Amy Finch

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.

The impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation

OBJECTIVE Prophylactic salpingo-oophorectomy is recommended to women who carry a BRCA1 or BRCA2 mutation to reduce the risks of breast, ovarian and fallopian tube cancer. We measured the impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual functioning in women with a BRCA mutation. METHODS Women who underwent prophylactic salpingo-oophorectomy between October 1, 2002 and June 26, 2008 for a known BRCA1 or BRCA2 mutation were invited to participate. Participants completed questionnaires before prophylactic surgery and again one year after surgery. Measures of sexual functioning and menopausal symptoms before and after surgery were compared. Satisfaction with the decision to undergo prophylactic salpingo-oophorectomy was evaluated. RESULTS 114 women who underwent prophylactic surgery completed questionnaires before and one year after surgery. Subjects who were premenopausal at the time of surgery (n=75) experienced a significant worsening of vasomotor symptoms (hot flashes, night sweats and sweating) and a decline in sexual functioning (desire, pleasure, discomfort and habit). The increase in vasomotor symptoms and the decline in sexual functioning were mitigated by HRT, but symptoms did not return to pre-surgical levels. HRT decreased vaginal dryness and dyspareunia; however, the decrease in sexual pleasure was not alleviated by HRT. Satisfaction with the decision to undergo prophylactic salpingo-oophorectomy remained high regardless of increased vasomotor symptoms and decreased sexual function. CONCLUSIONS Women who undergo prophylactic salpingo-oophorectomy prior to menopause experience an increase in vasomotor symptoms and a decrease in sexual functioning. These symptoms are improved by HRT, but not to pre-surgical levels.

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

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.

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.

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.

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.

BRCA mutations in Italian breast/ovarian cancer families.

Baudi et al. described the first example of a founder BRCA1 (MIM 113705) mutation specific to the Italian population. They studied 24 patients from unrelated breast/ovarian cancer families from the southern region of Calabria and found the 5083del19 mutation to be present four times. This single mutation accounted for four of the six BRCA1 mutations detected in the study. Haplotype analysis confirms the 5083del19 mutation to be a founder mutation. Here we present data on Italian breast/ovarian cancer families in North America, and ask whether or not this mutation is observed in these families. Founder mutations in BRCA1 and BRCA2 (MIM 600185) have been described in several Western European countries, but, to date, no population has demonstrated founder effects as striking as those observed for Icelandic and the Ashkenazi Jewish groups. ± 4 Table 1 summarises the different BRCA1 or BRCA2 mutations that have been reported in more than one family from various studies and regions of Italy. To date, only the BRCA1 5083del19 mutation is recurrent and specific to individuals of Italian descent; most mutations are also found in other European countries. At the Sunnybrook & Womens College Health Sciences Centre in Toronto, Canada, we evaluated DNA samples for germline mutations in BRCA1 and BRCA2 from 116 women with primary cancers of the breast or ovary, and with at least one parent with Italian ancestry. The 116 women participated in genetic studies for either clinical (high-risk families) or research (unselected patients) purposes. A variety of methods were employed for mutation analysis. All samples were tested for deleterious mutations in exons 10 and 11 of BRCA2 and exons 2, 5, 11, 16, 20 and exon 13 duplication of BRCA1. This testing covered the majority of mutations described previously for Italian patients (Table 1), revealing 29 of the 39 mutations (Table 2). Subsequent testing by direct sequencing (by Myriad Genetic Laboratories) revealed ten additional mutations in other exons. Thirty-nine BRCA1 or BRCA2 mutations were identified among the 116 families (33.6%); 23 in BRCA1 and 16 in BRCA2 (Table 2). In total, 19 of the 39 mutations (48.7%) were present in more than one family. Of particular significance was the detection of the BRCA1 exon 16 5083del19 in five families. Three of these five families, who European Journal of Human Genetics (2002) 10, 150 ± 152 ã 2002 Nature Publishing Group All rights reserved 1018-4813/02

The Effectiveness of Family History Questionnaires in Cancer Genetic Counseling

25.00