Publications by authors named "Judy Garber"

424 Publications

Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer.

NPJ Breast Cancer 2020 Sep 10;6(1):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 BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30, P = 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
September 2020

Phase II trial of veliparib and temozolomide in metastatic breast cancer patients with and without BRCA1/2 mutations.

Breast Cancer Res Treat 2021 Aug 20. Epub 2021 Aug 20.

Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA, 02141, USA.

Purpose: We evaluated the efficacy and safety of poly-(adenosine diphosphate-ribose) polymerase (PARP) 1 and 2 inhibitor veliparib and temozolomide in metastatic breast cancer patients with and without germline BRCA1/2 mutations.

Methods: In this single-arm phase II trial, patients with metastatic breast cancer received veliparib 30 to 40 mg twice daily on days 1 to 7 with concurrent temozolomide 150 mg/m on days 1 to 5 of a 28-day cycle. The primary cohort was unselected for BRCA mutation status, and an expansion cohort enrolled only BRCA1/2 carriers. The primary endpoint was objective response rate (ORR) in each cohort. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and evaluation of safety and tolerability.

Results: In the primary cohort of 41 unselected patients, which included 9 BRCA mutation carriers, the ORR was 10% and clinical benefit rate at 4 months (CBR) was 27%. In the expansion cohort of 21 BRCA1/2 carriers, the ORR was 14% and CBR was 43%. Among all 30 BRCA1/2 carriers, the ORR was 23% versus 0% among non-carriers. In the subset of BRCA1/2 carriers, the ORR was 32% among platinum-naïve patients versus 9% among platinum-exposed patients. The median PFS was 3.3 months among BRCA1/2 carriers compared to 1.8 months among non-carriers (HR: 0.48, p = 0.006). A longer median PFS of 6.2 months was observed among BRCA1/2 carriers who had no prior platinum therapy. The most common grade 3 and 4 toxicities were thrombocytopenia (32%) and neutropenia (21%) that generally improved with dose modifications.

Conclusion: Veliparib and temozolomide demonstrated clinical activity in platinum-naïve BRCA-associated metastatic breast cancer with manageable toxicity at doses of veliparib well below the single-agent active dose. Although the study did not meet its primary endpoint in unselected nor BRCA-associated breast cancer, this regimen was further evaluated in the BROCADE 2 study.

Trial Registration: NCT01009788 (ClinicalTrials.gov), November 9, 2009.
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http://dx.doi.org/10.1007/s10549-021-06292-7DOI 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

Does Quantitative Sensory Testing Improve Prediction of Chronic Pain Trajectories? A Longitudinal Study of Youth With Functional Abdominal Pain Participating in a Randomized Controlled Trial of Cognitive Behavioral Treatment.

Clin J Pain 2021 09;37(9):648-656

Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN.

Objectives: Youth with functional abdominal pain (FAP) experience significant pain-related distress and functional impairment. Although quantitative sensory testing protocols have identified alterations in pain modulatory systems that distinguish youth with FAP from healthy controls, the extent to which evoked pain responses predict subsequent trajectories of pain symptoms and disability over and above established psychosocial risk factors is unclear.

Methods: The present study included 183 adolescents with FAP who were enrolled in a randomized controlled trial comparing an 8-week, internet-delivered program of cognitive behavior therapy (n=90) or pain education (n=93). Participants completed a quantitative sensory testing protocol before the intervention and were followed for 12-month posttreatment.

Results: Whereas adolescents with FAP who exhibited stronger baseline conditioned pain modulation (CPM) reported decreases in pain-related interference over follow-up (b=-0.858, SE=0.396, P=0.032), those with weaker CPM exhibited high, relatively stable levels of pain-related interference over time (b=-0.642, SE=0.400, P=0.110). CPM status predicted changes in pain-related interference after controlling for the effects of treatment condition and psychosocial risk factors. Static measures of pain sensitivity (ie, pain threshold, pain tolerance) and temporal summation of second pain were not associated with changes in measures of abdominal pain, gastrointestinal symptom severity, or pain-related interference over follow-up.

