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BackgroundMaintaining men on active surveillance for prostate cancer can be challenging. Although most men who eventually undergo treatment have experienced clinical progression, a smaller subset elects treatment in the absence of disease reclassification. This study sought to understand factors associated with treatment in a large, contemporary, prospective cohort.MethodsThis study identified 1789 men in the Canary Prostate Cancer Active Surveillance Study cohort enrolled as of 2020 with a median follow-up of 5.6years. Clinical and demographic data as well as information on patient-reported quality of life and urinary symptoms were used in multivariable Cox proportional hazards regression models to identify factors associated with the time to treatment RESULTS: Within 4 years of their diagnosis, 33% of men (95% confidence interval [CI], 30%-35%) underwent treatment, and 10% (95% CI, 9%-12%) were treated in the absence of reclassification. The most significant factor associated with any treatment was an increasing Gleason grade group (adjusted hazard ratio [aHR], 14.5; 95% CI, 11.7-17.9). Urinary quality-of-life scores were associated with treatment without reclassification (aHR comparing "mostly dissatisfied/terrible" with "pleased/mixed," 2.65; 95% CI, 1.54-4.59). In a subset analysis (n=692), married men, compared with single men, were more likely to undergo treatment in the absence of reclassification (aHR, 2.63; 95% CI, 1.04-6.66).ConclusionsA substantial number of men with prostate cancer undergo treatment in the absence of clinical changes in their cancers, and quality-of-life changes and marital status may be important factors in these decisions.Lay summaryThis analysis of men on active surveillance for prostate cancer shows that approximately 1 in 10 men will decide to be treated within 4years of their diagnosis even if their cancer is stable. These choices may be related in part to quality-or-life or spousal concerns.

PurposeIn a large, prospective, multi-institutional active surveillance cohort we evaluated whether African American men are at higher risk for reclassification.Materials and methodsThe Canary PASS (Prostate Active Surveillance Study) is a protocol driven, active surveillance cohort with a prespecified prostate specific antigen and surveillance biopsy regimen. Men included in this study had Gleason Grade Group 1 or 2 disease at diagnosis and fewer than 5 years between diagnosis and enrollment, and had undergone 1 or more surveillance biopsies. The reclassification risk, defined as an increase in the Gleason score on subsequent biopsy, was compared between African American and Caucasian American men using Cox proportional hazards models. In the subset of men who underwent delayed prostatectomy the rate of adverse pathology findings, defined as pT3a or greater disease, or Gleason Grade Group 3 or greater, was compared in African American and Caucasian American men.ResultsOf the 1,315 men 89 (7%) were African American and 1,226 (93%) were Caucasian American. There was no difference in the treatment rate in African American and Caucasian American men. In multivariate models African American race was not associated with the risk of reclassification (HR 1.16, 95% CI 0.78-1.72). Of the 441 men who underwent prostatectomy after a period of active surveillance the rate of adverse pathology was similar in those who were African American and Caucasian American (46% vs 47%, p=0.99).ConclusionsOf men on active surveillance who followed a standardized protocol of regular prostate specific antigen testing and biopsy those who were African American were not at increased risk for pathological reclassification while on active surveillance, or for adverse pathology findings at prostatectomy. Active surveillance appears to be an appropriate management strategy for African American men with favorable risk prostate cancer.

BackgroundFor men on active surveillance for prostate cancer, biomarkers may improve prediction of reclassification to higher grade or volume cancer. This study examined the association of urinary PCA3 and TMPRSS2:ERG (T2:ERG) with biopsy-based reclassification.MethodsUrine was collected at baseline, 6, 12, and 24 months in the multi-institutional Canary Prostate Active Surveillance Study (PASS), and PCA3 and T2:ERG levels were quantitated. Reclassification was an increase in Gleason score or ratio of biopsy cores with cancer to ≥34%. The association of biomarker scores, adjusted for common clinical variables, with short- and long-term reclassification was evaluated. Discriminatory capacity of models with clinical variables alone or with biomarkers was assessed using receiver operating characteristic (ROC) curves and decision curve analysis (DCA).ResultsSeven hundred and eighty-two men contributed 2069 urine specimens. After adjusting for PSA, prostate size, and ratio of biopsy cores with cancer, PCA3 but not T2:ERG was associated with short-term reclassification at the first surveillance biopsy (OR = 1.3; 95% CI 1.0-1.7, p = 0.02). The addition of PCA3 to a model with clinical variables improved area under the curve from 0.743 to 0.753 and increased net benefit minimally. After adjusting for clinical variables, neither marker nor marker kinetics was associated with time to reclassification in subsequent biopsies.ConclusionsPCA3 but not T2:ERG was associated with cancer reclassification in the first surveillance biopsy but has negligible improvement over clinical variables alone in ROC or DCA analyses. Neither marker was associated with reclassification in subsequent biopsies.

