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Henry T. Lynch - One of the best experts on this subject based on the ideXlab platform.
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Bilateral Oophorectomy and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
2016Co-Authors: Joanne Kotsopoulos, Henry T. Lynch, Jacek Gronwald, Pal Moller, Tomasz Huzarski, Christian F. Singer, Susan ArmelAbstract:Background Whether oophorectomy reduces breast cancer risk among BRCA mutation carriers is a matter of debate. We undertook a prospective analysis of bilateral oophorectomy and breast cancer risk in BRCA mutation carriers. Methods Subjects had no history of cancer, had both breasts intact, and had information on oophorectomy status (n = 3722). Women were followed until breast cancer diagnosis, prophylactic bilateral mastectomy, or death. A Cox regression model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer associated with oophorectomy (coded as a time-dependent variable). All statistical tests were two-sided. Results Over a mean follow-up of 5.6 years, 350 new breast cancers were diagnosed. Among women with a BRCA1 or BRCA2 mutation, oophorectomy was not associated with breast cancer risk compared with women who did not undergo an oophorectomy. The age-adjusted hazard ratio associated with oophorectomy was 0.96 (95% CI = 0.73 to 1.26, P = 76) for BRCA1 and was 0.65 (95% CI = 0.37 to 1.16, P = 14) for BRCA2 mutation carriers. In stratified analyses, the effect of oophorectomy was statistically significant for breast cancer in BRCA2 mutation carriers diagnosed prior to age 50 years (age-adjusted HR = 0.18, 95% CI = 0.05 to 0.63, P = 007). Oophorectomy was not associated with risk of breast cancer prior to age 50 years among BRCA1 mutation carriers (age-adjusted HR = 0.79, 95% CI = 0.55 to 1.13, P = 51). Conclusions Findings from this large prospective study support a role of oophorectomy for the prevention of premenopausal breast cancer in BRCA2, but not BRCA1 mutation carriers. These findings warrant further evaluation.
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differences of variable number tandem repeats in xrcc5 promoter are associated with increased or decreased risk of breast cancer in brca gene mutation carriers
2016Co-Authors: Jian Cui, Henry T. Lynch, Carrie Snyder, Jiangtao Luo, Yeong C Kim, Dina Becirovic, Bradley Downs, San Ming WangAbstract:Ku80 is a subunit of the Ku heterodimer that binds to DNA double-strand break ends as part of the non-homologous end joining (NHEJ) pathway. Ku80 is also involved in homologous recombination (HR) via its interaction with BRCA1. Ku80 is encoded by the XRCC5 gene that contains a variable number tandem repeat (VNTR) insertion in its promoter region. Different VNTR genotypes can alter XRCC5 expression and affect Ku80 production, thereby affecting NHEJ and HR pathways. VNTR polymorphism is associated with multiple types of sporadic cancer. In this study, we investigated its potential association with familial breast cancer at germline level. Using PCR, PAGE, Sanger sequencing and statistical analyses, we compared VNTR genotypes in the XRCC5 promoter between healthy individuals and three types of familial breast cancer cases: mutated BRCA1 (BRCA1+), mutated BRCA2 (BRCA2+), and wildtype BRCA1/BRCA2 (BRCAx). We observed significant differences of VNTR genotypes between control and BRCA1+ group (P<0.0001) and BRCA2+ group (P=0.0042) but not BRCAx group (P=0.2185), and the differences were significant between control and cancer-affected BRCA1+ cases (P<0.0001) and BRCA2+ cases (P=0.0092) but not cancer-affected BRCAx cases (P=0.4251). Further analysis indicated that 2R/2R (OR=1.94, 95%CI=1.26-2.95, P=0.0096) and 2R/1R (OR=1.58, 95%CI=1.11-2.26, P=0.0038) were associated with increased risk but 1R/1R (OR=0.55, 95%CI=0.35-0.84, P=0.0196) and 1R/0R (OR=0, 95%CI=0-0.29, P=0.0012) were associated with decreased risk in cancer-affected BRCA1+ group; 2R/1R (OR=1.94, 95%CI=1.14-3.32, P=0.0242) was associated with increased risk in cancer-affected BRCA2+ group. No correlation was observed for the altered risk between cancer-affected or -unaffected carriers and between different age of cancer diagnosis in cancer-affected carriers. The frequently observed VNTR association with in BRCA1+ and BRCA2+ breast cancer group indicates that VNTR polymorphism in the XRCC5 promoter is associated with altered risk of breast cancer in BRCA1+ and BRCA2+ carriers.
