Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa-such as genetics-can impact PSA. Here we present ...findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10
) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.
Purpose
Our objective was to describe differences in treatment patterns and survival between early-onset (< 50 years old) and late-onset colorectal cancer (CRC) patients in community-based health ...systems.
Methods
We used tumor registry and electronic health record data to identify and characterize patients diagnosed with adenocarcinoma of the colon or rectum from 2010 to 2014 at six US health systems in the patient outcomes to advance learning (PORTAL) network. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing the distribution of tumor characteristics and treatment patterns in early-onset versus late-onset CRC. Cox regression models were used to estimate adjusted hazard ratios (HRs) and CIs comparing survival between early- and late-onset CRC patients.
Results
There were 1,424 early-onset and 10,810 late-onset CRC cases in our analyses. Compared to late-onset CRC, early-onset CRC was significantly associated with advanced-stage disease, high-grade histology, signet ring histology, and rectal or left colon location. After adjusting for differences in tumor and patient characteristics, early-onset patients were more likely than late-onset patients to have > 12 lymph nodes examined (OR 1.60, CI 1.37–1.87), to receive systemic therapy (chemotherapy or immunotherapy) within 6 months of diagnosis (OR 2.84, CI 2.40–3.37), and to have a reduced risk of CRC-specific death (HR 0.66, CI 0.56–0.79).
Conclusions
Early-onset CRC is associated with aggressive tumor characteristics, distal location, and systemic therapy use. Despite some adverse risk factors, these patients tend to have better survival than older onset patients.
The fecal immunochemical test (FIT) is commonly used for colorectal cancer (CRC) screening. Despite demographic variations in stool hemoglobin concentrations, few data exist regarding optimal ...positivity thresholds by age and sex.
To identify programmatic (multitest) FIT performance characteristics and optimal FIT quantitative hemoglobin positivity thresholds in a large, population-based, screening program.
Retrospective cohort study.
Kaiser Permanente Northern and Southern California.
Adults aged 50 to 75 years who were eligible for screening and had baseline quantitative FIT results (2013 to 2014) and 2 years of follow-up. Nearly two thirds (411 241) had FIT screening in the previous 2 years.
FIT programmatic sensitivity for CRC and number of positive test results per cancer case detected, overall and by age and sex.
Of 640 859 persons who completed a baseline FIT and were followed for 2 years, 481 817 (75%) had at least 1 additional FIT and 1245 (0.19%) received a CRC diagnosis. Cancer detection (programmatic sensitivity) increased at lower positivity thresholds, from 822 in 1245 (66.0%) at 30 µg/g to 925 (74.3%) at 20 µg/g and 987 (79.3%) at 10 µg/g; the number of positive test results per cancer case detected increased from 43 at 30 µg/g to 52 at 20 µg/g and 85 at 10 µg/g. Reducing the positivity threshold from 20 to 15 µg/g would detect 3% more cancer cases and require 23% more colonoscopies. At the conventional FIT threshold of 20 µg/g, programmatic sensitivity decreased with increasing age (79.0%, 73.4%, and 68.9% for ages 50 to 59, 60 to 69, and 70 to 75 years, respectively; P = 0.009) and was higher in men than women (77.0% vs. 70.6%; P = 0.011).
Information on advanced adenoma was lacking.
Increased cancer detection at lower positivity thresholds is counterbalanced by substantial increases in positive tests. Tailored thresholds may provide screening benefits that are more equal among different demographic groups, depending on local resources.
National Cancer Institute.
Multilevel barriers to colonoscopy after a positive fecal blood test for colorectal cancer (CRC) are well-documented. A less-explored barrier to appropriate follow-up is repeat fecal testing after a ...positive test. We investigated this phenomenon using mixed methods.
This sequential mixed methods study included quantitative data from a large cohort of patients 50-89 years from four healthcare systems with a positive fecal test 2010-2018 and qualitative data from interviews with physicians and patients.
Logistic regression was used to evaluate whether repeat testing was associated with failure to complete subsequent colonoscopy and to identify factors associated with repeat testing. Interviews were coded and analyzed to explore reasons for repeat testing.
