Racial Disparities in Glioblastoma Genomic Alterations: A Comprehensive Analysis of a Multi-institution Cohort of 2,390 patients.

BACKGROUND: While molecular biomarkers have significantly advanced precision oncology in glioblastoma, the prevalence of these biomarkers by race remains underexplored. This study aims to characterize the genomic alterations in glioblastoma across Asian, Black, and White patients, offering insights into racial disparities that may influence treatment outcomes and disease progression. METHODS: Analyzing data from the AACR-GENIE database V13.0, this study examined 2,390 primary glioblastoma samples from unique patients. Genomic alterations in 566 cancer-related genes were assessed using targeted next-generation sequencing (NGS) panels from three large cancer institutes. The patient cohort included 112 Asians, 67 Blacks, and 2,211 Whites. Statistical significance of associations between genomic alterations and race was evaluated using the Chi-squared test, with the Benjamini-Hochberg method applied to control for multiple testing adjustments. RESULTS: Significant racial differences were observed in the frequency of genomic alterations. Asians exhibited a higher frequency of TP53 alterations (52.68%, P<0.001), Blacks showed more frequent alterations in NRAS (7.46%, P<0.001), MTOR (10.45%, P=0.039), and TET2 (8.96%, P=0.039), and Whites had a higher occurrence of PTEN alterations (48.67%, P=0.045). Additionally, Black patients had an elevated rate of RET deletions (14.29%, P<0.001). CONCLUSIONS: This study identifies significant racial disparities in the alteration frequencies of six key glioblastoma genes: NRAS, TP53, MTOR, TET2, PTEN, and RET. These findings underscore the need for racial considerations in glioblastoma treatment strategies and highlight potential avenues for targeted therapeutic interventions. Further research is needed to explore the clinical implications of these genomic disparities.

Prostate Cancer Foundation Screening Guidelines for Black Men in the United States.

BACKGROUND: In the United States, Black men are at highest risk for being diagnosed with and dying from prostate cancer. Given this disparity, we examined relevant data to establish clinical prostate-specific antigen (PSA) screening guidelines for Black men in the United States. METHODS: A comprehensive literature search identified 1848 unique publications for screening. Of those screened, 287 studies were selected for full-text review, and 264 were considered relevant and form the basis for these guidelines. The numbers were reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Three randomized controlled trials provided Level 1 evidence that regular PSA screening of men 50 to 74 years of age of average risk reduced metastasis and prostate cancer death at 16 to 22 years of follow-up. The best available evidence specifically for Black men comes from observational and modeling studies that consider age to obtain a baseline PSA, frequency of testing, and age when screening should end. Cohort studies suggest that discussions about baseline PSA testing between Black men and their clinicians should begin in the early 40s, and data from modeling studies indicate prostate cancer develops 3 to 9 years earlier in Black men compared with non-Black men. Lowering the age for baseline PSA testing to 40 to 45 years of age from 50 to 55 years of age, followed by regular screening until 70 years of age (informed by PSA values and health factors), could reduce prostate cancer mortality in Black men (approximately 30% relative risk reduction) without substantially increasing overdiagnosis. CONCLUSIONS: These guidelines recommend that Black men should obtain information about PSA screening for prostate cancer. Among Black men who elect screening, baseline PSA testing should occur between ages 40 and 45. Depending on PSA value and health status, annual screening should be strongly considered. (Supported by the Prostate Cancer Foundation.).

Machine Evaluation of Catchment Area Relevance through Text Mining.

The University of Miami Sylvester Comprehensive Cancer Center Community Outreach and Engagement Office has developed an algorithm to aid in identifying catchment area relevant trials. We have developed this tool to capture a catchment area (South Florida) that represents the most racially, ethnically, and geographically diverse region in the US. Unfortunately, the area's tumor burden is also significant with many notable disparities, necessitating a prioritization of trials within Sylvester's catchment area. These trials address the needs of the population Sylvester serves by targeting cancers that are locally prevalent.

Disparities in Stage at Presentation Among Hispanic and Latinx Patients With Non-Small-Cell Lung Cancer in the United States.

