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

In 2019, professional guidelines incorporated low-dose tamoxifen as an option for breast cancer chemoprevention among women with atypical hyperplasia (AH), 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 2016-2019 and 2020-2023 compared to full-dose selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs) at Columbia University Irving Medical Center (CUIMC) in New York City. Univariate 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 lesion 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 vs. 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 to 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.

YAP1 is a co-transcription factor that promotes malignant and stem cell properties in cancer. We previously found that YAP1 dysregulation is associated with aging in human mammary epithelia. With increased age, YAP1 expression changes in luminal epithelial cells, the prospective breast cancer cell of origin. Because age is a significant risk factor for breast cancer, we tested if YAP1 dysregulation acted early in cancer progression by conferring cellular states associated with increased cancer susceptibility. Here we find, that with increased age and genetic risk for developing cancer, human breast tissues showed significantly increased YAP1 expression and cultured primary human mammary epithelial cells (HMEC) showed significantly increased expression of both YAP1 and its transcriptional targets. Increased YAP1 expression in cultured HMEC induced gene expression changes associated with increased cancer susceptibility such as genes associated with: stem cell fate, increased telomerase activity, breast cancer progression, and increased age and genetic breast cancer risk. Further, overexpression of YAP1 in post-stasis HMEC- finite lifespan cells which have bypassed a retinoblastoma-mediated senescence barrier- promoted properties related to an increased growth potential. We found that YAP1 dysregulation in finite epithelial cells allows for access to gene programs and functions that are typically thought to be restricted to stem cells. We hypothesize that YAP1 acts early in breast cancer progression, long before development of a tumor, to impose cancer susceptible molecular states.

Timely diagnosis and intervention in colorectal cancer (CRC) are critical to improving patient outcomes and limiting disease progression. Screening of average-risk individuals is essential for detecting tumors at an earlier, more treatable stage. However, adherence to current screening programs remains suboptimal. Liquid biopsies represent a promising alternative to stool-based tests and may play a key role in optimizing CRC detection and diagnostic pathways. In this study, 957 patients were recruited across various clinical sites in the USA: 48 CRC, 157 advanced precancerous lesions (APL), 331 non-advanced lesions (NAL) and 421 with a negative colonoscopy diagnosis. Blood was obtained from patients either prior to scheduled colonoscopy or before surgical resection and any anti-cancer therapies. Streck plasma samples were analyzed by the Dxcover® Liquid Biopsy Platform and classified with machine learning algorithms. When CRC was classified against all other groups, the receiver operating characteristic curve generated an area under the curve value of 0.95, and test sensitivity and specificity were 90% and 89%, respectively. The diagnostic model accurately predicted 75% of stage I (3/4), 100% of stage II (15/15), 93% of stage III (14/15) and 100% of stage IV (6/6) CRCs. For the advanced colorectal neoplasia model, 29% of APL were detected. A simple blood test with high sensitivity for early-stage colorectal cancer could significantly enhance patient outcomes. With continued development, this liquid biopsy has the potential to make a substantial impact on the early detection of CRC.

Lung cancer is the leading cause of cancer-related death. The incidence and mortality rates are higher for Black men than for White men. Protein arginine methyltransferase 6 (PRMT6) is known to be associated with lung cancer tumorigenesis and prognosis, and different levels of PRMT6 expression by race and sex may explain lung cancer disparities among Black men. To examine differences in PRMT6 by neighborhood violence as social stress, we obtained 88 formalin-fixed, paraffin-embedded tissue sections of patients with lung cancer. Using immunohistochemistry, samples were stained and scored [histochemical score (H-score)] for PRMT6 levels. Logistic regression was used to examine the likelihood of having a high H-score (≥ median) by race and sex, controlling for age, smoking status, tumor type, grade, stage at diagnosis, and neighborhood homicide rate. The odds of having a high H-score were higher for Blacks than Whites, but there was no sex difference when controlling for tumor characteristics. High homicide was negatively associated with high H-scores. Controlling for all other variables, the odds ratio (OR) of having a high H-score for Black versus White males was 7.8, and the OR for Black versus White females was 1.8 for the low homicide group. The ORs for both Black versus White males and Black versus White females were more than 3 times higher for the high homicide group. Overexpression of PRMT6 may explain the lung cancer disparity in Black men. Exposure to social stress may contribute to higher levels of PRMT6. Social and biological differences affecting race and sex groups need further investigation.

Prevention relevance: This study explores the impact of living in a high violence neighborhood, which may contribute to the elevated risk of lung cancer and tumor prognosis. Epigenetic modification may be a mechanism linking social exposure and biological changes. Addressing neighborhood-level social stress exposure may improve the prevention and intervention of lung cancer.

Oral epithelial dysplasia (OED) is the precursor to oral squamous cell carcinoma (OSCC), 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 (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. Chronological 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.

