Timing of Androgen Deprivation Treatment for Men with Biochemical Recurrent Prostate Cancer in the Context of Novel Therapies.

PURPOSE: There were 3 recent U.S. Food and Drug Administration approvals for drugs to be used in nonmetastatic castration resistant prostate cancer, a state that arises from the unproven start of continuous androgen deprivation therapy (ADT) for biochemical recurrent prostate cancer (BCR), before metastatic disease is evident. This report examines the outcome of men with BCR who defer ADT until time of metastasis. MATERIALS AND METHODS: Retrospective review of men diagnosed with clinically localized prostate cancer who underwent radical prostatectomy at Johns Hopkins Hospital and Walter Reed National Military Medical Center and developed BCR with a prostate specific antigen doubling time of not more than 10 months (806 patients). The primary end points were metastasis-free survival and overall survival from time of local treatment among men who delayed ADT until time of metastasis. RESULTS: The median metastasis-free survival of men with BCR and a prostate specific antigen doubling time <6 months and 10 months who delay ADT until metastasis is 144 months (95% CI 48-not reached) and 192 months (95% CI 72-not reached), respectively, with a median overall survival of 168 months (95% CI 96-276 months) and 204 months (95% CI 120-276), respectively. CONCLUSIONS: Metastasis-free survival and overall survival of men with BCR who delay hormone therapy is long. This underscores the need to reevaluate when to start primary ADT in this patient population.

Cardiorespiratory fitness and incident lung and colorectal cancer in men and women: Results from the Henry Ford Exercise Testing (FIT) cohort.

BACKGROUND: To the authors' knowledge, the relationship between cardiorespiratory fitness (CRF) and lung and colorectal cancer outcomes is not well established. METHODS: A retrospective cohort study was performed of 49,143 consecutive patients who underwent clinician-referred exercise stress testing from 1991 through 2009. The patients ranged in age from 40 to 70 years, were without cancer, and were treated within the Henry Ford Health System in Detroit, Michigan. CRF, measured in metabolic equivalents of task (METs), was categorized as <6 (reference), 6 to 9, 10 to 11, and ≥12. Incident cancer was obtained through linkage to the cancer registry and all-cause mortality from the National Death Index. RESULTS: Participants had a mean age of 54 ± 8 years. Approximately 46% were female, 64% were white, 29% were black, and 1% were Hispanic. The median follow-up was 7.7 years. Cox proportional hazard models, adjusted for age, race, sex, body mass index, smoking history, and diabetes, found that those in the highest fitness category (METs ≥12) had a 77% decreased risk of lung cancer (hazard ratio [HR], 0.23; 95% CI, 0.14-0.36) and a 61% decreased risk of incident colorectal cancer (HR, 0.39; 95% CI, 0.23-0.66; with additional adjustment for aspirin and statin use). Among those diagnosed with lung and colorectal cancer, those with high fitness had a decreased risk of subsequent death of 44% and 89%, respectively (HR, 0.56 [95% CI, 0.32-1.00] and HR, 0.11 [95% CI, 0.03-0.37], respectively). CONCLUSIONS: In what to the authors' knowledge is the largest study performed to date, higher CRF was associated with a lower risk of incident lung and colorectal cancer in men and women and a lower risk of all-cause mortality among those diagnosed with lung or colorectal cancer.

Coronary artery calcium is associated with increased risk for lung and colorectal cancer in men and women: the Multi-Ethnic Study of Atherosclerosis (MESA).

