Cancer Endpoints Research Articles

Cancer Metabolism: Current Understanding and Therapies.

Dysregulation of cancer cell metabolism contributes to abnormal cell growth, the biological end point of cancer. We review here numerous affected oncogenes and metabolic pathways common in cancer and how they contribute to cancer pathogenesis and malignancy. This review also discusses various pharmacological manipulations that take advantage of these metabolic abnormalities and the current targeted therapies that have arisen from this research.

Association of Nadir Prostate-specific Antigen >0.5 ng/mL after Dose-escalated External Beam Radiation with Prostate Cancer-specific Endpoints.

ObjectivePrior studies have suggested that prostate-specific antigen (PSA) nadir of 0.5 ng/mL is an important surrogate endpoint for prostate cancer-specific and all-cause mortality. This study analyzed our well-followed patient cohort to assess whether this endpoint was associated with differences in prostate cancer-specific endpoints in patients receiving dose-escalated radiation.MethodsPatients with intermediate- or high-risk prostate cancer (≥T2b, or prostate-specific antigen >10 ng/mL, or Gleason score ≥7) who were treated with external beam radiation to a minimum dose of 7560 cGy +/- androgen deprivation between 2003 and 2011 were identified. Biochemical control, distant metastasis-free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were compared between those who achieved a nadir PSA ≤0.5 ng/mL with those who did not via Kaplan-Meier analysis. Univariable and multivariable Cox regression was performed on all endpoints to assess their impact on OS.ResultsThere were 367 patients identified with a median follow-up of 99.5 months. Two hundred five patients (55.9%) received androgen deprivation for a median of 24 months (range 1-81 months). Most patients (n = 308, 83.9%) achieved a nadir PSA ≤0.5 ng/mL, which was associated with improvement across all endpoints at 10 years. This included biochemical control (68.0% versus 24.0%, p < 0.001), DMFS (89.6% versus 80.8%, p = 0.019), PCSS (91.1% versus 85.7%, p = 0.01), and OS (55.7% versus 45.8%, p = 0.048). On multivariable analysis, nadir PSA >0.5 ng/mL remained strongly associated with worse outcomes across all endpoints.ConclusionsAchievement of nadir PSA ≤0.5 ng/mL after completion of dose-escalated radiation therapy was associated with improvement of all prostate cancer endpoints.

Prioritization of reproductive toxicants in unconventional oil and gas operations using a multi-country regulatory data-driven hazard assessment

BackgroundRecent trends have witnessed the global growth of unconventional oil and gas (UOG) production. Epidemiologic studies have suggested associations between proximity to UOG operations with increased adverse birth outcomes and cancer, though specific potential etiologic agents have not yet been identified. To perform effective risk assessment of chemicals used in UOG production, the first step of hazard identification followed by prioritization specifically for reproductive toxicity, carcinogenicity and mutagenicity is crucial in an evidence-based risk assessment approach. To date, there is no single hazard classification list based on the United Nations Globally Harmonized System (GHS), with countries applying the GHS standards to generate their own chemical hazard classification lists. A current challenge for chemical prioritization, particularly for a multi-national industry, is inconsistent hazard classification which may result in misjudgment of the potential public health risks. We present a novel approach for hazard identification followed by prioritization of reproductive toxicants found in UOG operations using publicly available regulatory databases. MethodsGHS classification for reproductive toxicity of 157 UOG-related chemicals identified as potential reproductive or developmental toxicants in a previous publication was assessed using eleven governmental regulatory agency databases. If there was discordance in classifications across agencies, the most stringent classification was assigned. Chemicals in the category of known or presumed human reproductive toxicants were further evaluated for carcinogenicity and germ cell mutagenicity based on government classifications. A scoring system was utilized to assign numerical values for reproductive health, cancer and germ cell mutation hazard endpoints. Using a Cytoscape analysis, both qualitative and quantitative results were presented visually to readily identify high priority UOG chemicals with evidence of multiple adverse effects. ResultsWe observed substantial inconsistencies in classification among the 11 databases. By adopting the most stringent classification within and across countries, 43 chemicals were classified as known or presumed human reproductive toxicants (GHS Category 1), while 31 chemicals were classified as suspected human reproductive toxicants (GHS Category 2). The 43 reproductive toxicants were further subjected to analysis for carcinogenic and mutagenic properties. Calculated hazard scores and Cytoscape visualization yielded several high priority chemicals including potassium dichromate, cadmium, benzene and ethylene oxide. ConclusionsOur findings reveal diverging GHS classification outcomes for UOG chemicals across regulatory agencies. Adoption of the most stringent classification with application of hazard scores provides a useful approach to prioritize reproductive toxicants in UOG and other industries for exposure assessments and selection of safer alternatives.