Discussion: The present findings contribute to a growing literature on the predictive utility of quantitative sensory testing indices and suggest that CPM may complement existing psychosocial risk measures in determining individualized pain-related risk profiles.
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http://dx.doi.org/10.1097/AJP.0000000000000956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373792PMC
September 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

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

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

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

The clinical and functional effects of TERT variants in myelodysplastic syndrome.

Blood 2021 Sep;138(10):898-911

Division of Hematological Malignancies, Department of Medical Oncology, and.

Germline pathogenic TERT variants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of a telomere biology disorder who underwent allogeneic transplantation. Patients with a TERT rare variant had shorter telomere length (P < .001) and younger age at MDS diagnosis (52 vs 59 years, P = .03) than patients without a TERT rare variant. In multivariable models, TERT rare variants were associated with inferior overall survival (P = .034) driven by an increased incidence of nonrelapse mortality (NRM; P = .015). Death from a noninfectious pulmonary cause was more frequent among patients with a TERT rare variant. Most variants were missense substitutions and classified as variants of unknown significance. Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 90% of TERT rare variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants disrupt domain-specific functions, including catalysis, protein-RNA interactions, and recruitment to telomeres. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized. Routine screening for TERT rare variants in MDS patients regardless of age or clinical suspicion may identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.
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http://dx.doi.org/10.1182/blood.2021011075DOI Listing
September 2021

Developmental Psychopathology and the Research Domain Criteria: Friend or Foe?

J Clin Child Adolesc Psychol 2020 May-Jun;49(3):341-352

Department of Human Services, University of Virginia.

Developmental psychopathology (DP) is a conceptual approach to the study of the origins and course of individual patterns in the development of psychopathology across the lifespan. The Research Domain Criteria (RDoC) framework aims to study dimensions of neurobiology and behavior to construct a new classification of psychopathology that will advance the understanding and treatment of mental disorders. In this commentary, we describe aspects of overall convergence and divergence between these two approaches. Developmental psychopathology and RDoC overlap, in that they both (a) study the full range of variation from normality to psychopathology, (b) aim to understand the origins and mechanisms underlying psychopathology, (c) use multiple units of analysis to study salient domains of functioning, and (d) emphasize the importance of using reliable and valid measurement. There also are several differences between these perspectives. For example, RDoC is exclusively dimensional, whereas DP studies both continuities and discontinuities. According to RDoC, mental disorders are brain disorders and neurocircuitry is primary, whereas DP asserts that the development of psychopathology results from dynamic transactions among neurobiology, psychology, and social contexts. We conclude by identifying ways to leverage the DP and RDoC perspectives to advance progress in both, particularly regarding research and intervention for children and adolescents.
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http://dx.doi.org/10.1080/15374416.2020.1753205DOI Listing
August 2021

Psychological Treatments for Depression in Adolescents: More Than Three Decades Later.

Int J Environ Res Public Health 2021 04 26;18(9). Epub 2021 Apr 26.

Department of Health Psychology, Miguel Hernández University, 03202 Elche, Spain.

Depression is a common and impairing disorder which is a serious public health problem. For some individuals, depression has a chronic course and is recurrent, particularly when its onset is during adolescence. The purpose of the current paper was to review the clinical trials conducted between 1980 and 2020 in adolescents with a primary diagnosis of a depressive disorder, excluding indicated prevention trials for depressive symptomatology. Cognitive behavioral therapy (CBT) is the pre-eminent treatment and is well established from an evidence-based treatment perspective. The body of research on the remaining treatments is smaller and the status of these treatments is varied: interpersonal therapy (IPT) is well established; family therapy (FT) is possibly effective; and short-term psychoanalytic therapy (PT) is experimental treatment. Implementation of the two treatments that work well-CBT and IPT-has more support when provided individually as compared to in groups. Research on depression treatments has been expanding through using transdiagnostic and modular protocols, implementation through information and communication technologies, and indicated prevention programs. Despite significant progress, however, questions remain regarding the rate of non-response to treatment, the fading of specific treatment effects over time, and the contribution of parental involvement in therapy.
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http://dx.doi.org/10.3390/ijerph18094600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123571PMC
April 2021

The Influence of Vitamin D on Mammographic Density: Results from CALGB 70806 (Alliance) a Randomized Clinical Trial.

