Konrad H. Stopsack

Common medications and prostate cancer mortality: a review

PurposeMost prostate cancer patients also have comorbidities that are treated with both prescription and nonprescription medications; furthermore, many use dietary supplements. We assess their association with prognosis after prostate cancer diagnosis, and we discuss methodological challenges and clinical implications.MethodsWe reviewed high-quality observational studies investigating the association of commonly used medications and supplements with prostate cancer-specific mortality.ResultsThere is preliminary evidence that statins and metformin use may be associated with lower risk of cancer-specific mortality after prostate cancer diagnosis; conversely, high calcium and multivitamin supplementation may be associated with increased risk. Evidence is inconclusive for nonsteroidal anti-inflammatory drugs, acetylsalicylic acid (aspirin), insulin, antihypertensives such as angiotensin-converting enzyme inhibitors and beta-blockers, digoxin, and warfarin. Common limitations of the internal validity of studies examined include unmeasured confounding and confounding by indication, competing risks, and time-related biases such as immortal time bias. The majority of studies focused on Caucasian men with specific comorbidities, while heterogeneity among patients and tumors was mostly not assessed.ConclusionsCommonly prescribed medications and over-the-counter supplements may influence prognosis among prostate cancer patients. Further well-designed pharmacoepidemiologic studies and randomized controlled trials of selected medications in appropriate patient groups are necessary before these drugs can bear new indications for prostate cancer treatment. We discuss considerations when deciding about use of these drugs in clinical practice at the present time.

A product of immunoreactive trypsinogen and pancreatitis-associated protein as second-tier strategy in cystic fibrosis newborn screening.

BACKGROUND In cystic fibrosis newborn screening (CFNBS), immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) can be used as screening parameters. We evaluated the IRT×PAP product as second-tier parameter in CFNBS in newborns with elevated IRT. METHODS Data on 410,111 screened newborns including 78 patients with classical cystic fibrosis (CF) from two European centers were retrospectively analyzed by discrimination analysis to identify a screening protocol with optimal cutoffs. We also studied differences in PAP measurement methods and the association of IRT and PAP with age. RESULTS PAP values differed systematically between fluorometric and photometric assays. The IRT×PAP product showed better discrimination for classical CF than PAP only as second-tier screening parameter (p<0.001). In CF patients, IRT decreased while PAP values remained high over years. In newborns without CF, IRT decreased after birth over weeks while PAP increased within days. CONCLUSIONS The IRT×PAP product performs well as second-tier cutoff parameter for CFNBS. Screening quality parameters depend on the analytic method and on age at blood collection.

Association of genetic variation of the six gene prognostic model for castration-resistant prostate cancer with survival

We previously identified a blood RNA transcript‐based model consisting of six immune or inflammatory response genes (ABL2, SEMA4D, ITGAL, C1QA, TIMP1, and CDKN1A) that was prognostic for survival in cohorts of men with castration‐resistant prostate cancer (CRPC). We investigated whether inherited variation in these six genes was associated with overall survival (OS) in men with CRPC.

A Prospective Study of the Association between Physical Activity and Risk of Prostate Cancer Defined by Clinical Features and TMPRSS2:ERG