BackgroundDiagnosis of Gleason 6 prostate cancer can leave uncertainty about the presence of undetected aggressive disease.ObjectiveTo evaluate the utility of a four kallikrein (4K) panel in predicting the presence of high-grade cancer in men on active surveillance.Design, setting, and participantsPlasma collected before the first and subsequent surveillance biopsies was assessed for 718 men prospectively enrolled in the multi-institutional Canary PASS trial. Biopsy data were split 2:1 into training and test sets. We developed statistical models that included clinical information and either the 4Kpanel or serum prostate-specific antigen (PSA).Outcome measurements and statistical analysisThe endpoint was reclassification to Gleason ≥7. We used receiver operating characteristic (ROC) curve analyses and area under the curve (AUC) to assess discriminatory capacity, and decision curve analysis (DCA) to report clinical net benefit.Results and limitationsSignificant predictors for reclassification were 4Kpanel (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31-1.81) or PSA (OR 2.11, 95% CI 1.53-2.91), ≥20% cores positive (OR 2.10, 95% CI 1.33-3.32), two or more prior negative biopsies (OR 0.19, 95% CI 0.04-0.85), prostate volume (OR 0.47, 95% CI 0.31-0.70), and body mass index (OR 1.09, 95% CI 1.04-1.14). ROC curve analysis comparing 4K and base models indicated that the 4Kpanel improved accuracy for predicting reclassification (AUC 0.78 vs 0.74) at the first surveillance biopsy. Both models performed comparably for prediction of reclassification at subsequent biopsies (AUC 0.75 vs 0.76). In DCA, both models showed higher net benefit compared to biopsy-all and biopsy-none strategies. Limitations include the single cohort nature of the study and the small numbers; results should be validated in another cohort before clinical use.ConclusionsThe 4Kpanel provided incremental value over routine clinical information in predicting high-grade cancer in the first biopsy after diagnosis. The 4Kpanel did not add predictive value to the base model at subsequent surveillance biopsies.Patient summaryActive surveillance is a management strategy for many low-grade prostate cancers. Repeat biopsies monitor for previously undetected high-grade cancer. We show that a model with clinical variables, including a panel of four kallikreins, indicates the presence of high-grade cancer before a biopsy is performed.

PurposeDuring active surveillance for localized prostate cancer, the timing of the first surveillance biopsy varies. We analyzed the Canary PASS (Prostate Cancer Active Surveillance Study) to determine biopsy timing influence on rates of prostate cancer adverse reclassification at the first active surveillance biopsy.Materials and methodsOf 1,085 participants in PASS, 421 had fewer than 34% of cores involved with cancer and Gleason sum 6 or less, and thereafter underwent on-study active surveillance biopsy. Reclassification was defined as an increase in Gleason sum and/or 34% or more of cores with prostate cancer. First active surveillance biopsy reclassification rates were categorized as less than 8, 8 to 13 and greater than 13 months after diagnosis. Multivariable logistic regression determined association between reclassification and first biopsy timing.ResultsOf 421 men, 89 (21.1%) experienced reclassification at the first active surveillance biopsy. Median time from prostate cancer diagnosis to first active surveillance biopsy was 11 months (IQR 7.8-13.8). Reclassification rates at less than 8, 8 to 13 and greater than 13 months were 24%, 19% and 22% (p = 0.65). On multivariable analysis, compared to men biopsied at less than 8 months the OR of reclassification at 8 to 13 and greater than 13 months were 0.88 (95% CI 0.5,1.6) and 0.95 (95% CI 0.5,1.9), respectively. Prostate specific antigen density 0.15 or greater (referent less than 0.15, OR 1.9, 95% CI 1.1, 4.1) and body mass index 35 kg/m2 or greater (referent less than 25 kg/m2, OR 2.4, 95% CI 1.1,5.7) were associated with increased odds of reclassification.ConclusionsTiming of the first active surveillance biopsy was not associated with increased adverse reclassification but prostate specific antigen density and body mass index were. In low risk patients on active surveillance, it may be reasonable to perform the first active surveillance biopsy at a later time, reducing the overall cost and morbidity of active surveillance.