PURPOSE: Hispanic and Latinx people in the United States are the fastest-growing ethnic group. However, previous studies in non-small-cell lung cancer (NSCLC) often analyze these diverse communities in aggregate. We aimed to identify differences in NSCLC stage at diagnosis in the US population, focusing on disaggregated Hispanic/Latinx individuals. METHODS: Data from the National Cancer Database from 2004 to 2018 identified patients with primary NSCLC. Individuals were disaggregated by racial and ethnic subgroup and Hispanic country of origin. Ordinal logistic regression adjusting for age, facility type, income, educational attainment, comorbidity index, insurance, and year of diagnosis was used to create adjusted odds ratios (aORs), with higher odds representing diagnosis at later-stage NSCLC. RESULTS: Of 1,565,159 patients with NSCLC, 46,616 were Hispanic/Latinx (3.0%). When analyzed in the setting of race and ethnicity, Hispanic patients were more likely to be diagnosed with metastatic disease compared with non-Hispanic White (NHW) patients: 47.0% for Hispanic Black, 46.0% Hispanic White, and 44.3% of Hispanic other patients versus 39.1% of non-Hispanic White patients (P < .001 for all). By country of origin, 51.4% of Mexican, 41.7% of Puerto Rican, 44.6% of Cuban, 50.8% of South or Central American, 48.4% of Dominican, and 45.6% of other Hispanic patients were diagnosed with metastatic disease, compared with 39.1% of NHWs. Conversely, 20.2% of Mexican, 26.9% of Puerto Rican, 24.2% of Cuban, 22.5% of South or Central American, 23.7% of Dominican, and 24.5% of other Hispanic patients were diagnosed with stage I disease, compared with 30.0% of NHWs. All Hispanic groups were more likely to present with later-stage NSCLC than NHW patients (greatest odds for Mexican patients, aOR, 1.44; P < .001). CONCLUSION: Hispanic/Latinx patients with non-small-cell lung cancer were more likely to be diagnosed with advanced disease compared with NHWs. Disparities persisted upon disaggregation by both race and country of origin, with over half of Mexican patients with metastatic disease at diagnosis. Disparities among Hispanic/Latinx groups by race and by country of origin highlight the shortcomings of treating these groups as a monolith and underscore the need for disaggregated research and targeted interventions.

The Molecular, Immunologic, and Clinicodemographic Landscape of MYC-Amplified Advanced Prostate Cancer.

BACKGROUND: MYC is a commonly amplified, potentially targetable gene in prostate cancer (PCa). We sought to define the molecular, immunologic, and clinicodemographic landscape of MYC amplification (MYCamp) in advanced PCa to establish a rationale for personalized treatment combinations. METHODS: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on PCa tumor samples. MYCamp = copy number ≥6 (CN). Patients treated between January 2011 and December 2020 were selected from a nationwide deidentified (280 clinics) EHR-derived clinicogenomic database (CGDB). RESULTS: Of 12,528 hormone-sensitive and castrate-resistant (CRPC) samples, MYCamp was detected in 10.6% (median CN = 8). MYCamp was more frequent in men with African versus European ancestry (12.9% vs. 10.2% P = .002), in metastatic vs. primary tissue (15.7% vs. 6.2% P < .001), and enriched in metastatic liver lesions (20.2%), but inversely associated with high microsatellite-instability (0.8% vs. 2.4%, P < .001). MYC CN≥15 was associated with PD-L1 expression (26.1% vs. 9.8%, P = .025). Amplification of AR, RAD21, LYN, CCND1, ZNF703, FGF3/4/19, and FGFR1 was enriched in MYCamp vs. MYCwt (all P < .001). In liquid samples with tumor fraction [TF]>0, MYCamp was detected in 2.0% (28/1,402), and 4.5% (20/445) with TF>20%. In the CGDB, (67 MYCamp and 658 MYCwt), patients received similar treatments; most received hormone therapies (35.8% MYCamp vs. 31.5% MYCwt) or chemotherapy (37.3% MYCamp vs. 27.7% MYCwt) as first therapy after CGP report. CONCLUSION: MYCamp defines a biologically distinct subset of PCa patients and is characterized with multiple proxies of advanced disease. These data suggest that MYCamp may be prognostic; independent cohorts are needed to validate these findings.

Trends in Utilization and Medicare Spending on Short-Course Radiation Therapy for Breast and Prostate Cancer: An Episode-Based Analysis From 2015 to 2019.