BACKGROUND Growing evidence shows that clinical and molecular subtypes of prostate cancer (PCa) have specific risk factors. Observational studies suggest that physical activity may lower the risk of aggressive PCa. To our knowledge, the association between physical activity and PCa defined by TMPRSS2:ERG has not been evaluated. OBJECTIVE To prospectively examine the association between physical activity and risk of PCa defined by clinical features and TMPRSS2:ERG. DESIGN, SETTING, AND PARTICIPANTS We studied 49160 men aged 40-75 yr in the Health Professionals Follow-up Study from 1986 to 2012. Data was collected at baseline and every 2 yr with >90% follow-up. Total and vigorous physical activity were measured in metabolic equivalent of task (MET)-h/wk. OUTCOME MEASURES AND STATISTICAL ANALYSIS Advanced PCa was defined as stage T3b, T4, N1, or M1 at diagnosis and lethal PCa as distant metastases or death due to disease over follow-up. Presence of TMPRSS2:ERG was estimated by immunohistochemistry of ERG protein expression. Cox proportional hazards models were used to obtain multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for incidence of subtype-specific PCa. RESULTS AND LIMITATIONS During 26 yr of follow-up, 6411 developed PCa overall and 888 developed lethal disease. There were no significant associations between total physical activity and risk of PCa in the overall cohort. In multivariable-adjusted models, men in the highest quintile of vigorous activity had a significant 30% lower risk of advanced PCa (HR: 0.70, 95% CI: 0.53-0.92) and 25% lower risk of lethal PCa (HR: 0.75, 95% CI: 0.59-0.94) than men in the lowest quintile of vigorous activity. The association was independent of screening history. Vigorous activity was not associated with total PCa in the overall cohort but was inversely associated among highly screened men (top vs bottom quintile, HR: 0.83, 95% CI: 0.70-0.97). Of all cases, 945 were assayed for ERG (48% ERG-positive). Men with higher vigorous activity had a lower risk of ERG-positive PCa (top vs bottom quintile, HR: 0.71, 95% CI: 0.52-0.97). There was no significant association with the risk of ERG-negative disease (p heterogeneity=0.09). CONCLUSIONS Our study confirms that vigorous physical activity is associated with lower risk of advanced and lethal PCa and provides novel evidence for a lower risk of TMPRSS2:ERG-positive disease. PATIENT SUMMARY The identification of modifiable lifestyle factors for prevention of clinically important prostate cancer (PCa) is needed. In this report, we compared risk of PCa in men with different levels of physical activity. Men with higher vigorous activity had a lower risk of developing advanced and lethal PCa and PCa with the common TMPRSS2:ERG gene fusion.

Abstract A015: Molecular tumor profiling to identify mechanisms linking statin use with lower risk of lethal prostate cancer: Results from the Health Professionals Follow-up Study

Introduction: Epidemiologic data support an inverse association between statin use and risk of lethal prostate cancer, but contributing mechanisms have not been elucidated. Herein, using data from the Health Professionals Follow-up Study (HPFS), we updated our previous analysis of statins and lethal prostate cancer with a decade of additional follow-up, and incorporated immunohistochemistry (IHC)-based biomarkers and gene expression profiling to identify putative molecular mechanisms contributing to the association. Methods: We included data from 44,076 HPFS participants who were cancer free in 1990, with follow-up through 2012. Participants reported prediagnostic statin use on biennial questionnaires. Statin use was categorized as current vs. never/past use, with current users further categorized as long-term vs. short-term users (≥6 vs. Results: During 22 years of follow-up, 6,144 men were diagnosed with prostate cancer; 1,051 (17%) had advanced disease and 827 (13%) developed lethal prostate cancer. Of cases with molecular subtype available, 48% were ERG-positive and 14% PTEN-null. In multivariable analysis, relative to never/past use, current statin use was inversely associated with risk of advanced (HR 0.84; 95% CI 0.68-1.04) and lethal (HR 0.78; 95% CI 0.68-1.01) prostate cancer. These associations were more pronounced in long-term users, where ≥6 years of prediagnosis statin use was significantly associated with a lower risk of advanced (HR 0.72; 95% CI 0.53-0.97) and lethal prostate cancer (HR 0.64; 95% CI 0.45-0.92), relative to nonuse. Long-term statin use was not associated with overall prostate cancer risk, whether ERG-positive (HR 0.89; 95% CI 0.59-1.35) or ERG-negative (HR 1.06; 95% CI 0.74-1.50). However, relative to nonuse, a longer duration of prediagnosis statin use was associated with reduced risk of PTEN-null cancers (HR 0.42; 95% CI 0.20-0.90), but not PTEN-intact disease (HR 1.18; 95% CI 0.95-1.46; p-heterogeneity=0.01). In GSEA, we identified T cell, B cell, and phosphatidylinositol (PI3K) signaling among the top pathways enriched in tumor-adjacent normal prostate tissue of current statin users, relative to never users. Intriguingly, no gene sets were differentially expressed by statin use in the tumor. Discussion: Our updated findings from the HPFS are consistent with our prior findings and other epidemiologic data supporting a role for statins in lethal prostate cancer prevention. Molecular classification of tumors identified PTEN/PI3K signaling and inflammation/immune activation as two potential mechanisms contributing to this association. Elucidating molecular mechanisms mediating the association between statin use and lower risk of lethal prostate cancer will provide support for a causal effect of statins on lethal prostate cancer risk and could inform statin clinical trials with appropriate intermediate endpoints. Citation Format: Emma H. Allott, Ericka M. Ebot, Amparo G. Gonzalez-Feliciano, Sarah C. Markt, Kathryn M. Wilson, Thomas U. Ahearn, Travis A. Gerke, Mary K. Downer, Konrad H. Stopsack, Jennifer R. Rider, Stephen J. Freedland, Elizabeth A. Platz, Meir J. Stampfer, Edward L. Giovannucci, Christopher J. Sweeney, Stephen P. Finn, Lorelei A. Mucci. Molecular tumor profiling to identify mechanisms linking statin use with lower risk of lethal prostate cancer: Results from the Health Professionals Follow-up Study [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A015.

