Roman Gulati

Quantifying the role of PSA screening in the US prostate cancer mortality decline

ObjectiveTo quantify the plausible contribution of prostate-specific antigen (PSA) screening to the nearly 30% decline in the US prostate cancer mortality rate observed during the 1990s.MethodsTwo mathematical modeling teams of the US National Cancer Institute’s Cancer Intervention and Surveillance Modeling Network independently projected disease mortality in the absence and presence of PSA screening. Both teams relied on Surveillance, Epidemiology, and End Results (SEER) registry data for disease incidence, used common estimates of PSA screening rates, and assumed that screening, by shifting disease from distant to local-regional clinical stage, confers a corresponding improvement in disease-specific survival.ResultsThe teams projected similar mortality increases in the absence of screening and decreases in the presence of screening after 1985. By 2000, the models projected that 45% (Fred Hutchinson Cancer Research Center) to 70% (University of Michigan) of the observed decline in prostate cancer mortality could be plausibly attributed to the stage shift induced by screening.ConclusionsPSA screening may account for much, but not all, of the observed drop in prostate cancer mortality. Other factors, such as changing treatment practices, may also have played a role in improving prostate cancer outcomes.

Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer

BACKGROUND Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established. METHODS We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes. RESULTS A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001). CONCLUSIONS In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family history of prostate cancer. (Funded by Stand Up To Cancer and others.).

Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer

Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment-response durations to carboplatin than did men without defects in genes encoding DNA-repair proteins. Collectively, these data indicate that although exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.

Comparative Effectiveness of Alternative Prostate-Specific Antigen–Based Prostate Cancer Screening Strategies: Model Estimates of Potential Benefits and Harms

BACKGROUND The U.S. Preventive Services Task Force recently concluded that the harms of existing prostate-specific antigen (PSA) screening strategies outweigh the benefits. OBJECTIVE To evaluate comparative effectiveness of alternative PSA screening strategies. DESIGN Microsimulation model of prostate cancer incidence and mortality quantifying harms and lives saved for alternative PSA screening strategies. DATA SOURCES National and trial data on PSA growth, screening and biopsy patterns, incidence, treatment distributions, treatment efficacy, and mortality. TARGET POPULATION A contemporary cohort of U.S. men. TIME HORIZON Lifetime. PERSPECTIVE Societal. INTERVENTION 35 screening strategies that vary by start and stop ages, screening intervals, and thresholds for biopsy referral. OUTCOME MEASURES PSA tests, false-positive test results, cancer detected, overdiagnoses, prostate cancer deaths, lives saved, and months of life saved. RESULTS OF BASE-CASE ANALYSIS Without screening, the risk for prostate cancer death is 2.86%. A reference strategy that screens men aged 50 to 74 years annually with a PSA threshold for biopsy referral of 4 µg/L reduces the risk for prostate cancer death to 2.15%, with risk for overdiagnosis of 3.3%. A strategy that uses higher PSA thresholds for biopsy referral in older men achieves a similar risk for prostate cancer death (2.23%) but reduces the risk for overdiagnosis to 2.3%. A strategy that screens biennially with longer screening intervals for men with low PSA levels achieves similar risks for prostate cancer death (2.27%) and overdiagnosis (2.4%), but reduces total tests by 59% and false-positive results by 50%. RESULTS OF SENSITIVITY ANALYSIS Varying incidence inputs or reducing the survival improvement due to screening did not change conclusions. LIMITATION The model is a simplification of the natural history of prostate cancer, and improvement in survival due to screening is uncertain. CONCLUSION Compared with standard screening, PSA screening strategies that use higher thresholds for biopsy referral for older men and that screen men with low PSA levels less frequently can reduce harms while preserving lives. PRIMARY FUNDING SOURCE National Cancer Institute and Centers for Disease Control and Prevention.

The prostate cancer conundrum revisited: Treatment changes and prostate cancer mortality declines

Prostate cancer mortality rates in the United States declined by >40% between 1991 and 2005. The impact of changes in primary treatment and adjuvant and neoadjuvant hormone therapy on this decline is unknown.