Cancer Prev Res (Phila) 2021 Jul 13;14(7):753-762. Epub 2021 Apr 13.

University of Texas MD Anderson Cancer Center, Houston, Texas.

Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and toxicity limits use of these agents. Vitamin D is a potential prevention therapy for both ER+ and ER- disease and is safe with few side effects. This study evaluates the effect of 1-year of vitamin D supplementation on mammographic density (MD), a biomarker of breast cancer risk in a multicenter randomized controlled trial. Premenopausal women with ≥25% MD and no history of cancer were randomly assigned to 2,000 international units (IU) of vitamin D or placebo orally daily for 1 year. Change in percent MD was evaluated using Cumulus software after all participants completed treatment. Three hundred women enrolled between January 2011 and December 2013 with a mean age of 43 and diverse ethnicity [14% Hispanic, 12% African American (AA)]. Supplementation significantly increased vitamin D levels compared with placebo (14.5 ng/mL vs. -1.6 ng/mL; < 0.0001) with all participants on the vitamin D arm achieving vitamin D sufficiency at 12 months. Vitamin D was safe and well tolerated. After adjustment for baseline MD, the mean between-arm difference (vitamin D vs. placebo) at 1 year was -0.75 (-0.26, 1.76; = 0.56). A greater effect was seen for women with ≥50% MD and AA women, although neither reached significance. This randomized controlled trial demonstrated significant improvement in vitamin D levels with 2,000 IU for 1 year, with 100% of supplemented women achieving sufficiency. However, a null effect was seen regarding change in MD for premenopausal women (the primary outcome of the study). PREVENTION RELEVANCE: Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and are underutilized due to toxicity and side effects. Vitamin D is a potential prevention therapy for both ER+ and ER- disease and is safe with few side effects.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449513PMC
July 2021

Trans-ethnic variation in germline variants of patients with renal cell carcinoma.

Cell Rep 2021 Mar;34(13):108926

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine and Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Prior studies of the renal cell carcinoma (RCC) germline landscape investigated predominantly patients of European ancestry. We examine the frequency of germline pathogenic and likely pathogenic (P/LP) variants in 1,829 patients with RCC from various ancestries. Overall, P/LP variants are found in 17% of patients, among whom 10.3% harbor one or more clinically actionable variants with potential preventive or therapeutic utility. Patients of African ancestry with RCC harbor significantly more P/LP variants in FH compared to patients of non-African ancestry with RCC and African controls from the Genome Aggregation Database (gnomAD). Patients of non-African ancestry have significantly more P/LP variants in CHEK2 compared to patients of African ancestry with RCC and non-Finnish Europeans controls. Non-Africans with RCC have more actionable variants compared to Africans with RCC. This work helps understand the underlying biological differences in RCC between Africans and non-Africans and paves the way to more comprehensive genomic characterization of underrepresented populations.
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http://dx.doi.org/10.1016/j.celrep.2021.108926DOI Listing
March 2021

Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer.

Nat Cancer 2021 Jan 14;2(1):66-82. Epub 2020 Dec 14.

Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215.

Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway. Combined PARP inhibitor therapy with CSF-1R blocking antibodies significantly enhanced innate and adaptive anti-tumor immunity and extends survival in BRCA-deficient tumors and is mediated by CD8 T-cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate combined PARP inhibition and macrophage targeting therapy induces a durable reprogramming of the tumor microenvironment, thus constituting a promising therapeutic strategy for TNBC.
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http://dx.doi.org/10.1038/s43018-020-00148-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963404PMC
January 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

Unexpected Pathogenic RET p.V804M Variant Leads to the Clinical Diagnosis and Management of Medullary Thyroid Carcinoma.

