ABSTRACT
OBJECTIVES: Men treated with androgen deprivation therapy (ADT) or radiation therapy (RT) for prostate cancer have an increased risk for fractures. Given uncertainty as to whether specific clinical factors can identify men at increased risk, we sought to develop a prognostic index for risk of fracture in this population. MATERIALS AND METHODS: We used the Surveillance, Epidemiology, and End Results-Medicare database to identify men who received ADT or RT after being diagnosed with localized prostate cancer in 2007-2009. Cox proportional hazards models tested the association of potential risk factors with fracture. In a derivation group, hazard ratios were used to assign points for factors independently related to fracture. The prognostic index was then applied to a validation group. RESULTS: The sample of 5824 men had a median age of 73.0 years; 82.9% were white and 8.6% had a fracture within 2 years of treatment for prostate cancer. The Cox model identified 8 variables (age, race, hormone treatment, Elixhauser score, anxiety, Parkinson's, fall-inducing medications and disability status) independently associated with fracture. In the derivation cohort, 4.3% of the sample experienced a fracture in the low-risk group, 8.9% in the intermediate group, and 19.2% in the high-risk group (C statistic, 0.749). The index was applied to the validation cohort (C statistic, 0.782). CONCLUSION: The prognostic index can help to identify patients at increased risk for fracture. This underscores the importance of identifying risk factors for fracture, given the substantial variation in fracture risk in men treated with ADT or RT.
Subject(s)
Chemoradiotherapy/adverse effects , Fractures, Bone/epidemiology , Geriatric Assessment/methods , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/therapy , Age Factors , Aged , Aged, 80 and over , Androgen Antagonists/adverse effects , Androgen Antagonists/therapeutic use , Causality , Cohort Studies , Comorbidity , Fractures, Bone/etiology , Geriatric Assessment/statistics & numerical data , Gonadotropin-Releasing Hormone/agonists , Humans , Male , Nonsteroidal Anti-Androgens/adverse effects , Nonsteroidal Anti-Androgens/therapeutic use , Prognosis , Proportional Hazards Models , Reproducibility of Results , Retrospective Studies , Risk Assessment/methods , Risk Assessment/standards , Risk Factors , United States/epidemiologyABSTRACT
BACKGROUND: Reports suggest worse health-related outcomes among black (vs white) men diagnosed with prostate cancer, but appropriate cause-effect inferences are complicated by the relationship of race and other prognostic factors. METHODS: We searched the literature to find contemporary articles focusing on mortality among black and white men with prostate cancer in equal-access healthcare systems. We also directly assessed the association of race and prostate cancer mortality by conducting an observational cohort analysis of 1270 veterans diagnosed with prostate cancer and followed for 11 to 16 years at 9 medical centers within the Veterans Health Administration. RESULTS: Among 5 reports providing quantitative results for the association of race and mortality among men with prostate cancer in equal-access systems, outcomes were similar for black and white men. Race also was not a prognostic factor in the observational cohort analysis of US veterans, with an adjusted hazard ratio for black (vs white) men and prostate cancer mortality of 0.90 (95% confidence interval, 0.58-1.40; P = .65). CONCLUSIONS: Mortality among black and white patients with prostate cancer is similar in equal-access healthcare systems. Studies that find racial differences in mortality (including cause-specific mortality) among men with prostate cancer may not account fully for socioeconomic and clinical factors.
Subject(s)
Black or African American , Delivery of Health Care/statistics & numerical data , Prostatic Neoplasms/mortality , White People , Cohort Studies , Humans , Male , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/ethnology , United StatesABSTRACT
UNLABELLED: Resistance and partial responses to targeted monotherapy are major obstacles in cancer treatment. Systematic approaches to identify efficacious drug combinations for cancer are not well established, especially in the context of genotype. To address this, we have tested pairwise combinations of an array of small-molecule inhibitors on early-passage melanoma cultures using combinatorial drug screening. Results reveal several inhibitor combinations effective for melanomas with activating RAS or BRAF mutations, including mutant BRAF melanomas with intrinsic or acquired resistance to vemurafenib. Inhibition of both EGF receptor and AKT sensitized treatment-resistant BRAF mutant melanoma cultures to vemurafenib. Melanomas with RAS mutations were more resistant to combination therapies relative to BRAF mutants, but were sensitive to combinations of statins and cyclin-dependent kinase inhibitors in vitro and in vivo. These results show the use of combinatorial drug screening for discovering unique treatment regimens that overcome resistance phenotypes of mutant BRAF- and RAS-driven melanomas. SIGNIFICANCE: We have used drug combinatorial screening to identify effective combinations for mutant BRAF melanomas, including those resistant to vemurafenib, and mutant RAS melanomas that are resistant to many therapies. Mechanisms governing the interactions of the drug combinations are proposed, and in vivo xenografts show the enhanced benefit and tolerability of a mutant RAS -selective combination, which is currently lacking in the clinic.