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Jeffrey N Weitzel - One of the best experts on this subject based on the ideXlab platform.
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Limited family structure and BRCA Gene mutation status in single cases of breast cancer.
JAMA, 2007Co-Authors: Jeffrey N Weitzel, Kathleen R Blazer, Carey A Cullinane, Veronica I. Lagos, Patricia J. Gambol, Julie O. Culver, Melanie R. Palomares, Katrina Lowstuter, Deborah J MacdonaldAbstract:ContextAn autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression.ObjectiveTo determine if BRCA Gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models.Design, Setting, and ParticipantsA total of 1543 women seen at US high-risk clinics for Genetic cancer risk assessment and BRCA Gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers.Main Outcome MeasureThe main outcome measure was whether family structure, assessed from multiGenerational pedigrees, predicts BRCA Gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were Generated.ResultsFamily structure was limited in 153 cases (50%). BRCA Gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P = .02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA Gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P
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limited family structure and BRCA Gene mutation status in single cases of breast cancer
JAMA, 2007Co-Authors: Jeffrey N Weitzel, Kathleen R Blazer, Carey A Cullinane, Veronica I. Lagos, Patricia J. Gambol, Julie O. Culver, Melanie R. Palomares, Katrina Lowstuter, Deborah J MacdonaldAbstract:ContextAn autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression.ObjectiveTo determine if BRCA Gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models.Design, Setting, and ParticipantsA total of 1543 women seen at US high-risk clinics for Genetic cancer risk assessment and BRCA Gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers.Main Outcome MeasureThe main outcome measure was whether family structure, assessed from multiGenerational pedigrees, predicts BRCA Gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were Generated.ResultsFamily structure was limited in 153 cases (50%). BRCA Gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P = .02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA Gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P<.001) for single cases of breast cancer.ConclusionsFamily structure can affect the accuracy of mutation probability models. Genetic testing guidelines may need to be more inclusive for single cases of breast cancer when the family structure is limited and probability models need to be recreated using limited family history as an actual variable.
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Limited family structure and BRCA Gene mutation status in single cases of breast cancer modeling Genetic risk of breast cancer. Commentary
JAMA, 2007Co-Authors: Jeffrey N Weitzel, Kathleen R Blazer, Deborah J Macdonald, Carey A Cullinane, Veronica I. Lagos, Patricia J. Gambol, Julie O. Culver, Melanie R. Palomares, Katrina Lowstuter, Noah D. KauffAbstract:Context An autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression. Objective To determine if BRCA Gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models. Design, Setting, and Participants A total of 1543 women seen at US high-risk clinics for Genetic cancer risk assessment and BRCA Gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers. Main Outcome Measure The main outcome measure was whether family structure, assessed from multiGenerational pedigrees, predicts BRCA Gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were Generated. Results Family structure was limited in 153 cases (50%). BRCA Gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P=.02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA Gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P
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limited family structure and BRCA Gene mutation status in single cases of breast cancer modeling Genetic risk of breast cancer commentary
JAMA, 2007Co-Authors: Jeffrey N Weitzel, Kathleen R Blazer, Deborah J Macdonald, Carey A Cullinane, Veronica I. Lagos, Patricia J. Gambol, Julie O. Culver, Melanie R. Palomares, Katrina Lowstuter, Noah D. KauffAbstract:Context An autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression. Objective To determine if BRCA Gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models. Design, Setting, and Participants A total of 1543 women seen at US high-risk clinics for Genetic cancer risk assessment and BRCA Gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers. Main Outcome Measure The main outcome measure was whether family structure, assessed from multiGenerational pedigrees, predicts BRCA Gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were Generated. Results Family structure was limited in 153 cases (50%). BRCA Gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P=.02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA Gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P<.001) for single cases of breast cancer. Conclusions Family structure can affect the accuracy of mutation probability models. Genetic testing guidelines may need to be more inclusive for single cases of breast cancer when the family structure is limited and probability models need to be recreated using limited family history as an actual variable.