Time to treatment discontinuation (TTD) as a pragmatic endpoint in metastatic non-small cell lung cancer (mNSCLC): A pooled analysis of 8 trials.

9064Background: Progression-free survival (PFS) is an important efficacy endpoint in oncology trials. However, clinical trials increasingly allow treatment beyond objective radiographic progression...

Evidence for dose and dose rate effects in human and animal radiation studies.

For stochastic effects such as cancer, linear-quadratic models of dose are often used to extrapolate from the experience of the Japanese atomic bomb survivors to estimate risks from low doses and low dose rates. The low dose extrapolation factor (LDEF), which consists of the ratio of the low dose slope (as derived via fitting a linear-quadratic model) to the slope of the straight line fitted to a specific dose range, is used to derive the degree of overestimation (if LDEF > 1) or underestimation (if LDEF < 1) of low dose risk by linear extrapolation from effects at higher doses. Likewise, a dose rate extrapolation factor (DREF) can be defined, consisting of the ratio of the low dose slopes at high and low dose rates. This paper reviews a variety of human and animal data for cancer and non-cancer endpoints to assess evidence for curvature in the dose response (i.e. LDEF) and modifications of the dose response by dose rate (i.e. DREF). The JANUS mouse data imply that LDEF is approximately 0.2-0.8 and DREF is approximately 1.2-2.3 for many tumours following gamma exposure, with corresponding figures of approximately 0.1-0.9 and 0.0-0.2 following neutron exposure. This paper also cursorily reviews human data which allow direct estimates of low dose and low dose rate risk.

OC-0095: Use of a patient reported outcome as a potential radiobiological endpoint in oropharyngeal cancer

OC-0095: Use of a patient reported outcome as a potential radiobiological endpoint in oropharyngeal cancer

Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer

Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula. In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman ρ and 0.72 (95% CI, 0.68-0.77) by Kendall τ. Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients. clinicaltrials.gov Identifier: NCT01212991.

Abstract P6-08-14: Breast cancer risk in chronic users of phthalate-containing medications: A Danish nationwide cohort study

Abstract Background. Phthalates are ubiquitous in consumer goods (e.g., food containers, cosmetics, and pharmaceuticals), from which they readily leach into the environment. Phthalates interfere with hormonal signaling and may affect reproductive, developmental, and cancer endpoints. Preclinical evidence implicates some phthalates in breast cancer progression—particularly dibutyl phthalate (DBP), which potentiates the estrogen receptor (ER). Associations between phthalates and breast cancer incidence have not been thoroughly investigated. Users of phthalate-containing medications have up to 70-fold higher urinary phthalate levels than other individuals, and represent a highly exposed population for efficient study of phthalate health effects. Methods. We used the Danish Drug Information Database to identify all phthalate-containing oral medications marketed during the study period. We recorded the product code and the type and mass of phthalate per pill. We identified a nationwide cohort of women at risk for a first cancer between 2005—2015, and who had no previous exposure to a phthalate-containing drug. Using the National Prescription Registry we characterized time-varying, medication-borne phthalate exposure. Incident cancers were ascertained by linking to the Danish Cancer Registry. We fit Cox regression models to estimate associations between cumulative phthalate exposures and breast cancer incidence. Exposures were updated annually and lagged by 1 year. We adjusted for established risk factors, comorbidity, co-medications (e.g., HRT), and drug substances exposed to. Results. We identified 481 products from 24 drug classes containing either DBP, diethyl phthalate (DEP), cellulose acetate phthalate (CAP), hypromellose phthalate (HPMCP), or polyvinyl acetate phthalate (PVAP). Drugs with phthalate-containing products also included phthalate-free products. Phthalate masses ranged from 3 µg to 1.3 g per pill. We followed 1.12 million women over 9.99 million person-years, during which 27,111 women were diagnosed with invasive breast cancer. Fourteen percent of the cohort (n=161,751) was prescribed a phthalate-containing drug. We observed no breast cancer associations with exposure to CAP, DEP, HPMCP, and PVAP. However, the highest level of cumulative DBP exposure (&amp;gt;10,000 mg; range: 10,024 to 71,340 mg; median=15,390 mg) was associated with an 80% increase in breast cancer risk compared with no exposure (HRadj=1.8; 95% CI: 1.0, 3.1). The association was strongest for ER+ disease (HRadj=1.9; 95% CI: 1.1, 3.5) and among premenopausal women (HRadj=2.2; 95% CI: 0.91, 5.3). There was no evidence of a linear trend in the log-hazard across categories of cumulative DBP exposure. No published evidence links exposure to the drug substances represented by the DBP-containing products (bisacodyl, budesonide, mesalazine, multienzymes, diclofenac, and lithium) with breast cancer risk. Conclusions. High DBP exposure was associated with increased breast cancer incidence, particularly ER+ disease and among premenopausal women. This association merits further investigation. In the meantime, it may be prudent for women taking DBP-containing medications to substitute a phthalate-free version of the same drug, other considerations being equal. Citation Format: Ahern TP, Cronin-Fenton DP, Broe A, Pilgaard Ulrichsen S, Cole BF, Lash TL, Toft Sørensen H, Tamimi RM, Damkier P. Breast cancer risk in chronic users of phthalate-containing medications: A Danish nationwide cohort study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-08-14.

Lifetime physical inactivity is associated with lung cancer risk and mortality

IntroductionInvestigations of the independent associations of physical inactivity with cancer endpoints have been mounting in the epidemiological literature, in part due to the high prevalence of physical inactivity among cancer patients and to evidence that inactivity associates with carcinogenesis via pathways independent of obesity. Yet, physical inactivity is not currently recognized as a well-established risk or prognostic factor for lung cancer. As such, we examined the associations of lifetime physical inactivity with lung cancer risk and mortality in a hospital-based, case-control study. Presentation of case: materials and methodsThe analyses included data from 660 lung cancer patients and 1335 matched cancer-free controls. Multivariable logistic regression analyses were utilized to assess the association between lifetime physical inactivity and lung cancer risk, and Cox proportional hazards models were utilized to estimate the association between lifetime physical inactivity and mortality among lung cancer cases. ResultsWe observed a significant positive association between lifetime physical inactivity and lung cancer risk: [Odds ratio (OR)=2.23, 95% confidence interval (CI): 1.77–2.81]; the association remained significant among never smokers (OR=3.00, 95% CI:1.33-6.78) and non-smokers (OR=2.33, 95% CI: 1.79–3.02). We also observed a significant positive association between lifetime physical inactivity and lung cancer mortality [Hazard ratio (HR)=1.40, 95% CI: 1.14–1.71]; the association remained significant in non-smokers (HR=1.51, 95% CI: 1.16–1.96). Discussion/conclusionThese data add to the body of evidence suggesting that physical inactivity is an independent risk and prognostic factor for cancer. Additional research utilizing prospectively collected data is needed to substantiate the current findings.

Prediction of Clinical Endpoints in Breast Cancer Using NMR Metabolic Profiles.

Metabolic profiles reflect biological conditions as a result of biochemical changes within a living system. It is therefore possible to associate metabolic signatures with clinical endpoints of diseases, such as breast cancer. Nuclear magnetic resonance (NMR) spectroscopy is one of the most common techniques used for metabolic profiling, and produces high dimensional datasets from which meaningful biological information can be extracted. Here, we present an overview of data analysis techniques used to achieve this, describing key steps in the procedure. Moreover, examples of clinical endpoints of interest are provided. Although these are specific for breast cancer, the procedures for the analysis of NMR spectra as described here are applicable to any type of cancer and to other diseases.

Ensemble Methods with Voting Protocols Exhibit Superior Performance for Predicting Cancer Clinical Endpoints and Providing More Complete Coverage of Disease-Related Genes.

In genetic data modeling, the use of a limited number of samples for modeling and predicting, especially well below the attribute number, is difficult due to the enormous number of genes detected by a sequencing platform. In addition, many studies commonly use machine learning methods to evaluate genetic datasets to identify potential disease-related genes and drug targets, but to the best of our knowledge, the information associated with the selected gene set was not thoroughly elucidated in previous studies. To identify a relatively stable scheme for modeling limited samples in the gene datasets and reveal the information that they contain, the present study first evaluated the performance of a series of modeling approaches for predicting clinical endpoints of cancer and later integrated the results using various voting protocols. As a result, we proposed a relatively stable scheme that used a set of methods with an ensemble algorithm. Our findings indicated that the ensemble methodologies are more reliable for predicting cancer prognoses than single machine learning algorithms as well as for gene function evaluating. The ensemble methodologies provide a more complete coverage of relevant genes, which can facilitate the exploration of cancer mechanisms and the identification of potential drug targets.

Exceedance of environmental exposure limits to crystalline silica in communities surrounding gold mine tailings storage facilities in South Africa

BackgroundUnlike occupational silica exposures, the association between non-occupational silica exposures and adverse health effects is not well researched, despite its occurrence in communities close to dust-generating sources such as tailings storage facilities (TSFs). Recent studies have shown that communities surrounding TSFs in South Africa often complain about the onset of dust-related health effects. Even though international interim non-occupational crystalline silica limits have been established, South Africa is yet to enforce its own limits for residential areas close to TSF sites. ObjectiveThe objective of the study was to assess the need to enforce non-occupational crystalline silica limits for South Africa. MethodsThe methods involved (1) Quantifying the silica polymorph content in bulk dust collected from TSFs in South Africa; (2) Assessing the possibility of the dust to reach surrounding communities through ambient and personal filter sampling and; (3) Conducting risk characterisation for both cancer and non-cancer endpoints. ResultsAll bulk dust samples consisted mostly of crystalline silica (73.14–87.09%). Large percentages of nanoparticles were identified in all bulk samples (66.8–70.7%) indicating the possibility of the dust to lodge deep within the lungs. The crystalline silica levels obtained from ambient PM10 sampling and personal PM4 sampling all exceeded the international crystalline silica interim limits and reached maximum levels of 90 and 50.9μg·m−3, respectively. For three TSFs, sampling sites close to the TSFs showed higher PM4 silica levels compared to sites further from TSFs. Risk characterisation revealed the possibility of cancer and non-cancer health effects when chronically exposed to silica levels recorded during the study. ConclusionThe results indicate unacceptable crystalline silica exposures in surrounding communities and the need for enforcement of an ambient silica limit for South Africa.

Does Strength-Promoting Exercise Confer Unique Health Benefits? A Pooled Analysis of Data on 11 Population Cohorts With All-Cause, Cancer, and Cardiovascular Mortality Endpoints.

Public health guidance includes recommendations to engage in strength-promoting exercise (SPE), but there is little evidence on its links with mortality. Using data from the Health Survey for England and the Scottish Health Survey from 1994-2008, we examined the associations between SPE (gym-based and own-body-weight strength activities) and all-cause, cancer, and cardiovascular disease mortality. Multivariable-adjusted Cox regression was used to examine the associations between SPE (any, low-/high-volume, and adherence to the SPE guideline (≥2 sessions/week)) and mortality. The core sample comprised 80,306 adults aged ≥30 years, corresponding to 5,763 any-cause deaths (736,463 person-years). Following exclusions for prevalent disease/events occurring in the first 24 months, participation in any SPE was favorably associated with all-cause (hazard ratio (HR) = 0.77, 95% confidence interval (CI): 0.69, 0.87) and cancer (HR = 0.69, 95% CI: 0.56, 0.86) mortality. Adhering only to the SPE guideline was associated with all-cause (HR = 0.79, 95% CI: 0.66, 0.94) and cancer (HR = 0.66, 95% CI: 0.48, 0.92) mortality; adhering only to the aerobic activity guideline (equivalent to 150 minutes/week of moderate-intensity activity) was associated with all-cause (HR = 0.84, 95% CI: 0.78, 0.90) and cardiovascular disease (HR = 0.78, 95% CI: 0.68, 0.90) mortality. Adherence to both guidelines was associated with all-cause (HR = 0.71, 95% CI: 0.57, 0.87) and cancer (HR = 0.70, 95% CI: 0.50, 0.98) mortality. Our results support promoting adherence to the strength exercise guidelines over and above the generic physical activity targets.

