Validation of the cell cycle progression score to differentiate indolent from aggressive prostate cancer in men diagnosed through transurethral resection of the prostate biopsy.

BACKGROUND: Validation of biomarker-based prognostic models to improve risk stratification in men with localized prostate cancer (PrCa) remains a clinical need. It has previously been shown that the cell cycle progression (CCP) test provides significant, independent prognostic information for men who were incidentally diagnosed with PrCa after transurethral resection of the prostate (TURP) and were conservatively managed. AIM: The results have been extended in a newly analyzed retrospective cohort of UK men diagnosed through TURP biopsy (TURP1B; N = 305). METHODS AND RESULTS: The CCP score was derived from TURP biopsy tissue and combined with a modified UCSF Cancer of the Prostate Risk Assessment score (CAPRA) to generate the clinical cell-cycle risk score (CCR). The primary endpoint was PrCa-specific mortality (PSM). Hazard ratios (HR) were calculated for a one-unit change in score. Median follow-up was 9.6 (IQR: 5.4, 14.1) years, and 67 (22%) men died from PrCa within 10 years of diagnosis. The median CCP score was 1.1 (IQR: 0.6, 1.7). In univariate analyses, CCR proved a significant prognosticator of PSM (HR per unit score change = 2.28; 95% CI: 1.89, 2.74; P = 1.0 × 10-19 ). In multivariate analyses, CCR remained a significant prognosticator of PSM after adjusting for CAPRA (HR per unit score change = 4.36; 95% CI: 2.65, 7.16; P = 1.3 × 10-8 ), indicating that its molecular component, CCP, provides significant, independent prognostic information. CONCLUSION: These findings validate a combined clinicopathologic and molecular prognostic model for conservatively managed men who are diagnosed through TURP, supporting the use of CCR to inform clinical management.

Lifestyle behaviours and health measures of women at increased risk of breast cancer taking chemoprevention.

Women at increased breast cancer (BC) risk are eligible for chemoprevention. Healthy lifestyles are potentially important for these women to improve efficacy and minimise side effects of chemoprevention and reduce the risk of BC and other lifestyle-related conditions. We investigated whether women taking chemoprevention adhere to healthy lifestyle recommendations, how their lifestyle risk factors and health measures compare to women in the general population, and whether these change whilst taking chemoprevention. Lifestyle risk factors and health measures in 136 premenopausal women taking tamoxifen for prevention of BC (Tam-Prev study) were compared to both national recommendations and an age-matched female population from the Health Survey for England 2012. The Tam-Prev population had high rates of overweight and obesity (59.2%) and low adherence to physical activity recommendations (30.6%) which were comparable to the general population (55.2 and 35.1%, respectively). Fewer Tam-Prev participants were current smokers (10.5 vs. 18.2%, P = 0.032), but more exceeded alcohol recommendations (45.0 vs. 18.7%, P < 0.001). Tam-Prev participants had suboptimal diets; proportions not meeting fibre, saturated fat and non-milk extrinsic sugar recommendations were 87.8, 64.9 and 21.4% respectively. Many Tam-Prev participants had markers of cardiovascular disease risk and the metabolic syndrome. Health behaviours did not change during the first year on tamoxifen. Women taking chemoprevention had a high prevalence of unhealthy lifestyle behaviours and health measures, similar to an age-matched English cohort. Improving these measures in women at increased BC risk could significantly decrease rates of BC and other noncommunicable diseases.

RAZOR: A Phase II Open Randomized Trial of Screening Plus Goserelin and Raloxifene Versus Screening Alone in Premenopausal Women at Increased Risk of Breast Cancer.

Background: Ovarian suppression in premenopausal women is known to reduce breast cancer risk. This study aimed to assess uptake and compliance with ovarian suppression using the luteinizing hormone releasing hormone (LHRH) analogue, goserelin, with add-back raloxifene, as a potential regimen for breast cancer prevention.Methods: Women at ≥30% lifetime risk breast cancer were approached and randomized to mammographic screening alone (C-Control) or screening in addition to monthly subcutaneous injections of 3.6 mg goserelin and continuous 60 mg raloxifene daily orally (T-Treated) for 2 years. The primary endpoint was therapy adherence. Secondary endpoints were toxicity/quality of life, change in bone density, and mammographic density.Results: A total of 75/950 (7.9%) women approached agreed to randomization. In the T-arm, 20 of 38 (52%) of women completed the 2-year period of study compared with the C-arm (27/37, 73.0%). Dropouts were related to toxicity but also the wish to have established risk-reducing procedures and proven chemoprevention. As relatively few women completed the study, data are limited, but those in the T-arm reported significant increases in toxicity and sexual problems, no change in anxiety, and less cancer worry. Lumbar spine bone density declined by 7.0% and visually assessed mammographic density by 4.7% over the 2-year treatment period.Conclusions: Uptake is somewhat lower than comparable studies with tamoxifen for prevention with higher dropout rates. Raloxifene may preserve bone density, but reduction in mammographic density reversed after treatment was completed.Impact: This study indicates that breast cancer risk reduction may be possible using LHRH agonists, but reducing toxicity and preventing bone changes would make this a more attractive option. Cancer Epidemiol Biomarkers Prev; 27(1); 58-66. ©2017 AACR.

Quantitative DNA methylation and recurrence of breast cancer: a study of 30 candidate genes.

BACKGROUND: The need for new prognostic factors in breast cancer is ever increasing as breast cancer management evolves. Aberrant DNA methylation plays a pivotal role in cancer development and progression; DNA methylation-based biomarkers may provide independent prognostic information. We used pyrosequencing to investigate the prognostic potential of quantitative DNA methylation of a large set of candidate genes in a Korean single-institution series of operable breast cancer. METHODS: Absolute DNA methylation in 20 candidate genes from an initial set of 30 genes was measured by pyrosequencing of bisulfite converted DNA in 121 fresh frozen breast cancer cases. Survival analyses used continuous and categorized (quintile-based) gene methylation data with time to recurrence (TTR) as an endpoint. Prognostic abilities of gene-only and risk-score models were explored. RESULTS: Median follow-up was 5.1 years; 25 recurrences (21%) were observed. Nodal status, methylation of TWIST1, SLIT2 (both as continuous and categorized variables) and APC, HLA-A, NKX2-5, SERPINB5, SFN (as categorized variables) were significantly prognostic; grade showed a prognostic trend. A multivariate model containing nodal status, grade and TWIST1 was a best fit (p< 0.001) in stepwise regression; risk-score based on this model separated patients into 3 distinct risk-groups (p< 0.001). A gene-only model based on TWIST1 and SFN also classified patients into distinct risk-groups (p=0.009). CONCLUSIONS: This study shows that accurate quantitative measurement of DNA methylation by pyrosequencing identifies a small set of genes with independent prognostic potential in breast cancer. These genes complement the current clinico-pathological prognostic factors and appear to be potential biomarkers that warrant further validation.