Publications by authors named "Susan M Domchek"

254 Publications

Risk factors for breast cancer subtypes among Black women undergoing screening mammography.

Breast Cancer Res Treat 2021 Aug 3. Epub 2021 Aug 3.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.

Purpose: Black women are more likely than non-Hispanic White women to be diagnosed with triple negative breast cancer (TNBC), an aggressive subtype with limited treatment options. The study objective was to evaluate the associations of known breast cancer risk factors, including breast density, with TNBC among Black women.

Methods: This study included Black women who underwent screening mammography between the ages of 40-84 years at a University of Pennsylvania Health System between 2010 and 2015. Cox proportional hazard models using multiple imputation with chained equations were used to estimate hazard ratios and 95% confidence intervals for risk factors for ER/PR+/HER2- and TNBC.

Results: Among 25,013 Black women, there were 330 incident breast cancers (1.3%) during a mean follow-up of 5.8 years; 218 (66.1%) ER/PR+ HER- and 61 (18.1%) TNBC. Having dense breasts (heterogeneously dense or extremely dense) vs. non-dense breasts (almost entirely fatty or scattered areas of fibroglandular density) increased risk of ER/PR+/HER2- breast cancer almost 80% (HR 1.79, 95% CI 1.32-2.43) and TNBC more than twofold (HR 2.53, 1.45-4.44). Older age was associated with an increased risk for ER/PR+/HER2- (HR 1.04, 1.03-1.06) and TNBC (HR 1.03, 1.00-1.05). Having a BMI of > 30 kg/m was associated with an increased risk (HR 2.77, 1.05-7.30) for TNBC and an increased risk of ERPR+/HER2- breast cancer in postmenopausal but not pre-menopausal women (p-interaction = 0.016).

Conclusion: Our results suggest that breast density and obesity are strong risk factors for TNBC among Black women. Understanding breast cancer subtype specific risk factors among Black women can help improve risk assessment.
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http://dx.doi.org/10.1007/s10549-021-06340-2DOI Listing
August 2021

EUS-based pancreatic cancer surveillance in BRCA1/BRCA2/PALB2/ATM carriers without a family history of pancreatic cancer.

Cancer Prev Res (Phila) 2021 Aug 2. Epub 2021 Aug 2.

Columbia University Medical Center.

Carriers of a pathogenic/likely pathogenic (P/LP) BRCA1/BRCA2/ATM/PALB2 variant are at increased risk of pancreatic ductal adenocarcinoma (PDAC), yet current guidelines recommend surveillance only for those with a family history of PDAC. We aimed to investigate outcomes of endoscopic ultrasound (EUS)-based PDAC surveillance in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC. We performed a retrospective analysis of all P/LP BRCA1/BRCA2/ATM/PALB2 carriers who underwent endoscopic ultrasound (EUS) at a tertiary care center. Of 194 P/LP BRCA1/BRCA2/ATM/PALB2 carriers who underwent EUS, 64 (33%) had no family history of PDAC and had at least one EUS for PDAC surveillance. These individuals underwent 143 total EUSs, were predominantly female (72%) and BRCA2 carriers (73%), with the majority having a personal history of cancer other than PDAC (67%). The median age at time of first EUS was 62 years (IQR 53-67 years) and a median of 2 EUSs (IQR 1-3) were performed per patient, with a median of 3 years (IQR 2-4.5 years) between the first and last EUS for those with more than 1 EUS. Pancreatic abnormalities were detected in 44%, including cysts in 27%, and incidental luminal abnormalities in 41%. Eight percent developed a new pancreatic mass or cyst during surveillance, two individuals developed PDAC, and no serious complications resulted from surveillance. After discussion of the risks, limitations, and potential benefits, PDAC surveillance can be considered in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC, however the effectiveness of PDAC surveillance in this population requires further study.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0161DOI Listing
August 2021

Comprehensive Breast Cancer Risk Assessment for and Pathogenic Variant Carriers Incorporating a Polygenic Risk Score and the Tyrer-Cuzick Model.

JCO Precis Oncol 2021 Jun 24;5. Epub 2021 Jun 24.

Memorial Sloan Kettering Cancer Center, New York City, NY.

Purpose: Breast cancer risks for and pathogenic variant (PV) carriers are modified by an 86-single nucleotide polymorphism polygenic risk score (PRS) and individual clinical factors. Here, we describe comprehensive risk prediction models for women of European ancestry combining PV status, PRS, and individual clinical variables.

Materials And Methods: This study included deidentified clinical records from 358,095 women of European ancestry who received testing with a multigene panel (September 2013 to November 2019). Model development included PV carriers (n = 4,286), PV carriers (n = 2,666), and women negative for other breast cancer risk gene PVs (n = 351,143). Odds ratios (ORs) were calculated using multivariable logistic regression with adjustment for familial cancer history. Risk estimates incorporating PV status, PRS, and Tyrer-Cuzick v7.02 were calculated using a Fixed-Stratified method that accounts for correlations between risk factors. Stratification of PV carriers into risk categories on the basis of remaining lifetime risk (RLR) was assessed in independent cohorts of PV carriers.

