Cancer prevention research (Philadelphia, Pa.)最新文献

People with human immunodeficiency virus (HIV; PWH) smoke cigarettes at triple the rate of the general population in the United States. Efforts to increase quit rates in this group have met with limited success. The nicotine metabolite ratio (NMR) has shown promise as a phenotypic marker that may be useful in selecting the most appropriate cessation treatments for people who smoke cigarettes. We completed a randomized controlled trial of individual intensive counseling and/or varenicline treatment for PWH in the Baltimore area who smoke cigarettes, and we measured serum 3' hydroxycotinine and cotinine at baseline and calculated the ratio of these two values, i.e., the NMR, for each participant. Herein, we present summary statistics and measures of association, or lack thereof, of NMR values with a variety of behavioral parameters and clinical outcomes related to tobacco use and tobacco treatment. The NMR was calculated for 155 PWH who were currently using tobacco cigarettes. The mean age was 52.9 years, 62.3% male, 91.0% Black, and they smoked a mean of 10.6 cigarettes/day. The mean NMR was 0.43, similar to that reported from other PWH cohorts. We did not find any significant correlation between NMR and cigarettes/day, nicotine dependence, temptation to smoke, or nicotine withdrawal symptoms. We did not find that lower NMR was predictive of successful cessation, nor was it associated with varenicline intolerance in those who received varenicline. Prevention Relevance: People with HIV suffer disproportionately from lung, head and neck, and other tobacco-related cancers as a consequence of high smoking rates. There is an urgent need to mitigate this harm, and the use of the NMR to personalize tobacco treatment is an area of active interest.

In the cancer early detection field, logistic regression (LR) is a frequently used approach to establish a combination rule that differentiates cancer from noncancer. However, the application of LR relies on a maximum likelihood approach, which may not yield optimal combination rules for maximizing sensitivity at a clinically desirable specificity and vice versa. In this article, we have developed an improved regression framework, sensitivity maximization at a given specificity (SMAGS), for binary classification that finds the linear decision rule, yielding the maximum sensitivity for a given specificity or the maximum specificity for a given sensitivity. We additionally expand the framework for feature selection that satisfies sensitivity and specificity maximizations. We compare our SMAGS method with normal LR using two synthetic datasets and reported data for colorectal cancer from the 2018 CancerSEEK study. In the colorectal cancer CancerSEEK dataset, we report 14% improvement in sensitivity at 98.5% specificity (0.31 vs. 0.57; P value <0.05). The SMAGS method provides an alternative to LR for modeling combination rules for biomarkers and early detection applications. Prevention Relevance: This study introduces a new machine learning methodology that identifies the optimal features and combination rules to maximize sensitivity at a fixed specificity, making it applicable to many existing biomarker prevention studies.

Body mass index (BMI) may misclassify obesity-related cancer (ORC) risk, as metabolic dysfunction can occur across BMI levels. We hypothesized that metabolic dysfunction at any BMI increases ORC risk compared with normal BMI without metabolic dysfunction. Postmenopausal women (n = 20,593) in the Women's Health Initiative with baseline metabolic dysfunction biomarkers [blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, fasting glucose, homeostatic model assessment for insulin resistance (HOMA-IR), and high-sensitive C-reactive protein (hs-CRP)] were included. Metabolic phenotype (metabolically healthy normal weight, metabolically unhealthy normal weight, metabolically healthy overweight/obese, and metabolically unhealthy overweight/obese) was classified using four definitions of metabolic dysfunction: (i) Wildman criteria, (ii) National Cholesterol Education Program Adult Treatment Panel III, (iii) HOMA-IR, and (iv) hs-CRP. Multivariable Cox proportional hazards regression, with death as a competing risk, was used to assess the association between metabolic phenotype and ORC risk. After a median (IQR) follow-up duration of 21 (IQR, 15-22) years, 2,367 women developed an ORC. The risk of any ORC was elevated among metabolically unhealthy normal weight (HR = 1.12, 95% CI, 0.90-1.39), metabolically healthy overweight/obese (HR = 1.15, 95% CI, 1.00-1.32), and metabolically unhealthy overweight/obese (HR = 1.35, 95% CI, 1.18-1.54) individuals compared with metabolically healthy normal weight individuals using Wildman criteria. The results were similar using Adult Treatment Panel III criteria, hs-CRP alone, or HOMA-IR alone to define metabolic phenotype. Individuals with overweight or obesity with or without metabolic dysfunction were at higher risk of ORCs compared with metabolically healthy normal weight individuals. The magnitude of risk was greater among those with metabolic dysfunction, although the CIs of each category overlapped. Prevention Relevance: Recognizing metabolic dysfunction as a significant risk factor for ORCs underscores the importance of preventive measures targeting metabolic health improvement across all BMI categories.