PURPOSE: Evidence supports the value of shorter, similarly efficacious, and potentially more cost-effective hypofractionated radiation therapy (RT) regimens in many clinical scenarios for breast cancer (BC) and prostate cancer (PC). However, practice patterns vary considerably. We used the most recent Centers for Medicare and Medicaid Services data to assess trends in RT cost and practice patterns among episodes of BC and PC. METHODS AND MATERIALS: We performed a retrospective cohort analysis of all external beam RT episodes for BC and PC from 2015 to 2019 to assess predictors of short-course RT (SCRT) use and calculated spending differences. Multivariable logistic regression defined adjusted odds ratios of receipt of SCRT over longer-course RT (LCRT) by treatment modality, age, year of diagnosis, type of practice, and the interaction between year and treatment setting. Medicare spending was evaluated using multivariable linear regression controlling for duration of RT regimen (SCRT vs LCRT) in addition to the above covariables. RESULTS: Of 143,729 BC episodes and 114,214 PC episodes, 63,623 (44.27%) and 25,955 (22.72%) were SCRT regimens, respectively. Median total spending for SCRT regimens among BC episodes was $9418 (interquartile range [IQR], $7966-$10,983) versus $13,602 (IQR, $11,814-$15,499) for LCRT. Among PC episodes, median total spending was $6924 (IQR, $4,509-$12,905) for stereotactic body RT, $18,768 (IQR, $15,421-$20,740) for moderate hypofractionation, and $27,319 (IQR, $25,446-$29,421) for LCRT. On logistic regression, receipt of SCRT was associated with older age among both BC and PC episodes as well as treatment at hospital-affiliated over freestanding sites (P < .001 for all). CONCLUSIONS: In this evaluation of BC and PC RT episodes from 2015 to 2019, we found that shorter-course RT resulted in lower costs than longer-course RT. SCRT was also more common in hospital-affiliated sites. Future research focusing on potential payment incentives encouraging SCRT when clinically appropriate in the 2 most common cancers treated with RT will be valuable as the field continues to prospectively evaluate cost-effective hypofractionation in other disease sites.

Adding a Coefficient for Race to the 4Kscore Improves Calibration for Black Men.

PURPOSE: Black men face a higher incidence of high-risk prostate cancer (PCa) compared with non-Black men. While the 4Kscore is a widely utilized commercial test for PCa risk assessment, it does not currently account for racial differences. The aim of this study is to describe and validate a prespecified race coefficient for the 4Kscore with the goal of improving the accuracy of this test for Black men. MATERIALS AND METHODS: Using data from 85 Black men from the initial US prospective validation study, a race coefficient of 0.6 on the log-odds scale was prespecified. We calculated discrimination, calibration, and clinical utility of the 4Kscore with and without this coefficient for Black race in our primary analysis cohort of 205 Black men undergoing biopsy for PCa in a Veterans Affairs (VA) institution. We performed a sensitivity analysis using a combined cohort from the US prospective validation and the VA studies. RESULTS: The mean probability of high-grade PCa from the 4Kscore in the primary cohort increased from 25% to 37% with race coefficient addition. Incorporating the race coefficient improved 4Kscore's calibration in Black men, with consequent improvements in clinical utility based on decision curve analysis. Model discrimination was maintained (AUC 0.825 vs 0.828, P = .14) in the combined cohort of Black and non-Black men from the US prospective and VA studies and the calibration remained largely unchanged. CONCLUSIONS: Incorporating a prespecified coefficient for Black race improved calibration and clinical utility of the 4Kscore among Black men and should be added to the 4Kscore.

Racial and Ethnic Disparities in Use of Novel Hormonal Therapy Agents in Patients With Prostate Cancer.

