Yadav, Siddhartha

PURPOSE In studies of men of European ancestry, rare pathogenic variants in DNA repair pathway genes have been shown to be associated with risk of aggressive prostate cancer. The contribution of rare coding variation to prostate cancer risk in men of African ancestry has not been established. METHODS We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan cases and controls with prostate cancer. Rare variants were classified as pathogenic or putatively functionally disruptive and examined in association with prostate cancer risk and disease aggressiveness in gene and pathway-level association analyses. RESULTS Pathogenic variants were found in 75 of 2,098 cases (3.6%) and 31 of 1,481 controls (2.1%; odds ratio [OR], 1.82; 95% CI, 1.19 to 2.79; P = .0044), with the association being stronger for more aggressive disease phenotypes (OR, 3.10; 95% CI, 1.54 to 6.23; P = .0022). The highest risks for aggressive disease were observed with pathogenic variants in the ATM, BRCA2, PALB2, and NBN genes, with ORs ranging from approximately 4 to 15 in the combined study sample of African American and Ugandan men. Rare, nonpathogenic, nonsynonymous variants did not have a major impact on risk of overall prostate cancer or disease aggressiveness. CONCLUSION Rare pathogenic variants in DNA repair genes have appreciable effects on risk of aggressive prostate cancer in men of African ancestry. These findings have potential implications for panel testing and risk stratification in this high-risk population.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

INTRODUCTION: Frequent hospitalizations, antibiotic exposure, dysbiosis and impaired immune function associated with Sickle Cell Disease (SCD) predisposes pts to Clostridioides difficile infection (CDI). As a result, we hypothesize that the incidence of CDI in those with SCD has been increasing in the United States and that those with SCD and CDI have worse outcomes. METHODS: Using ICD-9 codes within the National Inpatient Sample Database, we identified pts between 2005–2012 with SCD. For each pt, we obtained various factors (e.g., demographics, medical co-morbidities and outcomes), grouped them as SCD and CDI (SCD + CDI) or those with SCD without CDI (SCD − CDI) and statistically compared. Using propensity score matching, SCD + CDI pts were matched with SCD − CDI in 1:1 ratio. All categorical variables were compared with Pearson's χ 2 test and continuous variables were analyzed with paired t-test (SAS 9.4, Cary, NC). RESULTS: Among 747,127 hospitalized pts with SCD, 804 (0.1%) had SCD + CDI. SCD + CDI were more likely to be African Americans (88.0% v 32.7%, P < 0.0001), smokers (10.5% v 7.1%, P < 0.0001), and had a higher association with HIV (2.2% v 0.9%, P = 0.0001), Hepatitis C (1.6% v 0.8%, P = 0.007), chronic liver disease (6.0% v 2.8%, P < 0.0001), cholelithiasis (4.0% v 2.2%, P < 0.001), acute pancreatitis (2.5% v 1.4%, P < 0.0001) and chronic pancreatitis (2.0% v 0.6%, P < 0.0001). SCD + CDI were less likely to be associated with atrial fibrillation (4.9% v 15.1%, P < 0.0001), CHF (13.9% v 18.5%, P = 0.001) and hypothyroidism (3.7% v 9.4%, P < 0.0001). SCD + CDI had significantly higher complication rates including acute chest syndrome (4.4% v 1.8%, P < 0.0001), splenic sequestration (1.6% v 0.3%, P < 0.0001), and vaso-occlusive crises (2.7% v 1.4%, P < 0.0001). Though prematch inpatient mortality was not different between the two groups (5.9% v 6.5%, P = 0.43), SCD + CDI pts had significantly higher inpatient mortality than SCD − CDI pts after match (5.6% v 3.3%, P = 0.04). Over time, we noted increases in hospitalization-requirement and inpatient mortality for SCD + CDI pts (Tables 1 and 2). CONCLUSION: Ours is the largest study exploring the association of CDI in SCD patients. Hospitalization rates and mortality rates for hospitalized SCD pts with CDI has been rising in the United States and it seems that hospitalized SCD pts with CDI are more likely to develop SCD related complications and have a higher mortality. In SCD+CDI pts, clinicians should consider more aggressive initial treatment to minimize these poor outcomes.