The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) has successfully implemented risk-adapted breast cancer surveillance for women at high breast cancer risk in Germany. Women with a family history of breast and ovarian cancer but without pathogenic germline variants in recognized breast cancer risk genes are recommended annual breast imaging if their predicted 10-year breast cancer risk is 5% or higher, using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) breast cancer risk model, as outlined in the current GC-HBOC guideline. However, women who initially do not meet this risk threshold may do so later, even if there is no new cancer in their family. To determine when this threshold is crossed, one could annually repeat BOADICEA calculations using an aging pedigree: the "prediction by aging pedigree" (AP) approach. Alternatively, we propose a simplified and more practical "'conditional probability" (CP) approach, which calculates future risks based on the initial BOADICEA assessment. Using data from 6,661 women registered with GC-HBOC, both methods were compared. Initially, 74% of women, ages 30 to 48 years, had a 10-year breast cancer risk below 5%, but 53% exceeded this threshold at an older age based on the AP approach. Among the women with an initial risk below the threshold, the CP approach revealed that 99% of women exceeded the 5% threshold at the same or an earlier age compared with the AP approach (88% of cases were within the same year or 1 year earlier). The CP approach has been implemented as a user-friendly web application. Prevention Relevance: The German Consortium for Hereditary Breast Cancer recommends annual breast imaging for women if their 10-year breast cancer risk is 5% or higher. Women who initially do not meet this risk threshold may do so later. We propose a simple method to determine future risks based on initial risk assessments.

Necroptosis triggers an inflammatory cascade associated with antimicrobial defense. No prospective human study has yet explored the role of necroptosis in colorectal cancer development. We conducted quantitative analysis of biomarkers for necroptosis [transient receptor potential cation channel subfamily M member 7 (TRPM7) and phosphorylated mixed lineage kinase domain-like protein], inflammation [cyclooxygenase-2 (COX-2)], apoptosis [BCL2-associated X (BAX) and terminal deoxynucleotidyl transferase dUTP nick end labeling], and cell proliferation (Ki67). This was done using tissue microarray biospecimens from the Cooperative Human Tissue Network and rectal biopsies from a longitudinal study within the Personalized Prevention of Colorectal Cancer Trial. In the human colorectal adenoma-carcinoma sequence, we observed an inverse expression trend between BAX and TRPM7; TRPM7 decreased from normal mucosa to small and large adenomas but significantly increased in early colorectal cancer stages (Ptrend = 0.004). It maintained high levels through all cancer stages. An increased COX-2 intensity in the epithelium was noted during tumorigenesis (Ptrend = 0.02) and was significantly associated with an elevated risk of metachronous polyps (odds ratio = 3.04; 95% confidence interval, 1.07-8.61; Ptrend = 0.02). The combined composite index scores of TRPM7 and COX-2 were strongly linked to 6- to 47-fold increased risks for metachronous adenoma/serrated polyps, whereas combined scores of phosphorylated mixed lineage kinase domain-like protein or TRPM7 with BAX were associated with an 11.5- or 13.3-fold elevated risk for metachronous serrated polyps. In conclusion, our findings suggest that COX-2 expression within normal-looking colorectal mucosa is significantly associated with an increased risk of metachronous colorectal polyp. Furthermore, our results propose the hypothesis that synergistic interactions among necroptosis, inflammation, and apoptosis could play a pivotal role in human colorectal tumorigenesis. Prevention Relevance: Our findings suggest that COX-2 expression and combined scores of COX-2, TRPM7, and BAX hold promise for predicting the risk of metachronous polyps and could potentially serve as a tool for assessing the effectiveness of chemopreventive agents in preventing colorectal cancer during intervention trials.