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effect of oophorectomy on survival after breast cancer in brca1 and BRCA2 mutation carriers
2015Co-Authors: Charmaine Kimsing, Kelly A. Metcalfe, Nadine Tung, Henry T. Lynch, Olufunmilayo I Olopade, Andrea Eisen, Barry P Rosen, Carrie SnyderAbstract:Importance Women who carry a germline mutation in either the BRCA1 or BRCA2 gene face a lifetime risk of breast cancer of up to 70%, and once they receive a diagnosis of breast cancer, they face high risks of both second primary breast and ovarian cancers. Preventive bilateral salpingo-oophorectomy is recommended to women with a BRCA mutation at age 35 years or thereafter to prevent breast and ovarian cancer, but it is unclear whether oophorectomy has an impact on survival in women with BRCA -associated breast cancer. Objective To estimate the impact of oophorectomy on survival in women with breast cancer with a BRCA1 or BRCA2 mutation. Design, Setting, and Participants Retrospective analysis of patients selected by pedigree review of families who received counseling at 1 of 12 participating clinical genetics centers. Patients were 676 women with stage I or II breast cancer and a BRCA1 or BRCA2 mutation who were observed for up to 20 years after receiving a diagnosis between 1975 and 2008. Survival experience was compared for women who did and who did not undergo oophorectomy. Main Outcomes and Measures In all analyses, the primary end point was death due to breast cancer. Results Of the 676 women, 345 underwent oophorectomy after the diagnosis of breast cancer and 331 retained both ovaries. The 20-year survival for the entire patient cohort was 77.4%. The adjusted hazard ratio for death attributed to breast cancer in women who underwent oophorectomy was 0.38 (95% CI, 0.19-0.77; P = .007) for BRCA1 carriers and 0.57 (95% CI, 0.23-1.43; P = .23) for BRCA2 carriers. The hazard ratio for breast cancer–specific mortality was 0.76 (95% CI, 0.32-1.78; P = .53) for women with estrogen receptor–positive breast cancer and 0.07 (95% CI, 0.01-0.51; P = .009) for women with estrogen receptor–negative breast cancer. Conclusions and Relevance Oophorectomy is associated with a decrease in mortality in women with breast cancer and a BRCA1 mutation. Women with estrogen receptor–negative breast cancer and a BRCA1 mutation should undergo oophorectomy shortly after diagnosis.
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international rates of breast reconstruction after prophylactic mastectomy in brca1 and BRCA2 mutation carriers
2013Co-Authors: John Semple, Charmaine Kimsing, Leigha Senter, Peter Ainsworth, Kelly A. Metcalfe, Nadine Tung, Jan Lubinski, Henry T. Lynch, Donna GilchristAbstract:Background Breast reconstruction is an option for women with BRCA1 or BRCA2 mutations who elect to undergo prophylactic mastectomy to prevent breast cancer. We report on the uptake of breast reconstruction after prophylactic mastectomy in women with BRCA mutations from eight countries.
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frequency of premature menopause in women who carry a brca1 or BRCA2 mutation
2013Co-Authors: Amy Finch, Charmaine Kimsing, Nadine Tung, Henry T. Lynch, Susan L Neuhausen, Adriana Valentini, Ellen M Greenblatt, Parviz Ghadirian, Susan Armel, Beth Y KarlanAbstract: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.
Kelly A. Metcalfe - One of the best experts on this subject based on the ideXlab platform.
