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

Lung cancer is the leading cause of cancer-related deaths. The human microbiome plays an important role in regulating response to cancer therapeutics, outcomes, and biological processes. However, little is known regarding the interplay between the lung microbiome and other biological processes in cancer. In an exploratory pilot study, we collected bronchoalveolar lavage fluid and brushings from 20 patients with early-stage lung cancer and performed microbial sequencing, untargeted metabolomics, and cytokine analysis. In addition, we employed computational and machine-learning approaches to identify integrated microbial-immunometabolic pathways. Finally, we performed preliminary mechanistic studies to confirm our findings. Previously, we published that upper airway microbiota were selectively enriched in tumor-affected lobes. In the present study we demonstrate that enrichment of pro-tumorigenic cytokines and specific fatty acids are associated with tumor-affected lobes. Finally, we find that long-chain fatty acid stimulation of macrophages leads to neoplastic transformation of lung epithelial cells. Therefore, the findings of this study identify a perturbed fatty acid-macrophage axis that is a potential biomarker of early-stage lung cancer and will lead to development of novel therapeutic agents.

Ovarian reserve is a crucial component of female reproductive traits. However, the possible causal effects between ovarian reserve and hormone-sensitive cancers remain incompletely understood. Two-sample Mendelian randomization analyses (MR) were performed to assess potential causal effects of reproductive traits on hormone-sensitive cancers. In addition, multivariable MR was applied to determine the potential mediation effects of reproductive traits on hormone-sensitive cancers. A one SD incremental increase in the anti-Müllerian hormone (AMH) level was associated with a higher risk of endometrial cancer (OR = 1.27, 95% CI = 1.05-1.54) but a lower risk of breast cancer (OR = 0.80, 95% CI = 0.69-0.94). Each 1-year incremental increase in age at natural menopause was associated with higher risks of breast (OR = 1.04, 95% CI, 1.02-1.05), ovarian (OR = 1.03, 95% CI, 1.01-1.05), and endometrial cancers (OR = 1.07, 95% CI, 1.04-1.09). Nulliparity increased the risk of breast cancer (OR = 1.07, 95% CI, 1.05-1.09). An elevated AMH level was indirectly associated with endometrial cancer risk with 2.67% of the effect attributed to later age at natural menopause (per 1-year increase). Each 1-year incremental increase in age at menarche was indirectly associated with endometrial cancer risk with 4.71% of the effect attributed to later age at natural menopause. The findings herein highlight AMH as a potential key biological marker for endometrial and breast cancer risk. Identifying natural menopause as a key modulator may enhance our understanding of the mechanisms underlying hormone-sensitive cancers.

Esophageal squamous cell carcinoma (ESCC) remains a leading cause of cancer-related mortality worldwide and there are limited molecular screening options. Following a prior discovery and validation studies in subjects from the United States, China, and Iran, we aimed to validate methylated DNA markers (MDMs) for ESCC detection in Malawi, a country with one of the highest ESSC incidence. Fourteen MDMs were tested on 177 tissue samples. Ten MDMs showed excellent performance (AUCs ≥0.85); a random forest model achieved an AUC of 0.97. The consistent cross-population performance suggests potential for universal application of these MDMs and further justifies exploring non-endoscopic sampling methods, such as swallowed cell collection devices in combination with MDMs, for efficient and cost-effective screening in high-incidence populations.

Cancer cells exhibit metabolic flexibility between anaerobic glycolysis and oxidative phosphorylation. Preclinical data showed that metformin, an oxidative phosphorylation inhibitor, combined with fasting-induced hypoglycemia led to activation of the PP2A-GSK3ß-Mcl1 axis and inhibition of tumor growth. A window-of-opportunity trial was designed to evaluate the effect of metformin and nightly fasting on proliferation in invasive breast cancer or ductal carcinoma in situ (DCIS). The primary endpoint is the pretreatment/posttreatment change of Ki67 in cancer tissue, and the co-primary endpoint is the difference in posttreatment Ki67 in cancer-adjacent DCIS or high-risk lesions. Participants with hormone receptor-positive invasive breast cancer or DCIS candidates to surgery are being accrued and randomized to either (i) fasting for ≥16 hours nightly, plus nutritional counseling and daily metformin with continuous glucose monitoring, or (ii) continuous glucose monitoring. The intervention lasts 4 to 6 weeks with gradual metformin ramp up to limit gastrointestinal disturbances. The safety of the combination was evaluated as a primary interim endpoint. The frequency of dose-limiting toxicity (≥G3 adverse events related to treatment) was assessed in the first 14 participants in the experimental arm. Most adverse events were of low grade (G1: 50; 90.9%) and unrelated to the treatment (G1: 26 unrelated; 52%). No one discontinued treatment because of toxicity, and no dose-limiting toxicities were observed, so the escalation phase of metformin was significantly shortened from 7 to 3 days. The results of this project will expand knowledge of this prevention approach and possibly provide the basis for large-scale primary prevention studies in at-risk women.