A systematic evaluation of compliance and reporting of patient-reported outcome endpoints in ovarian cancer randomised controlled trials: implications for generalisability and clinical practice

BackgroundThis study aimed to evaluate the patient-reported outcome (PRO) content of ovarian cancer randomised-controlled trial (RCT) publications, describe PRO compliance, and explore potential relationships among these and completeness of PRO protocol content.MethodsPublications of Phase III ovarian cancer RCTs with PRO endpoints were identified by Medline and Cochrane systematic search: January 2000 to February 2016. Two reviewers determined the number of Consolidated Standards of Reporting Trials (CONSORT)-PRO Extension items addressed in publications. Compliance rates (defined as the proportion of participants included in the principal PRO analysis, of those from whom PRO assessments were expected) were extracted. The relationship between CONSORT-PRO score and compliance rates was explored using scatter plots. Additionally CONSORT-PRO score and PRO compliance rates respectively were compared with corresponding PRO protocol scores obtained from a previous study.ResultsThirty-six eligible RCTs (n = 33 with secondary PRO endpoint) were identified and analysed. The average number of CONSORT-PRO items addressed in publications was 6.7 (48%; Range 0–13.5/14). Three RCTs did not report PRO results; in 1 case due to poor compliance. Some compliance information was reported in 26 RCTs, but was considered complete for only 10 (28%) RCTs. Compliance rates were poor overall, ranging from 59 to 83%; therefore missing PRO data from 17 to 41% of participants in these trials could have been avoided.Of the 26 (73%) RCTs for which PRO protocol completeness scores were available, 6 RCTs reported complete compliance information and the 3 of these RCTs with highest PRO compliance had highest protocol checklist scores.ConclusionsFew RCTs reported PRO compliance information in a manner enabling assessment of the generalisability of PRO results. This information is particularly important in RCTs of advanced ovarian cancer because it is important to be able to determine if missing data was due to worsening illness compared to methodological issues. Poor compliance appeared related to poor PRO protocol content, and in one case prevented PRO results from being reported, highlighting the need to address compliance strategies in the protocol. Adhering to protocol and CONSORT-PRO reporting guidance should improve PRO implementation and reporting respectively in ovarian cancer RCTs and allow results to meaningfully inform clinical practice.

Imaging and clinical end points in brain metastases trials.

Imaging and clinical end points in brain metastases trials.

Use of Monte Carlo analysis in a risk-based prioritization of toxic constituents in house dust

Many chemicals have been detected in house dust with exposures to the general public and particularly young children of potential health concern. House dust is also an indicator of chemicals present in consumer products and the built environment that may constitute a health risk. The current analysis compiles a database of recent house dust concentrations from the United States and Canada, focusing upon semi-volatile constituents. Seven constituents from the phthalate and flame retardant categories were selected for risk-based screening and prioritization: diethylhexyl phthalate (DEHP), butyl benzyl phthalate (BBzP), diisononyl phthalate (DINP), a pentabrominated diphenyl ether congener (BDE-99), hexabromocyclododecane (HBCDD), tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and tris(2-chloroethyl) phosphate (TCEP). Monte Carlo analysis was used to represent the variability in house dust concentration as well as the uncertainty in the toxicology database in the estimation of children's exposure and risk. Constituents were prioritized based upon the percentage of the distribution of risk results for cancer and non-cancer endpoints that exceeded a hazard quotient (HQ) of 1. The greatest percent HQ exceedances were for DEHP (cancer and non-cancer), BDE-99 (non-cancer) and TDCIPP (cancer). Current uses and the potential for reducing levels of these constituents in house dust are discussed. Exposure and risk for other phthalates and flame retardants in house dust may increase if they are used to substitute for these prioritized constituents. Therefore, alternative assessment and green chemistry solutions are important elements in decreasing children's exposure to chemicals of concern in the indoor environment.

Ten-year follow-up of human papillomavirus vaccine efficacy against the most stringent cervical neoplasia end-point—registry-based follow-up of three cohorts from randomized trials

ObjectiveDue to long lag time between infection/cancer diagnoses human papillomavirus (HPV) vaccination programs will deliver vaccine efficacy (VE) estimates against cancer end-points late. Cancer registry follow-up of population-based, randomised trial...

Surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal cancer trials with preoperative therapy: Literature-based meta-analysis

BackgroundThere have been no reports evaluating progression-free survival (PFS) as a surrogate endpoint in resectable esophageal cancer. This study was conducted to evaluate the trial level correlations between PFS and overall survival (OS) in resectable esophageal cancer with preoperative therapy and to explore the potential benefit of PFS as a surrogate endpoint for OS. MethodsA systematic literature search of randomized trials with preoperative chemotherapy or preoperative chemoradiotherapy for esophageal cancer reported from January 1990 to September 2014 was conducted using PubMed and the Cochrane Library. Weighted linear regression using sample size of each trial as a weight was used to estimate coefficient of determination (R2) within PFS and OS. The primary analysis included trials in which the HR for both PFS and OS was reported. The sensitivity analysis included trials in which either HR or median survival time of PFS and OS was reported. In the sensitivity analysis, HR was estimated from the median survival time of PFS and OS, assuming exponential distribution. ResultsOf 614 articles, 10 trials were selected for the primary analysis and 15 for the sensitivity analysis. The primary analysis did not show a correlation between treatment effects on PFS and OS (R2 0.283, 95% CI [0.00–0.90]). The sensitivity analysis did not show an association between PFS and OS (R2 0.084, 95% CI [0.00–0.70]). ConclusionAlthough the number of randomized controlled trials evaluating preoperative therapy for esophageal cancer is limited at the moment, PFS is not suitable for primary endpoint as a surrogate endpoint for OS.