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palb2 mutations in high risk women with breast or ovarian cancer
2017Co-Authors: Kelly A. Metcalfe, Steven A Narod, Mohammad R Akbari, Jordan LernerellisAbstract:1527Background: In Canada, genetic testing for BRCA1 and BRCA2 is available free of charge to women who meet eligibility criteria, based on personal and family history of cancer. Less than 10% of women are identified with a BRCA mutation, despite features of hereditary cancer. PALB2 has been identified as a moderate penetrance gene in various populations. In the current study, we examined the frequency of PALB2 mutations in women with breast or ovarian cancer who met criteria for genetic testing for BRCA1 and BRCA2and tested negative. Methods: DNA samples from women with breast or ovarian cancer, who met criteria for provincial BRCA1 and BRCA2 genetic testing and tested negative between the years of 2007 and 2014 were included in this study. All 13 coding exons of PALB2 plus 20 base pairs from the exon boundaries were amplified using Wafergen SmartChip technology. The amplified DNA were paired-end sequenced at 2x250 cycles using an Illumina MiSeq sequencer. Results: 2,225 women with breast cancer and 429 ...
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effect of oophorectomy on survival after breast cancer in brca1 and BRCA2 mutation carriers
2015Co-Authors: Charmaine Kimsing, Kelly A. Metcalfe, Nadine Tung, Henry T. Lynch, Olufunmilayo I Olopade, Andrea Eisen, Barry P Rosen, Carrie SnyderAbstract:Importance Women who carry a germline mutation in either the BRCA1 or BRCA2 gene face a lifetime risk of breast cancer of up to 70%, and once they receive a diagnosis of breast cancer, they face high risks of both second primary breast and ovarian cancers. Preventive bilateral salpingo-oophorectomy is recommended to women with a BRCA mutation at age 35 years or thereafter to prevent breast and ovarian cancer, but it is unclear whether oophorectomy has an impact on survival in women with BRCA -associated breast cancer. Objective To estimate the impact of oophorectomy on survival in women with breast cancer with a BRCA1 or BRCA2 mutation. Design, Setting, and Participants Retrospective analysis of patients selected by pedigree review of families who received counseling at 1 of 12 participating clinical genetics centers. Patients were 676 women with stage I or II breast cancer and a BRCA1 or BRCA2 mutation who were observed for up to 20 years after receiving a diagnosis between 1975 and 2008. Survival experience was compared for women who did and who did not undergo oophorectomy. Main Outcomes and Measures In all analyses, the primary end point was death due to breast cancer. Results Of the 676 women, 345 underwent oophorectomy after the diagnosis of breast cancer and 331 retained both ovaries. The 20-year survival for the entire patient cohort was 77.4%. The adjusted hazard ratio for death attributed to breast cancer in women who underwent oophorectomy was 0.38 (95% CI, 0.19-0.77; P = .007) for BRCA1 carriers and 0.57 (95% CI, 0.23-1.43; P = .23) for BRCA2 carriers. The hazard ratio for breast cancer–specific mortality was 0.76 (95% CI, 0.32-1.78; P = .53) for women with estrogen receptor–positive breast cancer and 0.07 (95% CI, 0.01-0.51; P = .009) for women with estrogen receptor–negative breast cancer. Conclusions and Relevance Oophorectomy is associated with a decrease in mortality in women with breast cancer and a BRCA1 mutation. Women with estrogen receptor–negative breast cancer and a BRCA1 mutation should undergo oophorectomy shortly after diagnosis.
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international rates of breast reconstruction after prophylactic mastectomy in brca1 and BRCA2 mutation carriers
2013Co-Authors: John Semple, Charmaine Kimsing, Leigha Senter, Peter Ainsworth, Kelly A. Metcalfe, Nadine Tung, Jan Lubinski, Henry T. Lynch, Donna GilchristAbstract:Background Breast reconstruction is an option for women with BRCA1 or BRCA2 mutations who elect to undergo prophylactic mastectomy to prevent breast cancer. We report on the uptake of breast reconstruction after prophylactic mastectomy in women with BRCA mutations from eight countries.