Importance: Novel hormonal therapy (NHT) agents have been shown to prolong overall survival in numerous randomized clinical trials for patients with advanced prostate cancer (PCa). There is a paucity of data regarding the pattern of use of these agents in patients from different racial and ethnic groups. Objective: To assess racial and ethnic disparities in the use of NHT in patients with advanced PCa. Design, Setting, and Participants: This cohort study comprised all men diagnosed with de novo advanced PCa (distant metastatic [M1], regional [N1M0], and high-risk localized [N0M0] per Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy [STAMPEDE] trial criteria) with Medicare Part A, B, and D coverage between January 1, 2011, and December 31, 2017, in a Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database including prescription drug records. Data analysis took place from January through May 2023. Exposures: Race and ethnicity (Black [non-Hispanic], Hispanic, White, or other [Alaska Native, American Indian, Asian, Pacific Islander, or not otherwise specified and unknown]) abstracted from the SEER data fields. Main Outcomes and Measures: The primary outcome was receipt of an NHT agent (abiraterone, enzalutamide, apalutamide, or darolutamide) using a time-to-event approach. Results: The study included 3748 men (median age, 75 years [IQR, 70-81 years]). A total of 312 (8%) were Black; 263 (7%), Hispanic; 2923 (78%), White; and 250 (7%) other race and ethnicity. The majority of patients had M1 disease (2135 [57%]) followed by high-risk N0M0 (1095 [29%]) and N1M0 (518 [14%]) disease. Overall, 1358 patients (36%) received at least 1 administration of NHT. White patients had the highest 2-year NHT utilization rate (27%; 95% CI, 25%-28%) followed by Hispanic patients (25%; 95% CI, 20%-31%) and patients with other race or ethnicity (23%; 95% CI, 18%-29%), with Black patients having the lowest rate (20%; 95% CI, 16%-25%). Black patients had significantly lower use of NHT compared with White patients, which persisted at 5 years (37% [95% CI, 31%-43%] vs 44% [95% CI, 42%-46%]; P = .02) and beyond. However, there was no significant difference between White patients and Hispanic patients or patients with other race or ethnicity in NHT utilization (eg, 5 years: Hispanic patients, 38% [95% CI, 32%-46%]; patients with other race and ethnicity: 41% [95% CI, 35%-49%]). Trends of lower utilization among Black patients persisted in the patients with M1 disease (eg, vs White patients at 5 years: 51% [95% CI, 44%-59%] vs 55% [95% CI, 53%-58%]). After adjusting for patient, disease, and sociodemographic factors in multivariable analysis, Black patients continued to have a significantly lower likelihood of NHT initiation (adjusted subdistribution hazard ratio, 0.76; 95% CI, 0.61-0.94, P = .01). Conclusions and Relevance: In this cohort study of Medicare beneficiaries with advanced PCa, receipt of NHT agents was not uniform by race, with decreased use observed in Black patients compared with the other racial and ethnic groups, likely due to multifactorial obstacles. Future studies are needed to identify strategies to address the disparities in the use of these survival-prolonging therapies in Black patients.

Mortality Risk for Docetaxel-Treated, High-Grade Prostate Cancer With Low PSA Levels: A Meta-Analysis.

Importance: Patients with high-grade prostate cancer with low levels of prostate-specific antigen (PSA; <4 ng/mL) are at high risk of mortality, necessitating an improved treatment paradigm. Objective: To assess for these patients whether adding docetaxel to standard of care (SOC) treatment is associated with decreased prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM). Data Sources: PubMed search from 2000 to 2022. Study Selection: Five prospective randomized clinical trials (RCTs) performed in the US, France, and the United Kingdom evaluating SOC treatment with radiotherapy and androgen deprivation therapy (ADT) or with radical prostatectomy vs SOC plus docetaxel. Data Extraction and Synthesis: Individual data were included from patients with nonmetastatic prostate cancer, a PSA level of less than 4 ng/mL, and a Gleason score of 8 to 10. Patients initiated treatment between February 21, 2006, and December 31, 2015 (median follow-up, 7.1 [IQR, 5.4-9.9] years). Data were analyzed on December 16, 2022. Main Outcomes and Measures: Hazard ratio (HR) of ACM and subdistribution HR (sHR) of PCSM adjusted for performance status (1 vs 0 or good health), Gleason score (9 or 10 vs 8), tumor category (T3-T4 vs T1-T2 or TX), and duration of ADT (2 years vs 4-6 months). Results: From a cohort of 2184 patients, 145 patients (6.6%) in 4 RCTs were eligible (median age, 63 [IQR, 46-67] years). Thirty-one patients died, and of these deaths, 22 were due to prostate cancer. Performance status was 0 for 139 patients (95.9%) and 1 for 6 patients (4.1%). A reduced but nonsignificant risk of ACM (HR, 0.51 [95% CI, 0.24-1.09]) and PCSM (sHR, 0.42 [95% CI, 0.17-1.02]) was associated with patients randomized to SOC plus docetaxel compared with SOC. The risk reduction in ACM (HR, 0.46 [95% CI, 0.21-1.02]) was more pronounced among patients with a performance status of 0 and was significant for PCSM (sHR, 0.30 [95% CI, 0.11-0.86]). Conclusions and Relevance: Adding docetaxel to SOC treatment for patients who are in otherwise good health with a PSA level of less than 4 ng/mL and a Gleason score of 8 to 10 was associated with a significant reduction in PCSM and therefore has the potential to improve prognosis.

Clinical and Genomic Factors Associated with Greater Tumor Mutational Burden in Prostate Cancer.

