Does a BRCA mutation plus tamoxifen equal hysterectomy?
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Antineoplastic Agents, Hormonal↗
Biomedical subjects
Noah D Kauff
Publications and source records attributed to Noah D Kauff.
The significance of cytological mesothelial atypia diagnosed from peritoneal washings performed during risk-reducing salpingo-oophorectomy.
OBJECTIVE: Occult cancer may be found in a small proportion of women undergoing risk-reducing salpingo-oophorectomy (RRSO). However, the results and significance of peritoneal wash cytology in this setting are not clear. The objective of this study was to determine the significance of cytologic mesothelial atypia in the peritoneal washings of patients undergoing RRSO. METHODS: We conducted a retrospective chart review of all patients undergoing RRSO from July 2002 to December 2003. Patient charts were reviewed for information regarding cytology, pathology, demographics, surgical procedure and findings, and outcome. RESULTS: One hundred thirty women underwent RRSO during the study period. One hundred seventeen had washings performed during the procedure and constitute the study cohort. The median age at the time of the procedure was 48 years (range, 33-78 years). Final cytology was reported as normal in 102 patients (87%), mesothelial atypia in 13 (11%), and non-satisfactory in 2 (2%). Ovarian and tubal histopathology was normal in all cases. No association was found between mesothelial atypia and age, prior breast cancer, or prior abdominal surgery. Twenty-nine patients had previously undergone genetic testing for BRCA1/2 mutations as part of ongoing prospective follow-up studies. Four (24%) of 17 patients with a known BRCA1 or BRCA2 mutation were found to have mesothelial atypia compared to 1 (8%) of 12 with no mutation. With a median follow-up time of 20 months (range, 1-40 months), none of the patients with mesothelial atypia were diagnosed with peritoneal malignancy following RRSO. CONCLUSION: In this study, mesothelial atypia was identified in 11% of patients who had peritoneal washings performed at the time of RRSO. No patients with mesothelial atypia went on to develop peritoneal carcinoma. The link between mesothelial atypia and mutations in BRCA1/2 and the need to perform peritoneal washings in this setting are both yet to be determined.
Adult↗
Reducing the risk of gynecologic cancer in the Lynch syndrome.
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Colorectal Neoplasms, Hereditary Nonpolyposis↗
Effect of mammography on breast cancer risk in women with mutations in BRCA1 or BRCA2.
Women who carry mutations in either the BRCA1 or BRCA2 genes are at risk for early-onset breast cancer and are recommended to begin screening mammography at age 25 to 30 years. Results of in vitro and animal studies suggest that BRCA1/BRCA2 mutation carriers are hypersensitive to ionizing radiation and possibly to radiation-induced breast cancer. This study was undertaken to investigate the association of low-dose radiation exposure from mammograms with breast cancer status in BRCA mutation carriers. One hundred sixty-two female mutation carriers provided information at time of genetic testing about exposure to mammograms before enrollment. Using unconditional logistic regression, breast cancer status was not associated with number of mammograms received before diagnosis (affected women) or ascertainment [unaffected women; adjusted odds ratio (OR), 0.94; P = not significant]. A larger group of 213 women provided information about lifetime number of mammograms. There was no association between mammogram exposure and risk in the group as a whole (adjusted OR, 1.04; P = not significant), although there was a modest association in BRCA1 carriers (adjusted OR, 1.08; P = 0.03). These findings indicate that screening mammography is unlikely to be associated with a large increase in breast cancer risk in this population.
Adult↗
Risk of ovarian cancer in BRCA1 and BRCA2 mutation-negative hereditary breast cancer families.
Women from site-specific hereditary breast cancer families who carry a BRCA1 or BRCA2 mutation are at increased risk for ovarian cancer. It is less clear, however, whether individuals from hereditary breast cancer families who do not carry such a mutation are also at increased ovarian cancer risk. To determine whether women from BRCA mutation-negative hereditary breast cancer families are at increased risk for ovarian cancer, 199 probands from BRCA mutation-negative, site-specific breast cancer kindreds who consented to prospective follow-up at the time of genetic testing were identified. The incidence of new breast and ovarian cancers in probands and their families since receipt of their genetic test results was determined by questionnaire. The expected number of cancers and standardized incidence ratios (SIRs) were determined from age-specific cancer incidence rates from the Surveillance, Epidemiology, and End Results (SEER) program by using the method of Byar. All statistical tests were two-sided. During 2534 women-years of follow-up in 165 kindreds, 19 new cases of breast cancer were diagnosed, whereas only 6.07 were expected (SIR = 3.13, 95% confidence interval [CI] = 1.88 to 4.89; P < .001), and one case of ovarian cancer was diagnosed, whereas only 0.66 was expected (SIR = 1.52, 95% CI = 0.02 to 8.46; P = .48). These results suggest that women from BRCA mutation-negative, site-specific breast cancer families are not at increased risk for ovarian cancer.