Background Male breast cancer (MBC) is a rare disease for which there is limited understanding of treatment patterns and prognostic factors. Methods Men with TNM stage I to stage III breast cancer diagnosed between 2004 and 2014 in the National Cancer Data Base were included. Trends in treatment modalities were described using the average annual percentage change (AAPC) and estimated using Joinpoint software for the analysis of trends. Kaplan‐Meier curves and the multivariate Cox proportional hazards regression model were used to compare survival between subgroups and to identify prognostic factors. Results A total of 10,873 MBC cases were included, with a median age at diagnosis of 64 years. Breast‐conserving surgery was performed in 24% of patients, and 70% of patients undergoing breast conservation received radiotherapy. Approximately 44% of patients received chemotherapy, and 62% of patients with estrogen receptor–positive disease received endocrine therapy. Oncotype DX was ordered in 35% of patients with lymph node–negative, estrogen receptor–positive/human epidermal growth factor receptor 2 (HER2)‐negative tumors. During the study period, there was a significant increase in the rates of total mastectomy, contralateral prophylactic mastectomy, radiotherapy after breast conservation, ordering of Oncotype DX, and the use of endocrine therapy ( P < .05). On multivariate analysis, factors found to be associated with worse overall survival were older age, black race, higher Charlson Comorbidity Index, high tumor grade and stage of disease, and undergoing total mastectomy. Residing in a higher income area; having progesterone receptor–positive tumors; and receipt of chemotherapy, radiotherapy, and endocrine therapy were associated with better overall survival. Conclusions Despite the lack of prospective randomized trials in patients with MBC, the results of the current study demonstrated that the treatment of this disease has evolved over the years. These findings further the understanding of the modern treatment and prognosis of MBC, and identify several areas for further research.

PURPOSE To compare the prevalence of germline mutations in metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castrate-resistant prostate cancer (mCRPC) and assess the impact of mutations on progression to castration resistance and overall survival. METHODS Targeted sequencing of germline DNA from 704 men (221 at the time of mHSPC and 483 at the time of mCRPC) enrolled in two advanced prostate cancer registries at Mayo Clinic between 2003 and 2013 was performed for 21 predisposition genes. Frequencies of pathogenic mutations were compared in patients and reference controls to identify genes enriched in metastatic prostate cancer. Multivariable Cox proportional hazards regression was used to identify predictors of progression to mCRPC and overall survival. RESULTS Sixty-eight germline mutations in 12 genes were identified in 66 men (9.4%). Mutations in ATM, BRCA2, CHEK2, FANCM, and TP53 were significantly enriched (odds ratio greater than 2.0) in the metastatic cohorts compared with reference controls. The frequency of germline mutations was similar for patients with mHSPC and mCRPC (11.8% v 8.3%; P = .16). The median time to progression from mHSPC to mCRPC was 23.1 and 32.5 months for patients with and without mutations, respectively ( P = .96). Although older age at diagnosis, Gleason score greater than 7, elevated alkaline phosphatase level, and high volume of disease were associated with shorter duration of progression to mCRPC and poor overall survival, mutation status was not (progression to mCRPC hazard ratio, 0.81; 95% CI, 0.61 to 1.09; P = .17; overall survival hazard ratio, 1.00; 95% CI, 0.75 to 1.34; P = .98). CONCLUSION Similarly elevated rates of germline predisposition gene mutations in mHSPC and mCRPC suggest that germline genetic testing may help to guide medical management for all patients with advanced metastatic prostate cancer. Mutation status was not associated with shorter progression to mCRPC or poor overall survival.