AIMS: This study explored the association of coronary artery calcium (CAC) with incident cancer subtypes in the Multi-Ethnic Study of Atherosclerosis (MESA). CAC is an established predictor of cardiovascular disease (CVD), with emerging data also supporting independent predictive value for cancer. The association of CAC with risk for individual cancer subtypes is unknown. METHODS AND RESULTS: We included 6271 MESA participants, aged 45-84 and without known CVD or self-reported history of cancer. There were 777 incident cancer cases during mean follow-up of 12.9 ± 3.1 years. Lung and colorectal cancer (186 cases) were grouped based on their strong overlap with CVD risk profile; prostate (men) and ovarian, uterine, and breast cancer (women) were considered as sex-specific cancers (in total 250 cases). Incidence rates and Fine and Gray competing risks models were used to assess relative risk of cancer-specific outcomes stratified by CAC groups or Log(CAC+1). The mean age was 61.7 ± 10.2 years, 52.7% were women, and 36.5% were White. Overall, all-cause cancer incidence increased with CAC scores, with rates per 1000 person-years of 13.1 [95% confidence interval (CI): 11.7-14.7] for CAC = 0 and 35.8 (95% CI: 30.2-42.4) for CAC ≥400. Compared with CAC = 0, hazards for those with CAC ≥400 were increased for lung and colorectal cancer in men [subdistribution hazard ratio (SHR): 2.2 (95% CI: 1.1-4.7)] and women [SHR: 2.2 (95% CI: 1.0-4.6)], but not significantly for sex-specific cancers across sexes. CONCLUSION: CAC scores were associated with cancer risk in both sexes; however, this was stronger for lung and colorectal when compared with sex-specific cancers. Our data support potential synergistic use of CAC scores in the identification of both CVD and lung and colorectal cancer risk.

Pooled Cohort Equations and the competing risk of cardiovascular disease versus cancer: Multi-Ethnic study of atherosclerosis.

BACKGROUND: many of the modifiable variables in the Pooled Cohort Equations (PCE) are shared risk factors for cardiovascular disease (CVD) and cancer, which are the two leading causes of death in the United States. We sought to determine the utility of the PCE risk for the synergistic risk prediction of CVD and cancer. METHODS: we identified 5,773 participants (61.5 years and 53% women) without baseline CVD or cancer from the Multi-Ethnic study of atherosclerosis. The primary outcome was time to first event of either incident CVD or incident cancer. We calculated competing risk and cause-specific hazard models to examine the association of the PCE groups (<7.5%, 7.5-<20%, ≥20%) with the competing risk of CVD and cancer. RESULTS: the rate of incident CVD and cancer was higher with higher PCE risk, but the absolute event rate was low for both CVD and cancer when the PCE risk was <7.5%. Participants with a PCE <7.5% had a higher rate of cancer (4.8) compared to CVD (3.3) per 1000 person-years, while the rate of CVD (11.5) was higher than cancer (8.6) for PCE between 7.5 and <20%. The ratio of CVD to cancer increased in a logarithmic manner and at a PCE risk of approximately 7.2% the risk for CVD and cancer was equal. In adjusted competing risk modeling, a PCE risk of ≥20% compared to <7.5% was associated with a greater risk of both CVD [7.18 (95% CI 5.77-8.94)] and cancer [3.59 (95% CI 2.91-4.43)]. CONCLUSIONS: these findings highlight the importance of age and modifiable risk factors for CVD and cancer prevention. In addition, it suggests that the PCE can provide important information for both CVD and cancer risk stratification, which may guide a synergistic approach to screening and preventive therapies for the two leading causes of death in the United States.

Multidisciplinary prevention and management strategies for colorectal cancer and cardiovascular disease.

Colorectal cancer (CRC) and cardiovascular disease (CVD) are leading causes of morbidity and mortality worldwide. Their numerous shared and modifiable risk factors underscore the importance of effective prevention strategies for these largely preventable diseases. Conventionally regarded as separate disease entities, clear pathophysiological links and overlapping risk factors represent an opportunity for synergistic collaborative efforts of oncologists and cardiologists. In addition, current CRC treatment approaches can exert cardiotoxicity and thus increase CVD risk. Given the complex interplay of both diseases and increasing numbers of CRC survivors who are at increased risk for CVD, multidisciplinary cardio-oncological approaches are warranted for optimal patient care from primary prevention to acute disease treatment and long-term surveillance.

Emerging treatments for metastatic castration-resistant prostate cancer: Immunotherapy, PARP inhibitors, and PSMA-targeted approaches.

