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

High endogenous estrogen levels contribute to the etiology of hormone-related cancers. 2-hydroxylation (2-OH) of estrogen exhibits potential antitumorigenic properties. We hypothesized that lifestyle patterns related to the ratio of 2-OH pathway estrogen metabolites (EM) to parent estrogens (2-OH EM/parent E ratio) might lower estrogen-related cancer risk. We applied elastic net regularized regression to derive lifestyle scores correlated with the 2-OH EM/parent E ratio separately using data from subsets of cancer-free, postmenopausal women in the Shanghai Women's Health Study (SWHS, n = 723) and the Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO, n = 635), in which blood (PLCO) or urine (SWHS) samples collected at baseline were profiled for parent Es and EMs. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of lifestyle scores with the risk of breast, endometrial, and ovarian cancers in SWHS (N = 35,453) and PLCO (N = 26,565). The lifestyle scores explained 10% to 11% of the total variance in the 2-OH EM/parent E ratio. In the SWHS, a higher score was associated with a 29% (HR = 0.71; 95% CI, 0.57-0.88; Ptrend < 0.001) and 61% (HR = 0.39; 95% CI, 0.21-0.71; Ptrend < 0.001) lower risk of breast and endometrial cancers when comparing the highest with the lowest quartile, respectively. The association was more apparent with estrogen receptor (ER)-positive than with ER-negative breast cancer. Similar inverse associations were observed in the PLCO. Lifestyle patterns linked to elevated 2-OH of estrogen were associated with a lower risk of postmenopausal breast and endometrial cancers. Our study provides evidence for lifestyle modifications for cancer prevention.

Prevention relevance: Elevated estrogen 2-OH has been linked to reduced breast cancer risk. We showed that lifestyle patterns increasing the 2-OH EM/parent E ratio were associated with lower postmenopausal breast and endometrial cancer risk. Our findings suggest that targeted lifestyle modifications may benefit postmenopausal women with a low 2-OH EM/parent E ratio.

Accurate and effective early detection of colorectal cancer (CRC) and advanced precancerous lesions (APLs) is still a challenge. The purpose of this study was to evaluate the clinical performance of a novel, non-invasive multimodal stool RNA test (mm-stRNA) that combines five human messenger RNA (mRNA) biomarkers and a fecal immunochemical test (FIT) in a machine learning (ML)-generated algorithm, for the sensitive detection of APLs and CRCs. For this purpose, stool samples from 265 subjects (34 CRCs, 68 APLs and 163 controls) were evaluated as part of the eAArly DETECT study, a US multi-site study with subjects suspected to have at least one APL or CRC, as well as average-risk individuals. FIT was evaluated with clinical positivity thresholds of 5 µg hemoglobin (Hb)/g of stool and 17 µg Hb/g. RNA was isolated from stabilized stool and analyzed for the expression levels of five mRNA biomarkers. Lab data were analyzed using a machine learning-generated algorithm that was developed in a stratified split-sample design and then applied as a locked model to the full 265-subject cohort. The mm-stRNA test achieved 97.1% sensitivity for CRC and 83.8% sensitivity for APLs, with 95.7% specificity. FIT sensitivity was 76.5 % vs. 70.6% for CRC and 45.6% vs. 36.8% for APL with a specificity of 84.0% vs. 90.8% when applying the cut-off levels 5 µg Hb/g vs. 17 µg Hb/g, respectively. The mm-stRNA approach appeared to have substantially improved performance compared to existing tests, but results need to be replicated in an independent prospective cohort.

Cross-sectional data indicates that the oral microbiota differs between people who smoke or use e-cigarettes, suggesting potential as a research tool in product-switching trials, as a biomarker of product use status and/or of long-term health effects. However, its sensitivity to short-term product switching remains unclear. We examined a subset of participants in an 8-week product-switching study who were asked to switch from smoking to exclusive e-cigarette use and had oral cells collected (n=58). Using available biomarker data, we determined that 12 achieved complete switching and 46 engaged in dual use. A subgroup of participants in the same study who continued exclusive smoking (n=20) was included for reference. Oral microbiota profiles were characterized at baseline and at the end of the study (week 8) using 16S rRNA gene sequencing targeting the V3-V4 hypervariable regions on an Illumina MiSeq platform. Participants who switched to exclusive e-cigarette use had a significant decrease in alpha diversity (Shannon Index) at week 8 compared to baseline smoking (p = 0.02), and their beta diversity at week 8 differed from those who engaged in dual use or continued exclusive smoking (r² = 0.04; p = 0.014). They also showed increased abundances of proinflammatory genera (Streptococcus, Veillonella, Haemophilus, Fusobacterium), whereas dual users had decreased abundances of several commensal genera, including Lactobacillus, Limosilactobacillus, and Neisseria. Our findings indicate that the oral microbiota may serve as a sensitive tool for detecting and interpreting changes in tobacco-related exposures, and potentially for monitoring product use compliance, in clinical studies of product switching.