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linkage of a pedigree drawing program and database to a program for determining BRCA mutation carrier probability
Familial Cancer, 2005Co-Authors: Sharon Sand, Kathleen R Blazer, Deborah J Macdonald, David S Deram, Jeffrey N WeitzelAbstract:An export module was developed for transferring primary relational pedigree data directly from a widely used pedigree program and relational database to the BRCAPRO program for calculation of BRCA Gene mutation probability estimation.
F Guidozzi - One of the best experts on this subject based on the ideXlab platform.
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hormone therapy after prophylactic risk reducing bilateral salpingo oophorectomy in women who have BRCA Gene mutation
Climacteric, 2016Co-Authors: F GuidozziAbstract:AbstractWomen with a BRCA1 or BRCA2 Gene mutation have substantially higher risk for developing not only breast and ovarian cancers, but also for primary peritoneal, Fallopian tube, colonic, pancreatic cancers, uterine papillary serous adenocarcinoma and malignant melanoma.The risk for ovarian cancer ranges from 39 to 49% by 70 years of age in BRCA1 mutation carriers and from 11 to 18% for those with a BRCA2 mutation, whilst breast cancer increases similarly within women who have either the BRCA1 mutation or the BRCA2 mutation, from about 20% in women in their forties, 37% by the age of 50 years, 55% by 60 years and more than 70% by the age of 70 years.Prophylactic risk-reducing bilateral salpingo-oophorectomy (RRBSO) provides significantly greater benefits with the view of reducing the risk for gynecological and breast cancer (decreasing ovarian cancer risk by 85–95%, breast cancer risk by about 53–68% and removes occult or undetected cancers in 2–18% of such women) compared to other conservative options...
Carey A Cullinane - One of the best experts on this subject based on the ideXlab platform.
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limited family structure and BRCA Gene mutation status in single cases of breast cancer
JAMA, 2007Co-Authors: Jeffrey N Weitzel, Kathleen R Blazer, Carey A Cullinane, Veronica I. Lagos, Patricia J. Gambol, Julie O. Culver, Melanie R. Palomares, Katrina Lowstuter, Deborah J MacdonaldAbstract:ContextAn autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression.ObjectiveTo determine if BRCA Gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models.Design, Setting, and ParticipantsA total of 1543 women seen at US high-risk clinics for Genetic cancer risk assessment and BRCA Gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers.Main Outcome MeasureThe main outcome measure was whether family structure, assessed from multiGenerational pedigrees, predicts BRCA Gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were Generated.ResultsFamily structure was limited in 153 cases (50%). BRCA Gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P = .02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA Gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P<.001) for single cases of breast cancer.ConclusionsFamily structure can affect the accuracy of mutation probability models. Genetic testing guidelines may need to be more inclusive for single cases of breast cancer when the family structure is limited and probability models need to be recreated using limited family history as an actual variable.
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Limited family structure and BRCA Gene mutation status in single cases of breast cancer.