Adult↗
Laparoscopic bilateral salpingo-oophorectomy in breast cancer patients after transverse rectus abdominus myocutaneous flap reconstructive surgery.
OBJECTIVE: The aim of this study was to describe the feasibility and outcome of laparoscopic risk-reducing salpingo-oophorectomy (RRSO) in patients with a history of breast cancer who previously had undergone a transverse rectus abdominus myocutaneous (TRAM) flap reconstruction. METHODS: We performed a retrospective review of patients with a history of breast cancer who had undergone laparoscopic RRSO between February 1995 and April 2002. Patients who had undergone TRAM flap reconstructive surgery were compared with patients who had undergone laparoscopic RRSO without prior reconstructive surgery. RESULTS: We identified 102 patients with a history of breast cancer who were candidates for a laparoscopic RRSO during the study period. One hundred one of these patients underwent the procedure, including 10 patients with a history of TRAM flap breast reconstructive surgery. One patient did not undergo the procedure because she was noted to be hypotensive prior to the procedure from her bowel preparation. There were no differences between the groups with or without prior history of TRAM flap reconstruction with respect to body mass index, prior abdominal surgery, menopausal status, or preoperative ultrasound characteristics. Operatively, there was no difference between the groups with respect to estimated blood loss, hospital stay, and intraoperative and postoperative complication rates. The only noted difference between the two groups was the estimated operating time (TRAM group, 91 min; non-TRAM group, 70 min [P<0.01]). CONCLUSIONS: Laparoscopic RRSO is safe and feasible in patients who have undergone a prior TRAM flap reconstruction.
Adult↗
Ovarian carcinoma screening in women at intermediate risk: impact on quality of life and need for invasive follow-up.
BACKGROUND: Women with family histories suggestive of an increased risk of ovarian carcinoma who have not had a deleterious BRCA1 or BRCA2 mutation identified are commonly suggested to consider ovarian carcinoma screening with transvaginal ultrasound and/or assessment of CA 125 levels. Limited information is available regarding the impact of this approach on either quality of life (QOL) or need for invasive follow-up in this group of women. METHODS: From November 1999 to October 2002, 184 women at intermediate risk of ovarian carcinoma were enrolled in a prospective study. Participants were screened with twice yearly transvaginal ultrasound and CA 125 assessments. Impact on QOL was measured using the Mental Component Summary (MCS) score of the Medical Outcomes Studies Short Form-36. Need for invasive follow-up was determined by questionnaire and medical record review. RESULTS: In the current study, 135 participants underwent > or = 1 follow-up assessment. During a mean of 19.8 months of follow-up, 12.9% of ultrasounds and 3.8% of CA 125 assessments were abnormal. The authors reported that 38.5% of participants had > or = 1 abnormal ovarian screen that required a short interval follow-up. Because of either abnormal bleeding or ultrasound abnormalities, 24% of participants underwent > or = 1 endometrial sampling. Controlling for a history of breast carcinoma and menopausal status, abnormal ovarian screening results were associated with a decrease in MCS score (P = 0.034), whereas the need for endometrial sampling was not (P = 0.87). CONCLUSIONS: Ovarian carcinoma screening in women at intermediate risk was associated with a substantial rate of abnormal screen results, endometrial sampling, and in women with abnormal ovarian screening findings, a decrease in MCS scores. These findings may have important implications for women considering ovarian carcinoma screening and for the design of future ovarian carcinoma screening trials.
CA-125 Antigen↗
BRCA mutations and risk of prostate cancer in Ashkenazi Jews.