The fatty acid synthesis pathway is a valid target for the prevention of prostate cancer. However, a clinical-grade inhibitor of fatty acid synthesis is still lacking. This bench-to-bedside study was undertaken to determine the feasibility of fatty acid synthesis inhibition using broccoli constituent sulforaphane (SFN) and its clinical-grade formulation BroccoMax (BMAX). Oral administration of SFN to Hi-Myc mice resulted in the inhibition of prostate adenocarcinoma burden by about 61% that was accompanied by a significant decrease in prostate tumor levels of c-Myc and proliferating cell nuclear antigen proteins and increased apoptosis. Expression of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN) was lower by about 46% and 31%, respectively, in the prostate tumor of SFN-treated mice when compared with that of control mice (P < 0.001). Plasma levels of total free fatty acids (TFFA), cholesterol, and total phospholipids were decreased significantly following SFN treatment. In a double-blind clinical trial, patients with histologically confirmed prostate cancer were randomized to the BMAX (n = 19) or placebo (PBO) group (n = 22). Patients were treated with four capsules of BMAX or four capsules of matching PBO orally two times daily after breakfast and dinner for 4 weeks. Prostate tumor expression of c-Myc, ACC1, FASN, and Ki-67 proteins was significantly lower in the BMAX arm when compared with the PBO group. However, the serum or prostate tumor level of acetyl-CoA or TFFA was not decreased by BMAX treatment. A longer duration treatment with BMAX in patients with early-stage prostate cancer may be necessary to lower the circulating or prostate tumor level of TFFA.

Prevention relevance: Fatty acid synthesis is a valid target for the prevention of human prostate cancer. In this study, we determined the feasibility of fatty acid synthesis inhibition using SFN in a mouse model and BMAX, its clinical-grade formulation, in prostatectomy patients.

Severe obesity is positively associated with the risk of multiple myeloma (MM) and mortality; thus, obesity has emerged as a target for MM prevention. Established dietary-based mouse models have proven useful in recapitulating obesity-related diseases in humans, but the multifaceted nature of obesity, cancer, and mouse models has led to a knowledge gap regarding which myeloma models can capture obesity-accelerated cancer. Thus, we tested the effect of obesity on MM in three high-fat diet (HFD) murine MM models: a SCID-beige MM.1SGFP+/Luc+ xenograft, a C57BL/6J Vk*MYC syngeneic, and a C57BL/6J 5TGM1-TKGFP+/Luc+ semi-syngeneic. Only the third model recapitulated obesity-accelerated MM, where incidence rates, serum IgG levels, and bioluminescent tumor signal in HFD-fed mice were significantly higher than controls. This HFD-C57BL/6J 5TGM1-TKGFP+/Luc+ model is the first bioluminescent assessment of myeloma engraftment in obese mice and allows for non-invasive spatiotemporal tumor tracking of features such as tumor growth and clearance. It can now be used to test the role of the immune system, or other factors, in obesity-accelerated myeloma. Finally, our analyses of Multiple Myeloma Research Foundation (MMRF) CoMMpass clinical data showed associations of moderate and severe obesity at diagnosis with increased patient mortality and revealed novel gene expression and pathway signatures that differed between MM cells from obese and normal patients. Overall, our work supports the hypothesis that obesity contributes to myeloma disease progression in humans and provides a novel mouse model with which to study this.