JAMA, 2007Co-Authors: Jeffrey N Weitzel, Kathleen R Blazer, Carey A Cullinane, Veronica I. Lagos, Patricia J. Gambol, Julie O. Culver, Melanie R. Palomares, Katrina Lowstuter, Deborah J MacdonaldAbstract:ContextAn autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression.ObjectiveTo determine if BRCA Gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models.Design, Setting, and ParticipantsA total of 1543 women seen at US high-risk clinics for Genetic cancer risk assessment and BRCA Gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers.Main Outcome MeasureThe main outcome measure was whether family structure, assessed from multiGenerational pedigrees, predicts BRCA Gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were Generated.ResultsFamily structure was limited in 153 cases (50%). BRCA Gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P = .02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA Gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P
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Limited family structure and BRCA Gene mutation status in single cases of breast cancer modeling Genetic risk of breast cancer. Commentary
JAMA, 2007Co-Authors: Jeffrey N Weitzel, Kathleen R Blazer, Deborah J Macdonald, Carey A Cullinane, Veronica I. Lagos, Patricia J. Gambol, Julie O. Culver, Melanie R. Palomares, Katrina Lowstuter, Noah D. KauffAbstract:Context An autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression. Objective To determine if BRCA Gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models. Design, Setting, and Participants A total of 1543 women seen at US high-risk clinics for Genetic cancer risk assessment and BRCA Gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers. Main Outcome Measure The main outcome measure was whether family structure, assessed from multiGenerational pedigrees, predicts BRCA Gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were Generated. Results Family structure was limited in 153 cases (50%). BRCA Gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P=.02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA Gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P
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limited family structure and BRCA Gene mutation status in single cases of breast cancer modeling Genetic risk of breast cancer commentary
JAMA, 2007Co-Authors: Jeffrey N Weitzel, Kathleen R Blazer, Deborah J Macdonald, Carey A Cullinane, Veronica I. Lagos, Patricia J. Gambol, Julie O. Culver, Melanie R. Palomares, Katrina Lowstuter, Noah D. KauffAbstract:Context An autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression. Objective To determine if BRCA Gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models. Design, Setting, and Participants A total of 1543 women seen at US high-risk clinics for Genetic cancer risk assessment and BRCA Gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers. Main Outcome Measure The main outcome measure was whether family structure, assessed from multiGenerational pedigrees, predicts BRCA Gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were Generated. Results Family structure was limited in 153 cases (50%). BRCA Gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P=.02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA Gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P<.001) for single cases of breast cancer. Conclusions Family structure can affect the accuracy of mutation probability models. Genetic testing guidelines may need to be more inclusive for single cases of breast cancer when the family structure is limited and probability models need to be recreated using limited family history as an actual variable.
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effect of Genetic cancer risk assessment on surgical decisions at breast cancer diagnosis
Archives of Surgery, 2003Co-Authors: Jeffrey N Weitzel, Kathleen R Blazer, Deborah J Macdonald, Sarah M Mccaffrey, Raluca Nedelcu, Carey A CullinaneAbstract:Hypothesis Breast cancer Gene ( BRCA ) mutation status affects patients' surgical decisions when Genetic cancer risk assessment is offered at the time of breast cancer diagnosis, prior to definitive treatment. Patients and Interventions Outcomes following Genetic cancer risk assessment were studied for women newly diagnosed as having breast cancer who were prospectively enrolled in an institutional review board–approved hereditary cancer registry during a 1-year sampling frame. BRCA Gene analysis was offered to subjects with a calculated mutation probability of 10% or higher. Review of medical records and telephone survey were used to document surgical treatment decisions following Genetic cancer risk assessment. Results Thirty-seven of 233 women in the registry were enrolled at the time of a breast cancer diagnosis. The interval from diagnosis to Genetic cancer risk assessment ranged from 3 to 60 days. The mean calculated probabil-ity of a BRCA Gene mutation was 21% across the cohort. Two women were not tested because of low prior probabilities of mutation detection, and 3 declined owing to intercurrent psychological stressors. Of the remaining 32 patients, no BRCA Gene mutation was detected in 22 (69%), 3 (9%) were found to carry a variant of uncertain significance, and 7 (22%) had a deleterious mutation. All 7 subjects with a deleterious mutation opted for bilateral mastectomy, whereas 20 of 22 patients with negative test results chose stage-appropriate treatment ( P Conclusions Genetic cancer risk assessment at the time of breast cancer diagnosis significantly affected women's treatment decisions. Although need and feasibility are demonstrated, the logistics of Genetic cancer risk assessment during breast cancer diagnosis prove challenging.
Deborah J Macdonald - One of the best experts on this subject based on the ideXlab platform.
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Limited family structure and BRCA Gene mutation status in single cases of breast cancer.