A prospective study of aspirin use and prostate cancer risk by TMPRSS2:ERG status

Background: In a case–control study, aspirin use was associated with a lower risk of a common prostate cancer molecular subtype, the TMPRSS2:ERG gene fusion. We sought to validate this finding in a prospective cohort. Methods: In the Health Professionals Follow-up Study, 49,395 men reported on aspirin use on biennial questionnaires and were followed for prostate cancer incidence over 23 years. TMPRSS2:ERG status was assessed by IHC for presence of ERG on archival tumor specimens for 912 patients with prostate cancer, of whom 48% were ERG-positive. Results: In multivariable models, we found no association between regular use of aspirin and risk of ERG-positive prostate cancer (HR, 1.02; 95% confidence interval, 0.85–1.23), nor any association with duration or frequency of aspirin use. In restricting to cases with either high Gleason grade or advanced stage disease, there remained no association with aspirin use. Conclusions: Data from this prospective study with repeated assessments of aspirin use do not support the hypothesis that aspirin use is associated with a lower risk of ERG-positive prostate cancer. Impact: Aspirin use is unlikely to lower the risk of this common molecular subtype of prostate cancer. However, there is emerging data supporting the role of other lifestyle and genetic factors underlying the development of the TMPRSS2:ERG fusion. Cancer Epidemiol Biomarkers Prev; 27(10); 1231–3. ©2018 AACR.

Regular aspirin use and gene expression profiles in prostate cancer patients

PurposePharmacoepidemiology studies suggest prognostic benefits of aspirin in prostate cancer. We hypothesized that aspirin induces transcriptional changes in tumors or normal prostate tissue.MethodsWe analyzed the prostatic transcriptome from men diagnosed with prostate cancer during follow-up of the Physicians’ Health Study 1 (PHS, n = 149), initially a randomized controlled trial of aspirin. Aspirin target genes were identified through systematic literature review and a drug target database. We compared target gene expression according to regular aspirin use at cancer diagnosis and used whole-transcriptome gene set enrichment analysis to identify gene sets associated with aspirin use. Results were validated in the Health Professionals Follow-up Study (HPFS, n = 254) and in Connectivity Map.ResultsOf 12 target genes identified from prior studies and 540 genes from the drug target database, none were associated with aspirin use. Twenty-one gene sets were enriched in tumor tissue of aspirin users, 18 of which were clustered around ribosome function and translation. These gene sets were associated with exposure to cyclooxygenase inhibitors in Connectivity Map. Their association with cancer prognosis was U-shaped in both cohorts. No gene sets were enriched in normal tissue. In HPFS, neither the target genes nor the gene sets were associated with aspirin use.ConclusionsRegular aspirin use may affect ribosome function in prostate tumors. Other putative target genes had similar expression in tumors from aspirin users and non-users. If results are corroborated by experimental studies, a potential benefit of aspirin may be limited to a subset of prostate cancer patients.

