Prostate cancer (PC) risk differs between races, and we previously showed prostate inflammation in benign prostate tissue was linked with a lower future PC risk. However, whether prostate tissue inflammation varies by race is unknown. We analyzed baseline acute and chronic prostate inflammation by race in REDUCE, a 4-year, multicenter, placebo-controlled study where all men had a negative prostate biopsy prior to enrollment. We included 7,982 men with standardized central pathology review to determine the presence or absence of chronic or acute inflammation in baseline prostate biopsy tissue. Logistic regression was used to compare prostate inflammation by race, adjusting for confounders. Of 7,982 men, 7,271 were white (91.1%), 180 (2.3%) black, 131 (1.6%) Asian, 319 (4.0%) Hispanic and 81 (1%) unknown. A total of 78% had chronic and 15% had acute inflammation. On multivariable analysis relative to white men, black men were less likely (OR = 0.65, 95%CI: 0.41-1.03, p = 0.07) and Asian men more likely to have acute inflammation (OR = 1.74, 95%CI: 1.14-2.65, p = 0.001). Hispanic men had similar levels of acute inflammation as white men. Chronic inflammation did not significantly differ across races. We identified racial differences in acute inflammation, particularly in Asian men, in benign prostate tissue that inversely mirrored population-level data on PC race disparity. As we showed in REDUCE that acute inflammation is linked with lower future PC risk, if validated in future studies, these data suggest racial differences in prostatic acute inflammation may contribute in part to race differences in PC risk, especially among Asian men.

Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been proven effective in BRAF-V600E mutant tumors, we have previously shown how the KIAA1549-BRAF fusion can be paradoxically activated by RAFi. While newer classes of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting strategies using clinically relevant MEK inhibitors (MEKi), along with potential escape mechanisms of acquired resistance to single-agent MAPK pathway therapies. We demonstrate effectiveness of multiple MEKi against diverse BRAF-fusions with novel N-terminal partners, with trametinib being the most potent. However, resistance to MEKi or PLX8394 develops via increased RTK expression causing activation of PI3K/mTOR pathway in BRAF-fusion expressing resistant clones. To circumvent acquired resistance, we show potency of combinatorial targeting with trametinib and everolimus, an mTOR inhibitor (mTORi) against multiple BRAF-fusions. While single-agent mTORi and MEKi PLGG clinical trials are underway, our study provides preclinical rationales for using MEKi and mTORi combinatorial therapy to stave off or prevent emergent drug-resistance in BRAF-fusion driven PLGGs.

AR-V7-expressing metastatic prostate cancer is an aggressive phenotype with poor progression-free survival (PFS) and overall survival (OS). Preliminary evidence suggests that AR-V7-positive tumors may be enriched for DNA-repair defects, perhaps rendering them more sensitive to immune-checkpoint blockade. We enrolled 15 metastatic prostate cancer patients with AR-V7-expressing circulating tumor cells into a prospective phase-2 trial. Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, then maintenance nivolumab 3 mg/kg every 2 weeks. Targeted next-generation sequencing was performed to determine DNA-repair deficiency (DRD) status. Outcomes included PSA response rates, objective response rates (ORR), PSA progression-free survival (PSA-PFS), clinical/radiographic PFS and OS. Median age of participants was 65, median PSA was 115 ng/mL, 67% had visceral metastases, and 60% had ≥4 prior systemic therapies. Six of 15 men (40%) had DRD mutations (three in BRCA2, two in ATM, one in ERCC4; none had microsatellite instability). Overall, the PSA response rate was 2/15 (13%), ORR was 2/8 (25%) in those with measurable disease, median PSA-PFS was 3.0 (95%CI 2.1-NR) months, PFS was 3.7 (95%CI 2.8-7.5) months, and OS was 8.2 (95%CI 5.5-10.4) months. Outcomes appeared generally better in DRD+ vs. DRD- tumors with respect to PSA responses (33% vs. 0%; P=0.14, nonsignificant), ORR (40% vs. 0%; P=0.46, nonsignificant), PSA-PFS (HR 0.19; P<0.01, significant), PFS (HR 0.31; P=0.01, significant), and OS (HR 0.41; P=0.11, nonsignificant). There were no new safety concerns. Ipilimumab plus nivolumab demonstrated encouraging efficacy in AR-V7-positive prostate cancers with DRD mutations, but not in the overall study population.

This study evaluated the expression of PD-L1 and markers of immune mediated resistance in human medulloblastoma (MB), the most common malignant pediatric brain tumor.