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predictors of contralateral breast cancer in brca1 and BRCA2 mutation carriers
2011Co-Authors: Kelly A. Metcalfe, Charmaine Kimsing, Nadine Tung, Henry T. Lynch, Susan M Domchek, Parviz Ghadirian, Olufunmilayo I Olopade, Shelley Gershman, Jane MclennanAbstract:The objective of this study was to estimate the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers; and measure the extent to which host, family history, and cancer treatment-related factors modify the risk. Patients were 810 women, with stage I or II breast cancer, for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until contralateral mastectomy, contralateral breast cancer, death, or last follow-up. Overall, 149 subjects (18.4%) developed a contralateral breast cancer. The 15-year actuarial risk of contralateral breast cancer was 36.1% for women with a BRCA1 mutation and was 28.5% for women with a BRCA2 mutation. Women younger than 50 years of age at the time of breast cancer diagnosis were significantly more likely to develop a contralateral breast cancer at 15 years, compared with those older than 50 years (37.6 vs 16.8%; P=0.003). Women aged <50 years with two or more first-degree relatives with early-onset breast cancer were at high risk of contralateral breast cancer, compared with women with fewer, or no first-degree relatives with breast cancer (50 vs 36%; P=0.005). The risk of contralateral breast cancer was reduced with oophorectomy (RR 0.47; 95% CI 0.30–0.76; P=0.002). The risk of contralateral breast cancer risk in BRCA mutation carriers declines with the age of diagnosis and increases with the number of first-degree relatives affected with breast cancer. Oophorectomy reduces the risk of contralateral breast cancer in young women with a BRCA mutation.
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family history of cancer and cancer risks in women with brca1 or BRCA2 mutations
2010Co-Authors: Kelly A. Metcalfe, Charmaine Kimsing, Nadine Tung, Jan Lubinski, Henry T. Lynch, Susan L Neuhausen, Parviz Ghadirian, Barry P Rosen, William D Foulkes, Jacek GronwaldAbstract:Women who carry a deleterious mutation in BRCA1 or BRCA2 have high lifetime risks of breast and ovarian cancers. However, the influence of a family history of these cancers on these risks in women with BRCA mutations is unclear. We calculated cancer incidence rates for a multinational cohort comprising 3011 women with BRCA1 or BRCA2 mutations who were followed up for a mean of 3.9 years, during which time 243 incident breast or ovarian cancers were recorded. The 10-year cumulative risks of breast cancer were 18.1% (95% confidence interval [CI] = 13.3% to 22.8%) for women with a BRCA1 mutation and 15.2% (95% CI = 9.1% to 21.2%) for women with a BRCA2 mutation. Among women with a BRCA1 mutation, the risk of breast cancer increased by 1.2-fold for each first-degree relative with breast cancer before age 50 years (hazard ratio [HR] = 1.21; 95% confidence interval [CI] = 0.94 to 1.57) and the risk of ovarian cancer increased by 1.6 fold for each first- or second-degree relative with ovarian cancer (HR = 1.61; 95% CI = 1.21 to 2.14). Among women with a BRCA2 mutation, the risk of breast cancer increased by 1.7-fold for each first-degree relative younger than 50 years with breast cancer (HR = 1.67; 95% CI = 1.04 to 2.07).
Mark E Robson - One of the best experts on this subject based on the ideXlab platform.
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twenty one gene recurrence score assay in brca associated versus sporadic breast cancers differences based on germline mutation status
2016Co-Authors: Payal D Shah, Kenneth Offit, Clifford A. Hudis, Sujata Patil, Maura N Dickler, Mark E RobsonAbstract:BACKGROUND Biological differences between BRCA-associated breast cancer and sporadic breast cancer may warrant different adjuvant chemotherapy (ACRx) recommendations despite similar phenotypic features. A 21-gene expression profile (Oncotype DX) generates a prognostic recurrence score (RS) that predicts the ACRx benefit in patients with hormone receptor–positive breast cancer. No reports describe assay results for BRCA-associated breast cancer. METHODS A review of Memorial Sloan Kettering Cancer Center databases identified 4908 patients with hormone receptor–positive, node-negative breast cancer who underwent Oncotype DX testing between July 2006 and March 2014. BRCA1/BRCA2 carriers (cases) were identified and matched (1:2) by age at diagnosis and tumor size to noncarrier controls. Two-sample nonparametric tests were used to compare the baseline characteristics, RSs, and risk stratification between BRCA1 and BRCA2 patients. Conditional logistic regression was used to assess these differences by mutational status. RESULTS Fifty mutation-associated cases (19 BRCA1 cases and 31 BRCA2 cases) and 100 controls who were well matched for age (P = .9) and tumor size (P = .6) were included. BRCA1 and BRCA2 carriers had similar median RSs (P = .6) and risk category stratification (P = .3). The median RS was higher for cases versus controls (24 vs 16; P < .0001). Risk stratification also differed by mutational status (P = .0002). Cases had more high-risk disease (28% vs 7%) and intermediate-risk disease (56% vs 36%) and less low-risk disease (16% vs 57%). Cases were more likely than controls to receive ACRx (74% vs 46%; P = .002). CONCLUSIONS Germline BRCA-associated hormone receptor–positive breast cancer may be associated with intrinsically less favorable biology. Few affected carriers have RS indicating a clear absence of benefit from ACRx. The increased use of ACRx and benefit from ACRx in BRCA carriers may mitigate otherwise inferior outcomes. Cancer 2016. © 2016 American Cancer Society.