A total of 316,443 patients had a positive fecal test. Within 1 year, 76.3% received a colonoscopy without repeat fecal testing, 3% repeated testing and then received a colonoscopy, 4.4% repeated testing without colonoscopy, and 16.3% did nothing. Among repeat testers (7.4% of total cohort, N = 23,312), 59% did not receive a colonoscopy within 1 year. In adjusted models, those with an initial positive test followed by a negative second test were significantly less likely to receive colonoscopy than those with two successive positive tests (OR 0.37, 95% CI 0.35-0.40). Older age (65-75 vs. 50-64 years: OR 1.37, 95% CI 1.33-1.41) and higher comorbidity score (≥ 4 vs. 0: OR 1.75, 95% CI 1.67-1.83) were significantly associated with repeat testing compared to those who received colonoscopy without repeat tests. Qualitative interview data revealed reasons underlying repeat testing, including colonoscopy avoidance, bargaining, and disbelief of positive results.
Among patients in this cohort, 7.4% repeated fecal testing after an initial positive test. Of those, over half did not go on to receive a colonoscopy within 1 year. Efforts to improve CRC screening must address repeat fecal testing after a positive test as a barrier to completing colonoscopy.
Introduction Timely follow-up of abnormal tests is critical to the effectiveness of cancer screening, but may vary by screening test, healthcare system, and sociodemographic group. Methods Timely ...follow-up of abnormal mammogram and fecal occult blood testing or fecal immunochemical tests (FOBT/FIT) were compared by race/ethnicity using Population-Based Research Optimizing Screening through Personalized Regimens consortium data. Participants were women with an abnormal mammogram (aged 40–75 years) or FOBT/FIT (aged 50–75 years) in 2010–2012. Analyses were performed in 2015. Timely follow-up was defined as colonoscopy ≤3 months following positive FOBT/FIT; additional imaging or biopsy ≤3 months following Breast Imaging Reporting and Data System Category 0, 4, or 5 mammograms; or ≤9 months following Category 3 mammograms. Logistic regression was used to model receipt of timely follow-up adjusting for study site, age, year, insurance, and income. Results Among 166,602 mammograms, 10.7% were abnormal; among 566,781 FOBT/FITs, 4.3% were abnormal. Nearly 96% of patients with abnormal mammograms received timely follow-up versus 68% with abnormal FOBT/FIT. There was greater variability in receipt of follow-up across healthcare systems for positive FOBT/FIT than for abnormal mammograms. For mammography, black women were less likely than whites to receive timely follow-up (91.8% vs 96.0%, OR=0.71, 95% CI=0.51, 0.97). For FOBT/FIT, Hispanics were more likely than whites to receive timely follow-up than whites (70.0% vs 67.6%, OR=1.12, 95% CI=1.04, 1.21). Conclusions Timely follow-up among women was more likely for abnormal mammograms than FOBT/FITs, with small variations in follow-up rates by race/ethnicity and larger variation across healthcare systems.
Endoscopist adenoma detection rates (ADRs) vary widely and are associated with patients’ risk of postcolonoscopy colorectal cancers (PCCRCs). However, few scalable physician-directed interventions ...demonstrably both improve ADR and reduce PCCRC risk.
Among patients undergoing colonoscopy, we evaluated the influence of a scalable online training on individual-level ADRs and PCCRC risk. The intervention was a 30-minute, interactive, online training, developed using behavior change theory, to address factors that potentially impede detection of adenomas. Analyses included interrupted time series analyses for pretraining versus posttraining individual-physician ADR changes (adjusted for temporal trends) and Cox regression for associations between ADR changes and patients’ PCCRC risk.
Across 21 endoscopy centers and all 86 eligible endoscopists, ADRs increased immediately by an absolute 3.13% (95% confidence interval CI, 1.31-4.94) in the 3-month quarter after training compared with .58% per quarter (95% CI, .40-.77) and 0.33% per quarter (95% CI, .16-.49) in the 3-year pretraining and posttraining periods, respectively. Posttraining ADR increases were higher among endoscopists with pretraining ADRs below the median. Among 146,786 posttraining colonoscopies (all indications), each 1% absolute increase in screening ADR posttraining was associated with a 4% decrease in their patients’ PCCRC risk (hazard ratio, .96; 95% CI, .93-.99). An ADR increase of ≥10% versus <1% was associated with a 55% reduced risk of PCCRC (hazard ratio, .45; 95% CI, .24-.82).