Am J Case Rep 2020 Dec 27;21:e927415. Epub 2020 Dec 27.

Harvard Medical School, Boston, MA, USA.

BACKGROUND RET p.V804M is a known activating oncogenic variant that confers an increased risk for medullary thyroid carcinoma (MTC). Based on age-specific penetrance, the American Thyroid Association (ATA) categorizes this variant as posing moderate risk. Therefore, ATA guidelines endorse prophylactic thyroidectomy for carriers in childhood (by age 5-10 years) or adulthood, or when the serum calcitonin level becomes elevated. The recommendation for thyroidectomy is increasingly controversial due to the recently reported low penetrance of the RET p.V804M variant in a large unbiased ascertainment cohort. CASE REPORT We describe the unexpected identification of this variant in a 62-year-old woman undergoing broad, multigene cancer panel testing for her personal and family history of breast cancer. There was no known family history of MTC. Biochemical screening prompted by the RET p.V804M result revealed a mildly elevated serum calcitonin. Pathology examination of her thyroidectomy specimen revealed multifocal medullary thyroid microcarcinoma; her sibling's prophylactic thyroidectomy after a RET p.V840M-positive result similarly revealed early-stage MTC. CONCLUSIONS This report demonstrates the value of genetic counseling, shared decision-making, cascade testing, and timely thyroidectomy in the management of a patient with an unexpected RET p.V804M result.
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http://dx.doi.org/10.12659/AJCR.927415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774021PMC
December 2020

Novel Pathogenic Germline Variant of the Adenomatous Polyposis Coli (APC) Gene, p.S2627Gfs*12 Identified in a Mild Phenotype of APC-Associated Polyposis: A Case Report.

Am J Case Rep 2020 Dec 11;21:e927293. Epub 2020 Dec 11.

Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.

BACKGROUND The diagnoses of adenomatous polyposis coli (APC)-associated polyposis conditions are typically based on suggestive personal features and/or family history, and the identification of a pathogenic variant in the APC gene. However, with large-scale genome sequencing, it is now possible to identify pathogenic variants before or even without the presentation of the expected clinical features. This case describes a novel pathogenic APC variant. CASE REPORT We report the unexpected identification of a rare, pathogenic germline APC variant, p.S2627Gfs*12 in an 80-year-old man with a diagnosis of renal cell carcinoma, without any family history of APC-associated polyposis or personal history of colorectal cancer. After the identification of the APC variant, a review of the patient's medical records showed a personal history of 15 adenomatous polyps over a decade ago, with no follow-up genetic testing at the time. CONCLUSIONS This novel APC variant has not been characterized to date. The presence of the APC-p.S2627Gfs*12 variant in this patient led to the recommendation of additional cascade genetic testing and surveillance measures for any family members who tested positive for this variant. This report highlights the broad spectrum of the APC-associated polyposis features, and a mild phenotype associated with the pathogenic APC p.S2627Gfs*12 variant.
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http://dx.doi.org/10.12659/AJCR.927293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737709PMC
December 2020

A Randomized Phase IIb Study of Low-dose Tamoxifen in Chest-irradiated Cancer Survivors at Risk for Breast Cancer.

Clin Cancer Res 2021 02 3;27(4):967-974. Epub 2020 Dec 3.

Dana Farber Cancer Institute, Boston, Massachusetts.

Purpose: Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors-a population with breast cancer risk comparable with mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk.

Patients And Methods: We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints.

Results: Seventy-two participants (low-dose tamoxifen: = 34, placebo: = 38) enrolled at a median age of 43.8 years (35-49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area ( = 0.02) and IGF1 levels ( < 0.0001), and higher IGFBP-3 levels ( = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3-4 adverse events related to low-dose tamoxifen.

Conclusions: In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887034PMC
February 2021

Embedding a genetic counselor into oncology clinics improves testing rates and timeliness for women with ovarian cancer.