Prevention relevance: In a context of rising cancer drug costs, this research explores a low-cost treatment to optimize breast cancer preventive intervention. The approach is safe and based on repurposed drugs that could enhance prevention strategies for obesity- and insulin-related cancers, offering immediate applicability to a large-scale trial in women at risk.

Anal cytology and human papillomavirus (HPV) testing are the most common tools for anal cancer screening. We conducted an exploratory survey on the use of anal cytology in Italy. The Italian Society of Cytology (SICi) disseminated a questionnaire to its members and contacts on screened populations, departments collecting the samples, devices used, type of cytology (conventional or liquid based), professionals evaluating cytology, reporting system, use of anal cytology alone or in combination-test modality, diagnostic procedure for screen-positive individuals, and departments involved. Eighteen centers participated in the survey. In 15 centers (83.3%), anal cytology is performed on more than one at-risk population: men who have sex with men (MSM)/transgender women (TW) living with human immunodeficiency virus (LWH 13 centers, 72.2%), women with a history of gynecologic (pre)cancer (10 centers, 55.6%), women LWH (nine centers, 50.0%), men who have sex with women LWH, and MSM/TW not LWH (eight centers, 44.4%). Samples mostly come from infectious disease (nine, 50.0%) and sexually transmitted infection units (seven, 38.9%). A median of 140 samples (IQR, 30-500) are collected per year, with 13 centers (72.2%) using a cytobrush. Cytology is generally conventional (11 centers, 61.1%) and is mainly interpreted by histopathologists (66.7%) and biologists (55.6%). All centers use the Bethesda System for reporting cytology. Most of the centers use cytology in co-testing with HPV (10, 55.6%). Twelve centers (66.7%) perform high-resolution anoscopy, and the diagnostic procedure is frequently performed in general surgery (eight, 44.6%). Most of the centers employ anal cytology in people LWH and perform conventional cytology. Screening modality is variable, with more than half of the centers using cytology in co-testing with HPV. The use of high-resolution anoscopy is still suboptimal.

Prevention relevance: Screening for anal cancer prevention in Italy relies on heterogeneous and not fully satisfactory tools. Further efforts should be made to implement the optimal strategies in order to address the needs of the populations with the highest anal cancer risk.

Aberrant DNA methylation and copy-number alterations (CNA) drive Barrett's esophagus progression to esophageal adenocarcinoma; however, their combined utility for early detection is unclear. We aimed to identify and validate methylated DNA markers (MDM) and CNAs to distinguish esophageal adenocarcinoma/high-grade dysplasia (HGD) from nondysplastic Barrett's esophagus (NDBE). In this multiphase, multicenter study, we discovered and validated MDMs and quantified CNAs utilizing whole-genome methylation sequencing of esophageal brushings. DNA biomarkers identified from discovery were further validated in independent patients with paired esophageal brushing and swallowed capsule sponge samples. MDMs were filtered against a reduced representation bisulfite sequencing dataset obtained from independent tissue samples to advance only concordant candidates. CNA burden was quantified using ichorCNA-derived aneuploidy scores (AS). Two hundred MDMs discovered in HGD (N = 18) and esophageal adenocarcinoma (N = 18) versus NDBE brushing samples (N = 18) were tested in independent samples (N = 146). A 52-MDM panel achieved a cross-validated AUC of 0.88 [95% confidence interval (CI), 0.82-0.95]; the addition of AS improved discrimination of HGD/esophageal adenocarcinoma from NDBE to 0.91 (95% CI, 0.86-0.97) AUC. At 80% specificity, the combined model detected 93% of esophageal adenocarcinoma and 88% of HGD cases. In paired capsule sponge samples, a 58-MDM panel achieved a cross-validated AUC of 0.77 (95% CI, 0.66-0.88); a combined 58-MDM and AS model achieved AUC 0.80 (95% CI, 0.7-0.9). MDMs and AS discerned HGD/esophageal adenocarcinoma from normal esophagus/NDBE in endoscopic brushing and capsule sponge samples. This approach may improve Barrett's esophagus surveillance.

Prevention relevance: This study demonstrates that combining epigenetic and genomic biomarkers across minimally invasive sampling methods can accurately distinguish HGD/esophageal adenocarcinoma from nondysplastic Barrett's esophagus, offering promising, less invasive strategies to improve BE surveillance and enable endoscopic therapy for esophageal adenocarcinoma prevention and treatment.

