Understanding of prognosis in non-metastatic prostate cancer: a randomised comparative study of clinician estimates measured against the PREDICT prostate prognostic model

Abstract: PREDICT Prostate is an individualised prognostic model that provides long-term survival estimates for men diagnosed with non-metastatic prostate cancer (www.prostate.predict.nhs.uk). In this study clinician estimates of survival were compared against model predictions and its potential value as a clinical tool was assessed. Prostate cancer (PCa) specialists were invited to participate in the study. 190 clinicians (63% urologists, 17% oncologists, 20% other) were randomised into two groups and shown 12 clinical vignettes through an online portal. Each group viewed opposing vignettes with clinical information alone, or alongside PREDICT Prostate estimates. 15-year clinician survival estimates were compared against model predictions and reported treatment recommendations with and without seeing PREDICT estimates were compared. 155 respondents (81.6%) reported counselling new PCa patients at least weekly. Clinician estimates of PCa-specific mortality exceeded PREDICT estimates in 10/12 vignettes. Their estimates for treatment survival benefit at 15 years were over-optimistic in every vignette, with mean clinician estimates more than 5-fold higher than PREDICT Prostate estimates. Concomitantly seeing PREDICT Prostate estimates led to significantly lower reported likelihoods of recommending radical treatment in 7/12 (58%) vignettes, particularly in older patients. These data suggest clinicians overestimate cancer-related mortality and radical treatment benefit. Using an individualised prognostic tool may help reduce overtreatment

Evidence of a Causal Association Between Cancer and Alzheimer’s Disease: a Mendelian Randomization Analysis

Abstract: While limited observational evidence suggests that cancer survivors have a decreased risk of developing Alzheimer’s disease (AD), and vice versa, it is not clear whether this relationship is causal. Using a Mendelian randomization approach that provides evidence of causality, we found that genetically predicted lung cancer (OR 0.91, 95% CI 0.84–0.99, p = 0.019), leukemia (OR 0.98, 95% CI 0.96–0.995, p = 0.012), and breast cancer (OR 0.94, 95% CI 0.89–0.99, p = 0.028) were associated with 9.0%, 2.4%, and 5.9% lower odds of AD, respectively, per 1-unit higher log odds of cancer. When genetic predictors of all cancers were pooled, cancer was associated with 2.5% lower odds of AD (OR 0.98, 95% CI 0.96–0.988, p = 0.00027) per 1-unit higher log odds of cancer. Finally, genetically predicted smoking-related cancers showed a more robust inverse association with AD than non-smoking related cancers (OR 0.95, 95% CI 0.92–0.98, p = 0.0026, vs. OR 0.98, 95% CI 0.97–0.995, p = 0.0091)

Individual prognosis at diagnosis in nonmetastatic prostate cancer: Development and external validation of the PREDICT Prostate multivariable model.

BACKGROUND: Prognostic stratification is the cornerstone of management in nonmetastatic prostate cancer (PCa). However, existing prognostic models are inadequate-often using treatment outcomes rather than survival, stratifying by broad heterogeneous groups and using heavily treated cohorts. To address this unmet need, we developed an individualised prognostic model that contextualises PCa-specific mortality (PCSM) against other cause mortality, and estimates the impact of treatment on survival. METHODS AND FINDINGS: Using records from the United Kingdom National Cancer Registration and Analysis Service (NCRAS), data were collated for 10,089 men diagnosed with nonmetastatic PCa between 2000 and 2010 in Eastern England. Median follow-up was 9.8 years with 3,829 deaths (1,202 PCa specific). Totals of 19.8%, 14.1%, 34.6%, and 31.5% of men underwent conservative management, prostatectomy, radiotherapy (RT), and androgen deprivation monotherapy, respectively. A total of 2,546 men diagnosed in Singapore over a similar time period represented an external validation cohort. Data were randomly split 70:30 into model development and validation cohorts. Fifteen-year PCSM and non-PCa mortality (NPCM) were explored using separate multivariable Cox models within a competing risks framework. Fractional polynomials (FPs) were utilised to fit continuous variables and baseline hazards. Model accuracy was assessed by discrimination and calibration using the Harrell C-index and chi-squared goodness of fit, respectively, within both validation cohorts. A multivariable model estimating individualised 10- and 15-year survival outcomes was constructed combining age, prostate-specific antigen (PSA), histological grade, biopsy core involvement, stage, and primary treatment, which were each independent prognostic factors for PCSM, and age and comorbidity, which were prognostic for NPCM. The model demonstrated good discrimination, with a C-index of 0.84 (95% CI: 0.82-0.86) and 0.84 (95% CI: 0.80-0.87) for 15-year PCSM in the UK and Singapore validation cohorts, respectively, comparing favourably to international risk-stratification criteria. Discrimination was maintained for overall mortality, with C-index 0.77 (95% CI: 0.75-0.78) and 0.76 (95% CI: 0.73-0.78). The model was well calibrated with no significant difference between predicted and observed PCa-specific (p = 0.19) or overall deaths (p = 0.43) in the UK cohort. Key study limitations were a relatively small external validation cohort, an inability to account for delayed changes to treatment beyond 12 months, and an absence of tumour-stage subclassifications. CONCLUSIONS: 'PREDICT Prostate' is an individualised multivariable PCa prognostic model built from baseline diagnostic information and the first to our knowledge that models potential treatment benefits on overall survival. Prognostic power is high despite using only routinely collected clinicopathological information.The Urology Foundatio