Abstract PR09: Prostate cancer prognostication based on an actionable metabolic pathway

Background: We recently discovered that mRNA expression of SQLE, coding for squalene monooxygenase, the second rate-limiting enzyme of cholesterol synthesis, is associated with lethality after prostate cancer diagnosis. Here, we investigate how expression of SQLE and other key regulators of cholesterol homeostasis, identified by prior mechanistic studies, aid risk prediction for lethal prostate cancer. Methods: The Health Professionals Follow-up Study and the Physicians9 Health Study prostate cancer tissue cohorts collected tissue from prostatectomy or transurethral resection of the prostate at cancer diagnosis. Whole-transcriptome profiling was performed. The outcome of interest was lethal cancer defined as prostate cancer mortality or development of metastases in contrast to non-lethal cancer without evidence of metastases after at least eight years of follow up. Discrimination for prostate lethal cancer was assessed by comparing c-statistics using bootstrap resampling. Results: Combining both cohorts, 112 men had lethal prostate cancer; 290 men had non-lethal cancer. A prognostic model for lethal cancer including Gleason grade, pathologic stage, age, and year of diagnosis had a high c = 0.885; adding body mass index, smoking status, family history of prostate cancer, and diabetes diagnosis increased c to 0.889. A model containing only SQLE (linear) achieved c = 0.663. Adding SQLE to the fully adjusted model increased c to 0.903 (p = 0.027). None of the other cholesterol regulators ABCA1, ACAT1, LDLR, and SCARB1 improved discrimination. Conclusions: SQLE performs well as a single biomarker of prostate cancer lethality after primary therapy, in contrast to other markers of intratumoral cholesterol regulation. Improvements in prognostication are minimal when SQLE is added to a model that contains a centrally re-reviewed Gleason grade. Most importantly, SQLE may be an actionable, predictive biomarker of benefit from statin therapy, which addresses the cholesterol synthesis pathway regulated by SQLE. Citation Format: Konrad H. Stopsack, Travis A. Gerke, Lorelei A. Mucci, Jennifer R. Rider. Prostate cancer prognostication based on an actionable metabolic pathway. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr PR09.

Abstract 60: PTEN expression, cholesterol metabolism, and lethal prostate cancer

BACKGROUND: We previously showed that mRNA expression of squalene monooxygenase (SQLE), part of the cholesterol synthesis pathway, is associated with lethal prostate cancer. In-vitro studies suggest that loss of PTEN expression and resulting PI3K pathway activation drive cholesterol ester accumulation in aggressive prostate cancers through sterol regulatory element-binding protein (SREBP) and acyl coenzyme A-cholesterol acyltransferase (ACAT1) activity. In two prospective cohorts, we studied whether lower PTEN expression is associated with cholesterol metabolism and how this relates to lethal prostate cancer. METHODS: We analyzed men with prostate cancer from the prospective prostatectomy Health Professionals Follow-up Study and Physicians’ Health Study. 105 men had lethal cancer and 284 men non-lethal disease without metastases at 8 years of follow-up. Whole-transcriptome mRNA expression profiling data was available from diagnostic prostate tumor specimens. Linear regression models were used to assess continuous and categorical associations, and Pearson correlation coefficients were calculated. Logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) of lethal prostate cancer. RESULTS: Both lower PTEN and higher SQLE expression were associated with higher Gleason grade (p trend 0.05). Adjusting for PTEN mildly attenuated the association of SQLE with lethal cancer (OR, 2.07; 95% CI, 1.57 to 2.73), as did additional adjustment for age, Gleason grade, and stage (SQLE: OR, 1.75; 95% CI, 1.29 to 2.40). In the lowest quartile of PTEN expression, SQLE was less strongly associated with lethal cancer (OR 1.74; 95% CI, 1.20 to 2.52) compared to the upper three quartiles (OR 2.47; 95% CI, 1.69 to 3.60; p interaction = 0.2). CONCLUSION: Low PTEN mRNA expression and high SQLE are features of aggressive prostate cancers. However, at the time of prostatectomy, SREBF1/2 expression and resulting ACAT1 expression do not appear to be major characteristics of prostate cancers with lethal outcomes. Citation Format: Konrad H. Stopsack, Travis A. Gerke, Lorelei A. Mucci, Jennifer R. Rider. PTEN expression, cholesterol metabolism, and lethal prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 60.