PurposeActive surveillance represents a strategy to address the overtreatment of prostate cancer, yet uncertainty regarding individual patient outcomes remains a concern. We evaluated outcomes in a prospective multicenter study of active surveillance.Materials and methodsWe studied 905 men in the prospective Canary PASS enrolled between 2008 and 2013. We collected clinical data at study entry and at prespecified intervals, and determined associations with adverse reclassification, defined as increased Gleason grade or greater cancer volume on followup biopsy. We also evaluated the relationships of clinical parameters with pathology findings in participants who underwent surgery after a period of active surveillance.ResultsAt a median followup of 28 months 24% of participants experienced adverse reclassification, of whom 53% underwent treatment while 31% continued on active surveillance. Overall 19% of participants received treatment, 68% withadverse reclassification, while 32% opted for treatment without disease reclassification. In multivariate Cox proportional hazards modeling the percent of biopsy cores with cancer, body mass index and prostate specific antigen density were associated with adverse reclassification (p=0.01, 0.04, 0.04, respectively). Of103participants subsequently treated with radical prostatectomy 34% had adverse pathology, defined as primary pattern 4-5 or nonorgan confined disease, including 2 with positive lymph nodes, with no significant relationship between risk category at diagnosis and findings at surgery (p=0.76).ConclusionsMost men remain on active surveillance at 5 years without adverse reclassification or adverse pathology at surgery. However, clinical factors had only a modest association with disease reclassification, supporting the need for approaches that improve the prediction of this outcome.

BackgroundInvestigations of folate-mediated one-carbon metabolism (FOCM) genes and gene-nutrient interactions with respect to colorectal cancer (CRC) risk are limited to candidate polymorphisms and dietary folate. This study comprehensively investigated associations between genetic variants in FOCM and CRC risk and whether the FOCM nutrient status modified these associations.MethodsTwo hundred eighty-eight candidate and tagging single-nucleotide polymorphisms (SNPs) in 30 FOCM genes were genotyped for 821 incident CRC case-control matched pairs in the Women's Health Initiative Observational Study cohort. FOCM biomarkers (red blood cell [RBC] folate, plasma folate, pyridoxal-5'-phosphate [PLP], vitamin B12, and homocysteine) and self-reported alcohol consumption were measured at the baseline. Conditional logistic regression was implemented; effect modification was examined on the basis of known enzyme-nutrient relations.ResultsStatistically significant associations were observed between CRC risk and functionally defined candidate SNPs of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1; K134R), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR; P450R), and PR domain containing 2 with ZNF domain (PRDM2; S450N) and a literature candidate SNP of thymidylate synthase (TYMS; g.676789A>T; nominal P

The relationship between folate and colorectal cancer (CRC) risk is unclear. We investigated the association of two biomarkers of folate status, plasma folate and red blood cell (RBC) folate, with CRC risk using a nested case-control design in the Women's Health Initiative Observational Study. Postmenopausal women (n = 93,676) aged 50-79 years were enrolled in the Women's Health Initiative Observational Study (1993-1998). A fasting blood draw and extensive health, dietary and lifestyle data were collected upon enrollment. Through 2008, 988 incident CRC cases were reported and confirmed with medical records adjudication. Cases and controls were matched on age (± 3 years), enrollment date (± 1 year), race/ethnicity, blood draw date (± 6 months) and hysterectomy status. Plasma and RBC folate were determined by radio assay. Folate biomarker values were divided into quartiles, and conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CI) for the associations of folate with total CRC, by tumor site and by stage at diagnosis. Additional analyses examined whether risks varied across time periods corresponding to the United States folic acid fortification policy: prefortification (1994-1995), perifortification (1996-1997) and postfortification (1998). ORs for overall CRC risk comparing Q4 vs. Q1 were 0.91 (95% CI 0.67-1.24) and 0.91 (95% CI 0.67-1.23) for RBC and plasma folate, respectively. There were no changes in risk attributable to food supply fortification. These results do not support an overall association of folate with CRC risk and suggest that folic acid fortification of the US food supply did not alter the associations in these postmenopausal women.

