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

Prophylactic treatment with selective estrogen receptor modulators (SERMs) and aroma-tase inhibitors (AIs) targeting the nuclear estrogen receptor (ER) can prevent the formation of ER-positive tumors in women at high risk for breast cancer but does not prevent ER-negative and triple-negative subtypes. In this study, we tested whether nuclear retinoid X receptor (RXR) ago-nists, IRX4204 and 9cUAB30, which have been evaluated in clinical trials, could prevent the de-velopment of ER-negative and triple-negative breast cancers (TNBCs). 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 pre-clinical study data support the further evaluation of use of RXR agonists for the prevention of TNBC.

The role of sex hormones in the sex difference between adiposity and cancer risk remains unclear. We examined body mass index (BMI) and visceral adipose tissue (VAT) estimated using a validated equation in relation to cancer incidence according to serum sex hormone-binding globulin (SHBG), testosterone, and estradiol among 451,500 UK Biobank participants. For cancers showing a sex-specific adiposity association, we used Cox regression to calculate multivariable HRs per increase between the 10th and 90th percentiles of adiposity according to low versus high sex hormone levels. We documented 42,949 cancers over a median follow-up of 13.1 years. BMI and VAT were more strongly associated with a higher risk of esophageal, liver, and colorectal cancers in males than in females. In males, BMI showed a stronger association with esophageal (HR for high vs. low SHBG = 2.38 vs. 1.62; Pinteraction = 0.04) and liver cancers (HR = 3.24 vs. 1.96; Pinteraction = 0.03) among those with high versus low SHBG, whereas an opposite pattern was observed for colorectal cancer (HR = 1.12 vs. 1.47; Pinteraction = 0.03). Among females, BMI was associated with a higher esophageal cancer risk in those with low (HR = 1.68) but not high SHBG (HR = 0.64; Pinteraction = 0.025); for liver cancer, results were similar but statistically nonsignificant. No interaction by estradiol or testosterone was detected. Similar results were observed for VAT. SHBG may be an important factor underlying the sex difference in adiposity-associated risk for colorectal, esophageal, and liver cancers.

Prevention relevance: Understanding the interactions between sex hormones and adiposity can help explain sex differences in cancer risk associated with body fat. Our findings suggest that SHBG may be a promising target for future research on strategies to reduce the risk of colorectal, esophageal, and liver cancers in individuals with excess adiposity.

Accumulation of the DNA adduct γ-hydroxy-1,N2-propanodeoxyguanosine (γ-OHPdG) is associated with hepatocellular carcinoma development. Theaphenon E-a green tea polyphenol extract dosed according to mg of epigallocatechin gallate-suppresses the formation of γ-OHPdG and reduces hepatocellular carcinoma development in preclinical models. This study aimed to evaluate the safety of Polyphenon E (Theaphenon E equivalent) and its effect on liver γ-OHPdG levels in patients with cirrhosis. This phase I trial used a 3 + 3 dose-escalation design with five planned Polyphenon E (epigallocatechin gallate) dose levels: 400, 800, 1,200, 1,600, and 2,000 mg daily, administered orally for 24 weeks. Each dose cohort was monitored for "discontinue therapy" criteria for 4 weeks before additional participants were enrolled in the next cohort. Participant liver samples were assessed for γ-OHPdG levels using LC/MS-MS and vibration-controlled transient elastography; endogenous catechin pharmacokinetic data were analyzed. Grade 1 and 2 treatment-related adverse events were observed in 38% of the participants. Liver γ-OHPdG levels declined after treatment in most participants. There was a decrease in the vibration-controlled transient elastography-controlled attenuation parameter in some participants. After Polyphenon E dosing, catechin pharmacokinetic clearance patterns were equivalent for all doses except 1,600 mg. Polyphenon E was well tolerated in participants with cirrhosis at a dose up to and including 1,600 mg/day. Therefore, the recommended starting dose for a phase II trial in a cirrhotic population is 1,200 mg. We observed promising Polyphenon E suppression of liver γ-OHPdG levels.

Prevention relevance: In this phase I dose-escalation trial, Polyphenon E was well tolerated in participants with cirrhosis at a dose up to and including 1,600 mg/day. We observed promising Polyphenon E suppression of liver γ-OHPdG levels and recommend 1,200 mg dose for a future phase II trial in a cirrhotic population.

Hereditary polyposis syndromes are inherited disorders with high malignancy risk. Management entails early genetic testing, structured surveillance, and risk-informed surgical intervention, yet current practice lacks pediatric-specific standardization. We propose targeted solutions: adoption of pediatric-focused protocols, development of decision-support tools for surgery timing, creation of multidisciplinary pediatric centers, inclusion of psychosocial services and standardized transition programs for lifelong care, and investment in genotype-phenotype research and chemoprevention trials. Coordinated efforts are needed to enhance evidence-based, equitable pediatric hereditary polyposis syndrome care. See related article by Kurowski et al., p. 603.