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an emerging entity pancreatic adenocarcinoma associated with a known brca mutation clinical descriptors treatment implications and future directions
2011Co-Authors: Maeve A Lowery, Mark E Robson, David P Kelsen, Zsofia K Stadler, Yelena Y Janjigian, Emmy Ludwig, David R Dadamo, Erin E Salomullen, Peter J Allen, Robert C KurtzAbstract:Background BRCA1 and BRCA2 germline mutations are associated with an elevated risk for pancreas adenocarcinoma (PAC). Other BRCA-associated cancers have been shown to have greater sensitivity to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors with better clinical outcomes than in sporadic cases; however, outcomes in BRCA-associated PAC have not been reported. Methods Patients with a known BRCA1 or BRCA2 mutation and a diagnosis of PAC were identified from the Gastrointestinal Oncology Service, Familial Pancreas Cancer Registry, and Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center. Results Fifteen patients, five male, with a BRCA1 (n = 4) or BRCA2 (n = 11) mutation and PAC and one patient with a BRCA1 mutation and acinar cell carcinoma of the pancreas were identified. Seven female patients (70%) had a prior history of breast cancer. Four patients received a PARP inhibitor alone or in combination with chemotherapy; three demonstrated an initial radiographic partial response by Response Evaluation Criteria in Solid Tumors whereas one patient had stable disease for 6 months. Six patients received platinum-based chemotherapy first line for metastatic disease; five of those patients had a radiographic partial response. Conclusion BRCA mutation-associated PAC represents an underidentified, but clinically important, subgroup of patients. This is of particular relevance given the ongoing development of therapeutic agents targeting DNA repair, which may potentially offer a significant benefit to a genetically selected population. We anticipate that further study and understanding of the clinical and biologic features of BRCA-mutant PAC will aid in the identification of tissue biomarkers indicating defective tumor DNA repair pathways in sporadic PAC.
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an emerging entity pancreatic adenocarcinoma associated with a known brca mutation clinical descriptors treatment implications and future directions
2011Co-Authors: Maeve A Lowery, Mark E Robson, David P Kelsen, Zsofia K Stadler, Kenneth H Yu, Yelena Y Janjigian, Emmy Ludwig, David R Dadamo, Erin E Salomullen, Peter J AllenAbstract:Background. BRCA1 and BRCA2 germline mutations are associated with an elevated risk for pancreas adenocarcinoma (PAC). Other BRCA-associated cancers have been shown to have greater sensitivity to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors with better clinical outcomes than in sporadic cases; however, outcomes in BRCA-associated PAC have not been reported. Methods. Patients with a known BRCA1 or BRCA2 mutationandadiagnosisofPACwereidentifiedfromtheGastrointestinal Oncology Service, Familial Pancreas Cancer Registry, and Clinical Genetics Service at Memorial SloanKettering Cancer Center. Results. Fifteen patients, five male, with a BRCA1 (n 4) or BRCA2 (n 11) mutation and PAC and one patient with a BRCA1 mutation and acinar cell carcinoma of the pancreas were identified. Seven female patients (70%) had a prior history of breast cancer. Four patients received a PARP inhibitor alone or in combination with chemotherapy; three demonstrated an initial radiographic partial response by Response Evaluation Criteria in Solid Tumors whereas one patient had stable disease for 6 months. Six patients received platinumbased chemotherapy first line for metastatic disease; five of those patients had a radiographic partial response. Conclusion. BRCA mutation–associated PAC represents an underidentified, but clinically important, subgroup of patients. This is of particular relevance given the ongoing development of therapeutic agents targeting DNA repair, which may potentially offer a significant benefit to a genetically selected population. We anticipate that further study and understanding of the clinical and biologic features of BRCA-mutant PAC will aid in the identification of tissue biomarkers indicating defective tumor DNA repair pathways in sporadic PAC. The Oncologist 2011;16:000–000
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risk reducing salpingo oophorectomy for the prevention of brca1 and BRCA2 associated breast and gynecologic cancer a multicenter prospective study
2008Co-Authors: Noah D Kauff, Claudine Isaacs, Henry T. Lynch, Susan M Domchek, Tara M Friebel, Mark E Robson, Judy Garber, Gareth D Evans, Rosalind A Eeles, Susan L NeuhausenAbstract:Purpose Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCAassociated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers.