High genetic risk and alcohol consumption ≥1 drink/day are associated with increased breast cancer risk. However, the interaction between alcohol and genetics on breast cancer risk is poorly understood, including in populations not enriched with daily drinkers. We prospectively studied 5,651 White and Black postmenopausal women in the Atherosclerosis Risk in Communities study. Alcohol intake was assessed by a food frequency questionnaire. The 313-SNP polygenic risk score (PRS) was calculated. Breast cancer cases were ascertained primarily by cancer registry linkage through 2015. Multivariable Cox regression was used to estimate HRs and 95% confidence intervals (CI) for the association of PRS and current ethanol intake with breast cancer, and their interaction. Of these individuals, 50.6% were current drinkers, and of them, 50.8% drank <1 drink/week and 12.8% drank >7 drinks/week. A higher PRS was associated with a higher breast cancer risk among White (HR1-SD, 1.48; 95% CI, 1.34-1.65) and Black (HR1-SD, 1.15; 95% CI, 0.96-1.38) women. Positive associations were not observed between current ethanol intake and breast cancer risk (White: HR13 g/week, 1.00; 95% CI, 0.98-1.03; Black: HR, 0.83; 95% CI, 0.69-1.00). Among both White and Black women, PRS generally seemed to be positively associated with risk in drinkers and nondrinkers. There was no evidence of a PRS-ethanol intake interaction among White or Black women. Patterns in Black women were similar when using an 89-SNP PRS developed among African ancestry women. In conclusion, in a prospective analysis of White and Black postmenopausal women in a study population not enriched with daily drinkers, our findings suggest that alcohol drinking does not modify the PRS-based genetic risk of breast cancer. Prevention Relevance: Although our findings suggest that alcohol drinking does not modify the PRS-based genetic risk of breast cancer among White and Black women with lower alcohol intake, nevertheless, women should consider limiting alcohol consumption as a general cancer prevention strategy, as indicated in dietary guidelines.

Epigenetic clocks can quantify DNA methylation by measuring the methylation levels at specific sites in the genome, which correlate with biological age (BA). Accelerated aging, where BA exceeds chronologic age, has been studied in relation to cancer development, but its utility in cancer prevention remains unclear. Accelerated aging holds promise as a tool to explain the increase in early-onset colorectal cancer (EOCRC). We investigate the association of accelerated aging and the presence of preneoplastic polyps (PNP) in the colon, defined as tubular adenomas and sessile serrated adenomas. In this study of persons under age 50 undergoing colonoscopy, we used peripheral blood samples to determine BA and age acceleration metrics. Age acceleration was determined by interrogating DNA methylation at specific CpG sites across the genome, which has been shown to correlate with age. We then conducted logistic regression analyses to evaluate the association between age acceleration and PNPs. In total, 51 patient samples were evaluated. We found that that the odds of harboring a PNP are 16% higher with 1 year of accelerated aging, as measured by GrimAge. However, the strongest risk factor for PNPs remained male sex. This represents one of the first studies to explore accelerated aging and PNP in patients under the age of 50. A risk-stratified approach to EOCRC screening would minimize unnecessary colonoscopies and minimize healthcare burden while addressing the increase in EOCRC. Our findings suggest that BA calculations with peripheral blood collections could be an important component of such a risk model. Prevention Relevance: Understanding the association of accelerated aging and colorectal PNPs presents an opportunity to develop a risk-stratified approach to colorectal cancer screening in young persons.

We performed a clinical trial in patients with non-muscle-invasive (NMI) urothelial cancer randomized (2:1) to the EGFR tyrosine kinase inhibitor erlotinib or placebo (either orally once weekly × 3 doses prior to scheduled surgery) to assess for a difference in EGFR phosphorylation in tumor-adjacent normal urothelium <24 hours post-study dose and tolerance of weekly erlotinib therapy. Thirty-seven volunteers (6 female/31 male; mean age 70; 35 White/2 non-White) with confirmed or suspected NMI urothelial cancer were enrolled into either erlotinib (n = 24; 900 mg-13, 600 mg-11) or placebo (n = 13). IHC assessment of phosphorylated and total EGFR in tumor-adjacent normal urothelium (20 erlotinib and 9 placebo subjects) or tumor (21 erlotinib and 11 placebo subjects) at study end showed no significant difference between those receiving erlotinib or placebo. This was also true for other assessed tissue biomarkers (phosphorylated ERK, ERK, E-cadherin, p53, and Ki67). Adverse events were more common, in a dose-related fashion, in participants receiving erlotinib, e.g., 38% experienced grade 1 with rare grade 2 diarrhea and skin toxicity versus 8% in placebo. Clinically insignificant but statistically significant (P = 0.001) elevations in serum total bilirubin and creatinine were observed in participants receiving erlotinib. Serum erlotinib and metabolite concentrations (OSI-420) confirmed compliance in all subjects receiving erlotinib and did not significantly differ between the 600 and 900 mg doses. Despite compelling preclinical and clinical data for targeted EGFR inhibition in bladder cancer prevention, these data do not support the use of weekly erlotinib therapy to prevent progression of NMI bladder cancer. Prevention Relevance: We evaluated the potential of erlotinib in preventing cancer by performing a randomized, double-blind, placebo-controlled trial of weekly erlotinib therapy in participants undergoing surgical removal of suspected noninvasive bladder neoplasia. Weekly erlotinib therapy was tolerated with common grade 1 to 2 toxicities but without evidence of beneficial effect upon urothelial tissue. See related Spotlight, p. 7.