Genetic Drivers of Quality of Life in Prostate Cancer: An Evaluation of Genetic Polymorphisms and Patient-reported Outcomes in the E3805 CHAARTED trial.

Background and objective: The rs4680 single-nucleotide polymorphism (SNP) of the COMT gene leads to a reduction in dopamine clearance, resulting in better mood and a decrease in symptoms in noncancer populations, but its influence on quality of life (QOL) during cancer treatment is undefined. We hypothesized that in comparison to wildtype (WT) COMT, the rs4680 SNP is associated with better QOL among men with metastatic hormone-sensitive prostate cancer receiving androgen deprivation therapy ± docetaxel (ADT ± D).

Methods: In this post hoc analysis, we tested the association between COMT rs4680 status and Functional Assessment of Cancer Therapy-Prostate (overall QOL), Functional Assessment of Chronic Illness Therapy-Fatigue, and Brief Pain Inventory scores at baseline and at 3, 6, 9, and 12 mo using Fisher's exact test and the Wilcoxon rank-sum test. Blood samples for genotyping were collected before treatment initiation.

Key findings and limitations: COMT SNP data were available for 550/790 men. Across the overall cohort, 3-mo pain severity was lower for rs4680 versus WT COMT (0.5 vs 1.25; p = 0.04). In the ADT arm, rs4680 versus WT COMT was associated with better overall QOL at 6 mo (128.9 vs 118.5; p = 0.04), less pain at 3 mo (no pain: 70.4% vs 41.5%; p = 0.01), and less pain interference at 3 mo (no interference: 76% vs 51.3%; p = 0.03), 6 mo (75% vs 48.7%; p = 0.02), and 9 mo (83.3% vs 52%; p = 0.02), with similar fatigue scores. Patients in the ADT + D arm had similar QOL regardless of COMT status.

Conclusions and clinical implications: Patients with the COMT rs4680 SNP experienced less pain and better global QOL after starting ADT alone. This is the first study to show that inherited genetic traits may influence treatment tolerability in men with prostate cancer.