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increased progesterone receptor expression in benign epithelium of brca1 related breast cancers
2004Co-Authors: Tari A King, Kenneth Offit, Mark E Robson, Mary L Gemignani, Dilip Giri, K S Panageas, Faina Bogomolniy, Crispinita D Arroyo, Narciso Olvera, Patrick I. BorgenAbstract:The study of pathologically normal breast epithelium of BRCA mutation carriers may yield insights into the early natural history of breast tumorigenesis. Hormone receptor expression was assessed in 24 cases of invasive breast cancer associated with a mutation in BRCA1 (n = 15) or BRCA2 (n = 9) and in 39 sporadic cases matched for patient age and tumor hormone receptor status. Expression of progesterone receptor was significantly (P = 0.0003) more common in normal breast epithelium adjacent to invasive breast carcinoma in BRCA1-linked cases compared with sporadic cases. The wild-type BRCA allele was retained in normal epithelium of all cases tested. We conclude that deregulation of progesterone receptor expression, as a result of BRCA1 haploinsufficiency, may represent an early event in BRCA1-linked breast tumorigenesis.
Susan L Neuhausen - One of the best experts on this subject based on the ideXlab platform.
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frequency of premature menopause in women who carry a brca1 or BRCA2 mutation
2013Co-Authors: Amy Finch, Charmaine Kimsing, Nadine Tung, Henry T. Lynch, Susan L Neuhausen, Adriana Valentini, Ellen M Greenblatt, Parviz Ghadirian, Susan Armel, Beth Y KarlanAbstract: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.
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the incidence of pancreatic cancer in brca1 and BRCA2 mutation carriers
2012Co-Authors: Javaid Iqbal, Jan Lubinski, Henry T. Lynch, Parviz Ghadirian, Susan Armel, Andrea Eisen, Pal Moller, A Ragone, William D Foulkes, Susan L NeuhausenAbstract:Germline mutations in BRCA1 and BRCA2 predispose to pancreatic cancer. We estimated the incidence of pancreatic cancer in a cohort of female carriers of BRCA1 and BRCA2 mutation. We also estimated survival rates in pancreatic cancer cases from families with a BRCA mutation. We followed 5149 women with a mutation for new cases of pancreatic cancer. The standardised incidence ratios (SIR) for pancreatic cancer were calculated based on age group and country of residence. We also reviewed the pedigrees of 8140 pedigrees with a BRCA1 or a BRCA2 mutation for those with a case of pancreatic cancer. We recorded the year of diagnosis and the year of death for 351 identified cases. Eight incident pancreatic cancer cases were identified among all mutation carriers. The SIR for BRCA1 carriers was 2.55 (95% CI=1.03–5.31, P=0.04) and for BRCA2 carriers was 2.13 (95% CI=0.36–7.03, P=0.3). The 5-year survival rate was 5% for cases from a BRCA1 family and 4% for cases from a BRCA2 family. The risk of pancreatic cancer is approximately doubled in female BRCA carriers. The poor survival in familial pancreatic cancer underscores the need for novel anti-tumoural strategies.
