Polley, Eric C.

PURPOSE To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

Abstract Introduction: The relationship between germline pathogenic variants (PVs) in cancer predisposition genes and ductal carcinoma in situ (DCIS) is not well established. The objective of this study is to determine the risks of DCIS and contralateral breast cancer among women with DCIS associated with germline PVs in cancer predisposition genes. Methods: Associations between pathogenic variants in 11 cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MSH6, PALB2, RAD51C, and RAD51D) and DCIS were determined in case control analyses of a population-based cohort of 3876 women with DCIS and age-matched unaffected women, and in a clinical cohort of 9887 DCIS cases undergoing clinical genetic testing at Ambry Genetics and unaffected reference controls. The incidence of contralateral breast cancer risk in BRCA1, BRCA2, and PALB2 PV carriers with DCIS was also evaluated in a time-to-event analysis. Results: The mean age at diagnosis of DCIS was 50 years in the clinical testing cohort and 59 years in the population-based cohort. The frequency of PVs in 11 predisposition genes among DCIS cases was 6.9% in the clinical testing cohort and 4.9% in the population-based cohort. PVs in ATM, BRCA1, BRCA2, CHEK2, MSH6, PALB2, and RAD51D were associated with significantly increased risks (Odds Ratio (OR) >2) of DCIS in the clinical testing cohort whereas only PVs in BRCA1, CHEK2, PALB2, and ATM were associated with significantly increased risks of DCIS in the population-based cohort. The cumulative incidence of contralateral breast cancer among BRCA1, BRCA2, and PALB2 PV carriers with DCIS was 11% in 5-years and 20% in 15-years. Conclusions: This study provides new insights into PVs that predispose to DCIS. In addition, it establishes an increased risk of contralateral breast cancer risk among women with DCIS who are carriers of PVs in BRCA1, BRCA2, or PALB2. These findings will guide surveillance and risk reducing strategies in germline PV carriers with DCIS. Citation Format: Huaizhi Huang, Ronan E. Couch, Holly LaDuca, Siddhartha Yadav, Eric C. Polley, Nicholas J. Boddicker, Jie Na, Rohan D. Gnanaolivu, David E. Goldgar, Tina Pesaran, Steven N. Hart, Jill S. Dolinsky, Julie R. Palmer, Lauren Teras, Alpa V. Patel, Kathryn J. Ruddy, Janet E. Olson, Celine M. Vachon, Peter Kraft, Song Yao, Amy Trentham-Dietz, Katherine L. Nathanson, Jeffrey N. Weitzel, Susan M. Domchek, Fergus J. Couch, Chunling Hu. Risks of ductal carcinoma in situ of the breast associated with pathogenic variants in cancer predisposition genes [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr A003.

Abstract Objective To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A 1c (HbA 1c ). Design Observational study. Setting OptumLabs® Data Warehouse (OLDW), a nationwide claims database in the US, 25 January 2010 to 30 June 2019. Participants Adults with type 2 diabetes and HbA 1c 6.8-8.5% while using metformin monotherapy, identified according to the GRADE trial specifications, who also used glimepiride, liraglutide, sitagliptin, or insulin glargine. Main outcome measures The primary outcome was time to HbA 1c ≥7.0%. Secondary outcomes were time to HbA 1c >7.5%, incident microvascular complications, incident macrovascular complications, adverse events, all cause hospital admissions, and all cause mortality. Propensity scores were estimated using the gradient boosting machine method, and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression. Results 8252 people were identified (19.7% of adults starting the study drugs in OLDW) who met eligibility criteria for the GRADE trial (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses owing to small sample size. Median times to HbA 1c ≥7.0% were 442 days (95% confidence interval 394 to 480 days) for glimepiride, 764 (741 to not calculable) days for liraglutide, and 427 (380 to 483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA 1c ≥7.0% compared with glimepiride (hazard ratio 0.57, 95% confidence interval 0.43 to 0.75) and sitagliptin (0.55, 0.41 to 0.73). Results were consistent for the secondary outcome of time to HbA 1c >7.5%. No significant differences were observed among treatment groups for the remaining secondary outcomes. Conclusions In this emulation of the GRADE trial, liraglutide was statistically significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. Generating timely evidence on medical treatments using real world data as a complement to prospective trials is of value.