JAMA, 2007Co-Authors: Jeffrey N Weitzel, Kathleen R Blazer, Carey A Cullinane, Veronica I. Lagos, Patricia J. Gambol, Julie O. Culver, Melanie R. Palomares, Katrina Lowstuter, Deborah J MacdonaldAbstract:ContextAn autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression.ObjectiveTo determine if BRCA Gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models.Design, Setting, and ParticipantsA total of 1543 women seen at US high-risk clinics for Genetic cancer risk assessment and BRCA Gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers.Main Outcome MeasureThe main outcome measure was whether family structure, assessed from multiGenerational pedigrees, predicts BRCA Gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were Generated.ResultsFamily structure was limited in 153 cases (50%). BRCA Gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P = .02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA Gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P
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limited family structure and BRCA Gene mutation status in single cases of breast cancer
JAMA, 2007Co-Authors: Jeffrey N Weitzel, Kathleen R Blazer, Carey A Cullinane, Veronica I. Lagos, Patricia J. Gambol, Julie O. Culver, Melanie R. Palomares, Katrina Lowstuter, Deborah J MacdonaldAbstract:ContextAn autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression.ObjectiveTo determine if BRCA Gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models.Design, Setting, and ParticipantsA total of 1543 women seen at US high-risk clinics for Genetic cancer risk assessment and BRCA Gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers.Main Outcome MeasureThe main outcome measure was whether family structure, assessed from multiGenerational pedigrees, predicts BRCA Gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were Generated.ResultsFamily structure was limited in 153 cases (50%). BRCA Gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P = .02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA Gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P<.001) for single cases of breast cancer.ConclusionsFamily structure can affect the accuracy of mutation probability models. Genetic testing guidelines may need to be more inclusive for single cases of breast cancer when the family structure is limited and probability models need to be recreated using limited family history as an actual variable.
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Limited family structure and BRCA Gene mutation status in single cases of breast cancer modeling Genetic risk of breast cancer. Commentary
JAMA, 2007Co-Authors: Jeffrey N Weitzel, Kathleen R Blazer, Deborah J Macdonald, Carey A Cullinane, Veronica I. Lagos, Patricia J. Gambol, Julie O. Culver, Melanie R. Palomares, Katrina Lowstuter, Noah D. KauffAbstract:Context An autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression. Objective To determine if BRCA Gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models. Design, Setting, and Participants A total of 1543 women seen at US high-risk clinics for Genetic cancer risk assessment and BRCA Gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers. Main Outcome Measure The main outcome measure was whether family structure, assessed from multiGenerational pedigrees, predicts BRCA Gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were Generated. Results Family structure was limited in 153 cases (50%). BRCA Gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P=.02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA Gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P
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limited family structure and BRCA Gene mutation status in single cases of breast cancer modeling Genetic risk of breast cancer commentary
JAMA, 2007Co-Authors: Jeffrey N Weitzel, Kathleen R Blazer, Deborah J Macdonald, Carey A Cullinane, Veronica I. Lagos, Patricia J. Gambol, Julie O. Culver, Melanie R. Palomares, Katrina Lowstuter, Noah D. KauffAbstract:Context An autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression. Objective To determine if BRCA Gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models. Design, Setting, and Participants A total of 1543 women seen at US high-risk clinics for Genetic cancer risk assessment and BRCA Gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers. Main Outcome Measure The main outcome measure was whether family structure, assessed from multiGenerational pedigrees, predicts BRCA Gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were Generated. Results Family structure was limited in 153 cases (50%). BRCA Gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P=.02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA Gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P<.001) for single cases of breast cancer. Conclusions Family structure can affect the accuracy of mutation probability models. Genetic testing guidelines may need to be more inclusive for single cases of breast cancer when the family structure is limited and probability models need to be recreated using limited family history as an actual variable.
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linkage of a pedigree drawing program and database to a program for determining BRCA mutation carrier probability
Familial Cancer, 2005Co-Authors: Sharon Sand, Kathleen R Blazer, Deborah J Macdonald, David S Deram, Jeffrey N WeitzelAbstract:An export module was developed for transferring primary relational pedigree data directly from a widely used pedigree program and relational database to the BRCAPRO program for calculation of BRCA Gene mutation probability estimation.
Kishan A T Naipal - One of the best experts on this subject based on the ideXlab platform.
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functional ex vivo assay reveals homologous recombination deficiency in breast cancer beyond BRCA Gene defects
Clinical Cancer Research, 2018Co-Authors: Titia G. Meijer, Kishan A T Naipal, Nicole S Verkaik, Carolien H M Van Deurzen, Anieta M Sieuwerts, H.j. Dubbink, Job Van Riet, Michael Den A Bakker, Hein F B M Sleddens, Dorine Den T ToomAbstract:Purpose: Tumors of germline BRCA1/2 mutated carriers show homologous recombination (HR) deficiency (HRD), resulting in impaired DNA double-strand break (DSB) repair and high sensitivity to PARP inhibitors. Although this therapy is expected to be effective beyond germline BRCA1/2 mutated carriers, a robust validated test to detect HRD tumors is lacking. In this study, we therefore evaluated a functional HR assay exploiting the formation of RAD51 foci in proliferating cells after ex vivo irradiation of fresh breast cancer tissue: the recombination REpair CAPacity (RECAP) test. Experimental Design: Fresh samples of 170 primary breast cancer were analyzed using the RECAP test. The molecular explanation for the HRD phenotype was investigated by exploring BRCA deficiencies, mutational signatures, tumor-infiltrating lymphocytes (TIL), and microsatellite instability (MSI). Results: RECAP was completed successfully in 125 of 170 samples (74%). Twenty-four tumors showed HRD (19%), whereas six tumors were HR intermediate (HRi; 5%). HRD was explained by BRCA deficiencies (mutations, promoter hypermethylation, deletions) in 16 cases, whereas seven HRD tumors were non-BRCA related. HRD tumors showed an increased incidence of high TIL counts (P = 0.023) compared with HR proficient (HRP) tumors and MSI was more frequently observed in the HRD group (2/20, 10%) than expected in breast cancer (1%; P = 0.017). Conclusions: RECAP is a robust functional HR assay detecting both BRCA1/2-deficient and BRCA1/2-proficient HRD tumors. Functional assessment of HR in a pseudo-diagnostic setting is achievable and produces robust and interpretable results.
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functional ex vivo assay to select homologous recombination deficient breast tumors for parp inhibitor treatment
Clinical Cancer Research, 2014Co-Authors: Kishan A T Naipal, Mark J Oconnor, Najim Ameziane, Nicole S Verkaik, Carolien H M Van Deurzen, Petra Ter Brugge, Matty Meijers, Anieta M Sieuwerts, John W M Martens, Harry VrielingAbstract:Purpose: Poly(ADP-ribose) polymerase (PARP) inhibitors are promising targeted treatment options for hereditary breast tumors with a homologous recombination (HR) deficiency caused by BRCA1 or BRCA2 mutations. However, the functional consequence of BRCA Gene mutations is not always known and tumors can be HR deficient for other reasons than BRCA Gene mutations. Therefore, we aimed to develop a functional test to determine HR activity in tumor samples to facilitate selection of patients eligible for PARP inhibitor treatment. Experimental design: We obtained 54 fresh primary breast tumor samples from patients undergoing surgery. We determined their HR capacity by studying the formation of ionizing radiation induced foci (IRIF) of the HR protein RAD51 after ex vivo irradiation of these organotypic breast tumor samples. Tumors showing impaired RAD51 IRIF formation were subjected to Genetic and epiGenetic analysis. Results: Five of 45 primary breast tumors with sufficient numbers of proliferating tumor cells were RAD51 IRIF formation deficient (11%, 95% CI, 5%–24%). This HR defect was significantly associated with triple-negative breast cancer (OR, 57; 95% CI, 3.9–825; P = 0.003). Two of five HR-deficient tumors were not caused by mutations in the BRCA Genes, but by BRCA1 promoter hypermethylation. Conclusion: The functional RAD51 IRIF assay faithfully identifies HR-deficient tumors and has clear advantages over Gene sequencing. It is a relatively easy assay that can be performed on biopsy material, making it a powerful tool to select patients with an HR-deficient cancer for PARP inhibitor treatment in the clinic. Clin Cancer Res; 20(18); 4816–26. ©2014 AACR .