Results: ORs for association of PV status with breast cancer were 2.01 (95% CI, 1.88 to 2.16) and 1.83 (95% CI, 1.68 to 2.00) for and PV carriers, respectively. ORs for PRS per one standard deviation were 1.51 (95% CI, 1.37 to 1.66) and 1.45 (95% CI, 1.30 to 1.64) in and PV carriers, respectively. Using the combined model (PRS plus Tyrer-Cuzick plus PV status), RLR was low (≤ 20%) for 24.2% of PV carriers, medium (20%-50%) for 63.8%, and high (> 50%) for 12.0%. Among PV carriers, RLR was low for 31.5% of patients, medium for 58.5%, and high for 9.7%.

Conclusion: In and PV carriers, risk assessment including PRS, Tyrer-Cuzick, and PV status has the potential for more precise direction of screening and prevention strategies.
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http://dx.doi.org/10.1200/PO.20.00484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238281PMC
June 2021

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

J Natl Cancer Inst 2021 Jul 28. Epub 2021 Jul 28.

Department of Molecular Medicine, University La Sapienza, Rome, Italy.

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.

Methods: 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk.

Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI = 1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR = 1.73, 95% CI = 1.28-2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.

Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.
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http://dx.doi.org/10.1093/jnci/djab147DOI Listing
July 2021

What happens after menopause? (WHAM): A prospective controlled study of vasomotor symptoms and menopause-related quality of life 12 months after premenopausal risk-reducing salpingo-oophorectomy.

Gynecol Oncol 2021 Jul 23. Epub 2021 Jul 23.

Centre for Longitudinal and Life Course Research, School of Public Health, University of Queensland, Brisbane, Queensland, Australia.

Objective: To measure menopausal symptoms and quality of life up to 12 months after risk-reducing salpingo-oophorectomy (RRSO) and to measure the effects of hormone therapy.

Methods: Prospective observational study of 95 premenopausal women planning RRSO and a comparison group of 99 who retained their ovaries. Vasomotor symptoms and menopausal-related quality of life (QoL) were measured by the Menopause-Specific QoL Intervention scale at baseline, 3, 6 and 12 months. Chi-square tests measured differences in prevalence of vasomotor symptoms between RRSO vs the comparison group and by hormone therapy use. Change in QoL were examined with multilevel modelling.

Results: Three months after RRSO hot flush prevalence increased from 5.3% to 56.2% and night sweats from 20.2% to 47.2%. Symptoms did not worsen between 3 and 12 months and remained unchanged in the comparison group (p<0.001). After RRSO, 60% commenced hormone therapy. However, 40% of hormone therapy uses continued to experience vasomotor symptoms. After RRSO, 80% of non-hormone therapy users reported vasomotor symptoms. Regardless of hormone therapy use, 86% categorized their vasomotor symptoms as "mild" after RRSO. Following RRSO, Menopause-related QoL deteriorated but was stable in the comparison group (adjusted coefficient = 0.75, 95%CI = 0.55-0.95). After RRSO, QoL was better in hormone therapy users vs non-users (adjusted coefficient = 0.49, 95%CI = 0.20-0.78).

Conclusions: Vasomotor symptoms increase by 3 months after RRSO but do not worsen over the next 12 months. Hormone Therapy reduces but does not resolve vasomotor symptoms and may improve QoL, but not to pre-oophorectomy levels.
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http://dx.doi.org/10.1016/j.ygyno.2021.07.029DOI Listing
July 2021

Risk of Late-Onset Breast Cancer in Genetically Predisposed Women.

J Clin Oncol 2021 Jul 22:JCO2100531. Epub 2021 Jul 22.

Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years.

Methods: A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs.

Results: The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in , , and were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in , , , and were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in , , and .

Conclusion: This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with and PVs and perhaps with and PVs should be considered for magnetic resonance imaging screening.
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http://dx.doi.org/10.1200/JCO.21.00531DOI Listing
July 2021

Uptake and acceptability of a mainstreaming model of hereditary cancer multigene panel testing among patients with ovarian, pancreatic, and prostate cancer.

Genet Med 2021 Jul 13. Epub 2021 Jul 13.

Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: To address demands for timely germline information to guide treatments, we evaluated experiences of patients with ovarian, pancreatic, and prostate cancer with a mainstreaming genetic testing model wherein multigene panel testing was ordered by oncologists with standardized pretest patient education, and genetic counselors delivered results and post-test genetic counseling via telephone.

Methods: Among 1,203 eligible patients, we conducted a prospective single-arm study to examine patient uptake and acceptability (via self-report surveys at baseline and three weeks and three months following result return) of this mainstreaming model.

Results: Only 10% of eligible patients declined participation. Among 1,054 tested participants, 10% had pathogenic variants (PV), 16% had variants of uncertain significance (VUS), and 74% had no variant identified (NV). Participants reported high initial acceptability, including high satisfaction with their testing decision. Variability over time in several outcomes existed for participants with PV or NV: those with NV experienced a temporary increase in depression (p < 0.001; p < 0.001), and those with PV experienced a small increase in genetic testing distress (p = 0.03). Findings suggested that result type, sex, and cancer type were also associated with outcomes including clinical depression and uncertainty.

Conclusion: This mainstreaming model may offer a feasible approach for extending access to germline genetic information.
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http://dx.doi.org/10.1038/s41436-021-01262-2DOI Listing
July 2021

Challenges and Opportunities in Engaging Primary Care Providers in BRCA Testing: Results from the BFOR Study.

J Gen Intern Med 2021 Jun 25. Epub 2021 Jun 25.

Brigham and Women's Hospital, Boston, MA, USA.