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family history of cancer and cancer risks in women with brca1 or BRCA2 mutations
2010Co-Authors: Kelly A. Metcalfe, Charmaine Kimsing, Nadine Tung, Jan Lubinski, Henry T. Lynch, Susan L Neuhausen, Parviz Ghadirian, Barry P Rosen, William D Foulkes, Jacek GronwaldAbstract:Women who carry a deleterious mutation in BRCA1 or BRCA2 have high lifetime risks of breast and ovarian cancers. However, the influence of a family history of these cancers on these risks in women with BRCA mutations is unclear. We calculated cancer incidence rates for a multinational cohort comprising 3011 women with BRCA1 or BRCA2 mutations who were followed up for a mean of 3.9 years, during which time 243 incident breast or ovarian cancers were recorded. The 10-year cumulative risks of breast cancer were 18.1% (95% confidence interval [CI] = 13.3% to 22.8%) for women with a BRCA1 mutation and 15.2% (95% CI = 9.1% to 21.2%) for women with a BRCA2 mutation. Among women with a BRCA1 mutation, the risk of breast cancer increased by 1.2-fold for each first-degree relative with breast cancer before age 50 years (hazard ratio [HR] = 1.21; 95% confidence interval [CI] = 0.94 to 1.57) and the risk of ovarian cancer increased by 1.6 fold for each first- or second-degree relative with ovarian cancer (HR = 1.61; 95% CI = 1.21 to 2.14). Among women with a BRCA2 mutation, the risk of breast cancer increased by 1.7-fold for each first-degree relative younger than 50 years with breast cancer (HR = 1.67; 95% CI = 1.04 to 2.07).
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genetic variation in insulin like growth factor signaling genes and breast cancer risk among brca1 and BRCA2 carriers
2009Co-Authors: Susan L Neuhausen, Henry T. Lynch, Judy Garber, Christian F. Singer, Katherine L Nathanson, Sean S Brummel, Yuan Chun Ding, Georg Pfeiler, Timothy R Rebbeck, Fergus J CouchAbstract:Introduction Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations.
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risk reducing salpingo oophorectomy for the prevention of brca1 and BRCA2 associated breast and gynecologic cancer a multicenter prospective study
2008Co-Authors: Noah D Kauff, Claudine Isaacs, Henry T. Lynch, Susan M Domchek, Tara M Friebel, Mark E Robson, Judy Garber, Gareth D Evans, Rosalind A Eeles, Susan L NeuhausenAbstract:Purpose Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCAassociated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers.
Parviz Ghadirian - One of the best experts on this subject based on the ideXlab platform.
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frequency of premature menopause in women who carry a brca1 or BRCA2 mutation
2013Co-Authors: Amy Finch, Charmaine Kimsing, Nadine Tung, Henry T. Lynch, Susan L Neuhausen, Adriana Valentini, Ellen M Greenblatt, Parviz Ghadirian, Susan Armel, Beth Y KarlanAbstract: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.
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the incidence of pancreatic cancer in brca1 and BRCA2 mutation carriers
2012Co-Authors: Javaid Iqbal, Jan Lubinski, Henry T. Lynch, Parviz Ghadirian, Susan Armel, Andrea Eisen, Pal Moller, A Ragone, William D Foulkes, Susan L NeuhausenAbstract:Germline mutations in BRCA1 and BRCA2 predispose to pancreatic cancer. We estimated the incidence of pancreatic cancer in a cohort of female carriers of BRCA1 and BRCA2 mutation. We also estimated survival rates in pancreatic cancer cases from families with a BRCA mutation. We followed 5149 women with a mutation for new cases of pancreatic cancer. The standardised incidence ratios (SIR) for pancreatic cancer were calculated based on age group and country of residence. We also reviewed the pedigrees of 8140 pedigrees with a BRCA1 or a BRCA2 mutation for those with a case of pancreatic cancer. We recorded the year of diagnosis and the year of death for 351 identified cases. Eight incident pancreatic cancer cases were identified among all mutation carriers. The SIR for BRCA1 carriers was 2.55 (95% CI=1.03–5.31, P=0.04) and for BRCA2 carriers was 2.13 (95% CI=0.36–7.03, P=0.3). The 5-year survival rate was 5% for cases from a BRCA1 family and 4% for cases from a BRCA2 family. The risk of pancreatic cancer is approximately doubled in female BRCA carriers. The poor survival in familial pancreatic cancer underscores the need for novel anti-tumoural strategies.