Tumor mutational burden (TMB) is a biomarker that predicts response to immune checkpoint inhibitor therapy. We currently lack a comprehensive understanding of how genomic and clinical factors correlate with TMB. We used a clinicogenomic database to assess independent predictors of TMB levels. The study included 2740 prostate cancer specimens from prostate gland (51.6%), lymph nodes (14.6%), and bone (10.4%). Androgen deprivation therapy use beyond 24 mo was weakly associated with high TMB (fold-change estimate [FCE] 1.14, 95% confidence interval [CI] 1.03-1.26; p = 0.009). In comparison to the prostate gland, metastases in the bladder (FCE 1.20, 95% CI 1.02-1.42; p = 0.029), liver (FCE 1.26, 95% CI 1.10-1.43; p < 0.001), and other locations (FCE 1.26, 95% CI 1.11-1.43; p < 0.001) were associated with high TMB. Microsatellite instability high (FCE 8.46, 95% CI 6.42-11.15; p < 0.001) and intermediate (FCE 1.77, 95% CI 1.46-2.14; p < 0.001) status were associated with greater TMB. Altered genes associated with greater TMB included MLH1 (FCE 1.81; p = 0.004), MSH2 (FCE 1.87; p < 0.001), MSH6 (FCE 1.92; p < 0.001), BRCA2 (FCE 1.69; p < 0.001), CDK12 (FCE 1.40; p < 0.001), MRE11 (FCE 2.28; p = 0.016), and PALB2 (FCE 2.08; p < 0.001). Our study demonstrates that TMB is relatively stable over lines of therapies and can be used to guide treatment at diagnosis or in later lines for patients with metastatic prostate cancer. Patient summary: The number of genetic mutations in a tumor (tumor mutational burden, TMB) may help in predicting a patient's response to immunotherapy in advanced prostate cancer. We evaluated clinical and genetic factors that may affect TMB. We found that metastases in the bladder and liver are more likely to have high TMB than the primary tumor. Some individual genes are associated with high TMB. No prior treatment type was strongly associated with TMB, suggesting that TMB can be used to guide treatment at any time point.These data were presented at the American Society of Clinical Oncology 2023 Genitourinary Cancers Symposium.

Disparities in time to prostate cancer treatment initiation before and after the Affordable Care Act.

BACKGROUND: Delayed access to care may contribute to disparities in prostate cancer (PCa). The Affordable Care Act (ACA) aimed at increasing access and reducing healthcare disparities, but its impact on timely treatment initiation for PCa men is unknown. METHODS: Men with intermediate- and high-risk PCa diagnosed 2010-2016 and treated with curative surgery or radiotherapy were identified in the National Cancer Database. Multivariable logistic regression modeled the effect of race and insurance type on treatment delay >180 days after diagnosis. Cochran-Armitage test measured annual trends in delays, and joinpoint regression assessed if 2014, the year the ACA became fully operationalized, was significant for inflection in crude rates of major delays. RESULTS: Of 422,506 eligible men, 18,720 (4.4%) experienced >180-day delay in treatment initiation. Compared to White patients, Black (OR 1.79, 95% CI 1.72-1.87, p < 0.001) and Hispanic (OR 1.37, 95% CI 1.28-1.48, p < 0.001) patients had higher odds of delay. Compared to uninsured, those with Medicaid had no difference in odds of delay (OR 0.94, 95% CI 0.84-1.06, p = 0.31), while those with private insurance (OR 0.57, 95% CI 0.52-0.63, p < 0.001) or Medicare (OR 0.64, 95% CI 0.58-0.70, p < 0.001) had lower odds of delay. Mean time to treatment significantly increased from 2010 to 2016 across all racial/ethnic groups (trend p < 0.001); 2014 was associated with a significant inflection for increase in rates of major delays. CONCLUSIONS: Non-White and Medicaid-insured men with localized PCa are at risk of treatment delays in the United States. Treatment delays have been consistently rising, particularly after implementation of the ACA.

Genomic Characterization of Aggressive Breast Cancer in Younger Women.