Purpose: Engaging primary care providers (PCPs) in BRCA1/2 testing and results disclosure would increase testing access. The BRCA Founder OutReach (BFOR) study is a prospective study of BRCA1/2 founder mutation screening among individuals of Ashkenazi Jewish descent that sought to involve participants' PCPs in results disclosure. We used quantitative and qualitative methods to evaluate PCPs' perspectives, knowledge, and experience disclosing results in BFOR.

Methods: Among PCPs nominated by BFOR participants to disclose BRCA1/2 results, we assessed the proportion agreeing to disclose. To examine PCP's perspectives, knowledge, and willingness to disclose results, we surveyed 501 nominated PCPs. To examine PCPs' experiences disclosing results in BFOR, we surveyed 101 PCPs and conducted 10 semi-structured interviews.

Results: In the BFOR study overall, PCPs agreed to disclose their patient's results 40.5% of the time. Two hundred thirty-four PCPs (46.7%) responded to the initial survey. Responding PCPs were more likely to agree to disclose patients' results than non-responders (57.3% vs. 28.6%, p<0.001). Among all respondents, most felt very (19.7%) or somewhat (39.1%) qualified to share results. Among PCPs declining to disclose, insufficient knowledge was the most common reason. In multivariable logistic regression, feeling qualified was the only variable significantly associated with agreeing to disclose results (OR 6.53, 95% CI 3.31, 12.88). In post-disclosure surveys (response rate=55%), PCPs reported largely positive experiences. Interview findings suggested that although PCPs valued the study-provided educational materials, they desired better integration of results and decision support into workflows.

Conclusion: Barriers exist to incorporating BRCA1/2 testing into primary care. Most PCPs declined to disclose their patients' BFOR results, although survey respondents were motivated and had positive disclosure experiences. PCP training and integrated decision support could be beneficial.

Trial Registration: ClinicalTrials.gov (NCT03351803), November 24, 2017.
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http://dx.doi.org/10.1007/s11606-021-06970-8DOI Listing
June 2021

What happens after menopause? (WHAM): A prospective controlled study of sleep quality up to 12 months after premenopausal risk-reducing salpingo-oophorectomy.

Gynecol Oncol 2021 Aug 8;162(2):447-453. Epub 2021 Jun 8.

Center for Health Sciences, SRI International, California, USA.

Objective: Sleep difficulties impair function and increase the risk of depression at menopause and premenopausal oophorectomy may further worsen sleep. However, prospective data are limited, and it remains uncertain whether Hormone Therapy (HT) improves sleep. This prospective observational study measured sleep quality before and up to 12 months after risk-reducing salpingo-oophorectomy (RRSO) compared to a similar age comparison group who retained their ovaries.

Methods: Ninety-five premenopausal women undergoing RRSO and 99 comparisons were evaluated over a 12-month period using the Pittsburgh Sleep Quality Index (PSQI).

Results: Almost half reported poor sleep quality at baseline. Overall sleep quality was not affected by RRSO until 12 months (p = 0.007). However, sleep disturbance increased by 3 months and remained significantly elevated at 12 months (p < 0.001). Trajectory analysis demonstrated that 41% had increased sleep disturbance after RRSO which persisted in 17.9%. Risk factors for sleep disturbance included severe vasomotor symptoms, obesity and smoking. Around 60% initiated HT after RRSO. Sleep quality was significantly better in HT users vs non users (p = 0.020) but HT did not restore sleep quality to baseline levels.

Conclusions: Overall sleep quality is not affected by RRSO, but new onset sleep disturbance is common, particularly in those with severe vasomotor symptoms. Clinicians should be alert to new-onset sleep disturbance and the potential for HT to improve sleep quality.
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http://dx.doi.org/10.1016/j.ygyno.2021.05.036DOI Listing
August 2021

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Genet Med 2021 Jun 10. Epub 2021 Jun 10.

Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Purpose: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS and CBC risk.

Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

Conclusion: The PRS can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
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http://dx.doi.org/10.1038/s41436-021-01198-7DOI Listing
June 2021

Randomized study of remote telehealth genetic services versus usual care in oncology practices without genetic counselors.

Cancer Med 2021 Jul 8;10(13):4532-4541. Epub 2021 Jun 8.

Penn Telegenetics Program, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: To examine the benefit of telehealth over current delivery options in oncology practices without genetic counselors.

Methods: Participants meeting cancer genetic testing guidelines were recruited to this multi-center, randomized trial comparing uptake of genetic services with remote services (telephone or videoconference) to usual care in six predominantly community practices without genetic counselors. The primary outcome was the composite uptake of genetic counseling or testing. Secondary outcomes compare telephone versus videoconference services.

Results: 147 participants enrolled and 119 were randomized. Eighty percent of participants in the telehealth arm had genetic services as compared to 16% in the usual care arm (OR 30.52, p < 0.001). Five genetic mutation carriers (6.7%) were identified in the telehealth arm, compared to none in the usual care arm. In secondary analyses, factors associated with uptake were lower anxiety (6.77 vs. 8.07, p = 0.04) and lower depression (3.38 vs. 5.06, p = 0.04) among those who had genetic services. There were no significant differences in change in cognitive or affective outcomes immediately post-counseling and at 6 and 12 months between telephone and videoconference arms.

Conclusion: Telehealth increases uptake of genetic counseling and testing at oncology practices without genetic counselors and could significantly improve identification of genetic carriers and cancer prevention outcomes.
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http://dx.doi.org/10.1002/cam4.3968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267134PMC
July 2021

Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score.

J Clin Oncol 2021 Jun 8:JCO2001992. Epub 2021 Jun 8.