Clinical cancer prevention and interception trials target high-risk populations and require agents with favorable risk-to-benefit ratios. Participant experiences are crucial in trial design, as highlighted in this issue of Cancer Prevention Research by Zahrieh and colleagues, which applied the "Was It Worth It?" questionnaire to evaluate participants' experiences in cancer chemoprevention trials. This study is the first examination of satisfaction in early-phase chemoprevention trials for high-risk individuals. This timely study underscores the need to assess and integrate participant and advocate feedback in completed, ongoing, and future trials. This spotlight commentary emphasizes the importance of participant experiences in enhancing trial designs for cancer prevention and interception. See related article by Zahrieh et al., p. 11.

The aim was to assess whether subject's participation in early-phase chemoprevention trials was satisfactory and identify features associated with subjects' satisfaction. Thirteen trials that investigated a range of candidate agents from 2006 to 2021 by the Cancer Prevention Network were included. The five-item "Was It Worth It?" (WIWI) questionnaire was administered to all subjects at the end of each trial's intervention or at early termination. Satisfied overall was defined as a participant response of "yes" to the first three questions. Six hundred ninety-one participants from the United States, Canada, Puerto Rico, and Honduras enrolled on a trial. Six hundred fifty-two (94.4%) completed the WIWI questionnaire. Of these, 493 (75.6%) were White, non-Hispanic/Latino; 39 (6.0%) Black, non-Hispanic/Latino; 98 (15.0%) Hispanic/Latino; and 8 (1.2%) of another race/ethnicity. One hundred ninety-three were women (29.6%), 121 (17.5%) were ≥65 years, and 517 (79.3%) participated in a placebo-controlled trial. Eighty-five percent indicated being satisfied overall. Compared with White, non-Hispanic/Latino, the odds of not satisfied overall were 2.96 times higher for Black/Asian/>1 race, non-Hispanic/Latino (P < 0.001) and 0.40 times lower for Hispanic/Latino (P = 0.004). The odds of not satisfied overall was 1.9 times higher when the number of preintervention adverse events experienced was ≥1 (P = 0.012), 1.8 times higher when the percentage of the intervention duration with adverse events was >5% (P = 0.024), and 7.4 times higher for subjects who terminated the intervention early (P < 0.001). These findings can inform the design of future chemoprevention trials and help investigators improve accrual, retention, adherence, and diversity in this underexplored research setting.

Prevention relevance: The five-item "WIWI?" questionnaire, which captures the participant-reported experience of trial participation, gives the subject a voice in the development of new chemopreventative agents. This study in 652 subjects looked at satisfaction with participation in early-phase chemoprevention trials for higher-risk, cancer-free men and women. See related Spotlight, p. 7.

Although chemoprevention medications, including selective estrogen receptor modulators and aromatase inhibitors, are recommended for women at high risk for breast cancer, their uptake remains low. In contrast, statin use for atherosclerotic cardiovascular disease (ASCVD) risk reduction is widely adopted. We conducted a retrospective cohort study among a population of women aged 40 to 79 who underwent screening mammograms at Columbia University Irving Medical Center (CUIMC) from 2014 to 2016. For each woman, we calculated breast cancer risk using the Breast Cancer Surveillance Consortium version 3 (BCSCv3) risk calculator and ASCVD risk using the American Heart Association (AHA) risk calculator. High risk using the BCSCv3 calculator was defined as ≥5% invasive breast cancer risk at 10 years, and high risk using the AHA calculator was defined as >7.5% ASCVD risk at 10 years. Average 10-year risk of invasive breast cancer was lower than that for ASCVD (2.47% vs. 7.53%, P < 0.001). Based on disease risk, 4.7% and 34.4% of participants met high risk criteria for breast cancer and ASCVD, respectively. Chemoprevention uptake among women at high risk for breast cancer was lower than statin uptake among women at high risk for ASCVD (4.6% vs. 72.9%). Numerous barriers likely contribute to this discrepancy in uptake, including provider familiarity with and knowledge of chemoprevention, patient concerns about medication safety, absence of routine breast cancer risk assessment, and lack of intermediate biomarkers to monitor treatment response. Given the increased acceptance and uptake of statins relative to chemoprevention, there is potential value in putting chemoprevention in the context of statins to promote awareness and uptake.

Prevention relevance: Among women undergoing screening mammograms, for women at high risk for breast cancer and ASCVD, chemoprevention uptake was lower than that of statins. We propose multiple barriers to account for this difference and describe how acceptance of statins could serve as a model for promoting the uptake of chemoprevention medications.