AbstractBackgroundMany hospitalized patients do not understand or agree with their clinicians about their discharge plan. However, the effect of disagreement on discharge outcomes is unknown.ObjectiveTo measure the correlation between patient‐clinician care agreement and discharge outcomes.DesignA prospective cohort study was performed from September 2019 to March 2020 (Rochester, MN, USA).Setting and ParticipantsInternal medicine patients and their primary clinician (resident, advanced practice clinician or attending) hospitalized from September 2019‐March 2020 at Mayo Clinic Hospital. Participants were independently surveyed following hospital day #3 ward rounds regarding the goals of the hospitalization and discharge planning.Main Outcome and MeasuresPatient–clinician agreement for main diagnosis, patient's main concern, and four domains of discharge planning was assessed. Readiness for hospital discharge, delayed discharge, and 30‐day readmission was measured. Then, associations between patient‐clinician agreement, delayed discharge, and 30‐day readmissions were analyzed using multivariable logistic regression.ResultsOf the 436 patients and clinicians, 17.7% completely agreed about what needs to be accomplished before dismissal, 40.8% agreed regarding discharge date, and 71.1% agreed regarding discharge location. In the multivariable model, patient–clinician agreement scores were not significantly correlated with discharge outcomes. Patient–clinician agreement on discharge location was higher for those discharged to home (81.5%) versus skilled nursing facility (48.5%) or assisted living (42.9%) (p < .0001). The agreement on the expected length of stay was highest for home‐goers (45.9%) compared to skilled nursing (32.0%) or assisted living (21.4%) (p = .004).ConclusionsPatients and their clinicians frequently disagree about when and where a patient will go after hospitalization, particularly for those discharged to a skilled nursing facility. While disagreement did not predict discharge outcomes, our findings suggest opportunities to improve effective communication and promote shared mental models regarding discharge earlier in the hospital stay.

Abstract Purpose: The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance of 133 single-nucleotide substitution variants encoding missense variants in the DNA-binding domain (DBD) of BRCA2 by incorporating results from a validated functional assay into an ACMG/AMP-variant classification model from a hereditary cancer–testing laboratory. Experimental Design: The 133 selected VUS were evaluated using a validated homology-directed double-strand DNA break repair (HDR) functional assay. Results were combined with clinical and genetic data from variant carriers in a rules-based variant classification model for BRCA2. Results: Of 133 missense variants, 44 were designated as non-functional and 89 were designated as functional in the HDR assay. When combined with genetic and clinical information from a single diagnostic laboratory in an ACMG/AMP-variant classification framework, 66 variants previously classified by the diagnostic laboratory were correctly classified, and 62 of 67 VUS (92.5%) were reclassified as likely pathogenic (n = 22) or likely benign (n = 40). In total, 44 variants were classified as pathogenic/likely pathogenic, 84 as benign/likely benign, and 5 remained as VUS. Conclusions: Incorporation of HDR functional analysis into an ACMG/AMP framework model substantially improves BRCA2 VUS re-classification and provides an important tool for determining the clinical relevance of individual BRCA2 VUS.

Abstract Introduction: The risk of specific clinical subtype of breast cancer (defined by ER and HER2 status) among women in the general population who are carriers of germline pathogenic variants (PVs) in cancer predisposition genes is not well-defined. Methods: A total of 13,153 women with breast cancer (ER+/HER2-: 9381; ER+/HER2+: 1462; ER-/HER2+: 690; and ER-/HER2-: 1620) and 25,005 unaffected women (controls) from nine studies within the CAnceR RIsk Estimates Related to Susceptibility (CARRIERS) consortium that were not enriched for family history or early onset disease were included in the present analysis. A multiplex amplicon-based panel was used to perform germline sequencing for cancer predisposition genes. Case-control associations for each of the four clinical subtype of breast cancer was performed for PVs in 5 common breast cancer predisposition genes (ATM, BRCA1, BRCA2, CHEK2 and PALB2) utilizing a logistic regression model adjusting for study, age at diagnosis, race/ethnicity and family history of breast cancer. Results: The frequency of PVs in 5 genes was 3.8% for ER+/HER2-, 6.2% for ER+/HER2+, 4.2% for ER-/HER2+ and 9.3% for ER-/HER2- subtypes. PVs in BRCA1 and BRCA2 were associated with high risk (Odds Ratio (OR) &gt;4) for all clinical subtypes of breast cancer, but the risk was highest (OR&gt;8) for ER-/HER2- breast cancer. PVs in PALB2 were associated with high risk (OR&gt;4) of ER-/HER2- and ER+/HER2+ subtypes and moderate risk (OR: 2-4) of ER+/HER2- breast cancer. Irrespective of the HER2 status, PVs in ATM were associated with a moderately increased risk (OR: 2-4) of ER+ breast cancer but the risk of ER- breast cancer was not elevated. In contrast, PVs in CHEK2 were associated with high risk (OR&gt;4) of ER+/HER2+ breast cancer and moderate risk (OR: 2-4) of ER+/HER2- and ER-/HER2+ breast cancer, but the risk of ER-/HER2- breast cancer was not elevated. Conclusions: This study provides population-based estimates of risk of specific clinical subtypes of breast cancer which will be useful for genetic counseling and targeting appropriate screening strategies in PV carriers based on subtype specific risks of breast cancer. Citation Format: Siddhartha Yadav, Chunling Hu, Nicholas J. Boddicker, Eric Polley, Steven Hart, Rohan Gnanaolivu, Jie Na, Hongyan Huang, Song Yao, Celine M. Vachon, Lauren Teras, Jack A. Taylor, Dale P. Sandler, Julie R. Palmer, Janet E. Olson, Susan Neuhausen, Elena Martinez, Sara Lindstroem, Loic Le Marchand, Charles Kooperberg, Christopher Haiman, Mia M. Gaudet, James V. Lacey, Kimberly A. Bertrand, Leslie Bernstein, Paul W. Auer, Christine Ambrosone, Jeffrey N. Weitzel, Peter Kraft, David E. Goldgar, Katherine L. Nathanson, Susan M. Domchek, Fergus J. Couch, CARRIERS Consortium. Population-based risk estimates of clinical subtypes of breast cancer among carriers of germline pathogenic variants in cancer predisposition genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-01.