Population Health Sciences Department, Weill Cornell Medicine, New York, NY.

Purpose: This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population.

Methods: A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in , , , , , , , , and . PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor-specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC.

Results: The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of , , and carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of and carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk.

Conclusion: PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of and nearly half of carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.
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http://dx.doi.org/10.1200/JCO.20.01992DOI Listing
June 2021

Adjuvant Olaparib for Patients with - or -Mutated Breast Cancer.

N Engl J Med 2021 06 3;384(25):2394-2405. Epub 2021 Jun 3.

From the Breast Cancer Now Toby Robins Research Centre, the Institute of Cancer Research (A.N.J.T.), and the Breast Cancer Now Unit, Guy's Hospital Cancer Centre, King's College London (A.N.J.T.), London, AstraZeneca, Cambridge (S.J.H., N.B.), and Frontier Science (Scotland), Kincraig (R.M.C., E.M.F., C.C.) - all in the United Kingdom; Dana-Farber Cancer Institute, Harvard Medical School (J.E.G., R.D.G.), Frontier Science Foundation (R.D.G.), and Harvard T.H. Chan School of Public Health (R.D.G.) - all in Boston; the Breast Oncology Institute, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel (B.K.); the University of Milan, European Institute of Oncology IRCCS, Milan (G.V.); Breast International Group (D.F., A.A.) and Institut Jules Bordet, l'Université Libre de Bruxelles (E.A., M.P.), Brussels; NRG Oncology (P.R., H.B., P.C.L., N.W., G.Y., C.E.G.) and the Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania (S.M.D.), Philadelphia, and the UPMC Hillman Cancer Center (P.R., P.C.L., N.W.) and the Department of Biostatistics (H.B., J.P.C., G.Y.), University of Pittsburgh, and the NSABP Foundation (N.W.), Pittsburgh - all in Pennsylvania; AstraZeneca, Gaithersburg (A.F.), and the National Cancer Institute, Rockville (L.A.K.) - both in Maryland; Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital (J.B.) - both in Barcelona; BC Cancer, Vancouver, BC, Canada (K.A.G.); Sahlgrenska University Hospital (B.L.) and the Institute of Clinical Sciences, Department of Oncology, Sahlgrenska Academy, Gothenburg University (B.L.) - both in Gothenburg, Sweden; the Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk (E.S.), the Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw (Z.N.), the International Hereditary Cancer Center, Pomeranian Medical University, Szczecin (T.H.), and Read-Gene, Grzepnica (T.H.) - all in Poland; Kaiser Permanente Vallejo Medical Center, Vallejo (J.M.S.), and the UCLA Fielding School of Public Health, David Geffen School of Medicine at UCLA (P.A.G.), and the UCLA Jonsson Comprehensive Cancer Center (P.A.G.), Los Angeles - all in California; Fudan University Shanghai Cancer Center, Shanghai, China, (Z.S.); Georgia NCORP, Northside Hospital Cancer Institute (A.W.P.), and Piedmont Healthcare (A.W.P.) - both in Atlanta; German Breast Group, Neu-Isenburg (S.L.), the Center for Hematology and Oncology Bethanien and Goethe University, Frankfurt (S.L.), and the Center for Familial Breast and Ovarian Cancer and the Center for Integrated Oncology, Faculty of Medicine, University Hospital Cologne, Cologne (R.S.) - all in Germany; the Department of Internal Medicine I and Gaston H. Glock Research Center, Medical University of Vienna, Vienna (G.G.S.); Merck, Kenilworth, NJ (V.K.); the University of Queensland Centre for Clinical Research and Pathology Queensland (S.R.L.) - both in Brisbane, QLD, Australia; and Houston Methodist Cancer Center (C.E.G.) and Weill Cornell Medical College (C.E.G.) - both in Houston.

Background: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with or germline mutation-associated early breast cancer.

Methods: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with or germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival.

Results: A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest.

Conclusions: Among patients with high-risk, HER2-negative early breast cancer and germline or pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).
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http://dx.doi.org/10.1056/NEJMoa2105215DOI Listing
June 2021

Comparison of the Prevalence of Pathogenic Variants in Cancer Susceptibility Genes in Black Women and Non-Hispanic White Women With Breast Cancer in the United States.

JAMA Oncol 2021 Jul;7(7):1045-1050

Slone Epidemiology Center at Boston University, Boston, Massachusetts.

Importance: The prevalence of germline pathogenic variants (PVs) in cancer susceptibility genes in US Black women compared with non-Hispanic White women with breast cancer is poorly described.

Objective: To determine whether US Black and non-Hispanic White women with breast cancer have a different prevalence of PVs in 12 cancer susceptibility genes.

Design, Setting, And Participants: Multicenter, population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Participants were Black and non-Hispanic White women diagnosed with breast cancer, unselected for family history or age at diagnosis. Data were collected from June 1993 to June 2020; data analysis was performed between September 2020 and February 2021.

Main Outcomes And Measures: Prevalence of germline PVs in 12 established breast cancer susceptibility genes.