Germline and somatic alterations in the epidermal growth factor receptor (EGFR) gene contribute to the pathogenesis and therapeutic response of non-small cell lung cancer (NSCLC). This retrospective single-center study analyzed 507 Azerbaijani patients with NSCLC who were genotyped for EGFR mutations between 2009 and 2024. Real-time PCR identified somatic EGFR mutations in 137 cases (27.0%), whereas next-generation sequencing confirmed germline EGFR T790M variants in 11 patients (2.1%). Among these, nine carried concurrent somatic EGFR alterations, and two harbored only germline variants; the latter are excluded from the present analysis and will be reported separately. All germline carriers had a positive family history of lung cancer. Germline carriers were more often diagnosed at early stages (I-II, 45.5% vs. 18.2% in noncarriers; P = 0.03), and four developed tyrosine kinase inhibitors resistance within 6 to 8 months of treatment. Kaplan-Meier and Cox regression analyses revealed no significant survival difference between hereditary and somatic mutation groups (median overall survival 24.9 vs. 24.0 months; log-rank P = 0.69; hazard ratio = 1.19; 95% confidence interval, 0.52-2.73). These findings indicate that germline EGFR T790M represents a measurable hereditary variant within the South Caucasus population and emphasize the need to integrate germline testing into diagnostic workflows and familial risk assessment strategies for EGFR-driven NSCLC.

Prevention relevance: This study underscores the clinical importance of the rare germline EGFR T790M mutation in lung cancer. Detecting carriers with a family history may allow earlier diagnosis and inform targeted prevention, supporting more precise screening for high-risk individuals.

Lung cancer is the leading cause of cancer-related death. The incidence and mortality rates are higher for Black men than for White men. Protein arginine methyltransferase 6 (PRMT6) is known to be associated with lung cancer tumorigenesis and prognosis, and different levels of PRMT6 expression by race and sex may explain lung cancer disparity among Black men. To examine differences in PRMT6 by neighborhood violence as social stress, we obtained 88 formalin-fixed paraffin-embedded tissue sections of lung cancer patients. Using immunohistochemistry, samples were stained and scored (H-score) for PRMT6 levels. Logistic regression was used to examine the likelihood of having a high H-score (≥ median) by race and sex, controlling for age, smoking status, tumor type, grade, stage at diagnosis, and neighborhood homicide rate. The odds of having a high H-score were higher for Blacks than Whites, but there was no sex difference, controlling for tumor characteristics. High Homicide was negatively associated with high H-scores. Controlling for all other variables, the odds ratio (OR) of having a high H-score for Black vs. White males was 7.8, and the OR for Black vs. White females was 1.8 for the low homicide group. The ORs for both Black vs. White males and Black vs. White females were more than 3 times higher for the high homicide group. Overexpression of PRMT6 may explain lung cancer disparity in Black men. Exposure to social stress may contribute to higher levels of PRMT6. Social and biological differences affecting race and sex groups need further investigation.

Implementation of invitation systems has been shown to increase breast cancer screening rates. However, implementation of active outreach strategies in Latin American programs is limited. We conducted a pragmatic randomized controlled trial-the breast cancer ATICA study-to evaluate the effectiveness and implementation of a digital messaging-based intervention to increase breast cancer screening. A total of 248 Argentinian women ages 50+ years were recruited from 10 health care centers in Santa Fe, Argentina, and randomly assigned (1:1) to the intervention (n = 123) or control group (n = 125). The intervention included up to four Short Message Service (SMS) messages inviting participants to schedule an appointment for mammography through WhatsApp or the usual care control group (n = 125). Effectiveness outcomes were the proportion of women who underwent mammography within 105 or 45 days of enrollment. The reach, effectiveness, adoption, implementation, and maintenance framework was used to evaluate the implementation of the intervention. Our results showed that women in the intervention group (n = 123) were significantly more likely than women in the control group (n = 125) to undergo a mammography within 105 days (23.6% vs. 6.4%, difference 17%, 95% confidence interval, 7.7%-27.0%) and within 45 days (15.4% vs. 3.2%; difference 12%, 95% confidence interval, 4.3%-20.0%; P = 0.02). Our results also showed high acceptability and appropriateness of the intervention. Our study demonstrates that sending consecutive SMS messages, including a WhatsApp number to ask for an appointment, effectively increased breast cancer screening. This mobile health intervention could be an excellent option to improve access to breast cancer screening in low- and middle-resource settings in which active invitation systems are challenging to implement.

Prevention relevance: Breast cancer remains a significant public health concern, and strategies to improve access to screening are urgently needed. This study is one of the first pragmatic randomized controlled trials in Latin America that demonstrate the effectiveness and real-world implementation of an SMS-based intervention to increase participation in breast cancer screening.

Although the majority of gastric cancer research has focused on the treatment of late-stage tumor masses, intervention at precancerous stages represents a far more amenable strategy to achieve long-term prevention of cancer. In contrast with preventative strategies focusing on lifestyle changes and nutritional alterations, few efforts have evaluated the ability to use short-term therapeutic interventions to reverse precancer and thereby reduce risk for developing cancer. The distinct advantage of this approach lies in the recognition that precancerous lesions are far more homogeneous with fewer, if any, driver mutations that can lead to therapy resistance. Our recent studies have demonstrated that a limited 2- to 4-week course of MEK inhibitor in rodent models, and now in a human phase I trial, reduced intestinal metaplasia and increased normal acid-secreting parietal cells in the gastric mucosa. These findings demonstrate the efficacy of targeting the precancerous metaplasia with limited duration treatments that allow recrudescence of normal gastric lineages. Further progress to bring these approaches to clinical utility will require a major change in the outlook of pharmaceutical companies and physicians for initiatives to target precancer.