e15799 Background: Lymphocyte to monocyte ratio (LMR) has been described as a prognostic factor in many solid tumors including colorectal adenocarcinoma. LMR has not been investigated as a prognostic factor in small bowel cancers. In this study, we aimed to evaluate prognostic factors in resected small bowel adenocarcinoma including LMR. Methods: Two hundred forty-one patients who underwent resection for stage I-III small bowel adenocarcinoma were retrospectively identified utilizing the pathology database at a single tertiary referral institution from 1994 to 2015. All patients had complete follow up data and were included in the survival analysis. One hundred sixty-nine patients had preoperative peripheral blood counts available for analysis. Plot of martingale residuals against LMR were used to establish best cutoff points for LMR. A training set for LMR included consecutively identified patients from 2006 to 2015, and a validation cohort including patients identified from 1994 to 2005 was used. Overall survival was performed utilizing Kaplan-Meier method, and Wilcoxon tests were used for statistical comparisons. Cox proportional hazards were performed and all tests were two sided. P value of < 0.05 was considered significant. Results: Median overall survival for the entire group was 54.5 months (95% CI: 37.2-81.2 months) with 5- and 10-year overall survival of 48% and 35%. The training set for LMR included 81 patients, and the validation set included 88 patients. The cutoff of 1.56 was chosen based on most significant p value (p = 0.002). When combined, the overall area under the curve (AUC) for LMR was 0.63, p < 0.01, (specificity 37.3%, sensitivity 90.1%, positive predictive value 33.1%, and negative predictive value 92.2%). There were 126 patients with LMR > 1.56 and 43 patients with LMR < 1.56 in the entire cohort. In multivariate analysis, LMR under 1.56 was a negative prognostic factor, HR = 2.20 (95% CI: 1.27-3.84, p < 0.01). In addition to LMR, age > 60 years and advanced T stage were independently negative predictors of overall survival in all patients. Conclusions: Lymphocyte-to-monocyte ratio < 1.56 is a validated negative prognostic factor in resected small bowel adenocarcinoma.

4091 Background: Optimal management of ECCA patients with elevated CA19-9 remains undefined. We hypothesized CA 19-9 elevation as a marker of aggressive biology in ECCA and that inclusion of CA 19-9 in the staging may improve OS discrimination. Methods: Patients with ECCA with CA 19-9 levels reported to the National Cancer Database (years 2004-2015) were included. The patients were classified based on their CA19-9 levels and a new staging system was proposed. Based on the current knowledge, we considered 37 U/ml as our cut off. Kaplan Meier method was used to compare OS between the groups. The net reclassification improvement (NRI) model was used to assess the predictive improvement in the proposed survival model. Results: A total of 2100 patients met the inclusion criteria: 601 (32%) and 1436 (68%) had normal and elevated CA19-9 levels, respectively. Rates of chemo (p=0.16) and radiation therapy (p=0.07) were similar between groups, but patients with elevated CA19-9 were less likely to undergo resection. Resected patients with CA19-9 elevation had higher 30-day mortality (p=0.02) and lower median OS (p<0.01). Patients with elevated CA 19-9 levels had decreased stage-specific survival in all stages (p<0.01). On adjusted analysis, CA19-9 elevation independently predicted poor OS (HR: 1.67 [1.42-1.97]) with impact resembling nodal metastasis, positive resection margin, lymphovascular invasion, and non-receipt of surgery or chemotherapy (p<0.01). CA 19-9 included proposed staging system (Table) had a better OS discrimination over AJCC 7th edition. The new staging system had a concordance of 60% as opposed to 58% for the AJCC staging, leading to an improvement of 2% (p<0.01). NRI of 46% (95% CI: 39-57) indicates that the new staging system is substantially effective at re-classifying events at 12 months as compared to AJCC staging. Conclusions: Elevated CA19-9 was found to be an independent risk factor for mortality in ECCA and its inclusion in the newly proposed staging system markedly improved OS discrimination.[Table: see text]