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breast cancer risk in relation to alcohol consumption and brca gene mutations a case only study of gene environment interaction
2011Co-Authors: Jessica Dennis, Parviz Ghadirian, Daniel Krewski, Frederiquesophie Cote, Eve Fafard, Julian LittleAbstract:The variable penetrance of the BRCA1 and BRCA2 genes suggests that other genetic or environmental factors may interact with these mutations to modify breast cancer risk. The objective of this study was to measure departures from multiplicative effects of alcohol consumption and BRCA gene mutations. A cohort of French-Canadian breast cancer patients was tested for BRCA gene mutations and completed a food frequency questionnaire. The case-only odds ratio (COR) was calculated. A total of 857 women, including 10 BRCA1 and 33 BRCA2 mutation carriers, participated in the study. No significant interaction between alcohol consumption and BRCA1 mutations was detected, although the interaction with wine consumption suggested a sub-multiplicative effect (COR = 0.38, 95% CI: 0.08-1.81). Consumption of alcohol other than wine interacted significantly with BRCA2 mutations (COR = 2.15, 95% CI: 1.03-4.49). Consumption of wine may protect against BRCA1-associated tumors, while women with BRCA2 mutations may be at greater risk of alcohol-induced breast cancer.
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predictors of contralateral breast cancer in brca1 and BRCA2 mutation carriers
2011Co-Authors: Kelly A. Metcalfe, Charmaine Kimsing, Nadine Tung, Henry T. Lynch, Susan M Domchek, Parviz Ghadirian, Olufunmilayo I Olopade, Shelley Gershman, Jane MclennanAbstract:The objective of this study was to estimate the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers; and measure the extent to which host, family history, and cancer treatment-related factors modify the risk. Patients were 810 women, with stage I or II breast cancer, for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until contralateral mastectomy, contralateral breast cancer, death, or last follow-up. Overall, 149 subjects (18.4%) developed a contralateral breast cancer. The 15-year actuarial risk of contralateral breast cancer was 36.1% for women with a BRCA1 mutation and was 28.5% for women with a BRCA2 mutation. Women younger than 50 years of age at the time of breast cancer diagnosis were significantly more likely to develop a contralateral breast cancer at 15 years, compared with those older than 50 years (37.6 vs 16.8%; P=0.003). Women aged <50 years with two or more first-degree relatives with early-onset breast cancer were at high risk of contralateral breast cancer, compared with women with fewer, or no first-degree relatives with breast cancer (50 vs 36%; P=0.005). The risk of contralateral breast cancer was reduced with oophorectomy (RR 0.47; 95% CI 0.30–0.76; P=0.002). The risk of contralateral breast cancer risk in BRCA mutation carriers declines with the age of diagnosis and increases with the number of first-degree relatives affected with breast cancer. Oophorectomy reduces the risk of contralateral breast cancer in young women with a BRCA mutation.
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family history of cancer and cancer risks in women with brca1 or BRCA2 mutations
2010Co-Authors: Kelly A. Metcalfe, Charmaine Kimsing, Nadine Tung, Jan Lubinski, Henry T. Lynch, Susan L Neuhausen, Parviz Ghadirian, Barry P Rosen, William D Foulkes, Jacek GronwaldAbstract:Women who carry a deleterious mutation in BRCA1 or BRCA2 have high lifetime risks of breast and ovarian cancers. However, the influence of a family history of these cancers on these risks in women with BRCA mutations is unclear. We calculated cancer incidence rates for a multinational cohort comprising 3011 women with BRCA1 or BRCA2 mutations who were followed up for a mean of 3.9 years, during which time 243 incident breast or ovarian cancers were recorded. The 10-year cumulative risks of breast cancer were 18.1% (95% confidence interval [CI] = 13.3% to 22.8%) for women with a BRCA1 mutation and 15.2% (95% CI = 9.1% to 21.2%) for women with a BRCA2 mutation. Among women with a BRCA1 mutation, the risk of breast cancer increased by 1.2-fold for each first-degree relative with breast cancer before age 50 years (hazard ratio [HR] = 1.21; 95% confidence interval [CI] = 0.94 to 1.57) and the risk of ovarian cancer increased by 1.6 fold for each first- or second-degree relative with ovarian cancer (HR = 1.61; 95% CI = 1.21 to 2.14). Among women with a BRCA2 mutation, the risk of breast cancer increased by 1.7-fold for each first-degree relative younger than 50 years with breast cancer (HR = 1.67; 95% CI = 1.04 to 2.07).