PURPOSE: The Breast Cancer Linkage Consortium and other family-based ascertainments have suggested that male carriers of BRCA mutations are at increased risk of prostate cancer. Several series looking at the frequency of BRCA mutations in unselected patients with prostate cancer have not confirmed this finding. To clarify this issue, we conducted a large case-control study. EXPERIMENTAL DESIGN: Blood specimens from 251 unselected Ashkenazi men with prostate cancer were screened for the presence of one of the three common Ashkenazi founder mutations in BRCA1 and BRCA2. The incidence of founder mutations was compared with the incidence of founder mutations in 1472 male Ashkenazi volunteers without prostate cancer using logistic regression analysis after adjusting for age. RESULTS: Thirteen (5.2%) cases had a deleterious mutation in BRCA1 or BRCA2 compared with 28 (1.9%) controls. After adjusting for age, the presence of a BRCA1 or BRCA2 mutation was associated with the development of prostate cancer (odds ratio, 3.41; 95% confidence interval, 1.64-7.06; P = 0.001). When results were stratified by gene, BRCA2 mutation carriers demonstrated an increased risk of prostate cancer (odds ratio, 4.78; 95% confidence interval, 1.87-12.25; P = 0.001), whereas the risk in BRCA1 mutation carriers was not significantly increased. CONCLUSIONS: BRCA2 mutations are more likely to be found in unselected individuals with prostate cancer than age-matched controls. These results support the hypothesis that deleterious mutations in BRCA2 are associated with an increased risk of prostate cancer.
Adult↗
Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer.
Mutations in BRCA1 and BRCA2 that predispose to breast and ovarian cancer are detected in approximately 2.5% of the Ashkenazi Jewish population. To explore whether carriers of Ashkenazi founder mutations in BRCA1 or BRCA2 have an increased risk for colorectal cancer, we screened 586 unselected Ashkenazi Jewish case patients with colorectal cancer for the three common founder mutations in BRCA1 and BRCA2. We identified six carriers (1.02%) among these case patients. After adjusting for age at diagnosis and sex by use of logistic regression analysis, we compared the incidence of carriers in this group of 586 case patients with that of 5012 Ashkenazi Jewish control subjects without a known history of colorectal cancer. The presence of a founder BRCA mutation was not associated with the risk of colorectal cancer (relative risk = 0.50, 95% confidence interval = 0.22 to 1.14). We thus recommend that counseling for colorectal cancer screening and prevention in individuals with BRCA mutations be based on the personal and family history of colorectal cancer or associated syndromic malignancies.
Adult↗
Hereditary ovarian cancer in Ashkenazi Jews.
Ovarian cancer is the fourth leading cause of cancer deaths among American women. While women in both the Ashkenazi and non-Ashkenazi populations have an estimated 1.7% lifetime risk of acquiring malignancy, the proportion of hereditary ovarian cancer is much higher in the Ashkenazim. Most of this increased proportion of hereditary ovarian cancer risk is accounted for by inherited mutations in the BRCA1 and BRCA2 genes. In the Ashkenazi Jewish population, 29 to 41% of ovarian cancer is believed to be secondary to inheriting one of three founder mutations in BRCA 1 and BRCA 2, while only 10% of ovarian cancer is attributed to mutations of these genes in non-Ashkenazim. In the US population in general, it is estimated that between 1 out of 345 and 1 out of 1000 individuals carries a BRCA mutation, compared with approximately 1 in 40 individuals of Ashkenazi Jewish descent. The ovarian cancer risk up to age 70 associated with BRCA mutation carriers has been reported to be as high as 66% for BRCA1 and 27% for BRCA2 mutation carriers. Ovarian cancer in Ashkenazi kindreds has served as a model for the study of the histopathology of inherited ovarian cancers as well as for the study of risk reduction and screening among all women at inherited risk of ovarian cancer.
Adult↗
Surgical risk-reduction in carriers of BRCA mutations: where do we go from here?
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Fallopian Tube Neoplasms↗
Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations.
BACKGROUND: It has been suggested that BRCA-associated breast carcinoma may often lack a detectable preinvasive phase. To investigate this hypothesis, the authors compared the prevalence of histopathologic lesions in prophylactic mastectomy (PM) specimens from women with BRCA mutations and in mastectomy specimens obtained at autopsy from an age and race-matched comparison group without a known cancer predisposition. METHODS: All specimens from women with a deleterious BRCA1 or BRCA2 mutation who participated in an ongoing follow-up study and underwent PM at Memorial Sloan-Kettering Cancer Center between November 1, 1987 and May 31, 2001 were reviewed. For each case, breast tissue from two age and race-matched women without a known cancer predisposition was also reviewed. The prevalence of benign, premalignant, and cancerous lesions was compared. RESULTS: Mastectomy specimens from 24 cases and 48 comparison subjects were reviewed. Ductal carcinoma in situ (DCIS), atypical ductal hyperplasia (ADH), and atypical lobular hyperplasia (ALH) were all more common in PM specimens from women with BRCA mutations than in those from the comparison group. The odds ratio for the detection of any high-risk lesion (DCIS, lobular carcinoma in situ, ADH, or ALH) in specimens from BRCA mutation carriers was 12.7 (95% confidence interval, 3.1-52.4; P < 0.001). CONCLUSIONS: Lesions associated with an increased risk of subsequent malignancy are more common in PM specimens from women with BRCA mutations than in breast tissue obtained at autopsy from unaffected women without a known predisposition. This finding suggests that hereditary breast carcinoma has a preinvasive phase that may be detectable with aggressive surveillance.