Genomic risk prediction of coronary artery disease in women with breast cancer: a prospective cohort study.

Funder: Wellcome TrustBackgroundAdvancements in cancer therapeutics have resulted in increases in cancer-related survival; however, there is a growing clinical dilemma. The current balancing of survival benefits and future cardiotoxic harms of oncotherapies has resulted in an increased burden of cardiovascular disease in breast cancer survivors. Risk stratification may help address this clinical dilemma. This study is the first to assess the association between a coronary artery disease-specific polygenic risk score and incident coronary artery events in female breast cancer survivors.MethodsWe utilized the Studies in Epidemiology and Research in Cancer Heredity prospective cohort involving 12,413 women with breast cancer with genotype information and without a baseline history of cardiovascular disease. Cause-specific hazard ratios for association of the polygenic risk score and incident coronary artery disease (CAD) were obtained using left-truncated Cox regression adjusting for age, genotype array, conventional risk factors such as smoking and body mass index, as well as other sociodemographic, lifestyle, and medical variables.ResultsOver a median follow-up of 10.3 years (IQR: 16.8) years, 750 incident fatal or non-fatal coronary artery events were recorded. A 1 standard deviation higher polygenic risk score was associated with an adjusted hazard ratio of 1.33 (95% CI 1.20, 1.47) for incident CAD.ConclusionsThis study provides evidence that a coronary artery disease-specific polygenic risk score can risk-stratify breast cancer survivors independently of other established cardiovascular risk factors

Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model.

PURPOSE: The proliferation of gene panel testing precipitates the need for a breast cancer (BC) risk model that incorporates the effects of mutations in several genes and family history (FH). We extended the BOADICEA model to incorporate the effects of truncating variants in PALB2, CHEK2, and ATM. METHODS: The BC incidence was modeled via the explicit effects of truncating variants in BRCA1/2, PALB2, CHEK2, and ATM and other unobserved genetic effects using segregation analysis methods. RESULTS: The predicted average BC risk by age 80 for an ATM mutation carrier is 28%, 30% for CHEK2, 50% for PALB2, and 74% for BRCA1 and BRCA2. However, the BC risks are predicted to increase with FH burden. In families with mutations, predicted risks for mutation-negative members depend on both FH and the specific mutation. The reduction in BC risk after negative predictive testing is greatest when a BRCA1 mutation is identified in the family, but for women whose relatives carry a CHEK2 or ATM mutation, the risks decrease slightly. CONCLUSIONS: The model may be a valuable tool for counseling women who have undergone gene panel testing for providing consistent risks and harmonizing their clinical management. A Web application can be used to obtain BC risks in clinical practice (http://ccge.medschl.cam.ac.uk/boadicea/).Genet Med 18 12, 1190-1198.This work was funded by Cancer Research UK Grants C12292/A11174 and C1287/A10118. ACA is a Cancer Research UK Senior Cancer Research Fellow. This work was supported by the Governement of Canada through Genome Canada and the Canadian Institutes of Health Research, and the Ministère de l'enseignement supérieur, de la recherche, de la science et de la technologie du Québec through Génome Québec.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/gim.2016.3

Polygenic risk-tailored screening for prostate cancer: A benefit-harm and cost-effectiveness modelling study.