Quantitative assessment of lung and bladder cancer risk and oral exposure to inorganic arsenic: Meta-regression analyses of epidemiological data

Inorganic arsenic (iAs) in drinking water varies geographically and is prevalent worldwide. While exposures in the US are generally low, there are some areas with higher levels of naturally occurring iAs (potentially >100μg/L) where residents rely on unregulated drinking water wells. Much of the evidence on the association between iAs and cancer comes from epidemiological studies conducted in South American and Asian populations. These populations have generally been exposed to much higher levels of iAs and have differing underlying characteristics, both of which make comparing them to Western populations difficult. A key question is whether and how one should extrapolate from these high exposure studies to estimate cancer risk at lower exposures. We conducted an independent analysis to determine the most appropriate cancer endpoints, studies, and models to support an oral carcinogenicity assessment of iAs, taking into consideration factors that affect the apparent potency of iAs across geographically and culturally distinct populations. We identified bladder and lung cancer as high-priority endpoints and used meta-regression to pool data across studies from different regions of the world to derive oral cancer slope factors (CSFs) and unit risks (excess risk per μg/L) for iAs based on the background risks of bladder and lung cancer in the US. We also calculated concentrations of iAs in water that are not likely to result in cancer risk above what is considered acceptable by the United States Environmental Protection Agency (US EPA). While we derived these factors assuming a linear, no-threshold relationship between iAs and cancer risk, we also evaluated the shape of the dose-response curves and assessed the evidence for overall nonlinearity. Overall, we found that the incremental risks of bladder and lung cancer associated with iAs were relatively low. The sensitivity analyses we conducted suggested that populations with relatively high iAs exposures appeared to drive the pooled cancer risk estimates, but many of our other tested assumptions did not substantially alter these estimates. Finally, we found that the mode of action evidence supports there being a threshold, but making a robust quantitative demonstration of a threshold using epidemiological data is difficult. When considered in the context of typical exposure levels in the US, our potency estimates indicate that iAs-induced cancer risk is much lower than observed bladder and lung cancer incidences. This suggests that the low iAs levels to which much of the general US population is exposed likely do not result in substantial additional cancer risk.

Plasma Urate, Cancer Incidence, and All-Cause Mortality: A Mendelian Randomization Study.

Observationally, high plasma urate is associated with high risk of cancer. We used a Mendelian randomization design to test the hypothesis that high concentrations of plasma urate are associated with high cancer incidence and all-cause mortality observationally and genetically. We performed observational and genetic analyses using plasma urate and the urate solute carrier family 2 member 9 (SLC2A9) rs7442295 genotype in 86210 individuals from the Copenhagen General Population Study. Cancer and mortality end points were from national cancer and death registries. Incidences and risk of cancer and all-cause mortality were calculated using Cox regression, Fine and Gray competing-risks regression, and instrumental variable analyses. During a median follow-up time of 3.9 years for cancer and 4.9 years for all-cause mortality, 3243 individuals received a diagnosis of cancer and 3978 died. Observationally, 50% higher plasma urate was associated with multivariable-adjusted hazard ratios of 1.11 (95% CI, 1.05-1.18) for cancer incidence and 1.07 (1.01-1.13) for all-cause mortality. Each A-allele of the SLC2A9 rs7442295 was associated with 9% higher plasma urate and hazard ratios of 1.07 (1.01-1.14) for cancer incidence and 1.07 (1.02-1.13) for all-cause mortality. In instrumental variable analyses, the odds ratios for a genetically determined 50% higher plasma urate was 1.22 (1.02-1.47) for cancer incidence and 1.49 (1.13-1.93) for all-cause mortality. High plasma urate was both observationally and genetically associated with high cancer incidence and high all-cause mortality, suggesting causal relationships.