1514 Background: The prevalence of germline mutations in non-white patients with breast cancer and the germline genetic drivers of breast cancer risk in non-white populations are largely unknown. Methods: The study population included 77,900 women with breast cancer (Non-Hispanic white: 57,003; Black: 6,722; Asian: 4,183; Hispanic: 5,194; Ashkenazi-Jewish: 4,798) who underwent germline multigene panel testing of cancer predisposition genes from March 2012 to December 2016. The prevalence of predisposition gene mutations in racial and ethnic populations relative to non-Hispanic Whites was assessed while accounting for age at diagnosis of breast cancer, family history of breast and ovarian cancer, and estrogen receptor status of breast tumors. Associations between mutations in each gene and breast cancer risk were evaluated using reference controls. Results: The overall frequency of pathogenic mutations in known breast cancer predisposition genes was 9.1% for non-Hispanic Whites, 9.8% for African Americans, 10.2% for Hispanics, 7.6% for Ashkenazi-Jewish, and 7.5% for Asians. BRCA1 mutations were enriched (p < 0.05) and CHEK2 mutations were under-represented in all racial and ethnic populations relative to non-Hispanic Whites. BRCA2 and BARD1 mutations were enriched in African Americans and Hispanics relative to non-Hispanic Whites, whereas PALB2 and RAD51C mutations were enriched in Hispanics. Among genes with mutation counts large enough for assessment, mutations in BARD1, BRCA1, BRCA2, PALB2 and TP53 were significantly associated with clinically relevant increased risks (odds ratio (OR) > 2) of breast cancer across all ethnicities and races. Rates of variants of uncertain significance were highest among Asians (29%), followed by blacks (27%), Hispanics (21%), non-Hispanic whites (16%) and Ashkenazi-Jews (14%). Conclusions: While there is some similarity across ethnic groups, substantial heterogeneity exists in the prevalence of mutations in breast cancer predisposition genes across major racial and ethnic groups in the US population. These findings contribute to our understanding of breast cancer risk and have significant implications for genetic testing, screening, and management of patients with an inherited predisposition to breast cancer, with a need for continued analysis with increased cohort size in ethnic minority groups.

The field of germline genetic testing for breast cancer (BC) risk has evolved substantially in the last decade. The introduction of multigene panel testing (MGPT) led to an urgent need to understand the cancer risk associated with several genes included in the panels. Although the research on understanding the cancer risk associated with mutations in several genes continues, there is also a need to understand the modifying effects of race and ethnicity, family history, and BC pathology on the prevalence of germline mutations and associated BC risk. Furthermore, polygenic risk scores (PRSs) to predict BC risk in patients with or without germline mutations in cancer-predisposition genes are now available for clinical use, although data on the clinical utility of PRSs are lacking. In patients with advanced BC associated with BRCA1/2 mutation, olaparib and talazoparib are now approved for treatment. In addition, molecular profiling studies are being used to clarify the BC tumor biology in mutation carriers to identify potential therapeutic options. In this article, we discuss these advances in the field of germline genetic testing and highlight current limitations and implications for clinical care.

Abstract Background Immune-related adverse events (irAEs) have emerged as a serious clinical issue in the use of immune checkpoint inhibitors (ICIs). Risk factors for irAEs remain controversial. Therefore, we studied sex differences in irAEs in patients treated with anti-programmed cell death protein 1 (PD-1) therapy. Materials and Methods All patients with metastatic melanoma and non-small cell lung cancer (NSCLC) treated with anti-PD-1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Kaplan-Meier method and log-rank test was used for time-to-event analysis. Results In 245 patients with metastatic melanoma, premenopausal women were more likely to experience irAEs (all grades) compared with postmenopausal women and men (67% vs. 60% vs. 46%), primarily because of an increase in endocrinopathies (33% vs. 12% vs. 10%, respectively). In patients with NSCLC (231 patients), women (all ages) were also more likely to develop irAEs of all grades (48% vs. 31%). Women with NSCLC were more likely to develop pneumonitis (11% vs. 4%) and endocrinopathies (14% vs. 5%). No differences in grade ≥3 toxicities were seen across sexes in both cohorts, but women were more likely to receive systemic steroids for the treatment of irAEs compared with men. Better progression-free-survival was observed in women with NSCLC and irAEs (10 months vs. 3.3 months) compared with women without irAEs. Conclusion Women with metastatic melanoma and NSCLC are more likely to experience irAEs compared with men. We also observed differences between sexes in the frequency of certain irAEs. Larger studies are needed to investigate the mechanisms underlying these associations. Implications for Practice The results of this study suggest that women may be at a higher risk for immune-related adverse events (irAEs) compared with men when treated with anti-programmed cell death protein 1 therapy. In addition, women were more likely to develop certain irAEs, including endocrinopathies and pneumonitis. Close follow-up of women undergoing treatment with immune checkpoint inhibitors will allow clinicians to diagnose these treatment-related complications early, potentially reducing their associated morbidity and mortality. In addition, a possible association between irAEs and response to therapy was observed.