Gynecol Oncol 2021 02 21;160(2):457-463. Epub 2020 Nov 21.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.

Objective: Germline genetic testing is crucial to the care of ovarian cancer patients, and as part of the guideline-based care for ovarian cancer patient's adherence to this recommendation has been low. We sought to determine whether embedding a genetic counselor (GC) within a medical and gynecologic oncology clinic would increase testing rates and improve the timeliness of testing.

Methods: Prospective cohort study of 358 ovarian cancer patients seen by medical and gynecologic oncologists between 2013 and 2015. Rates of referrals, completion of counseling, and genetic testing and timeliness of counseling were abstracted before and after a GC was embedded in the clinic in 2014. An additional year of data (2015) was collected to evaluate sustainability of the intervention.

Results: Between 2013 and 2015, 88-92% of women were referred for genetic testing, but in 2013 only 66% completed counseling and 61% were tested. After a GC was embedded in the clinic in 2014, more than 80% of referred women completed counseling and germline genetic testing. Time to genetic counseling also decreased from a median of 107 to 40 days, irrespective of age and cancer family history (p < 0.01).

Conclusions: Embedding a GC into the workflow for ovarian cancer patients is an effective way of improving access to genetic counseling, testing rates, and the timeliness of testing.
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http://dx.doi.org/10.1016/j.ygyno.2020.11.003DOI Listing
February 2021

Personalized Depression Prevention: A Randomized Controlled Trial to Optimize Effects Through Risk-Informed Personalization.

J Am Acad Child Adolesc Psychiatry 2021 Sep 13;60(9):1116-1126.e1. Epub 2020 Nov 13.

University of Illinois Urbana-Champaign, Illinois.

Objective: To evaluate whether evidence-based depression prevention programs can be optimized by matching youths to interventions that address their psychosocial vulnerabilities.

Method: This randomized controlled trial included 204 adolescents (mean [SD] age = 14.26 [1.65] years; 56.4% female). Youths were categorized as high or low on cognitive and interpersonal risks for depression and randomly assigned to Coping With Stress (CWS), a cognitive-behavioral program, or Interpersonal Psychotherapy-Adolescent Skills Training (IPT-AST), an interpersonal program. Some participants received a match between risk and prevention (eg, high cognitive-low interpersonal risk teen in CWS, low cognitive-high interpersonal risk teen in IPT-AST), others received a mismatch (eg, low cognitive-high interpersonal risk teen in CWS). Outcomes were depression diagnoses and symptoms through 18 months postintervention (21 months total).

Results: Matched adolescents showed significantly greater decreases in depressive symptoms than mismatched adolescents from postintervention through 18-month follow-up and across the entire 21-month study period (effect size [d] = 0.44, 95% CI = 0.02, 0.86). There was no significant difference in rates of depressive disorders among matched adolescents compared with mismatched adolescents (12.0% versus 18.3%, t = .78, p = .44).

Conclusion: This study illustrates one approach to personalizing depression prevention as a form of precision mental health. Findings suggest that risk-informed personalization may enhance effects beyond a one-size-fits-all approach.

Clinical Trial Registration Information: Bending Adolescent Depression Trajectories Through Personalized Prevention; https://www.clinicaltrials.gov/; NCT01948167.
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http://dx.doi.org/10.1016/j.jaac.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116944PMC
September 2021

TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes.

J Clin Oncol 2020 12 29;38(36):4274-4282. Epub 2020 Oct 29.

Harvard Medical School, Boston, MA.

Purpose: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline (g)/ mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)/ mutations or g/s mutations in homologous recombination (HR)-related genes other than 2.

Methods: Eligible patients had MBC with measurable disease and germline mutations in non-/ HR-related genes (cohort 1) or somatic mutations in these genes or / (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS).

Results: Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in s/, or . In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with g (ORR, 82%) and s/ (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for g and 6.3 months (90% CI, 4.4 months to NA) for s/ mutation carriers. No responses were observed with or mutations alone.