PURPOSE: Although breast cancer (BC) risk increases with age, BC in younger women is more aggressive with higher mortality compared with older women. We characterize the genomic landscape of BCs in younger women. METHODS: Clinicopathologic, molecular, and genomic differences across age groups (< 40 years, 40-60 years, > 60 years) in female BC patients were investigated in two large cohorts [AACR-GENIE8.1 (n = 11,594) and METABRIC (n = 2509)]. Cox-proportional regression analyzed the prognostic impact of age groups for disease-specific survival (DSS) and recurrence-free survival (RFS) in METABRIC and progression-free survival (PFS) in GENIE cohorts. Chi-squared test was used to assess statistical associations between genomic alterations and age groups. RESULTS: Survival analysis showed that women < 40 years had shorter DSS [hazard ratio (HR): 1.52, p = 0.005], RFS (HR: 1.4, p = 0.006), and PFS (HR: 1.82, p = 0.0003) compared with women 40-60 years, and shorter RFS (HR: 1.5, p = 0.001) and PFS (HR: 2.95, p < 0.0001) compared with women > 60 years. Molecular subtypes in the METABRIC cohort showed women < 40 years were enriched with basal, and HER2+ subtypes, and less enriched with luminal A and B subtype (p < 0.0001). Characterization of genomic alterations in both cohorts demonstrated that BCs in women < 40 years were more enriched with TP53 mutations (FDR < 0.0001), BRCA1 mutations (FDR = 0.01), ERBB2 amplifications (FDR < 0.001), CDK12 amplifications (FDR < 0.001), and PPM1D amplifications (FDR < 0.001). In contrast, BCs in older women (> 60 years) were more enriched with PIK3CA, KMT2C, and CDH1 mutations (FDR < 0.0001). CONCLUSIONS: BCs in young women are associated with shorter survival and more aggressive genomic features, including mutations in TP53 and BRCA1, and amplifications in ERBB2 and CDK12. These findings have the potential to impact clinical trial design and treatment.

Unique Spectrum of Activating BRAF Alterations in Prostate Cancer.

PURPOSE: Alterations in BRAF have been reported in 3% to 5% of prostate cancer, although further characterization is lacking. Here, we describe the nature of BRAF alterations in prostate cancer using a large cohort from commercially available tissue and liquid biopsies subjected to comprehensive genomic profiling (CGP). EXPERIMENTAL DESIGN: Tissue and liquid biopsies from patients with prostate cancer were profiled using FoundationOne CDx and FoundationOne Liquid CDx CGP assays, respectively. Tissue biopsies from non-prostate cancer types were used for comparison (n = 275,151). Genetic ancestry was predicted using a single-nucleotide polymorphism (SNP) based approach. RESULTS: Among 15,864 tissue biopsies, BRAF-activating alterations were detected in 520 cases (3.3%). The majority (463 samples, 2.9%) harbored class II alterations, including BRAF rearrangements (243 samples, 1.5%), K601E (101 samples, 0.6%), and G469A (58 samples, 0.4%). BRAF-altered prostate cancers were enriched for CDK12 mutations (OR, 1.87; 9.2% vs. 5.2%; P = 0.018), but depleted in TMPRSS2 fusions (OR, 0.25; 11% vs. 32%; P < 0.0001), PTEN alterations (OR, 0.47; 17% vs. 31%; P < 0.0001), and APC alterations (OR, 0.48; 4.4% vs. 8.9%; P = 0.018) relative to BRAF wild-type (WT) disease. Compared with patients of European ancestry, BRAF alterations were more common in tumors from patients of African ancestry (5.1% vs. 2.9%, P < 0.0001) and Asian ancestry (6.0% vs. 2.9%, P < 0.001). CONCLUSIONS: Activating BRAF alterations were detected in approximately 3% of prostate cancers, and most were class II mutations and rearrangements; BRAF V600 mutations were exceedingly rare. These findings suggest that BRAF activation in prostate cancer is unique from other cancers and supports further clinical investigation of therapeutics targeting the mitogen-activated protein kinase (MAPK) pathway.

Disparities in Diagnosis, Treatment Access, and Time to Treatment Among Hispanic Men With Metastatic Prostate Cancer.