BACKGROUND: The United States Preventive Services Task Force supports individualised decision-making for prostate-specific antigen (PSA)-based screening in men aged 55-69. Knowing how the potential benefits and harms of screening vary by an individual's risk of developing prostate cancer could inform decision-making about screening at both an individual and population level. This modelling study examined the benefit-harm tradeoffs and the cost-effectiveness of a risk-tailored screening programme compared to age-based and no screening. METHODS AND FINDINGS: A life-table model, projecting age-specific prostate cancer incidence and mortality, was developed of a hypothetical cohort of 4.48 million men in England aged 55 to 69 years with follow-up to age 90. Risk thresholds were based on age and polygenic profile. We compared no screening, age-based screening (quadrennial PSA testing from 55 to 69), and risk-tailored screening (men aged 55 to 69 years with a 10-year absolute risk greater than a threshold receive quadrennial PSA testing from the age they reach the risk threshold). The analysis was undertaken from the health service perspective, including direct costs borne by the health system for risk assessment, screening, diagnosis, and treatment. We used probabilistic sensitivity analyses to account for parameter uncertainty and discounted future costs and benefits at 3.5% per year. Our analysis should be considered cautiously in light of limitations related to our model's cohort-based structure and the uncertainty of input parameters in mathematical models. Compared to no screening over 35 years follow-up, age-based screening prevented the most deaths from prostate cancer (39,272, 95% uncertainty interval [UI]: 16,792-59,685) at the expense of 94,831 (95% UI: 84,827-105,630) overdiagnosed cancers. Age-based screening was the least cost-effective strategy studied. The greatest number of quality-adjusted life-years (QALYs) was generated by risk-based screening at a 10-year absolute risk threshold of 4%. At this threshold, risk-based screening led to one-third fewer overdiagnosed cancers (64,384, 95% UI: 57,382-72,050) but averted 6.3% fewer (9,695, 95% UI: 2,853-15,851) deaths from prostate cancer by comparison with age-based screening. Relative to no screening, risk-based screening at a 4% 10-year absolute risk threshold was cost-effective in 48.4% and 57.4% of the simulations at willingness-to-pay thresholds of GBP£20,000 (US$26,000) and £30,000 ($39,386) per QALY, respectively. The cost-effectiveness of risk-tailored screening improved as the threshold rose. CONCLUSIONS: Based on the results of this modelling study, offering screening to men at higher risk could potentially reduce overdiagnosis and improve the benefit-harm tradeoff and the cost-effectiveness of a prostate cancer screening program. The optimal threshold will depend on societal judgements of the appropriate balance of benefits-harms and cost-effectiveness

Association between tumour infiltrating lymphocytes, histotype and clinical outcome in epithelial ovarian cancer.

BACKGROUND: There is evidence that some ovarian tumours evoke an immune response, which can be assessed by tumour infiltrating lymphocytes (TILs). To facilitate adoption of TILs as a clinical biomarker, a standardised method for their H&E visual evaluation has been validated in breast cancer. METHODS: We sought to investigate the prognostic significance of TILs in a study of 953 invasive epithelial ovarian cancer tumour samples, both primary and metastatic, from 707 patients from the prospective population-based SEARCH study. TILs were analysed using a standardised method based on H&E staining producing a percentage score for stromal and intratumoral compartments. We used Cox regression to estimate hazard ratios of the association between TILs and survival. RESULTS: The extent of stromal and intra-tumoral TILs were correlated in the primary tumours (n = 679, Spearman's rank correlation = 0.60, P < 0.001) with a similar correlation in secondary tumours (n = 224, Spearman's rank correlation = 0.62, P < 0.001). There was a weak correlation between stromal TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.29, P < 0.001) and intra-tumoral TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.19, P = 0.0094). The extent of stromal TILs differed between histotypes (Pearson chi2 (12d.f.) 54.1, P < 0.0001) with higher levels of stromal infiltration in the high-grade serous and endometriod cases. A significant association was observed for higher intratumoral TIL levels and a favourable prognosis (HR 0.74 95% CI 0.55-1.00 p = 0.047). CONCLUSION: This study is the largest collection of epithelial ovarian tumour samples evaluated for TILs. We have shown that stromal and intratumoral TIL levels are correlated and that their levels correlate with clinical variables such as tumour histological subtype. We have also shown that increased levels of both intratumoral and stromal TILs are associated with a better prognosis; however, this is only statistically significant for intratumoral TILs. This study suggests that a clinically useful immune prognostic indicator in epithelial ovarian cancer could be developed using this technique