High endogenous estrogen levels contribute to the etiology of hormone-related cancers. 2-hydroxylation (2-OH) of estrogen exhibits potential anti-tumorigenic properties. We hypothesized that lifestyle patterns related to the ratio of 2-OH pathway estrogen metabolites (EMs) to parent estrogens (2-OH EM/parent E ratio) might lower estrogen-related cancer risk. We applied elastic net regularized regression to derive lifestyle scores correlated with the 2-OH EM/parent E ratio separately using data from subsets of cancer-free, postmenopausal women in Shanghai Women's Health Study (SWHS, n=723) and Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO, n=635), where blood (PLCO) or urine (SWHS) samples collected at baseline were profiled for parent estrogens and EMs. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of lifestyle scores with risk of breast, endometrial, and ovarian cancers in SWHS (N=35,453) and PLCO (N=26,565). The lifestyle scores explained 10-11% of total variance in the 2-OH EM/parent E ratio. In the SWHS, a higher score was associated with 29% (HR=0.71, 95% CI=0.57-0.88, Ptrend<0.001) and 61% (HR=0.39, 95% CI=0.21-0.71, Ptrend<0.001) lower risk of breast and endometrial cancers comparing the highest to lowest quartile, respectively. The association was more apparent with estrogen receptor (ER)-positive than ER-negative breast cancer. Similar inverse associations were observed in the PLCO. Lifestyle patterns linked to elevated 2-OH of estrogen were associated with lower risk of postmenopausal breast and endometrial cancers. Our study provides evidence for lifestyle modifications for cancer prevention.

Gastric adenocarcinoma (GC) is the fifth leading cause of global cancer mortality and a major health disparity in the U.S. Effective chemoprevention strategies are limited for high-risk individuals with gastric premalignant conditions (GPMC). We conducted an NCI-DCP-funded, double-blind, Phase IIa randomized, placebo-controlled trial evaluating eflornithine for chemoprevention in GPMC (NCT02794428). The study was executed in rural Honduras and Puerto Rico, regions with a high prevalence of H. pylori (Hp) and gastric intestinal metaplasia (GIM), from September 2016 to December 2022. Eligible subjects (ages 30-69; Hp-positive or Hp-negative) were randomized 1:1 to receive 500 mg/day eflornithine or placebo for 18 months. Upper endoscopy was performed at baseline, 6, 18, and 24 months. Hp-positive patients were offered antibiotic treatment at 6 months. A total of 211 patients were screened, and 91 randomized (45 eflornithine, 46 placebo). The mean age was 45.2 years (SD 8.8), and 74% were female. At baseline, 46% and 54% had gastric atrophy and GIM, respectively. 80% were Hp-positive. Follow-up completion rates were 78 (6 months), 69 (18 months), and 55 (24 months) patients. Eflornithine was well tolerated, with fewer grade 1-2 adverse events in the eflornithine group (81 vs. 108, placebo). No significant histology score differences were observed. A significant reduction in DNA damage (pH2AX-positive cells) was observed in the 24-month versus 18-month assessments (P = 0.012). Eflornithine was safe and well tolerated in patients with GPMC. The findings suggest that eflornithine reduces long-term DNA damage, supporting further trials to refine treatment duration and patient selection.

Oral epithelial dysplasia (OED) is the precursor to oral squamous cell carcinoma, but histologic grading alone lacks reproducibility and prognostic power. This study evaluates whether pattern-based p53 and p16 immunohistochemistry (IHC) can serve as alternative markers to genomic loss of heterozygosity (LOH) testing in predicting OED progression. From a previously characterized LOH cohort, 64 patients were assessed with IHC for p53 and p16 using defined abnormal staining patterns (overexpression, cytoplasmic, or null). Abnormal p53 expression occurred in 19% of cases, with 93% specificity, and was significantly associated with reduced progression-free survival (PFS; 8-year PFS, 25% vs. 74%; P = 0.0011). Abnormal p16 expression was observed in 56% of cases with 95% sensitivity and was significantly associated with 8-year PFS (42% vs. 96%; P < 0.0001). Combined p53/p16-abnormal IHCs identified 95% of the progressing lesions and yielded superior risk discrimination (log-rank P < 0.0001), particularly at the 3-year follow-up mark. Concordance analysis revealed moderate agreement between p16 IHC and 9p LOH (κ = 0.39) and fair agreement between p53 IHC and 17p LOH (κ = 0.21), indicating that IHC and LOH detect related but distinct molecular disruptions. Chronologic evaluation of serial biopsies supported a sequential model in which p16 alteration precedes p53 alteration during malignant progression. Taken together, these findings highlight the potential of a pattern-based approach with combined p53/p16 IHC as a feasible, scalable, and clinically accessible tool to guide surveillance intensity and timely clinical intervention, thereby reducing progression risks.