Results: Among 3946 Black women (mean [SD] age at diagnosis, 56.5 [12.02] y) and 25 287 non-Hispanic White women (mean [SD] age at diagnosis, 62.7 [11.14] y) with breast cancer, there was no statistically significant difference by race in the combined prevalence of PVs in the 12 breast cancer susceptibility genes evaluated (5.65% in Black vs 5.06% in non-Hispanic White women; P = .12). The prevalence of PVs in CHEK2 was higher in non-Hispanic White than Black patients (1.29% vs 0.38%; P < .001), whereas Black patients had a higher prevalence of PVs in BRCA2 (1.80% vs 1.24%; P = .005) and PALB2 (1.01% vs 0.40%; P < .001). For estrogen receptor-negative breast cancer, the prevalence of PVs was not different except for PALB2, which was higher in Black women. In women diagnosed before age 50 years, there was no difference in overall prevalence of PVs in Black vs non-Hispanic White women (8.83% vs 10.04%; P = .25), and among individual genes, only CHEK2 PV prevalence differed by race. After adjustment for age at diagnosis, the standardized prevalence ratio of PVs in non-Hispanic White relative to Black women was 1.08 (95% CI, 1.02-1.14), and there was no longer a statistically significant difference in BRCA2 PV prevalence.

Conclusions And Relevance: This large population-based case-control study revealed no clinically meaningful differences in the prevalence of PVs in 12 breast cancer susceptibility genes between Black and non-Hispanic White women with breast cancer. The findings suggest that there is not sufficient evidence to make policy changes related to genetic testing based on race alone. Instead, all efforts should be made to ensure equal access to and uptake of genetic testing to minimize disparities in care and outcomes.
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http://dx.doi.org/10.1001/jamaoncol.2021.1492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160931PMC
July 2021

Integrating Clinical and Polygenic Factors to Predict Breast Cancer Risk in Women Undergoing Genetic Testing.

JCO Precis Oncol 2021 28;5. Epub 2021 Jan 28.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Screening and prevention decisions for women at increased risk of developing breast cancer depend on genetic and clinical factors to estimate risk and select appropriate interventions. Integration of polygenic risk into clinical breast cancer risk estimators can improve discrimination. However, correlated genetic effects must be incorporated carefully to avoid overestimation of risk.

Materials And Methods: A novel Fixed-Stratified method was developed that accounts for confounding when adding a new factor to an established risk model. A combined risk score (CRS) of an 86-single-nucleotide polymorphism polygenic risk score and the Tyrer-Cuzick v7.02 clinical risk estimator was generated with attenuation for confounding by family history. Calibration and discriminatory accuracy of the CRS were evaluated in two independent validation cohorts of women of European ancestry (N = 1,615 and N = 518). Discrimination for remaining lifetime risk was examined by age-adjusted logistic regression. Risk stratification with a 20% risk threshold was compared between CRS and Tyrer-Cuzick in an independent clinical cohort (N = 32,576).

Results: Simulation studies confirmed that the Fixed-Stratified method produced accurate risk estimation across patients with different family history. In both validation studies, CRS and Tyrer-Cuzick were significantly associated with breast cancer. In an analysis with both CRS and Tyrer-Cuzick as predictors of breast cancer, CRS added significant discrimination independent of that captured by Tyrer-Cuzick ( < 10 in validation 1; < 10 in validation 2). In an independent cohort, 18% of women shifted breast cancer risk categories from their Tyrer-Cuzick-based risk compared with risk estimates by CRS.

Conclusion: Integrating clinical and polygenic factors into a risk model offers more effective risk stratification and supports a personalized genomic approach to breast cancer screening and prevention.
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http://dx.doi.org/10.1200/PO.20.00246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140787PMC
January 2021

What Happens After Menopause? (WHAM): A prospective controlled study of cardiovascular and metabolic risk 12 months after premenopausal risk-reducing bilateral salpingo-oophorectomy.

Gynecol Oncol 2021 Jul 7;162(1):88-96. Epub 2021 May 7.

Departments of Obstetrics and Gynecology, Biostatistics and Epidemiology, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA.

Objective: To prospectively measure cardiometabolic risk 12 months after premenopausal risk-reducing bilateral salpingo-oophorectomy (RRBSO) compared to a similar age comparison group, and the effects of Hormone Therapy (HT) on cardiometabolic risk.

Methods: Prospective observational study of 95 premenopausal women planning RRBSO and 99 comparisons who retained their ovaries. At baseline and 12 months, blood pressure (BP), Body Mass Index (BMI), waist and hip circumference, fasting total, HDL and LDL cholesterol, triglycerides, high-sensitivity C-reactive protein, glucose and insulin were measured and HOMA-IR was calculated. Chi-square tests, t-tests and adjusted logistic regression models were used to compare groups.

Results: Baseline cardiometabolic phenotypes were similar between groups but more RRBSO participants were overweight/obese with higher waist/hip ratios. By 12 months, BP and cardiometabolic phenotypes were largely unchanged. Paired t-tests showed statistically significant increases in BMI (p = 0.037) and weight (p = 0.042) and larger increases in waist circumference (p < 0.001) and waist-hip ratio (p = 0.009) after RRBSO vs comparisons. However, these were not significant when adjusted for baseline values. After RRBSO 60% initiated Hormone Therapy (HT). Paired t-tests demonstrated that non-HT users had a significantly greater mean increase in waist circumference of 4.3 cm (95% CI 2.0-6.5) compared to 1.3 cm in HT users (95% CI -0.2-2.7, p < 0.001), which remained significant when adjusted for baseline values (p = 0.02). At 12 months, mean waist circumference was 2.94 cm greater in non-HT users compared to HT users.

Conclusions: Cardiometabolic risk markers are largely unchanged 12 months after RRBSO. Hormone Therapy after RRBSO may prevent against an increase in waist circumference.
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http://dx.doi.org/10.1016/j.ygyno.2021.04.038DOI Listing
July 2021

Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in , , or .

J Clin Oncol 2021 Aug 10;39(22):2497-2505. Epub 2021 May 10.

Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Purpose: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved as maintenance therapy for patients with advanced pancreatic cancer (PC) and a germline or pathogenic variant (PV). This investigator-initiated, single-arm phase II study assessed the role of the PARPi rucaparib as maintenance therapy in advanced PC with germline or somatic PV in , , or .

Patients And Methods: Eligible patients had advanced PC; germline (g) or somatic (s) PVs in , , or , and received at least 16 weeks of platinum-based chemotherapy without evidence of platinum resistance. Chemotherapy was discontinued and patients received rucaparib 600 mg orally twice a day until progression. The primary end point was the progression-free survival (PFS) rate at 6 months (PFS6). Secondary end points included safety, ORR, disease control rate, duration of response, and overall survival.

Results: Of 46 enrolled patients, 42 were evaluable (27 g, seven g, six g, and two s). PFS6 was 59.5% (95% CI, 44.6 to 74.4), median PFS was 13.1 months (95% CI, 4.4 to 21.8), and median overall survival was 23.5 months (95% CI, 20 to 27). The PFS at 12 months was 54.8%. ORR of the 36 patients with measurable disease was 41.7% (3 complete responses; 12 partial responses; 95% CI, 25.5 to 59.2), and disease control rate was 66.7% (95% CI, 49.0 to 81.4). Median duration of response was 17.3 months (95% CI, 8.8 to 25.8). Responses occurred in patients with (41%, 11 out of 27), (50%, 3 out of 6), and (50%, 1 out of 2). No new safety signals were noted.

Conclusion: Maintenance rucaparib is a safe and effective therapy for platinum-sensitive, advanced PC with a PV in , , or . The finding of efficacy in patients with g and s PVs expands the population likely to benefit from PARPi beyond g/ PV carriers.
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http://dx.doi.org/10.1200/JCO.21.00003DOI Listing
August 2021

A prospective controlled study of sexual function and sexually related personal distress up to 12 months after premenopausal risk-reducing bilateral salpingo-oophorectomy.

Menopause 2021 03 15;28(7):748-755. Epub 2021 Mar 15.

Department of Obstetrics and Gynaecology, University of Melbourne and The Royal Women's Hospital, Melbourne, Australia.

Objective: Premenopausal risk-reducing bilateral salpingo-oophorectomy (RRBSO) may impair sexual function, but the nature and degree of impairment and impact of estrogen therapy on sexual function and sexually related personal distress after RRBSO are uncertain.

Methods: Prospective observational study of 73 premenopausal women at elevated risk of ovarian cancer planning RRBSO and 68 premenopausal controls at population risk of ovarian cancer. Participants completed the Female Sexual Function Index and the Female Sexual Distress Scale-Revised. Change from baseline in sexual function following RRBSO was compared with controls at 12 months according to estrogen therapy use.

Results: Baseline sexual function domains did not differ between controls and those who underwent RRBSO and subsequently initiated (56.2%) or did not initiate (43.8%) estrogen therapy. At 12 months, sexual desire and satisfaction were unchanged in the RRBSO group compared with controls. After RRBSO, nonestrogen therapy users demonstrated significant impairment in sexual arousal (β-coefficient (95% confidence interval) -2.53 (-4.86 to -0.19), P < 0.03), lubrication (-3.40 (-5.84 to -0.96), P < 0.006), orgasm (-1.64 (-3.23 to -0.06), P < 0.04), and pain (-2.70 (-4.59 to 0.82), P < 0.005) compared with controls. Although sexually related personal distress may have been more likely after RRBSO, irrespective of estrogen therapy use, there was insufficient data to formally test this effect.

Conclusions: The findings suggest premenopausal RRBSO adversely affects several aspects of sexual function which may be mitigated by the use of estrogen therapy. Further research is needed to understand the effects of RRBSO on sexual function and sexually related personal distress, and the potential for estrogen therapy to mitigate against any adverse effects.
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http://dx.doi.org/10.1097/GME.0000000000001766DOI Listing
March 2021

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Nat Commun 2021 02 17;12(1):1078. Epub 2021 Feb 17.

Copenhagen General Population Study, Herlev and Gentofte Hospital Copenhagen University Hospital, Herlev, Denmark.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1038/s41467-020-20496-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890067PMC
February 2021

What happens after menopause? (WHAM): A prospective controlled study of depression and anxiety up to 12 months after premenopausal risk-reducing bilateral salpingo-oophorectomy.

Gynecol Oncol 2021 May 11;161(2):527-534. Epub 2021 Feb 11.

Psychiatry Department and Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Objective: Risk-reducing bilateral salpingo-oophorectomy (RRBSO) substantially reduces ovarian cancer risk in women with pathogenic gene variants and is generally recommended by age 34-45 years. Natural menopause is a vulnerable period for mood disturbance, but the risk of depression and anxiety in the first 12 months after RRBSO and potential modifying effect of hormone therapy are uncertain.

Methods: Prospective controlled observational study of 95 premenopausal women planning RRBSO and a Comparison group of 99 premenopausal women who retained their ovaries,- 95% of whom were at population level risk of ovarian cancer. Clinically significant symptoms of depression and anxiety were measured using standardised instruments at baseline, 3, 6 and 12 months. Chi-square tests and adjusted logistic regression models compared differences between groups.

Results: Baseline symptoms and previous depression or anxiety did not differ between groups. At 3 months after RRBSO clinically significant depressive symptoms were doubled (14.5% vs 27.1%, p = 0.010), which persisted at 12 months. Depressive symptoms were stable in comparisons. At 3 months after RRBSO, clinically significant anxiety symptoms almost trebled (6.1% vs 17.7%, p = 0.014) before plateauing at 6 months and returning to baseline at 12 months. Compared to comparisons, RRBSO participants were at 3.0-fold increased risk of chronic depressive symptoms (Wald 95% CI 1.27-7.26), 2.3-fold increased risk of incident depression (95% Wald CI 1.08-5.13) and 2.0-fold increase of incident anxiety (Wald 95% CI 0.78-5.00). Depression and anxiety were slightly more common in Hormone Therapy users after RRBSO vs non-users.

Conclusions: RRBSO leads to a rapid increase in clinically significant depressive and anxiety symptoms despite Hormone Therapy use.
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http://dx.doi.org/10.1016/j.ygyno.2021.02.001DOI Listing
May 2021

A Population-Based Study of Genes Previously Implicated in Breast Cancer.

N Engl J Med 2021 02 20;384(5):440-451. Epub 2021 Jan 20.

From Mayo Clinic, Rochester, MN (C. Hu, S.N.H., R.G., K.Y.L., J.N., J.L., S. Yadav, N.J.B., T.L., J.E.O., C.S., C.M.V., E.C.P., F.J.C.); Harvard University T.H. Chan School of Public Health (H.H., C.G., D.J.H., P.K.), Slone Epidemiology Center at Boston University (K.A.B., J.R.P., L.R.), and Brigham and Women's Hospital (H.E.) - all in Boston; Qiagen, Hilden, Germany (R.S., J.K.); Roswell Park Comprehensive Cancer Center, Buffalo (C.B.A., S. Yao), and Weill Cornell Medicine, New York (R.T.) - both in New York; the University of California, Irvine (H.A.-C., A.Z.), Beckman Research Institute of City of Hope, Duarte (L.B., H.M., S.N., J.N.W.), Keck School of Medicine, University of Southern California, Los Angeles (C. Haiman), and Stanford University School of Medicine, Stanford (E.M.J., A.W.K.) - all in California; the University of Wisconsin-Milwaukee Joseph J. Zilber School of Public Health, Milwaukee (P.A.), and the University of Wisconsin-Madison, Madison (E.S.B., I.M.O., A.T.-D.); the Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, State University of New Jersey, New Brunswick (E.V.B.); the Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta (B.D.C., S.M.G., M.G., J.M.H., E.J.J., A.V.P.); the University of Oxford, Oxford, United Kingdom (D.J.H.); the Fred Hutchinson Cancer Research Center (C.K., P.A.N.) and the Department of Epidemiology, University of Washington (S.L.) - both in Seattle; the Epidemiology Program, University of Hawaii Cancer Center, Honolulu (L.L.M.); the National Institute of Environmental Health Sciences, Durham, NC (K.M.O., D.P.S., J.A.T., C.W.); Vanderbilt University, Nashville (T.P., S.R.); the University of Utah, Salt Lake City (D.E.G.); and the Department of Medicine and the Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (S.M.D., K.L.N.).

Background: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.

Methods: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed.

Results: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in and were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in , , and were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in , , and were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in , were not associated with an increased risk of breast cancer.

Conclusions: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).
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http://dx.doi.org/10.1056/NEJMoa2005936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127622PMC
February 2021

Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2021 01 6;19(1):77-102. Epub 2021 Jan 6.

The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.
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http://dx.doi.org/10.6004/jnccn.2021.0001DOI Listing
January 2021

Upper Gastrointestinal Cancer Risk and Surveillance Outcomes in Li-Fraumeni Syndrome.

Am J Gastroenterol 2020 12;115(12):2095-2097

Division of Hematology and Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Introduction: To assess the upper gastrointestinal (UGI) cancer risk and surveillance outcomes in Li-Fraumeni syndrome (LFS).

Methods: Analysis of the International Agency for Research on Cancer database and a single-center adult LFS cohort.

Results: UGI cancer was present in 7.2% of families and 3.9% of individuals with a pathogenic/likely pathogenic TP53 mutation in International Agency for Research on Cancer; 29% occurred before age 30. Our institutional cohort had 35 individuals (31% of the LFS cohort) with 48 cumulative upper endoscopies; 3 (8.5%) individuals had concerning UGI findings.

Discussion: UGI cancer is observed in LFS. Upper endoscopy should be part of a comprehensive LFS surveillance program.
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http://dx.doi.org/10.14309/ajg.0000000000000935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263231PMC
December 2020

Association of germline variation with the survival of women with pathogenic variants and breast cancer.

NPJ Breast Cancer 2020 10;6:44. Epub 2020 Sep 10.

Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON Canada.

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in or genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30,  = 3.1 × 10). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.
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http://dx.doi.org/10.1038/s41523-020-00185-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483417PMC
September 2020

Mutation Rates in Cancer Susceptibility Genes in Patients With Breast Cancer With Multiple Primary Cancers.

JCO Precis Oncol 2020 19;4. Epub 2020 Aug 19.

Basser Center for BRCA and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Purpose: Women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. Whether mutations in genes other than are enriched in patients with breast and another primary cancer over those with a single breast cancer (S-BC) is unknown.