A systematic review assessing the existence of pneumothorax-only variants of FLCN. Implications for lifelong surveillance of renal tumours

Abstract: Individuals with Birt–Hogg–Dubé syndrome (BHDS) may develop fibrofolliculomas, pneumothorax and/or renal cell carcinoma (RCC). Currently, all patients with pathogenic FLCN variants are recommended to have renal surveillance. It has however been suggested that some FLCN variants only cause pneumothorax, which would make surveillance unnecessary in certain cases. This review assesses this possibility. We provide an up-to-date analysis of clinical and genetic features of BHDS. The PUBMED database was systematically searched to find all articles describing patients with pathogenic FLCN variants. The relevant clinical and genetic features of these patients were recorded and analysed. The prevalence of pneumothorax, pulmonary cysts, RCC and characteristic skin lesions in BHDS were 50.9% (n = 1038), 91.9% (n = 720), 22.5% (n = 929) and 47.9% (n = 989), respectively. There was a higher prevalence of pneumothoraces (p < 0.0001) but lower prevalence of dermatological findings (p < 0.0001) in patients from East Asia compared to North America or Europe. Of the 194 pathogenic FLCN variants, 76 could be defined as ‘pneumothorax-only’. Pneumothorax only pathogenic variants (POPVs) were distributed throughout the gene, and there were no statistical differences in variant type. The majority of POPVs (65/76) affected no more than three individuals. Individuals with ‘POPVs’ also tended to be younger (45 vs. 47 years, p < 0.05). Many apparent POPVs in the literature could result from variable expressivity, age-related penetrance and other confounding factors. We therefore recommend that all individuals found to carry a pathogenic FLCN variant be enroled in lifelong surveillance for RCC

Common variation in EMSY and risk of breast and ovarian cancer: a case-control study using HapMap tagging SNPs.

BACKGROUND: EMSY could be involved in low-level susceptibility to breast and ovarian cancer. Gene amplification is seen in a proportion of breast and ovarian tumours and correlates with poor prognosis in breast cancer patients. Furthermore, the EMSY protein silences a transcription activation domain in BRCA2 exon 3. METHODS: We used a genetic association study design to determine if common genetic variation (frequency > or = 5%) in EMSY was associated with breast or ovarian cancer risk in the British population. Haplotype tagging single-nucleotide polymorphisms (htSNPs) were selected from the HapMap database and genotyped using Taqman in two large study sets of white British women (n [breast set] = 2343 cases and 2284 controls, n [ovarian set] = 864 cases and 864 controls). HapMap data might be insufficient to tag genetic variation in EMSY comprehensively. We therefore screened the gene promoter and coding sequences with denaturing high performance liquid chromatography in order to identify additional SNPs that are most likely to be functional. RESULTS: HapMap data on 22 SNPs show that 4 htSNPs tag 4 common haplotypes: rs2282611 (5'up t > g), rs4245443 (IVS7 g > a), rs2513511 (IVS16 a > g), rs2155220 (3'down c > t). We observed no association between any of the genotypes or associated haplotypes and breast or ovarian cancer risk. Seventeen out of the 18 remaining HapMap polymorphisms (94%) were well tagged by the 4 selected htSNPs (r2s > 0.8). Genotype frequencies for two further SNPs identified by screening and located near exon-intron boundaries, rs2508740 (IVS9 a > g) and rs11600501 (IVS10 c > t), were also similar in cases and controls. In order to simulate unidentified SNPs, we performed the leave-one-out cross-validation procedure on the HapMap data; over 95% of the common genetic variation was well represented by tagging polymorphisms. We are therefore likely to have tagged any common, functional variants present in our population. CONCLUSION: We found no association between common genetic variation in EMSY and risk of breast or ovarian cancer in two large study sets of white British women

A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus

Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus ..