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

Protein advanced glycation end products (AGE) formed by nonenzymatic glycation can disrupt the normal structure and function of proteins, and stimulate the receptor for AGEs (RAGE), triggering intricate mechanisms that are etiologically related to various chronic diseases, including pancreatic cancer. Many common risk factors of pancreatic cancer are the major sources for the formation of protein AGEs and glycative stress in the human body. Abnormal accumulation of protein AGEs can impair the cellular proteome and promote AGE-RAGE driven pro-inflammatory signaling cascades, leading to increased oxidative stress, protease resistance, protein dysregulation, transcription activity of STAT, NF-κB, and AP-1, aberrant status in ubiquitin-proteasome system and autophagy, as well as other molecular events that are susceptible for the carcinogenic transformation towards the development of neoplasms. Here, we review studies to highlight our understanding in the orchestrated molecular events in bridging the impaired proteome, dysregulated functional networks, and cancer hallmarks initiated upon protein AGE formation and accumulation in pancreatic cancer.

Rutgers Cancer Institute of New Jersey (New Brunswick, NJ) is committed to providing cancer prevention education, outreach, and clinical services in our catchment area (CA). Our approach to cancer prevention includes ongoing surveillance to better understand the CA cancer burden and opportunities for intervention, leveraging community partnerships, and vigorously engaging diverse communities to understand and address their needs. This approach considers individual, sociocultural, environmental, biologic, system, and policy-level factors with an equity lens. Rutgers Cancer Institute has had substantial impact on cancer prevention (risk reduction, screening, and early detection) over the past five years, including the development of a CA data dashboard advancing implementation of evidence-based cancer control actions by leveraging 357 healthcare and community partners (with 522 partner sites). Furthermore, we provided professional education (attendance 19,397), technical assistance to community organizations (1,875 support sessions), educational outreach for community members (87,000+ through direct education), facilitated access to preventive services (e.g., 60,000+ screenings resulting in the detection of >2,000 malignant and premalignant lesions), contributed to advances in health policy and population-level improvements in risk reduction behaviors, screening, and incidence. With longer-term data, we will assess the impact of our cancer prevention efforts on cancer incidence, downward shifts in stage at diagnosis, mortality, and disparities.

Predicting an individual's risk of treatment discontinuation is critical for the implementation of precision chemoprevention. We developed partly conditional survival models to predict discontinuation of tamoxifen or anastrozole using patient-reported outcome (PRO) data from postmenopausal women with ductal carcinoma in situ enrolled in the NSABP B-35 clinical trial. In a secondary analysis of the NSABP B-35 clinical trial PRO data, we proposed two models for treatment discontinuation within each treatment arm (anastrozole or tamoxifen treated patients) using partly conditional Cox-type models with time-dependent covariates. A 70/30 split of the sample was used for the training and validation datasets. The predictive performance of the models was evaluated using calibration and discrimination measures based on the Brier score and AUC from time-dependent ROC curves. The predictive models stratified high-risk versus low-risk early discontinuation at a 6-month horizon. For anastrozole-treated patients, predictive factors included baseline body mass index (BMI) and longitudinal patient-reported symptoms such as insomnia, joint pain, hot flashes, headaches, gynecologic symptoms, and vaginal discharge, all collected up to 12 months [Brier score, 0.039; AUC, 0.76; 95% confidence interval (CI), 0.57-0.95]. As for tamoxifen-treated patients, predictive factors included baseline BMI, and time-dependent covariates: cognitive problems, feelings of happiness, calmness, weight problems, and pain (Brier score, 0.032; AUC, 0.78; 95% CI, 0.65-0.91). A real-time calculator based on these models was developed in Shiny to create a web-based application with a future goal to aid healthcare professionals in decision-making.

Prevention relevance: The dynamic prediction provided by partly conditional models offers valuable insights into the treatment discontinuation risks using PRO data collected over time from clinical trial participants. This tool may benefit healthcare professionals in identifying patients at high risk of premature treatment discontinuation and support interventions to prevent potential discontinuation.

Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.

Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgical prophylaxis.To validate a panel of methylated DNA markers (MDM) previously identified in sporadic colorectal cancer and endometrial cancer for discrimination of these cancers in LS.In a case-control design, previously identified MDMs for the detection of colorectal cancer and endometrial cancer were assayed by qMSP on tissue-extracted DNA. Results were normalized to ACTB values within each sample. Least absolute shrinkage and selection operator models to classify colorectal cancer and endometrial cancer were trained on sporadic cases and controls and then applied to classify colorectal cancer and endometrial cancer, in those with LS, and cross-validated.We identified colorectal cancer cases (23 with LS, 48 sporadic), colorectal controls (32 LS, 48 sporadic), endometrial cancer cases (30 LS, 48 sporadic), and endometrial controls (29 LS, 37 sporadic). A 3-MDM panel (LASS4, LRRC4, and PPP2R5C) classified LS-CRC from LS controls with an AUC of 0.92 (0.84-0.99); results were similar for sporadic colorectal cancer. A 6-MDM panel (SFMBT2, MPZ, CYTH2, DIDO1, chr10.4479, and EMX2OS) discriminated LS-EC from LS controls with an AUC of 0.92 (0.83-1.0); the AUC for sporadic endometrial cancer versus sporadic controls was nominally higher, 0.99 (0.96-1.0).MDMs previously identified in sporadic endometrial cancer and colorectal cancer discriminate between endometrial cancer and benign endometrium and colorectal cancer and benign colorectum in LS. This supports the inclusion of patients with LS within future prospective clinical trials evaluating endometrial cancer and colorectal cancer MDMs and may provide a new avenue for cancer screening or surveillance in this high-risk population.

Prevention relevance: Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgery. Methylated DNA markers previously identified in sporadic endometrial cancer and colorectal cancer discriminate between benign and cancer tissue in LS.

Although pediatric, adolescent, and young adult (PAYA) cancer survivors are at increased risks for secondary cancers, their HPV vaccine uptake rates are poor. Therefore, we conducted a mixed-methods study to identify the barriers and opportunities for HPV vaccine delivery among PAYA cancer care providers. We distributed a semistructured questionnaire to a professional organization comprised of PAYA oncology and hematology healthcare providers between April and July 2022. Questionnaire measures included demographic and practice characteristics, HPV vaccine knowledge, willingness, barriers, opportunities, and roles for HPV vaccine delivery. Descriptive characteristics were generated for quantitative data, and content analysis was used to identify themes. A total of 49 providers responded to our survey. A majority were female (68%) and non-Hispanic white (74%). Approximately 76% were oncology or hematology physicians, and most worked in a cancer center or children's hospital (86%). Over half (63%) had been practicing for >15 years, and a majority saw patients ages 11 to 17. Although less than half reported discussing HPV vaccination with their patients, 69% were willing to become involved in HPV vaccine delivery. The most frequently reported barriers identified in our content analysis were related to system-level factors. Furthermore, providers identified opportunities within cancer prevention education, transitions in care, and at the system-level. Although barriers to HPV vaccination persist in cancer care, most providers perceived there to be opportunities to become involved in HPV vaccine delivery. Identifying strategies for PAYA oncology and hematology healthcare providers to adopt a stronger role in HPV vaccination remains a significant opportunity for future implementation research.

Prevention relevance: This mixed-methods study is the first to investigate and assess barriers and opportunities for HPV vaccine delivery among PAYA cancer healthcare providers. Our findings can serve as an important framework for future implementation research targeted towards HPV vaccine delivery in cancer clinical settings. See related Spotlight, p. 545.

FGFR3 and PIK3CA are among the most frequently mutated genes in bladder tumors. We hypothesized that recurrent mutations in these genes might be caused by common carcinogenic exposures such as smoking and other factors. We analyzed 2,816 bladder tumors with available data on FGFR3 and/or PIK3CA mutations, focusing on the most recurrent mutations detected in ≥10% of tumors. Compared to tumors with other FGFR3/PIK3CA mutations, FGFR3-Y375C was more common in tumors from smokers than never-smokers (P = 0.009), while several APOBEC-type driver mutations were enriched in never-smokers: FGFR3-S249C (P = 0.013) and PIK3CA-E542K/PIK3CA-E545K (P = 0.009). To explore possible causes of these APOBEC-type mutations, we analyzed RNA sequencing (RNA-seq) data from 798 bladder tumors and detected several viruses, with BK polyomavirus (BKPyV) being the most common. We then performed IHC staining for polyomavirus (PyV) Large T-antigen (LTAg) in an independent set of 211 bladder tumors. Overall, by RNA-seq or IHC-LTAg, we detected PyV in 26 out of 1,010 bladder tumors with significantly higher detection (P = 4.4 × 10-5), 25 of 554 (4.5%) in non-muscle-invasive bladder cancers (NMIBC) versus 1 of 456 (0.2%) of muscle-invasive bladder cancers (MIBC). In the NMIBC subset, the FGFR3/PIK3CA APOBEC-type driver mutations were detected in 94.7% (18/19) of PyV-positive versus 68.3% (259/379) of PyV-negative tumors (P = 0.011). BKPyV tumor positivity in the NMIBC subset with FGFR3- or PIK3CA-mutated tumors was also associated with a higher risk of progression to MIBC (P = 0.019). In conclusion, our results support smoking and BKPyV infection as risk factors contributing to bladder tumorigenesis in the general patient population through distinct molecular mechanisms.