Although screening, treatment, and human papillomavirus vaccination can prevent cervical cancer, 17.7% new Indian cases were still recorded in 2022. Illiteracy, undesirable attitudes, and ineffective screening services undermine the effectiveness of cervical cancer screening. We evaluated the knowledge (K), attitude (A), and practices (P) toward cervical cancer and their influence on screening acceptance among urban and tribal women of Maharashtra, India. A cross-sectional study was conducted among 500 urban and 500 tribal women, recruited to equally represent both populations. KAP data on cervical cancer were collected using a structured questionnaire. Participants received free cervical cancer screening. KAP scores were calculated, and their associations with sociodemographic factors and cervical cancer screening were assessed using logistic regression. A total of 939 participants were enrolled. Considering both populations, a total of 530 (56%) participants were unaware about cervical cancer, 296 (72%) about its symptoms, and 250 (61%) of risk factors. Common misconceptions were that only women with symptoms of cervical cancer (166, 18%) or a family history of cervical cancer (385, 41%) needed screening. Fear of pain, bad result, and embarrassment were major perceived barriers. Whereas 65 (6.85%) participants had previously undergone screening, 756 (81%) desired screening and 670 (71.40%) underwent screening. Although women had limited cervical cancer knowledge, their attitude for screening is favorable. Generating awareness and implementing socioculturally acceptable strategies are crucial for amplifying cervical cancer screening among vulnerable women.

Prevention relevance: Despite limited awareness and prevalent misconceptions about cervical cancer screening, the women expressed willingness to undergo screening following appropriate counseling. This highlights the potential for targeted educational interventions to enhance cervical cancer prevention through early detection and improving uptake of screening.

Data on the care of pediatric patients with hereditary polyposis syndromes (HPS) including familial adenomatous polyposis (FAP), juvenile polyposis syndrome, and Peutz-Jeghers syndrome are limited. We aim to describe the current practice patterns for HPS. An anonymous survey was distributed to pediatric gastroenterologists, pediatric surgeons, and adult colorectal surgeons. A total of 150 pediatric gastroenterologists and 129 surgeons started the survey, and 80 gastroenterologists and 70 surgeons completed the survey. A total of 62% of pediatric gastroenterologists identified that their clinical care most closely follows the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition position statement and 42% of surgeons reported following the National Comprehensive Cancer Network guidelines (P < 0.001). For gastroenterologists, 76% currently manage FAP (61% follow 1-5 patients) and 34% recommended genetic testing at birth or first presentation. At 10 to 14 years, 91% recommended initial colonoscopy. High-grade dysplasia (78%) was the most important factor for surgical referral for colectomy. A total of 43% reported documenting the number of rectal polyps and 31% referred to a surgeon for <50 polyps. Seventy-five percent manage juvenile polyposis syndrome and 56% manage Peutz-Jeghers syndrome. For surgeons, 81% currently manage FAP (56% follow 1-5 patients) and 68% follow patients <18 years. Twelve to 15 years was the most common age (47%) at colectomy. High-grade dysplasia (57%) was the most important factor for surgery. In the previous 12 months, 56% had not performed a colectomy. Ileal pouch-anal anastomosis was the most common reported surgery for FAP. Pediatric gastroenterologists and surgeons typically manage few pediatric patients with HPS, with significant heterogeneity and deviation from guidelines. Continued medical education is critical to standardizing care for pediatric HPS.

Prevention relevance: Appropriate screening and surveillance in pediatric hereditary polyposis are critical in the early detection of intestinal cancers. See related Spotlight, p. 579.

The role of sex hormones in the sex difference between adiposity and cancer risk remains unclear. We examined body mass index (BMI) and visceral adipose tissue (VAT) estimated using a validated equation in relation to cancer incidence according to serum sex hormone binding globulin (SHBG), testosterone, and estradiol among 451,500 UK Biobank participants. For cancers showing a sex-specific adiposity association, we used Cox regression to calculate multivariable hazard ratios (HR) per increase between the 10th to 90th percentiles of adiposity according to low versus high sex hormone levels. We documented 42,949 cancers over a median follow-up of 13.1 years. BMI and VAT were more strongly associated with a higher risk of esophageal, liver, and colorectal cancer in males than in females. In males, BMI showed a stronger association with esophageal (HR for high vs low SHBG = 2.38 vs 1.62, P-interaction = 0.04) and liver cancer (HR = 3.24 vs 1.96, P-interaction = 0.03) among those with high versus low SHBG, while an opposite pattern was observed for colorectal cancer (HR = 1.12 vs 1.47, P-interaction = 0.03). Among females, BMI was associated with a higher esophageal cancer risk in those with low (HR = 1.68) but not high SHBG (HR = 0.64, P-interaction = 0.025); for liver cancer, results were similar but statistically nonsignificant. No interaction by estradiol or testosterone was detected. Similar results were observed for VAT. SHBG may be an important factor underlying the sex difference in adiposity-associated risk for colorectal, esophageal, and liver cancer.