Recently there has been an explosion of new agents being investigated for the treatment of prostate cancer. These modalities represent new therapies aimed at old targets, and new therapies addressing new targets. This review will highlight three novel and emerging areas of treatment that have the potential to significantly impact the management of metastatic castration-resistant prostate cancer (mCRPC) in the near future: immunotherapy, poly ADP-ribose polymerase (PARP) inhibitors, and prostate-specific membrane antigen (PSMA)-targeted modalities. Immunotherapy, particularly immune checkpoint blockers, PARP inhibitors, and PSMA-targeted therapies are all increasingly being studied for the treatment of mCRPC although none are currently FDA-approved specifically for prostate cancer. Together these three classes of treatments may drastically change the future landscape of mCRPC. This review will cover what is currently known about the utility of these agents for the treatment of mCRPC, the areas of active research, and how these agents may be useful for patients in the future. It will also emphasize the notion of biomarker selection to help inform which patients are more likely to respond to these therapies.

Coronary Artery Calcium and the Age-Specific Competing Risk of Cardiovascular Versus Cancer Mortality: The Coronary Artery Calcium Consortium.

BACKGROUND: Coronary artery calcium (CAC) is a guideline recommended cardiovascular disease (CVD) risk stratification tool that increases with age and is associated with non-cardiovascular disease outcomes including cancer. We sought to define the age-specific change in the association between CAC and cause-specific mortality. METHODS: The Coronary Artery Calcium Consortium includes 59,502 asymptomatic patients age 40-75 without known CVD. Age-stratified mortality rates and parametric survival regression modeling was performed to estimate the age-specific CAC score at which CVD and cancer mortality risk were equal. RESULTS: The mean age was 54±8 years (67% men) and there were 2,423 deaths over a mean 12±3 years follow-up. Among individuals with CAC = 0, cancer was the leading cause of death, with low CVD mortality rates for both younger (40-54 years) 0.2/1,000 person-years and older participants (65-75 years) 1.3/1,000 person-years. When CAC ≥400, CVD was consistently the leading cause of death among younger (71% of deaths) and older participants (56% of deaths). The CAC score at which CVD overtook cancer as the leading cause of death increased exponentially with age and was approximately 115 at age 50 and 380 at age 65. CONCLUSIONS: Regardless of age, when CAC = 0 cancer was the leading cause of death and the cardiovascular disease mortality rate was low. Our age-specific estimate for the CAC score at which CVD overtakes cancer mortality allows for a more precise approach to synergistic prediction and prevention strategies for CVD and cancer.

Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage.

BACKGROUND: DNA repair gene mutations are present in 8-10% of localized prostate cancers. It is unknown whether this is influenced by clinicopathologic factors. METHODS: We interrogated localized prostate adenocarcinomas with tumor DNA sequencing information from the TCGA validated (n = 333) and Nature Genetics (n = 377) datasets. Homologous recombination repair genes included in our analysis were: ATM, BRCA1/2, CDK12, CHEK1/2, FANCA, FANCD2, FANCL, GEN1, NBN, PALB2, RAD51, and RAD51C. Proportions of cases with pathogenic DNA repair mutations (and in ATM/BRCA1/2 specifically) were reported by Gleason grade group, clinical T, pathologic T, and pathologic N stage. Odds ratios and Fisher's exact tests were used to compare proportions between categories. RESULTS: Patients with Gleason grade groups 3 and higher were 2.2 times more likely to harbor any DNA repair mutation (95% CI: 1.2-4.2; 10.3% versus 5.0%) and were 2.7 times more likely to have BRCA1/2 or ATM mutations (95% CI: 1.3-6.6; 7.0% versus 2.7%) compared to those in Gleason grade groups 1-2. Patients with pathologic T3 and T4 stage (pT3/pT4) were 2.6 times more likely to have any DNA repair mutation (95% CI: 1.3-6.6; 13.0% versus 5.5%) and were 3.2 times more likely to have BRCA1/2 or ATM mutations (95% CI: 1.2-11.3; 9.5% versus 3.1%) compared to those with pT2 disease. There was no difference by clinical tumor or nodal stage. Among men with Gleason grade group ≥ 3 and clinical stage ≥ cT3, 21.3% (1 in 5) had a DNA repair mutation in any gene and 11.7% (1 in 9) had a mutation in ATM/BRCA1/2. CONCLUSIONS: The prevalence of pathogenic DNA repair gene alterations is enriched in men with advanced tumor stages and higher Gleason grade groups, with maximal enrichment observed in those with Gleason grade group ≥ 3 and clinical stage ≥ cT3 disease. This information can be used to guide eligibility criteria for genomically targeted clinical trials in the neoadjuvant/adjuvant settings.