Impact of PSA Screening on the Incidence of Advanced Stage Prostate Cancer in the United States: A Surveillance Modeling Approach

Background and objective. Both the detection and the treatment of prostate cancer have undergone important clinical advances. Simultaneously, both distant stage incidence and disease-specific mortality have fallen in the United States. A recent study suggests that if prostate-specific antigen (PSA) testing explains the decline in distant stage incidence, then it may be largely responsible for the decline in mortality. The objective was to quantify this link between PSA screening and the decline in distant stage incidence. Methods. A fixed-cohort simulation model of prostate cancer progression and screening was adapted to a population-based model that integrates new data on trends in testing and biopsy practices. The model was calibrated to pre-PSA incidence and then screening was superimposed, obtaining incidence projections in the absence and presence of testing. This approach permits calculation of clinically relevant measures for model validation and direct assessment of the role of testing in the distant stage incidence decline. Results. The model validated well with prior studies of natural history, and the sensitivity analysis indicated that the findings were robust to variation in model parameters. Model results indicate that PSA screening accounts for approximately 80% of the observed decline in distant stage incidence. Conclusions. PSA screening contributed to the observed declines in distant stage incidence and mortality in the 1990s. However, additional factors, such as increasing awareness of prostate cancer and advances in treatment, have probably also played a role in these trends.

Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel.

Background:Enzalutamide and abiraterone are new androgen-axis disrupting treatments for metastatic castration-resistant prostate cancer (mCRPC). We examined the response and outcomes of enzalutamide-treated mCRPC patients in the real-world context of prior treatments of abiraterone and/or docetaxel.Methods:We conducted a seven-institution retrospective study of mCRPC patients treated with enzalutamide between January 2009 and February 2014. We compared the baseline characteristics, PSA declines, PSA progression-free survival (PSA-PFS), duration on enzalutamide and overall survival (OS) across subgroups defined by prior abiraterone and/or docetaxel.Results:Of 310 patients who received enzalutamide, 36 (12%) received neither prior abiraterone nor prior docetaxel, 79 (25%) received prior abiraterone, 30 (10%) received prior docetaxel and 165 (53%) received both prior abiraterone and prior docetaxel. Within these groups, respectively, ⩾30% PSA decline was achieved among 67, 28, 43 and 24% of patients; PSA-PFS was 5.5 (95% CI 4.2–9.1), 4.0 (3.2–4.8), 4.1 (2.9–5.4) and 2.8 (2.5–3.2) months; median duration of enzalutamide was 9.1 (7.3–not reached), 4.7 (3.7–7.7), 5.4 (3.8–8.4) and 3.9 (3.0–4.6) months. Median OS was reached only for the patients who received both prior abiraterone and docetaxel and was 12.2 months (95% CI 10.7–16.5). 12-month OS was 78% (59–100%), 64% (45–90%), 77% (61–97%) and 51% (41–62%). Of 70 patients who failed to achieve any PSA decline on prior abiraterone, 19 (27%) achieved ⩾30% PSA decline with subsequent enzalutamide.Conclusions:The activity of enzalutamide is blunted after abiraterone, after docetaxel, and still more after both, suggesting subsets of overlapping and distinct mechanisms of resistance.

Effect of artemisinin derivatives on apoptosis and cell cycle in prostate cancer cells