Prevention relevance: Tobacco smoking likely causes one of the most common mutations in bladder tumors (FGFR3-Y375C), while viral infections might contribute to three others (FGFR3-S249C, PIK3CA-E542K, and PIK3CA-E545K). Understanding the causes of these mutations may lead to new prevention and treatment strategies, such as viral screening and vaccination.

The incidence of second primary cancers is rising particularly among pediatric, adolescent, and young adult (PAYA) cancer survivors. While human papillomavirus (HPV)-associated cancers can be prevented by vaccination, their uptake is lower and delayed in this group. Because a recommendation from a health care provider is the strongest predictor of HPV vaccination, there are great opportunities for PAYA cancer care providers to positively impact HPV vaccination rates. Prioritizing PAYA cancer care provider education as well as improving the education of and coordination with primary care providers are viewed as opportunities to encourage HPV vaccine uptake and prevent future cancers. See related article by Garcia et al., p. 581.

Therapeutic targeting of RAS-mutated cancers is difficult, whereas prevention or interception (treatment before or in the presence of preinvasive lesions) preclinically has proven easier. In the A/J mouse lung model, where different carcinogens induce tumors with different KRAS mutations, glucocorticoids and retinoid X receptor (RXR) agonists are effective agents in prevention and interception studies, irrespective of specific KRAS mutations. In rat azoxymethane-induced colon tumors (45% KRAS mutations), cyclooxygenase 1/2 inhibitors and difluoromethylornithine are effective in preventing or intercepting KRAS-mutated or wild-type tumors. In two KRAS-mutant pancreatic models multiple COX 1/2 inhibitors are effective. Furthermore, combining a COX and an EGFR inhibitor prevented the development of virtually all pancreatic tumors in transgenic mice. In the N-nitroso-N-methylurea-induced estrogen receptor-positive rat breast model (50% HRAS mutations) various selective estrogen receptor modulators, aromatase inhibitors, EGFR inhibitors, and RXR agonists are profoundly effective in prevention and interception of tumors with wild-type or mutant HRAS, while the farnesyltransferase inhibitor tipifarnib preferentially inhibits HRAS-mutant breast tumors. Thus, many agents not known to specifically inhibit the RAS pathway, are effective in an organ specific manner in preventing or intercepting RAS-mutated tumors. Finally, we discuss an alternative prevention and interception approach, employing vaccines to target KRAS.

Health behavior theories have identified predictors of colorectal cancer screening. This study aimed to determine the psychosocial profiles of a predominantly Hispanic population of primarily Mexican origin receiving a colorectal cancer screening intervention and whether a specific combination of psychosocial profiles modified the effect of colorectal cancer screening intervention on colorectal cancer screening uptake.A total of 467 participants aged 50 to 75 years due for colorectal cancer screening received an educational intervention. Latent profile analysis (LPA) was performed on baseline psychosocial constructs to identify the homogenous clustering of individuals with similar psychosocial constructs. In addition, colorectal cancer screening rates and changes in psychosocial scores between the latent groups were compared.Three psychosocial profiles, including a low benefit and high susceptibility group (LBHS), a high benefit and low susceptibility group (HBLS), and a high barrier and high susceptibility group (HBHS), were identified in this study. The HBLS group had the lowest susceptibility, with no improvement in benefits and barriers. This group had the lowest screening rate (80.85%) compared with 88.8% in LBHS and 86.3% in HBHS following the intervention. Finally, the intervention effect size on psychosocial score changes was smaller in HBLS than in other groups.This subgroup analysis suggests that colorectal cancer educational interventions should be tailored to improve the benefits and barriers among individuals with high susceptibility scores.

Prevention relevance: This LPA analysis provides some direction for tailoring colorectal cancer educational interventions to improve the benefits and barriers among individuals with high susceptibility scores in hard-to-screen populations such as our border population.