PURPOSE: Reporting racial/ethnic disparities in aggregate obscures within-group heterogeneity. We sought to identify disparities in diagnosis and treatment in Hispanic subpopulations with metastatic prostate cancer (mPCa). METHODS: We disaggregated men with prostate adenocarcinoma from the National Cancer Database from 2004 to 2017 by racial subgroup and Hispanic background. We assessed (1) presenting with mPCa, (2) receiving any treatment, and (3) receiving delayed treatment beyond 90 days. Logistic regression and adjusted odds ratios (aOR) were reported. RESULTS: Hispanic men had greater odds of presenting with mPCa (aOR, 1.54; 95% CI, 1.50 to 1.58; P < .001) compared with non-Hispanic White (NHW) men. All Hispanic racial subgroups were more likely to present with mPCa, with the highest risk in Hispanic Black (HB) men (aOR, 1.68; 95% CI, 1.46 to 1.93; P < .01). Men from all Hispanic backgrounds had higher odds of presenting with mPCa, especially Mexican men (aOR, 1.99; 95% CI, 1.86 to 2.12; P < .01). Hispanic men were less likely to receive any treatment (aOR, 0.60; 95% CI, 0.53 to 0.67; P < .001), and this effect was particularly strong for Hispanic White patients (aOR, 0.58; 95% CI, 0.52 to 0.66; P < .001) and Dominican men (aOR, 0.52; 95% CI, 0.28 to 0.98; P = .044). Hispanic men were more likely to experience treatment delays compared with NHW men (aOR, 1.38; 95% CI, 1.26 to 1.52; P < .001) and in particular HB (aOR, 1.83; 95% CI, 1.22 to 2.75; P = .002) and South/Central American men (aOR, 1.48; 95% CI, 1.07 to 2.04; P = .018). CONCLUSION: Differences exist in stage at presentation, treatment receipt, and delays in treatment on disaggregation by racial subgroup and Hispanic heritage. We need to study the potential mechanisms of the observed variations to help develop targeted interventions.

Comprehensive genomic profiling and treatment patterns across ancestries in advanced prostate cancer: a large-scale retrospective analysis.

BACKGROUND: Men of African ancestry experience the greatest burden of prostate cancer globally, but they are under-represented in genomic and precision medicine studies. Therefore, we sought to characterise the genomic landscape, comprehensive genomic profiling (CGP) utilisation patterns, and treatment patterns across ancestries in a large, diverse, advanced prostate cancer cohort, to determine the impact of genomics on ancestral disparities. METHODS: In this large-scale retrospective analysis, the CGP-based genomic landscape was evaluated in biopsy sections from 11 741 patients with prostate cancer, with ancestry inferred using a single nucleotide polymorphism-based approach. Admixture-derived ancestry fractions for each patient were also interrogated. Independently, clinical and treatment information was retrospectively reviewed for 1234 patients in a de-identified US-based clinicogenomic database. Prevalence of gene alterations, including actionable gene alterations, was assessed across ancestries (n=11 741). Furthermore, real-world treatment patterns and overall survival was assessed in the subset of patients with linked clincogenomic information (n=1234). FINDINGS: The CGP cohort included 1422 (12%) men of African ancestry and 9244 (79%) men of European ancestry; the clinicogenomic database cohort included 130 (11%) men of African ancestry and 1017 (82%) men of European ancestry. Men of African ancestry received more lines of therapy before CGP than men of European ancestry (median of two lines [IQR 0-8] vs one line [0-10], p=0·029). In genomic analyses, ancestry-specific mutational landscapes were observed, but the prevalence of alterations in AR, the DNA damage response pathway, and other actionable genes were similar across ancestries. Similar genomic landscapes were observed in analyses that accounted for admixture-derived ancestry fractions. After undergoing CGP, men of African ancestry were less likely to receive a clinical study drug compared with men of European ancestry (12 [10%] of 118 vs 246 [26%] of 938, p=0·0005). INTERPRETATION: Similar rates of gene alterations with therapy implications suggest that differences in actionable genes (including AR and DNA damage response pathway genes) might not be a main driver of disparities across ancestries in advanced prostate cancer. Later CGP utilisation and a lower rate of clinical trial enrolment observed in men of African ancestry could affect genomics, outcomes, and disparities. FUNDING: American Society for Radiation Oncology, Department of Defense, Flatiron Health, Foundation Medicine, Prostate Cancer Foundation, and Sylvester Comprehensive Cancer Center.

Colon Cancer Disparities in Stage at Presentation and Time to Surgery for Asian Americans, Native Hawaiians, and Pacific Islanders: A Study with Disaggregated Ethnic Groups.