Adult↗
Pre- and postmenopausal high-risk women undergoing screening for ovarian cancer: anxiety, risk perceptions, and quality of life.
OBJECTIVE: Recommendations for women at high risk of ovarian cancer include prophylactic salpingo-oophorectomy (PSO) or screening with transvaginal ultrasonography (TVUS) and CA125 levels. The best strategy for improving survival and maintaining quality of life in high-risk women is not known. Premenopausal women may be more reluctant than postmenopausal women to undergo PSO. However, the risk of false-positive screening results may be more likely in premenopausal women, posing potential psychological risk for those enrolled in high-risk ovarian cancer surveillance programs. We sought to determine whether anxiety, depression, perception of ovarian cancer risk, and false-positive test frequency differed between high-risk premenopausal and postmenopausal women initiating ovarian cancer screening. METHODS: High-risk women aged > or = 30 years enrolling in a TVUS plus CA125 ovarian cancer screening study completed standard QOL (SF-36), cancer-specific anxiety (IES), depression (CES-D), and ovarian cancer risk perception measures. CA125 > 35 and TVUS showing solid or complex cystic ovarian masses were considered abnormal. Abnormal tests were repeated after 4-6 weeks. Persistently abnormal tests prompted a search for malignancy. Tests that normalized on repeat were considered false positive. RESULTS: One hundred forty-seven high-risk women, median age 46 (range, 30-78), 78 premenopausal and 69 postmenopausal, had > or = 1 TVUS/CA125/outcome assessment. Premenopausal women were more likely than postmenopausal women to consider themselves at higher risk of ovarian cancer compared with women their age (P < 0.001) and compared with women with similar family histories (P < 0.001). Mean personal perception of lifetime risk of ovarian cancer among premenopausal women was 37% (range, 0-90%) versus 26% (range, 0-60%) among postmenopausal women (P = 0.02). While general QOL and depression scores were similar, 38% of premenopausal women reported high anxiety versus 27% of postmenopausal women (P = 0.03). Thirty percent of women required repeat CA125 or TVUS after first screening; 10.8% of premenopausal women versus 4.6% of postmenopausal women required repeat CA125; and 23.3% of premenopausal and 20.6% of postmenopausal women required repeat TVUS. One postmenopausal woman with persistently rising CA125 >100 had negative mammography, colonoscopy, and dilation and curettage/bilateral salpingo-oophorectomy. All other abnormal tests normalized on repeat. Two premenopausal women withdrew due to anxiety following false-positive CA125 results. Five women (2 premenopausal, 3 postmenopausal) with normal TVUS/CA125 screening tests elected PSO, with benign findings. CONCLUSION: Premenopausal women perceive their ovarian cancer risk to be higher, report greater ovarian cancer risk-related anxiety, and are more likely to have false-positive screening results than postmenopausal women. Few high-risk women elect PSO in the short term. Knowledge of the frequency of false-positive screening results and psychosocial outcomes is important for high-risk women choosing strategies for managing ovarian cancer risk.
Adult↗
Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation.
BACKGROUND: Risk-reducing salpingo-oophorectomy is often considered by carriers of BRCA mutations who have completed childbearing. However, there are limited data supporting the efficacy of this approach. We prospectively compared the effect of risk-reducing salpingo-oophorectomy with that of surveillance for ovarian cancer on the incidence of subsequent breast cancer and BRCA-related gynecologic cancers in women with BRCA mutations. METHODS: All women with BRCA1 or BRCA2 mutations identified during a six-year period were offered enrollment in a prospective follow-up study. A total of 170 women 35 years of age or older who had not undergone bilateral oophorectomy chose to undergo either surveillance for ovarian cancer or risk-reducing salpingo-oophorectomy. Follow-up involved an annual questionnaire, telephone contact, and reviews of medical records. The time to cancer in the two groups was compared by Kaplan-Meier analysis and a Cox proportional-hazards model. RESULTS: During a mean follow-up of 24.2 months, breast cancer was diagnosed in 3 of the 98 women who chose risk-reducing salpingo-oophorectomy and peritoneal cancer was diagnosed in 1 woman in this group. Among the 72 women who chose surveillance, breast cancer was diagnosed in 8, ovarian cancer in 4, and peritoneal cancer in 1. The time to breast cancer or BRCA-related gynecologic cancer was longer in the salpingo-oophorectomy group, with a hazard ratio for subsequent breast cancer or BRCA-related gynecologic cancer of 0.25 (95 percent confidence interval, 0.08 to 0.74). CONCLUSIONS: Salpingo-oophorectomy in carriers of BRCA mutations can decrease the risk of breast cancer and BRCA-related gynecologic cancer.