A scalable, online behavior change training intervention focused on modifiable factors was associated with significant and sustained improvements in ADR, particularly among endoscopists with lower ADRs. These ADR changes were associated with substantial reductions in their patients’ risk of PCCRC.
Postcolonoscopy colorectal cancers (PCCRCs) are defined as those detected ≤10 years after an index colonoscopy negative for cancer, but modifiable risk factors are not well established in large, ...community-based populations.
We evaluated risk factors from the index colonoscopy for PCCRCs diagnosed 1 to 10 years after an index colonoscopy using a case-control design. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for potential confounders.
A proximal polyp ≥10 mm (OR, 8.18; 95% CI, 4.59-14.60), distal polyp ≥10 mm (OR, 3.30; 95% CI, 1.65-6.58), adenoma with (OR, 3.23; 95% CI, 1.83-5.68) and without advanced histology (OR, 1.87; 95% CI, 1.37-2.55), and an incomplete colonoscopy (OR, 5.52; 95% CI, 2.98-10.21) were associated with PCCRC. Risk factors for early versus late cancers (12-36 months vs >36 months to 10 years after examination) included incomplete polyp excision in the colonic segment of the subsequent cancer (OR, 4.76; 95% CI, 2.35-9.65); failure to examine the segment (OR, 2.42; 95% CI, 1.27-4.60); and a polyp ≥10 mm in the segment (OR, 2.38; 95% CI, 1.53-3.70). A total of 559 of 1206 patients with PCCRC (46.4%) had 1 or more risk factors that were significant for PCCRC (incomplete examination, large polyp, or any adenoma).
In a large community-based study with comprehensive capture of PCCRCs, almost half of PCCRCs had potentially modifiable factors related to polyp surveillance or removal and examination completeness. These represent potential high-yield targets to further increase the effectiveness of colorectal cancer screening.
To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an ...integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (
), as well as a novel candidate gene (
), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at
and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th-60th percentile OR = 2.62,
= 2.55 × 10
). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. SIGNIFICANCE: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.
.
A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and ...7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10(-19) (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10(-23)) and SLC22A3 (P = 3.2 × 10(-52)). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10(-13); OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004).
Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations.
AbstractTo lower risk from cardiovascular disease (CVD), national guidelines recommend lifestyle changes followed by use of lipid-lowering medications when appropriate. Previous studies have ...questioned whether individuals taking these medications are less likely to modify their dietary intake and physical activity, resulting in increased body mass index (BMI). We assessed BMI and CVD clinical risk factors over time between lipid-lowering medication users and nonusers in a diverse cohort of middle-aged and older men. The cohort consisted of 63,357 men who enrolled in the California Men's Health Study between 2002 and 2003 and were not taking lipid-lowering medications at baseline. Lipid-lowering medication use was determined over twelve years of follow-up. BMI and other CVD risk factors were assessed with longitudinal linear mixed effect models adjusting for possible confounders. Overall, lipid-lowering medication users had higher BMI than nonusers ( p < .0001); however, there was a decrease over time for both groups ( p < .0001). Total cholesterol, LDL-C, and triglycerides decreased for users and nonusers ( p < .0001). While HDL-C was higher for nonusers ( p < .05), over time this measure increased in both groups (p < .0001). We found no evidence of increases in BMI after initiation of lipid-lowering medication in this cohort. Instead, BMI decreased and several cholesterol-related CVD risk factors improved for lipid-lowering medication users and nonusers. This suggests that men placed on lipid-lowering medications do not view them as a panacea for their increased risk of cardiovascular disease. Instead, they appear to perceive them as one component of a multi-pronged strategy including lifestyle and nutrition as suggested by current guidelines.
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