Histologic patterns in prostatic adenocarcinoma are not predictive of mutations in the homologous recombination repair pathway.

Somatic or germline homologous recombination repair (HRR) pathway gene mutations are commonly detected in prostate cancer, especially in advanced disease, and are associated with response to poly (ADP-ribose) polymerase (PARP) inhibitors. In this study, we evaluated whether histological patterns are predictive of HRR pathway gene mutations. The study population comprised 130 patients with advanced prostate carcinoma who underwent comprehensive genomic profiling (CGP) of tumor tissue at a CLIA-certified laboratory. HRR genes in the study included BRCA1, BRCA2, ATM, BARD1, BRIP, CHEK2, MRE11A, NBN, PALB2, RAD51C, RAD51D, EMSY, ATR, CHEK1, and FAM175A. Overall, 38 patients had mutations in BRCA1/2, 36 in other HRR genes, and 56 were negative for HRR mutations. All cases were re-reviewed and quantified by two genitourinary pathologists blinded to mutational status for the following histological patterns of prostate carcinoma: cribriform, ductal, intraductal carcinoma (IDC), small cell carcinoma, signet ring-like pattern, and lobular carcinoma-like pattern. Discordances were resolved by consensus review. Histologic patterns were analyzed for any correlation with mutations in HRR pathway genes (grouped as BRCA1/2 mutated or non-BRCA1/2 mutated) compared to tumors without mutations in HRR genes by Chi-square testing. Patterns with >20 % and >30 % of tumor volume were additionally evaluated for correlation with mutational status. We found no significant association between HRR pathway mutations and cribriform pattern, IDC, ductal carcinoma, small cell carcinoma, signet ring-like pattern, or lobular carcinoma-like patterns. Tumors with >20 % or >30 % histologic patterns by volume also demonstrated no significant association with mutational status. This study suggests that histopathologic examination alone is insufficient to distinguish prostate cancer with germline or somatic mutations in HRR pathway genes, highlighting the continuing importance of ancillary molecular diagnostics in guiding therapy selection for prostate cancer patients who may benefit from PARP inhibitors.

Survival outcomes of real world patients with metastatic hormone-sensitive prostate cancer who do not achieve optimal PSA response with intensified androgen deprivation therapy with docetaxel or androgen receptor pathway inhibitors.

INTRODUCTION: In patients with metastatic hormone-sensitive prostate cancer (mHSPC) undergoing intensified androgen deprivation therapy (ADT), not achieving an optimal PSA response, defined as PSA nadir >0.2 ng/ml (PSAsubOR) has been associated with worse survival outcomes in clinical trials (1)(10)(11). Here, we externally evaluate, the impact of optimal PSA response on survival outcomes in these patients and provide absolute PFS and OS measures in those with PSAsubOR in the context of ADT intensification in real world setting. METHODS: In this retrospective study, all consecutive patients with mHSPC who underwent intensified ADT treated at our institution, and whose outcomes data were available, were included. We classified patients based on their PSA nadir on treatment: those with a on treatment PSAOR (PSA nadir ≤0.2 ng/ml) versus PSAsubOR. RESULTS: A total of 205 patients were eligible: 136 (66.3%) patients achieved PSAOR versus 69 (33.7%) patients had PSAsubOR. Patients who experienced a PSAOR had significantly improved PFS and OS from the start of intensified ADT versus who did not: PFS was not reached (NR) versus 11 months (hazard ratio (HR) 0.20, P < 0.001) and OS was NR versus 38.9 months (HR 0.21, P < 0.001). Survival outcomes were poor with PSAsubOR regardless of intensification with docetaxel or an ARPI (absolute PFS and OS measures for each group are provided in the text). CONCLUSION: Our study is the first to explore the negative impact of PSAsubOR in patients with mHSPC undergoing intensified ADT in the real-world setting, and is the first to provide absolute PFS and OS in patients with PSAsubOR receiving ADT intensification with ARPIs or docetaxel outside of clinical trial setting. These data will aid with prognostication, patient counseling, and for designing future clinical trials for patients with PSAsubOR.

What is the relationship between falls, functional limitations, and depressive symptoms among Chinese older adults? The role of living alone.

OBJECTIVES: Although the association between falls and depressive symptoms is well documented, the mechanisms underlying this association remain largely unexplored. We investigated the mediation role of functional limitations in the association between falls and depressive symptoms among Chinese older adults and determined whether the living arrangement (living alone or not) is a significant moderator of the above-mentioned mediation pathway. STUDY DESIGN: Cross-sectional study. MAIN OUTCOME MEASURES: Depressive symptoms were measured using the 10-item Center for Epidemiologic Studies Depression Scale short form (CESD-10), on which higher scores indicate higher levels of depressive symptoms. RESULTS: We used the harmonized China Health and Retirement Longitudinal Study national baseline data (2011-2012 year) involving 7410 participants aged 60 years and over. After adjusting for covariates (e.g., age and sex), the effects of falls on depressive symptoms were seen to be mediated by functional limitations among Chinese older adults (ß = 0.82, p < .001). The moderated mediation analysis, which assesses whether an indirect effect is conditional on values of a moderating variable, found that the mediation effect was contingent upon the living arrangement (ß = -0.60, p = .029). Specifically, the levels of functional limitations and depressive symptoms were higher for people with falls who were living with others relative to those living alone. CONCLUSIONS: These results suggest that functional limitations are an important intervening variable that links falls to depressive symptoms among Chinese older adults. Interventions to promote older adults' physical function and prevent falls are recommended to decrease the risk of depressive symptoms. These interventions can particularly benefit those who live with others.