Conclusion: PARP inhibition is an effective treatment for patients with MBC and g or s/ mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond g/ mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.
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http://dx.doi.org/10.1200/JCO.20.02151DOI Listing
December 2020

'Case of the Month' from Brigham and Women's Hospital, Boston, MA, USA: a 70-year-old man with lung cysts and bilateral renal masses.

BJU Int 2020 10;126(4):428-432

Division of Urological Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1111/bju.15234DOI Listing
October 2020

Subgroups of Pediatric Patients With Functional Abdominal Pain: Replication, Parental Characteristics, and Health Service Use.

Clin J Pain 2020 12;36(12):897-906

Pediatrics, Vanderbilt University Medical Center.

Objectives: Prior work in a cohort of youth with functional abdominal pain (FAP) identified patient subgroups (High Pain Dysfunctional, High Pain Adaptive, Low Pain Adaptive) that predicted differences in the course of FAP from childhood into young adulthood. We aimed to replicate these subgroups in a new sample of adolescents with FAP using the original classification algorithm and to extend subgroup characteristics to include parental characteristics and health service use.

Methods: Adolescents (n=278; ages 11 to 17 y, 66% females) presenting to a gastroenterology clinic for abdominal pain, and their parents (92% mothers) completed self-report measures; adolescents also completed a 7-day pain diary.

Results: The replicated patient subgroups exhibited distress and impairment similar to subgroups in the original sample. Moreover, in novel findings, the High Pain Dysfunctional subgroup differed from other subgroups by the predominance of mother-daughter dyads jointly characterized by high levels of anxiety, depressive symptoms, pain behavior, and pain catastrophizing. The High Pain Dysfunctional subgroup used more health care services than Low Pain Adaptive but did not differ from High Pain Adaptive.

Discussion: Findings replicate and extend the original FAP classification and suggest that the subgroups have unique patient and parent features that may reflect distinct illness mechanisms requiring different treatments.
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http://dx.doi.org/10.1097/AJP.0000000000000882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666007PMC
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

Development and Validation of a Clinical Polygenic Risk Score to Predict Breast Cancer Risk.

JCO Precis Oncol 2020 8;4. Epub 2020 Jun 8.

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

Purpose: Women with a family history of breast cancer are frequently referred for hereditary cancer genetic testing, yet < 10% are found to have pathogenic variants in known breast cancer susceptibility genes. Large-scale genotyping studies have identified common variants (primarily single-nucleotide polymorphisms [SNPs]) with individually modest breast cancer risk that, in aggregate, account for considerable breast cancer susceptibility. Here, we describe the development and empirical validation of an SNP-based polygenic breast cancer risk score.

Methods: A panel of 94 SNPs was examined for association with breast cancer in women of European ancestry undergoing hereditary cancer genetic testing and negative for pathogenic variants in breast cancer susceptibility genes. Candidate polygenic risk scores (PRSs) as predictors of personal breast cancer history were developed through multivariable logistic regression models adjusted for age, cancer history, and ancestry. An optimized PRS was validated in 2 independent cohorts (n = 13,174; n = 141,160).

Results: Within the training cohort (n = 24,259), 4,291 women (18%) had a personal history of breast cancer and 8,725 women (36%) reported breast cancer in a first-degree relative. The optimized PRS included 86 variants and was highly predictive of breast cancer status in both validation cohorts ( = 6.4 × 10; < 10). The odds ratio (OR) per unit standard deviation was consistent between validations (OR, 1.45 [95% CI, 1.39 to 1.52]; OR 1.47 [95% CI, 1.45 to 1.49]). In a direct comparison, the 86-SNP PRS outperformed a previously described PRS of 77 SNPs.

Conclusion: The validation and implementation of a PRS for women without pathogenic variants in known breast cancer susceptibility genes offers potential for risk stratification to guide surveillance recommendations.
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http://dx.doi.org/10.1200/PO.19.00360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446363PMC
June 2020

Informing models of cancer genetics care in the era of multigene panel testing with patient-led recommendations.