Artemisinin is a plant-derived anti-malarial drug that has relatively low toxicity in humans and is activated by heme and/or intracellular iron leading to intracellular free radical formation. Interestingly, artemisinin has displayed anti-cancer activity, with artemisinin dimers being more potent than monomeric artemisinin. Intracellular iron uptake is regulated by the transferrin receptor (TfR), and the activity of artemisinin depends on the availability of iron. We examined the level of TfR in prostate cancer (PCa) tumor cells, synthesized two new artemisinin dimers, and evaluated the effect of dihydroartemisinin and artemisinin dimers, ON-2Py and 2Py, on proliferation and apoptosis in PCa cells. TfR was expressed in the majority of PCa bone and soft tissue metastases, all 24 LuCaP PCa xenografts, and PCa cell lines. After treatment with dihydroartemisinin, ON-2Py, or 2Py all PCa cell lines displayed dose-dependent decrease in cell number. 2Py was most effective in decreasing cell number. An increase in apoptotic events and growth arrest was observed in the C4-2 and LNCaP cell lines. Growth arrest was observed in PC-3 cells, but no significant change was observed in DU 145 cells. Treatment with 2Py resulted in a loss of the anti-apoptotic protein survivin in all four cell lines. 2Py treatment also decreased androgen receptor and prostate-specific antigen expression in C4-2 and LNCaP cells, with a concomitant loss of cell cycle regulatory proteins cyclin D1 and c-Myc. This study shows the potential use of artemisinin derivatives as therapeutic candidates for PCa and warrants the initiation of preclinical studies.

Personalizing Age of Cancer Screening Cessation Based on Comorbid Conditions: Model Estimates of Harms and Benefits

BACKGROUND Harms and benefits of cancer screening depend on age and comorbid conditions, but reliable estimates are lacking. OBJECTIVE To estimate the harms and benefits of cancer screening by age and comorbid conditions to inform decisions about screening cessation. DESIGN Collaborative modeling with 7 cancer simulation models and common data on average and comorbid condition level-specific life expectancy. SETTING U.S. population. PATIENTS U.S. cohorts aged 66 to 90 years in 2010 with average health or 1 of 4 comorbid condition levels: none, mild, moderate, or severe. INTERVENTION Mammography, prostate-specific antigen testing, or fecal immunochemical testing. MEASUREMENTS Lifetime cancer deaths prevented and life-years gained (benefits); false-positive test results and overdiagnosed cancer cases (harms). For each comorbid condition level, the age at which harms and benefits of screening were similar to that for persons with average health having screening at age 74 years. RESULTS Screening 1000 women with average life expectancy at age 74 years for breast cancer resulted in 79 to 96 (range across models) false-positive results, 0.5 to 0.8 overdiagnosed cancer cases, and 0.7 to 0.9 prevented cancer deaths. Although absolute numbers of harms and benefits differed across cancer sites, the ages at which to cease screening were consistent across models and cancer sites. For persons with no, mild, moderate, and severe comorbid conditions, screening until ages 76, 74, 72, and 66 years, respectively, resulted in harms and benefits similar to average-health persons. LIMITATION Comorbid conditions influenced only life expectancy. CONCLUSION Comorbid conditions are an important determinant of harms and benefits of screening. Estimates of screening benefits and harms by comorbid condition can inform discussions between providers and patients about personalizing screening cessation decisions. PRIMARY FUNDING SOURCE National Cancer Institute and Centers for Disease Control and Prevention.

Limitations of basing screening policies on screening trials: The US Preventive Services Task Force and Prostate Cancer Screening.

Background:The US Preventive Services Task Force recently recommended against prostate-specific antigen screening for prostate cancer based primarily on evidence from the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. Objective:To examine limitations of basing screening policy on evidence from screening trials. Methods:We reviewed published modeling studies that examined population and trial data. The studies (1) project the roles of screening and changes in primary treatment in the US mortality decline; (2) extrapolate the ERSPC mortality reduction to the long-term US setting; (3) estimate overdiagnosis based on US incidence trends; and (4) quantify the impact of control arm screening on PLCO mortality results. Results:Screening plausibly explains 45% and changes in primary treatment can explain 33% of the US prostate cancer mortality decline. Extrapolating the ERSPC results to the long-term US setting implies an absolute mortality reduction at least 5 times greater than that observed in the trial. Approximately 28% of screen-detected cases are overdiagnosed in the United States versus 58% of screen-detected cases suggested by the ERSPC results. Control arm screening can explain the null result in the PLCO trial. Conclusions:Modeling studies indicate that population trends and trial results extended to the long-term population setting are consistent with greater benefit of prostate-specific antigen screening—and more favorable harm-benefit tradeoffs—than has been suggested by empirical trial evidence.