BACKGROUND: Vast differences in barriers to care exist among Asian American, Native Hawaiian, and Pacific Islander (AANHPI) groups and may manifest as disparities in stage at presentation and access to treatment. Thus, we characterized AANHPI patients with stage 0-IV colon cancer and examined differences in (1) stage at presentation and (2) time to surgery relative to white patients. PATIENTS AND METHODS: We assessed all patients in the National Cancer Database (NCDB) with stage 0-IV colon cancer from 2004 to 2016 who identified as white, Chinese, Japanese, Filipino, Native Hawaiian, Korean, Vietnamese, Laotian, Hmong, Kampuchean, Thai, Asian Indian or Pakistani, and Pacific Islander. Multivariable ordinal logistic regression defined adjusted odds ratios (AORs), with 95% confidence intervals (CI), of (1) patients presenting with advanced stage colon cancer and (2) patients with stage 0-III colon cancer receiving surgery at ≥ 60 days versus 30-59 days versus < 30 days postdiagnosis, adjusting for sociodemographic/clinical factors. RESULTS: Among 694,876 patients, Japanese [AOR 1.08 (95% CI 1.01-1.15), p < 0.05], Filipino [AOR 1.17 (95% CI 1.09-1.25), p < 0.001], Korean [AOR 1.09 (95% CI 1.01-1.18), p < 0.05], Laotian [AOR 1.51 (95% CI 1.17-1.95), p < 0.01], Kampuchean [AOR 1.33 (95% CI 1.04-1.70), p < 0.01], Thai [AOR 1.60 (95% CI 1.22-2.10), p = 0.001], and Pacific Islander [AOR 1.41 (95% CI 1.20-1.67), p < 0.001] patients were more likely to present with more advanced colon cancer compared with white patients. Chinese [AOR 1.27 (95% CI 1.17-1.38), p < 0.001], Japanese [AOR 1.23 (95% CI 1.10-1.37], p < 0.001], Filipino [AOR 1.36 (95% CI 1.22-1.52), p < 0.001], Korean [AOR 1.16 (95% CI 1.02-1.32), p < 0.05], and Vietnamese [AOR 1.55 (95% CI 1.36-1.77), p < 0.001] patients were more likely to experience greater time to surgery than white patients. Disparities persisted when comparing among AANHPI subgroups. CONCLUSIONS: Our findings reveal key disparities in stage at presentation and time to surgery by race/ethnicity among AANHPI subgroups. Heterogeneity upon disaggregation underscores the importance of examining and addressing access barriers and clinical disparities.

Determinants of widespread metastases and of metastatic tropism in patients with prostate cancer: A genomic analysis of primary and metastatic tumors.

INTRODUCTION: Emerging evidence suggests that metastasis is better described as a spectrum of disease rather than a binary state. A greater understanding of the genomic features that determine extent and location of metastatic spread may inform risk stratification and monitoring. Here, we identify genomic alterations from primary prostate carcinomas that are predictive of wide-spread metastatic potential. METHODS: Genomic and clinical data from 1,312 patients with primary prostate carcinoma were extracted from the MSK-MET cohort through cBioPortal. Metastatic site counts and overall survival (OS) data were publicly available and used as the primary outcomes. Primary tumor samples were profiled using the MSK-IMPACT targeted sequencing platform. We focused on 58 genes frequently altered in prostate cancer. Cox proportional hazard analyses defined hazard ratios (HRs) and 95% confidence intervals (CIs) for overall mortality in patients with different metastatic outcomes. RESULTS: Out of the 1,312 patients in our cohort, 939 (71%) developed metastases, of whom 113 (8.6%) had metastases to 5 or more distinct anatomical sites (defining wide-spread metastases, WSM). Bone was the most common site of metastasis (36%), and 80% of patients with liver metastases had 4 or more additional sites of metastasis. Among patients with metastasis, increasing number of metastatic sites was associated with increased risk of death (HR: 1.8, 95%CI: 1.63-1.99, P < 0.001). Alterations in the following genes were enriched in tumors from patients with WSM vs. others: TP53 (40% vs. 20%, P < 0.0001), FOXA1-amplification (8% vs. 3%, P = 0.02), AR-amplification (4.4% vs. 1%, P = 0.01), RB1-deletion (5.3% vs. 0.7%, P = 0.001), and BRCA2-deletion (4.4% vs. 0.7%, P = 0.01). Univariable survival analysis showed all these alterations were predictive of OS (P < 0.05). On multivariable analysis, only TP53 mutations, and FOXA1 and AR amplifications were independent prognostic factors. FOXA1 (n = 37) and AR (n = 13) amplifications were mutually exclusive and patients with these experienced very poor OS (HR: 3.57, 95%CI:2.26-5.6, P < 0.001]. CONCLUSIONS: We identified genomic alterations (TP53 mutations, FOXA1/AR amplification, RB1/BRCA2 deletion) from primary prostate carcinomas that are predictive of wide-spread metastases and poor outcome.