J Genet Couns 2021 02 26;30(1):268-282. Epub 2020 Aug 26.

Cancer Genetics and Prevention Program, Dana-Farber Cancer Institute, Boston, MA, USA.

The study describes patient-reported experiences and recommendations to improve the genetic counseling and multigene panel testing (MGPT) process. A descriptive mixed-method study with concurrently collected and integrated qualitative and quantitative data was conducted. Eligible participants were English-speaking adults with a breast or gynecologic cancer diagnosis who had received genetic counseling and testing with a MGPT from one Comprehensive Cancer Center. Satisfaction with the genetic counseling, genetic knowledge using a recently validated scale (KnowGene), the multidimensional impact of cancer risk assessment (MICRA), family communication, and the association with demographic factors were evaluated. To supplement the large quantitative data set, qualitative focus group responses and open-ended text items were collected. Univariate and multivariable associations between each outcome of interest and personal characteristics were assessed. Qualitative data were content-analyzed. 603 participants completed the survey (48% response rate) and 10 individuals participated in the focus groups. Participants were mostly Caucasian, educated with a college degree or more, and female with median age 58 (24-91), and 78% of participants had a breast cancer diagnosis. Of all individuals undergoing genetic testing using a MGPT, 13% had a pathogenic variant identified, and 30% had a variant of uncertain significance (VUS). Overall, participants reported satisfaction with the genetic counseling and testing process (mean 36.9 [SD 4.7]). On average, participants had 7 incorrect answers out of 19 on the genetic knowledge scale (mean 12.3 [SD 3.4]). MICRA scores showed overall low levels of distress and uncertainty, as well as positive experiences, with wide variability (median 17 [0-84]). Age, marital status, education level, type of cancer diagnosis, and genetic testing results were significantly associated with outcomes. Most participants communicated genetic testing results to mainly female first-degree relatives. A wide range of individual preferences affecting overall satisfaction, or suggestions for improvement were shared. As new models of streamlined cancer genetic services are being clinically implemented, approaches should continue to assess and tailor the process based on patients' informational and emotional needs.
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http://dx.doi.org/10.1002/jgc4.1317DOI Listing
February 2021

A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome.

Genome Res 2020 08 18;30(8):1170-1180. Epub 2020 Aug 18.

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

De novo mutations (DNMs) are increasingly recognized as rare disease causal factors. Identifying DNM carriers will allow researchers to study the likely distinct molecular mechanisms of DNMs. We developed Famdenovo to predict DNM status (DNM or familial mutation [FM]) of deleterious autosomal dominant germline mutations for any syndrome. We introduce Famdenovo.TP53 for Li-Fraumeni syndrome (LFS) and analyze 324 LFS family pedigrees from four US cohorts: a validation set of 186 pedigrees and a discovery set of 138 pedigrees. The concordance index for Famdenovo.TP53 prediction was 0.95 (95% CI: [0.92, 0.98]). Forty individuals (95% CI: [30, 50]) were predicted as DNM carriers, increasing the total number from 42 to 82. We compared clinical and biological features of FM versus DNM carriers: (1) cancer and mutation spectra along with parental ages were similarly distributed; (2) ascertainment criteria like early-onset breast cancer (age 20-35 yr) provides a condition for an unbiased estimate of the DNM rate: 48% (23 DNMs vs. 25 FMs); and (3) hotspot mutation R248W was not observed in DNMs, although it was as prevalent as hotspot mutation R248Q in FMs. Furthermore, we introduce Famdenovo.BRCA for hereditary breast and ovarian cancer syndrome and apply it to a small set of family data from the Cancer Genetics Network. In summary, we introduce a novel statistical approach to systematically evaluate deleterious DNMs in inherited cancer syndromes. Our approach may serve as a foundation for future studies evaluating how new deleterious mutations can be established in the germline, such as those in .
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http://dx.doi.org/10.1101/gr.249599.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462073PMC
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
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