Abstract Introduction: Prostate Cancer (PCa) risk is influenced by both rare germline pathogenic variants (GPVs) in DNA damage repair genes and common variants as measured by polygenic risk scores (PRS) however, the combined effect of GPVs and PRS on PCa risk in men of African ancestry has not been investigated. Methods: We examined the combined effect of rare GPVs and PRS on PCa risk in 1,795 PCa cases and 1,424 controls of African ancestry men from the Multiethnic Cohort, the Los Angeles Study of Aggressive Prostate Cancer, and the Uganda Prostate Cancer Study. GPVs in 19 DNA genes were defined as clinically validated missense variants and variants that alter the protein sequence. The PRS was constructed as a weighted sum of 267 established PCa risk variants. The combined effect of the PRS and GPV status on PCa risk was evaluated using logistic regression models adjusting for age, study, and the first 10 principal components of ancestry to account for population stratification. Results: We identified 91 GPVs carried by 31 controls and 68 cases. Among GPV non-carriers, compared to those with average PRS (33.3-66.7%), odds ratios for PCa ranged from 0.56 (95% CI=0.45-0.70; P=1.2E-7) in low PRS men (0-33.3%) to 3.04 (95% CI=2.54-3.63; P=5.6E-35) in high PRS men (66.7-100%). Among GPV carriers, odds ratios for PCa ranged from 2.09 (95% CI=0.85-5.12; P=0.11) in low PRS men to 5.03 (95% CI=2.37-10.66; P=2.5E-5) in high PRS men, compared to GPV non-carriers with average PRS. Next, we restricted GPVs to ATM, BRCA2, PALB2, and NBN[BD2] (n=51 variants carried by 8 controls and 44 cases), which we previously reported as being the genes most strongly associated with advanced PCa in this population and study sample. Among GPV non-carriers, odds ratios for PCa ranged from 0.56 (95% CI=0.46-0.71; P=2.7E-7) in low PRS men to 5.03 (95% CI=0.85-5.12; P=0.11) in high PRS men, while among GPV carriers, odd ratios for PCa ranged from 2.08 (95% CI=0.58-7.49; P=0.26) in low PRS men to 18.06 (95% CI=4.24-76.84; P=9.0E-5) in high PRS men, compared to average PRS GPV non-carriers. When comparing aggressive cases to controls, considering the top four genes, GPV non-carrier odds ratios for PCa ranged from 0.52 (95% CI=0.40-0.70; P=6.2E-6) in low PRS men to 3.16 (95% CI=2.56-3.91; P=1.6E-26) in high PRS men, while among GPV carriers, odd ratios for PCa ranged from 2.97 (95% CI=073-12.16; P=0.13) in low PRS men to 23.58 (95% CI=5.39-103.20; P=2.7E-5) in high PRS men, compared to average PRS GPV non-carriers. Conclusion: We found that PCa risk in African ancestry men carrying GPVs in DNA damage repair and cancer predisposition genes, particularly ATM, BRCA2, PALB2, and NBN, varied depending on an individual's PRS. This implies that to comprehensively assess genetic risk of PCa, it is important to consider both rare and common variants. These findings could have implications for risk stratification in this high-risk population and emphasize the need for larger genetic studies of PCa in African ancestry men to identify and characterize genetic risk factors in this population. Citation Format: Raymond W. Hughley, Burcu F. Darst, Marco Matejcic, Yesha Patel, Jenna Lilyquist, Steven N. Hart, Eric C. Polley, Lucy Xia, Xin Sheng, Alexander Lubmawa, Sue A. Ingles, Lynne Wilkens, Loïc L. Marchand, Stephen Watya, Fergus J. Couch, David V. Conti, Christopher A. Haiman. Combined effect of a prostate cancer polygenic risk score and germline pathogenic variants in DNA damage repair genes on prostate cancer risk in men of African ancestry [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-197.

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 BRCA1, BRCA2, and PALB2 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 CHEK2, PALB2, BRCA2, and BRCA1 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 BRCA1, BRCA2, and PALB2. 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 BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.