Patients And Methods: We identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with -negative breast cancer in 2 different cohorts: cohort 1, high-risk breast cancer program (multiple primary breast cancer [MP-BC], n = 551; S-BC, n = 449) and cohort 2, familial breast cancer research study (MP-BC, n = 340; S-BC, n = 1,464). Mutation rates in these 2 cohorts were compared with a control data set (Exome Aggregation Consortium [ExAC]).

Results: Overall, pathogenic mutation rates for autosomal, dominantly inherited genes were higher in patients with MP-BC versus S-BC in both cohorts (8.5% 4.9% [ = .02] and 7.1% 4.2% [ = .03]). There were differences in individual gene mutation rates between cohorts. In both cohorts, younger age at first breast cancer was associated with higher mutation rates; the age of non-breast cancers was unrelated to mutation rate. and mutations were significantly enriched in patients with MP-BC but not S-BC, whereas and mutations were significantly enriched in both groups compared with ExAC.

Conclusion: Mutation rates are at least 7% in all patients with mutation-negative MP-BC, regardless of age at diagnosis of breast cancer, with mutation rates up to 25% in patients with a first breast cancer diagnosed at age < 30 years. Our results suggest that all patients with breast cancer with a second primary cancer, regardless of age of onset, should undergo multigene panel testing.
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http://dx.doi.org/10.1200/PO.19.00301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496037PMC
August 2020

Comparison of up-front cash cards and checks as incentives for participation in a clinician survey: a study within a trial.

BMC Med Res Methodol 2020 08 17;20(1):210. Epub 2020 Aug 17.

Brigham and Women's Hospital, 75 Francis St, Boston, MA, 02115, USA.

Background: Evidence is needed regarding effective incentive strategies to increase clinician survey response rates. Cash cards are increasingly used as survey incentives; they are appealing because of their convenience and because in some cases their value can be reclaimed by investigators if not used. However, their effectiveness in clinician surveys is not known. In this study within the BRCA Founder OutReach (BFOR) study, a clinical trial of population-based BRCA1/2 mutation screening, we compared the use of upfront cash cards requiring email activation versus checks as clinician survey incentives.

Methods: Participants receiving BRCA1/2 testing in the BFOR study could elect to receive their results from their primary care provider (PCP, named by the patient) or from a geneticist associated with the study. In order to understand PCPs' knowledge, attitudes, experiences and willingness to disclose results we mailed paper surveys to the first 501 primary care providers (PCPs) in New York, Boston, Los Angeles and Philadelphia who were nominated by study participants to disclose their BRCA1/2 mutation results obtained through the study. We used alternating assignment stratified by city to assign the first 303 clinicians to receive a $50 up-front incentive as a cash card (N = 155) or check (N = 148). The cash card required PCPs to send an activation email in order to be used. We compared response rates by incentive type, adjusting for PCP characteristics and study site.

Results: In unadjusted analyses, PCPs who received checks were more likely to respond to the survey than those who received cash cards (54.1% versus 41.9%, p = 0.046); this remained true when we adjusted for provider characteristics (OR for checks 1.61, 95% CI 1.01, 2.59). No other clinician characteristics had a statistically significant association with response rates in adjusted analyses. When we included an interaction term for incentive type and city, the favorable impact of checks on response rates was evident only in Los Angeles and Philadelphia.

Conclusions: An up-front cash card incentive requiring email activation may be less effective in eliciting clinician responses than up-front checks. However, the benefit of checks for clinician response rates may depend on clinicians' geographic location.

Trial Registration: ClinicalTrials.gov ( NCT03351803 ), November 24, 2017.
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http://dx.doi.org/10.1186/s12874-020-01086-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430023PMC
August 2020

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study.

Lancet Oncol 2020 09 6;21(9):1155-1164. Epub 2020 Aug 6.

Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer.

Methods: The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004.

Findings: Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3-90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks.

Interpretation: Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(20)30324-7DOI Listing
September 2020

The contemporary landscape of genetic testing and breast cancer: Emerging issues.

Breast J 2020 08 20;26(8):1549-1555. Epub 2020 Jul 20.

Basser Center for BRCA at the Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.

The landscape of genetic testing for breast cancer susceptibility has transformed dramatically over the last decade and a half. Traditionally, the process of genetic testing resided fully within a medical infrastructure, from identification of appropriate testing candidates to gene selection to risk mitigation recommendations. More recently, decreasing costs, advancing technology, and a growing understanding of therapeutic implications of certain genetic test results have led to more widespread uptake of testing that increasingly involves broad multigene panels. Germline genetic testing for breast cancer susceptibility can now be obtained through one of three approaches: through clinical care; a direct-to-consumer (DTC) approach that is entirely consumer-driven; or a hybrid, patient-initiated, provider-mediated model. Increased access to testing has led to extensive dialogue about the best way to conduct testing and act on results. Points of discussion include: selection of appropriate candidates for genetic testing; optimal composition of genes on panels; informed consent; safe return of results; privacy; and legal protections for those found to have relevant pathogenic or likely pathogenic variants. As more individuals undergo genetic testing, a growing population of individuals with inherited breast cancer predisposition informs optimal management of cancer risk and also highlights unanswered questions. This article aims to review the current state of genetic testing for inherited breast cancer susceptibility including testing approaches, the legal, ethical and social landscape, and selected contemporary management issues.
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http://dx.doi.org/10.1111/tbj.13968DOI Listing
August 2020
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