Folate-mediated one-carbon metabolism is essential for DNA synthesis, repair, and methylation. Perturbations in one-carbon metabolism have been implicated in increased risk of some cancers and may also affect inflammatory processes. We investigated these interrelated pathways to understand their relation. The objective was to explore associations between inflammation and biomarkers of nutritional status and one-carbon metabolism. In a cross-sectional study in 1976 women selected from the Women's Health Initiative Observational Study, plasma vitamin B-6 [pyridoxal-5'-phosphate (PLP)], plasma vitamin B-12, plasma folate, and RBC folate were measured as nutritional biomarkers; serum C-reactive protein (CRP) and serum amyloid A (SAA) were measured as biomarkers of inflammation; and homocysteine and cysteine were measured as integrated biomarkers of one-carbon metabolism. Student's t, chi-square, and Spearman rank correlations, along with multiple linear regressions, were used to explore relations between biomarkers; additionally, we tested stratification by folic acid fortification period and multivitamin use. With the use of univariate analysis, plasma PLP was the only nutritional biomarker that was modestly significantly correlated with serum CRP and SAA (ρ = -0.22 and -0.12, respectively; P < 0.0001). Homocysteine (μmol/L) showed significant inverse correlations with all nutritional biomarkers (ranging from ρ = -0.30 to ρ = -0.46; all P < 0.0001). With the use of multiple linear regression, plasma PLP, RBC folate, homocysteine, and cysteine were identified as independent predictors of CRP; and PLP, vitamin B-12, RBC folate, and homocysteine were identified as predictors of SAA. When stratified by folic acid fortification period, nutrition-homocysteine correlations were generally weaker in the postfortification period, whereas associations between plasma PLP and serum CRP increased. Biomarkers of inflammation are associated with PLP, RBC folate, and homocysteine in women. The connection between the pathways needs to be further investigated and causality established. The trial is registered at clinicaltrials.gov as NCT00000611.

Few detailed data are available on the wide range of determinants of vitamin D status among postmenopausal women, and it is also unclear whether there may be undiscovered determinants. The objective of this study was to comprehensively evaluate determinants of serum 25-hydroxyvitamin D [25(OH)D] concentrations in a large cohort of postmenopausal women. Data from a subset of the Women's Health Initiative Observational Study were analyzed (50-79 y; n = 3345). Information on diet, lifestyle behaviors, secondhand smoke, use of dietary supplements and medication, chronic diseases, and anthropometry was collected at baseline (1993-1998) and on sun exposure at year 4 follow-up. Linear regression was performed to estimate regression coefficients (β). Significant determinants were total vitamin D intake (food plus supplements per 100 IU/d, β = 2.08), years of supplemental vitamin D use (β = 0.15), total fat intake (grams per day, β = -0.03), smoking status (β = -2.64, current vs. never), regional solar irradiance (β = 6.26, 475-500 vs. 300-325 Langleys), daylight time spent outdoors in summer (β = 5.15, >2 h vs.

BackgroundPrior research suggests that vitamin D protects against lung cancer only among certain subgroups.ObjectivesWe investigated whether vitamin D intake was associated with lung cancer and explored whether vitamin A intake modified the association.DesignProspective cohort data from 128,779 postmenopausal women, including 1771 incident lung cancers in the Women's Health Initiative (Clinical Trials and Observational Study) 1993-2010, were analyzed. Twelve percent of women received active intervention (1 g Ca + 400 IU vitamin D3/d) in the Calcium/Vitamin D Trial. Baseline total intake included both dietary intake (from food-frequency questionnaires) and supplement intake (from bottle labels). HRs were estimated by Cox proportional hazard models.ResultsNo significant association was observed overall. Among never smokers, a total vitamin D intake ≥400 IU/d was significantly associated with lower risks of lung cancer (HR: 0.37; 95% CI: 0.18, 0.77 for ≥800 compared with