Prevention relevance: In this study, we demonstrate that p53/p16 pattern-based IHC provides a practical and sensitive tool for predicting progression in OED. Its clinical accessibility may facilitate early detection of high-risk lesions, optimizing triage, surveillance, and preventative treatment strategies to reduce the incidence of high-grade lesions or oral cancer.

In 2019, professional guidelines incorporated low-dose tamoxifen as an option for breast cancer chemoprevention among women with atypical hyperplasia (AH) or lobular or ductal carcinoma in situ (LCIS/DCIS). We assessed factors associated with low-dose tamoxifen use among women diagnosed with AH, LCIS, or DCIS from 2016 to 2019 and from 2020 to 2023 compared with full-dose selective estrogen receptor modulators (SERM) or aromatase inhibitors (AI) at Columbia University Irving Medical Center in New York City. Uni- and multivariable logistic regression were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for variables associated with low-dose tamoxifen use. Among 2,260 evaluable women, 834 (36.9%) initiated a SERM or AI, and 140 (6.2%) took low-dose tamoxifen. Comparing women diagnosed before or after 2019, chemoprevention uptake significantly increased (33.9% vs. 39.3%, P = 0.008), particularly low-dose tamoxifen (3.3% vs. 8.6%). Among women who initiated chemoprevention, diagnosis of high-risk breast lesions before age 50 (OR = 3.02; 95% CI, 1.99-4.58), diagnosis after 2019 (OR = 2.83; 95% CI, 1.81-4.41), AH/LCIS versus DCIS (OR = 2.90; 95% CI, 1.95-4.31), and medical oncology referral (OR = 1.61; 95% CI, 1.02-2.54) were significant predictors of low-dose tamoxifen use. Those who initiated low-dose tamoxifen as their first chemoprevention had the lowest 1-year discontinuation rate (24.3%) compared with full-dose SERMs/AIs (32.3%-37.9%, P = 0.027). Since 2019, we observed a significant increase in low-dose tamoxifen use and chemoprevention uptake overall. Among women who initiated chemoprevention, low-dose tamoxifen uptake was higher among younger women and those with less advanced breast lesions. Low-dose options of proven chemopreventive agents may increase acceptance of risk-reducing medications for breast cancer prevention.

Prevention relevance: This study provides evidence of increased use of low-dose tamoxifen in a prevention setting, particularly among younger women and those with less advanced breast lesions. Further research is needed to understand how to incorporate low-dose tamoxifen into patient-provider discussions to improve chemoprevention decision-making.

Prophylactic treatment with selective estrogen receptor (ER) modulators and aromatase inhibitors targeting the nuclear ER can prevent the formation of ER-positive tumors in women at high risk of breast cancer but does not prevent ER-negative and triple-negative subtypes. In this study, we tested whether nuclear retinoid X receptor (RXR) agonists, IRX4204 and 9cUAB30, which have been evaluated in clinical trials, could prevent the development of ER-negative and triple-negative breast cancers. Our study demonstrates that IRX4204 significantly delays the formation of mammary tumors in three ER-negative mouse models: MMTV-ErbB2, C3(1)/SV40-TAg, and Brca1-deficient with modest toxicities. In some of the MMTV-ErbB2 mice, IRX4204 completely prevented mammary tumor formation, and 60% of the IRX4204-treated Brca1-deficient mice remained tumor-free when all vehicle-treated mice had formed tumors. 9cUAB30 treatment also delays tumor formation in Brca1-deficient mice, albeit to a lesser extent. Biomarker analysis revealed that delayed tumors arising after IRX4204 treatment had decreased Ki-67 expression and increased infiltration of cytotoxic T cells. Our preclinical study data support the further evaluation of use of RXR agonists for the prevention of triple-negative breast cancer.

Prevention relevance: Treatment with the RXR agonist IRX4204 significantly delays tumor formation and increases CD8-positive T-cell infiltration in ER-negative murine breast cancer models. This suggests that immune modulation may be critical for rexinoid-based prevention of ER-negative mammary tumors and supports their use in future breast cancer prevention trials for high-risk individuals. See related Spotlight, p. 133.