Actuarial Analysis↗
Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations.
PURPOSE: Several studies to date have reported ovarian cancer risk due to inherited BRCA1 and BRCA2 mutations using familial data or population-based series of probands. Familial aggregation associated with both of these methods may result in a substantial ascertainment bias. To address this, we have used a case-control design that does not involve familial aggregation to estimate the lifetime penetrance of ovarian cancer due to BRCA1 and BRCA2 mutations. EXPERIMENTAL DESIGN: A total of 382 ovarian cancer cases self-identified as being Jewish with no prior diagnosis of breast cancer were derived from two hospital-based series. In the first series, all 197 invasive epithelial ovarian cancer cases self-identified as Jewish and without a prior history of breast cancer, diagnosed and treated at Memorial Sloan-Kettering Cancer Center between 1986 and 2000, were identified. In the second series, 185 Jewish invasive epithelial ovarian cancer patients without prior breast cancer were identified in a study conducted at 11 centers in North America and Israel from 1995 to 1996. Controls were 3434 Jewish women without any prior history of breast or ovarian cancer from a large study of genotyped volunteers of Jewish origin in the Washington, D. C. area recruited by investigators at the National Cancer Institute. The cases and controls were genotyped for three Ashkenazi Jewish founder mutations, namely 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. The lifetime penetrances were estimated using the odds ratios, mutation prevalence in the controls, and ovarian cancer incidence rates in the general American population obtained from the Surveillance, Epidemiology and End Results database adjusted for the incidence of ovarian cancer following breast cancer. RESULTS: Mutations were identified in 147 cases and 62 controls. The estimated penetrances at age 70 years were 37% (95% confidence interval, 25-71%) for a BRCA1 mutation and 21% (95% CI, 13-41%) for a BRCA2 mutation. CONCLUSIONS: The lifetime penetrances of BRCA1 mutations are lower than estimates obtained using familial data with multiple affected members but larger than estimates from some population-based proband series. The lifetime penetrance estimate of a BRCA2 mutation is in the range reported by some of the studies based on familial data. These results could have implications for clinical counseling, surgical interventions, and screening recommendations in women carrying these founder mutations.
Adult↗
Rare variants of ATM and risk for Hodgkin's disease and radiation-associated breast cancers.
PURPOSE: In this study, we first sought to evaluate whether individuals heterozygous for ATM mutations may have an increased susceptibility to radiation-induced breast cancer (BC) after treatment for Hodgkin's disease (HD). We next sought to determine the frequency of ATM variants in patients with Hodgkin's lymphoma, regardless of coexisting BC, compared with healthy volunteers. EXPERIMENTAL DESIGN: Full sequence analysis of ATM was performed on cDNA from peripheral blood lymphocytes from 37 cases of BC after therapeutic radiation therapy for HD and 27 comparison cases with HD and no BC treated during the same time period. The frequency of ATM variants was analyzed in the total group of 64 cases of HD and compared to allele frequencies in 128 ethnically matched controls from the same geographical region. RESULTS: No protein-truncating ATM mutations were observed in cases with HD with or without BC. Missense mutations were more frequent in the cohort with HD compared with patients with BC following HD (P = 0.02). The median time from HD to the development of BC was 18 years in patients with ATM variants compared with 16 years in those with no ATM variants (P = 0.04). Multiple ATM variants, including one homozygous mutation, were observed in 9 HD cases. CONCLUSIONS: Heterozygous protein-truncating or missense mutations of ATM were not associated with increased radiation-associated risk of BC after HD. The observation of multiple germ-line mutations and a homozygote suggests that rare ATM variants may constitute cancer-susceptibility alleles in a subset of cases.
Adolescent↗