Purpose: Reducing colorectal cancer incidence and mortality through early detection would improve efficacy if targeted. We developed a colorectal cancer risk prediction model incorporating personal, family, genetic, and environmental risk factors to enhance prevention. Methods: A familial risk profile (FRP) was calculated to summarize individuals' risk based on detailed cancer family history (FH), family structure, probabilities of mutation in major colorectal cancer susceptibility genes, and a polygenic component. We developed risk models, including individuals' FRP or binary colorectal cancer FH, and colorectal cancer risk factors collected at enrollment using population-based colorectal cancer cases (N = 4,445) and controls (N = 3,967) recruited by the Colon Cancer Family Registry Cohort (CCFRC). Model validation used CCFRC follow-up data for population-based (N = 12,052) and clinic-based (N = 5,584) relatives with no cancer history at recruitment to assess model calibration [expected/observed rate ratio (E/O)] and discrimination [area under the receiver-operating-characteristic curve (AUC)]. Results: The E/O [95% confidence interval (CI)] for FRP models for population-based relatives were 1.04 (0.74–1.45) for men and 0.86 (0.64–1.20) for women, and for clinic-based relatives were 1.15 (0.87–1.58) for men and 1.04 (0.76–1.45) for women. The age-adjusted AUCs (95% CI) for FRP models for population-based relatives were 0.69 (0.60–0.78) for men and 0.70 (0.62–0.77) for women, and for clinic-based relatives were 0.77 (0.69–0.84) for men and 0.68 (0.60–0.76) for women. The incremental values of AUC for FRP over FH models for population-based relatives were 0.08 (0.01–0.15) for men and 0.10 (0.04–0.16) for women, and for clinic-based relatives were 0.11 (0.05–0.17) for men and 0.11 (0.06–0.17) for women. Conclusions: Both models calibrated well. The FRP-based model provided better risk stratification and risk discrimination than the FH-based model. Impact: Our findings suggest detailed FH may be useful for targeted risk-based screening and clinical management.

Author(s): Cheng, Ting-Yuan David; Lacroix, Andrea Z; Beresford, Shirley AA; Goodman, Gary E; Thornquist, Mark D; Zheng, Yingye; Chlebowski, Rowan T; Ho, Gloria YF; Neuhouser, Marian L | Abstract: BackgroundPrior research suggests that vitamin D protects against lung cancer only among certain subgroups.ObjectivesWe investigated whether vitamin D intake was associated with lung cancer and explored whether vitamin A intake modified the association.DesignProspective cohort data from 128,779 postmenopausal women, including 1771 incident lung cancers in the Women's Health Initiative (Clinical Trials and Observational Study) 1993-2010, were analyzed. Twelve percent of women received active intervention (1 g Ca + 400 IU vitamin D3/d) in the Calcium/Vitamin D Trial. Baseline total intake included both dietary intake (from food-frequency questionnaires) and supplement intake (from bottle labels). HRs were estimated by Cox proportional hazard models.ResultsNo significant association was observed overall. Among never smokers, a total vitamin D intake ≥400 IU/d was significantly associated with lower risks of lung cancer (HR: 0.37; 95% CI: 0.18, 0.77 for ≥800 compared with l100 IU/d; P-trend = 0.01). No significant effect modification of total vitamin A intake on the association between total vitamin D intake and lung cancer was found. However, the Calcium/Vitamin D Trial active intervention was significantly associated with a lower lung cancer risk only among women with a vitamin A intake l1000 μg/d retinol activity equivalents (HR: 0.69; 95% CI: 0.50, 0.96; P-interaction = 0.09).ConclusionsVitamin D intake was associated with a lower lung cancer risk in never-smoking, postmenopausal women. Lower vitamin A intake may be important for a beneficial association of 1 g Ca + 400 IU vitamin D3 supplementation with lung cancer. This trial was registered at clinicaltrials.gov as NCT00000611.