A competing risks model with binary time varying covariates for estimation of breast cancer risks in BRCA1 families

Mammographic screening and prophylactic surgery such as risk-reducing salpingo oophorectomy can potentially reduce breast cancer risks among mutation carriers of BRCA families. The evaluation of these interventions is usually complicated by the fact that their effects on breast cancer may change over time and by the presence of competing risks. We introduce a correlated competing risks model to model breast and ovarian cancer risks within BRCA1 families that accounts for time-varying covariates. Different parametric forms for the effects of time-varying covariates are proposed for more flexibility and a correlated gamma frailty model is specified to account for the correlated competing events.We also introduce a new ascertainment correction approach that accounts for the selection of families through probands affected with either breast or ovarian cancer, or unaffected. Our simulation studies demonstrate the good performances of our proposed approach in terms of bias and precision of the estimators of model parameters and cause-specific penetrances over different levels of familial correlations. We applied our new approach to 498 BRCA1 mutation carrier families recruited through the Breast Cancer Family Registry. Our results demonstrate the importance of the functional form of the time-varying covariate effect when assessing the role of risk-reducing salpingo oophorectomy on breast cancer. In particular, under the best fitting time-varying covariate model, the overall effect of risk-reducing salpingo oophorectomy on breast cancer risk was statistically significant in women with BRCA1 mutation.

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Predictors of risk-reducing surgery intentions following genetic counseling for hereditary breast and ovarian cancer

Translational Behavioral Medicine ◽

10.1093/tbm/iby101 ◽

2018 ◽

Vol 10 (2) ◽

pp. 337-346 ◽

Cited By ~ 3

Author(s):

Mary Kathleen Ladd ◽

Beth N Peshkin ◽

Leigha Senter ◽

Shari Baldinger ◽

Claudine Isaacs ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Genetic Counseling ◽

Cancer Risk ◽

Prophylactic Surgery ◽

Ovarian Cancer Risk ◽

Breast And Ovarian Cancer ◽

Affective Factors ◽

Risk Reducing

Abstract Risk-reducing mastectomy (RRM) and salpingo-oophorectomy (RRSO) are increasingly used to reduce breast and ovarian cancer risk following BRCA1/BRCA2 testing. However, little is known about how genetic counseling influences decisions about these surgeries. Although previous studies have examined intentions prior to counseling, few have examined RRM and RRSO intentions in the critical window between genetic counseling and test result disclosure. Previous research has indicated that intentions at this time point predict subsequent uptake of surgery, suggesting that much decision-making has taken place prior to result disclosure. This period may be a critical time to better understand the drivers of prophylactic surgery intentions. The aim of this study was to examine predictors of RRM and RRSO intentions. We hypothesized that variables from the Health Belief Model would predict intentions, and we also examined the role of affective factors. Participants were 187 women, age 21–75, who received genetic counseling for hereditary breast and ovarian cancer. We utilized multiple logistic regression to identify independent predictors of intentions. 49.2% and 61.3% of participants reported intentions for RRM and RRSO, respectively. Variables associated with RRM intentions include: newly diagnosed with breast cancer (OR = 3.63, 95% CI = 1.20–11.04), perceived breast cancer risk (OR = 1.46, 95% CI = 1.17–1.81), perceived pros (OR = 1.79, 95% CI = 1.38–2.32) and cons of RRM (OR = 0.81, 95% CI = 0.65–0.996), and decision conflict (OR = 0.80, 95% CI = 0.66–0.98). Variables associated with RRSO intentions include: proband status (OR = 0.28, 95% CI = 0.09–0.89), perceived pros (OR = 1.35, 95% CI = 1.11–1.63) and cons of RRSO (OR = 0.72, 95% CI = 0.59–0.89), and ambiguity aversion (OR = 0.79, 95% CI = 0.65–0.95). These data provide support for the role of genetic counseling in fostering informed decisions about risk management, and suggest that the role of uncertainty should be explored further.

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Decision Analysis of Prophylactic Surgery or Screening for BRCA1 Mutation Carriers: A More Prominent Role For Oophorectomy

Journal of Clinical Oncology ◽

10.1200/jco.2002.08.035 ◽

2002 ◽

Vol 20 (8) ◽

pp. 2092-2100 ◽

Cited By ~ 72

Author(s):

Mariëlle S. van Roosmalen ◽

Lia C.G. Verhoef ◽

Peep F.M. Stalmeier ◽

Nicoline Hoogerbrugge ◽

Willem A.J. van Daal

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Risk Group ◽

Prophylactic Mastectomy ◽

Brca1 Mutation ◽

Prophylactic Surgery ◽

Breast And Ovarian Cancer ◽

Prophylactic Oophorectomy ◽

Mutation Carriers ◽

Medium Risk

PURPOSE: BRCA1 mutation carriers have a high risk of developing breast and ovarian cancer. Carriers may opt for prophylactic surgery and screening. Recent data suggesting that prophylactic oophorectomy reduces breast cancer risk have been incorporated in a decision analysis. METHODS: A Markov model was developed to compare LE and QALE following four strategies: (1) prophylactic mastectomy and prophylactic oophorectomy (PMPO), (2) screening for breast cancer and prophylactic oophorectomy (BSPO), (3) prophylactic mastectomy and screening for ovarian cancer (PMOS), and (4) screening for breast and ovarian cancer (BSOS). The analysis was performed for a high (85% breast cancer, 63% ovarian cancer) and medium (56% breast cancer, 16% ovarian cancer) risk level. Utilities for the health states after prophylactic surgery were obtained from mutation carriers. Other model parameter values were obtained from the literature. Sensitivity analyses were performed. RESULTS: When compared with BSOS, the average gain in LE for 30-year-old carriers in the high (medium) risk group was 11.7 (6.6) years for PMPO, 9.5 (5.3) years for BSPO, and 4.9 (4.4) years for PMOS. For 30-year-old carriers, BSPO had a QALE advantage when PO was performed before age 40. In the medium-risk group, there was a stronger advantage for BSPO when QALE was considered. CONCLUSION: PMPO is the most effective strategy to prolong life. However, if patient preferences were taken into account, BSPO tends to be a better strategy in most women at medium risk or in young women at high risk when PO was performed before age 40.

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BRCA1/2 associated cancer susceptibility: a clinical overview

Forum of Clinical Oncology ◽

10.1515/fco-2015-0022 ◽

2016 ◽

Vol 7 (2) ◽

pp. 16-24

Author(s):

Georgios Lypas

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

High Risk ◽

Physical Examination ◽

Transvaginal Ultrasound ◽

Parp Inhibitors ◽

Prophylactic Surgery ◽

Ca 125 ◽

Cancer Risks ◽

Increased Risk

Abstract The most frequently identified genetic cause of breast cancer is the germline mutation of BRCA1 and 2 genes. The carriers of these mutations are at high risk for breast and ovarian cancers and increased risk for pancreatic and prostate cancers. Personal and family history are routinely used to identify individuals at risk for carrying such mutations. Genetic counselling is required to guide them through genetic testing and risk management. Positive testing corresponds to a deleterious mutation, whereas negative testing is considered as uninformative; variants of unknown clinical significance are also classified as uninformative. The most effective risk reduction strategy involves bilateral prophylactic mastectomy and bilateral salpingo-oophorectomy, eliminating 90% of breast and 97% of ovarian cancer risks, respectively. Before and until such surgery, surveillance with physical examination, mammography and magnetic resonance mammography, starting at 25–30 years of age, are recommended for the early diagnosis of breast cancer; semi-annual surveillance with physical examination, transvaginal ultrasound and serum CA-125 is recommended for women who have not had prophylactic surgery. Carriers diagnosed with breast cancer run a high risk for a new breast primary and this information should be used accordingly. PARP inhibitors is a new class of antineoplastic agents, already approved for advanced BRCA1/2 mutant (germline or somatic) ovarian cancer. Multigene panel testing may follow a negative BRCA genetic test, often identifying other genetic causes of cancer, expanding its role in oncology. Further adoption of PARP inhibitors, refinement in estimation of BRCA-associated cancer risks and wider population testing, through NGS technology, may become available in the near future.

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Penetrance of Breast and Ovarian Cancer in Women Who Carry a BRCA1/2 Mutation and Do Not Use Risk-Reducing Salpingo-Oophorectomy: An Updated Meta-Analysis

JNCI Cancer Spectrum ◽

10.1093/jncics/pkaa029 ◽

2020 ◽

Vol 4 (4) ◽

Cited By ~ 1

Author(s):

Jinbo Chen ◽

Eunchan Bae ◽

Lingjiao Zhang ◽

Kevin Hughes ◽

Giovanni Parmigiani ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Meta Analysis ◽

Brca1 Mutation ◽

Brca2 Mutation ◽

Breast And Ovarian Cancer ◽

Mutation Carriers ◽

Risk Reducing ◽

Good Calibration

Abstract Background Use of risk-reducing Salpingo-oophorectomy (RRSO) substantially reduces the risk of ovarian and breast cancer for women who carry a BRCA1/2 mutation. It is important to adjust for RRSO use in the estimation of BRCA1/2 penetrance of breast and ovarian cancer. Methods We searched PubMed for penetrance estimates of breast and ovarian cancer from studies that genotyped individual patients and explicitly adjusted for RRSO use by censoring follow-up at the age of RRSO. We meta-analyzed penetrance estimates from 7 identified studies. We implemented the resulting penetrance estimates in a Mendelian risk prediction model as iplemented in the software package BRCAPRO, which we applied to estimate carrier probabilities in 2 BRCA cohorts. Results Penetrance estimates by age 70 years for breast cancer were 64.6% (95% confidence interval [CI] = 59.5% to 69.4%) for BRCA1 mutation carriers and 61.0% (95% CI = 48.1% to 72.5%) for BRCA2 mutation carriers, and for ovarian cancer they were 48.3% (95% CI = 38.8% to 57.9%) and 20.0% (95% CI = 13.3% to 29.0%), respectively. When integrated into BRCAPRO, our estimates led to good calibration and different estimates of carrier probabilities for some individuals when evaluating the models in 2 cohorts. Conclusions The report updates penetrance estimates for BRCA1/2-associated cancer. We report higher estimates than previously reported, which did not adjust for RRSO. Differential use of RRSO may partially explain heterogeneity in the currently available penetrance estimates. For some individuals, using our estimates in BRCAPRO may result in changes in estimated carrier probabilities, which warrants validation in future studies.

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Videolaparoscopic propylactic salpingo-oophorectomy: initial experience

Mastology ◽

10.29289/259453942020v30s1096 ◽

2020 ◽

Vol 30 (Suppl 1) ◽

Author(s):

Sabas Carlos Vieira ◽

Danilo Rafael da Silva Fontinele

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Brca Mutation ◽

Brca1 Mutation ◽

Committee Report ◽

Initial Experience ◽

The Mean ◽

Reduction Of Mortality ◽

Risk Reducing

Introduction: The BRCA mutation substantially increases the risk of ovarian cancer, from 20% to 60% when the mutation is in BRCA1, and 10% to 20% in BRCA1. Bilateral salpingo-oophorectomy may be the most important intervention in these patients, with clear impact on the reduction of mortality caused by ovarian cancer, and about 85% to 50% of reduction in the incidence of breast cancer. Salpingo-oophorectomy should be performed from the ages of 35 to 40 in patients with BRCA1 mutation, and after the age of 40 for BRCA2 carriers. Objectives: To present our initial experience of prophylactic bilateral salpingo-oophorectomy in patients with BRCA mutation. Method: This is a retrospective study. We included all patients who had tested positive for the BRCA mutation assisted from 1999 to 2019. Seven patients were identified with BRCA mutation and underwent videolaparoscopic salpingo-oophorectomy. The procedure was classic. The pieces were removed in endobags and sent to histological analysis with serial sections. The study was approved by the Research Ethics Committee, report n. 2.817.502. Results: No tumor was found in the surgical piece. The mean age of patients when they underwent surgery was 45.8 years. The patients, together, added 21 cases of breast cancer and 4 cases of ovarian cancer among 1st, 2nd and 3rd degree relatives. Five (71.4%) patients presented with BRCA1 mutation. Three patients had been diagnosed with breast cancer, none with previous ovarian cancer. As to the surgery: 3 (42.8%) also underwent bilateral or contralateral risk-reducing mastectomy with reconstruction, and 4 (57.2%) only underwent bilateral salpingo-oophorectomy. All patients are alive and without an active oncologic disease, with mean follow-up of 32 months. Conclusions: In this sample, we did not find any occult tumor in patients submitted to bilateral salpingo-oophorectomy due to BRCA mutation.

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Identification and management of familial breast cancer in Austria

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2017-0025 ◽

2017 ◽

Vol 32 (2) ◽

Cited By ~ 1

Author(s):

Christian F. Singer ◽

Yen Y. Tan ◽

Christine Rappaport

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Genetic Counseling ◽

Genetic Testing ◽

Familial Breast Cancer ◽

Prophylactic Surgery ◽

Management Options ◽

Counseling And Testing ◽

Legal Implications

AbstractAimThe aim of this study is to review the legal implications, the technology, the indications and the management of women with a familial background of breast and/or ovarian cancer.MethodsWe have reviewed the literature and national Austrian guidelines to describe the uptake of genetic counseling and the management options offered in Austria.ResultsGenetic testing for theConclusionWhile readily available country-wide counseling has led to an increase in counseling and testing, Austrian legislation mandates “non-directional counseling” resulting in a comparatively low uptake of prophylactic surgery.

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