated with reduced risks of fallopian tube cancer. In contrast, hormone replacement therapy may be associated with an increase in the risk of fallopian tube cancer.

The effectiveness of family history questionnaires in cancer genetic counseling.

The number of individuals receiving genetic counseling for hereditary breast and ovarian cancer syndrome has steadily risen. To triage patients for genetic counseling and to help reduce the amount of time needed by a genetic counselor in direct patient contact, many clinics have implemented the use of family history questionnaires. Although such questionnaires are widely used, scant literature exists evaluating their effectiveness. This article explores the extent to which family history questionnaires are being used in Ontario and addresses the utility of such questionnaires in one familial cancer clinic. By comparing the pedigrees created from questionnaires to those updated during genetic counseling, the accuracy and effectiveness of the questionnaires was explored. Of 121 families recruited into the study, 12% acquired changes to their pedigree that led to a revised probability estimate for having a BRCA1 or BRCA2 mutation and 5% acquired changes that altered their eligibility for genetic testing. No statistically significant difference existed between the eligibility for genetic testing prior to and post counseling. This suggests that family history questionnaires can be effective at obtaining a family history and accurately assessing eligibility for genetic testing. Based on the variables that were significantly associated with a change in probability estimate, we further present recommendations for improving the clarity of such questionnaires and therefore the ease of use by patients.

Variation in rates of uptake of preventive options by Canadian women carrying the BRCA1 or BRCA2 genetic mutation.

BACKGROUND: Women with a BRCA1 or BRCA2 genetic mutation have several options for cancer prevention, including prophylactic surgery, chemoprevention and screening. In this study we report on preventive practices used by women with and without breast cancer and examine differences in their selection of preventive practices according to geographic area in Canada. METHODS: Canadian women with a BRCA1 or BRCA2 mutation were followed after genetic testing and questioned about their preventive practices. Women reported on uptake of prophylactic mastectomy, prophylactic oophorectomy, tamoxifen or raloxifene usage and screening practices. We analyzed the uptake of each preventive option and completed a subanalysis according to the geographic area in Canada where genetic testing was provided. RESULTS: The study included 672 women. Follow-up questionnaires were completed after a mean of 4.0 years (range 1.6-9.1 years). Of the 342 women without breast cancer, 72 (21%) had had a prophylactic bilateral mastectomy. Three hundred and sixty-three women (54%) had had a bilateral prophylactic oophorectomy. Seventeen (6%) of the 270 women without breast cancer who had not had a prophylactic mastectomy took tamoxifen, and 12 (4%) reported taking raloxifene. Of the 342 women without breast cancer, 157 (46%) had not undertaken any cancer prevention option (mastectomy, oophorectomy or treatment with tamoxifen or raloxifene). Sixty-five (39%) of the 167 women from Ontario, 19 (34%) of the 56 women from Western Canada and 73 (62%) of the 119 women from Quebec had not undertaken any preventive procedure. CONCLUSION: Significant differences in the uptake of preventive options by women with a BRCA1 or BRCA2 mutation were observed across 3 regions of Canada. Future research is needed to explain why these differences exist.

The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study.

OBJECTIVE: To evaluate the risk of endometrial cancer in women who carry a deleterious mutation in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: Women known to carry a BRCA1 or BRCA2 mutation, aged 45 to 70, were identified from an international registry and were followed prospectively. A total of 857 women completed a baseline questionnaire and one or more follow-up questionnaires. Study subjects were followed until diagnosis of endometrial cancer, ovarian cancer, death or the date of completion of the last questionnaire. The expected number of endometrial cancers was calculated using age and country-specific incidence rates. RESULTS: After an average follow-up period of 3.3 years, six women were diagnosed with endometrial cancer, compared to 1.13 cancers expected (SIR=5.3, p=0.0011). Four of these six patients used tamoxifen in the past. The risk among women who were never exposed to tamoxifen treatment was not significantly elevated (SIR=2.7, p=0.17), but among the 226 participants who had used tamoxifen (220 as treatment and six for the primary prevention of breast cancer) the relative risk for endometrial cancer was 11.6 (p=0.0004). CONCLUSION: The main contributor to the increased risk of endometrial cancer among BRCA carriers is tamoxifen treatment for a previous breast cancer. The risk and benefits of prophylactic hysterectomy should be discussed with women with a BRCA mutation considering tamoxifen therapy.

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

CONTEXT: Women with BRCA1 or BRCA2 mutation are often advised to undergo preventive oophorectomy. The effectiveness of this intervention has not been prospectively evaluated in a large cohort. OBJECTIVES: To estimate the incidence of ovarian, fallopian tube, and primary peritoneal cancer in women who carry a deleterious mutation in BRCA1 or BRCA2. To estimate the reduction in risk of these cancers associated with a bilateral prophylactic salpingo-oophorectomy. DESIGN, SETTING, AND PARTICIPANTS: Women known to carry a BRCA1 or BRCA2 mutation were identified from an international registry between 1992 and 2003. A total of 1828 carriers at 1 of 32 centers in Canada, the United States, Europe, and Israel completed questionnaires at baseline and follow-up. Participants were observed from the date of study entry until: diagnosis of ovarian, fallopian tube, or peritoneal cancer; death; or the date of the most recent follow-up. INTERVENTION: Participants were divided into women who had undergone bilateral prophylactic oophorectomy and those who had not. MAIN OUTCOME MEASURE: The incidence of ovarian, peritoneal, and fallopian tube cancer was determined by survival analysis. The risk reduction associated with prophylactic salpingo-oophorectomy was evaluated by a time-dependent survival analysis, adjusting for covariates. RESULTS: After a mean follow-up of 3.5 years, 50 incident ovarian, fallopian tube, and peritoneal cancer cases were reported in the cohort. Of the 1828 women, 555 (30%) underwent a bilateral prophylactic salpingo-oophorectomy prior to study entry, 490 (27%) underwent the procedure after entering the study, and 783 (43%) did not undergo the procedure. There were 32 incident cancers diagnosed in women with intact ovaries (1015/100,000 per year). Eleven cancer cases were identified at the time of prophylactic oophorectomy and 7 were diagnosed following prophylactic oophorectomy (217/100,000 per year). The estimated cumulative incidence of peritoneal cancer is 4.3% at 20 years after oophorectomy. The overall (adjusted) reduction in cancer risk associated with bilateral oophorectomy is 80% (multivariate hazard ratio = 0.20; 95% confidence interval, 0.07-0.58; P = .003). CONCLUSION: Oophorectomy is associated with reduced risk of ovarian and fallopian tube cancer in high-risk women, although there is a substantial residual risk for peritoneal cancer in BRCA1 and BRCA2 mutation carriers following prophylactic salpingo-oophorectomy.