Approach For Cancer Prevention Research Articles

Challenges associated with follow-up care after implementation of an HPV screen-and-treat program with ablative therapy for cervical cancer prevention

BackgroundCervical cancer is a preventable cancer; however, decreasing its prevalence requires early detection and treatment strategies that reduce rates of loss to follow-up. This study explores factors associated with loss to follow-up among HPV-positive women after implementation of a new HPV-based screen-and-treat approach for cervical cancer prevention in Iquitos, Peru.MethodsWe conducted semi-structured interviews with “obstetras” (i.e., midwives) (n = 15) working in cervical cancer prevention and women (n = 24) who were recorded as lost to follow-up after positive HPV results. We used the Health Care Access Barriers Model to guide analyses. We utilized manifest content analysis to describe barriers to follow-up according to the obstetras and thematic analysis to report themes from the women’s perspectives. We also report the steps and time taken to contact women.ResultsWe found an incomplete and fragmented patient monitoring system. This incomplete system, in conjunction with challenges in contacting some of the women, led to structural barriers for the obstetras when attempting to deliver positive results. Women in this study expressed a desire to receive treatment, however, faced cognitive barriers including a lack of understanding about HPV results and treatment procedures, fear or anxiety about HPV or treatment, and confusion about the follow-up process. Women also reported having important work matters as a barrier and reported frequently using natural medicine. Reported financial barriers were minimal.ConclusionThis study highlights the barriers to follow-up after implementation of a primary-level HPV-based screen-and-treat approach. While some barriers that have previously been associated with loss to follow-up were not as prominently observed in this study (e.g., financial), we emphasize the need for screen-and-treat programs to focus on strategies that can address incomplete registry systems, structural challenges in results delivery, cognitive barriers in understanding results and treatment, and work-related barriers.

A computational approach for screening of phytochemicals from Oxalis corniculata as promising anti-cancer candidates

Objectives.In silico techniques are a highly efficient, cost-effective, and rapid approach to identify potent herbal lead compounds with therapeutic potential against cancer. Phytochemicals are abundant in plants and may represent a promising cancer prevention and treatment approach. The plant species Oxalis corniculata has long been employed in traditional medicine to treat various diseases. Indeed, previous studies have demonstrated the anti-cancer properties of the crude extract obtained from this plant. However, further research is essential to elucidate precisely the underlying molecular mechanisms responsible for these activities.Methods.The study investigated the potential of bioactive compounds from O. corniculata to bind with different targets of anti-cancer drugs. Employing molecular docking and drug-likeness, 19 bioactive compounds from the plant were tested as potential anti-cancer leads. Compounds that exhibit both favorable drug-likeness and binding energies comparable to those of standard drugs like curcumin, doxorubicin, and paclitaxel were selected for further evaluation of their pharmacokinetic properties.Results and Conclusions.Among the 19 selected phytoconstituents of O. corniculata, compounds 15 and 16 exhibited the most effective binding energy (−8.68, −8.22 and −8.70, −8.22, −8.52 kcal/mol, respectively) with key cancer targets including Programmed death-ligand 1 (PDB: 7bea), B-Raf proto-oncogene, serine/threonine kinase (PDB: 8c7y) and poly (ADP-ribose) polymerase (PDB: 7kk4). Pharmacokinetic and toxicity analysis provided additional insights into the potential of these compounds as anti-cancer drugs. The computational analysis holds promise in accelerating the development of novel drug therapies aimed at treating various cancer types.

Awareness of cervical cancer risk factors and preventive approaches, and perceived causes of cervical cancer among secondary school girls: a cross-sectional study in Northern Uganda

Background The majority of women in low- and middle-income countries have low awareness of cervical cancer. This study sought to establish awareness of cervical cancer risk factors and preventive approaches, as well as sources of information and perceived causes of cervical cancer among secondary school girls in northern Uganda. Methods This was a cross-sectional study conducted in rural northern Uganda. We collected data using an investigator administered pre-tested questionnaire. Analysis was done with STATA version 14.0. Multivariate analyses with logistic regressions models were used to determine magnitudes of association between independent and outcome variables. Odds ratios and accompanying 95% confidence intervals are reported. Statistical significance was considered if the two sided p-value <.05. Results Most participants (97%; n = 624) had heard of cervical cancer before this study. The most common source of information about cervical cancer was friends (31.1%; n = 194). More than half of the participants (59%; n = 380) had heard about a vaccine that prevents cervical cancer, but only a third (33%; n = 124) had ever received a dose of the vaccine. The majority of participants (89%; n = 550) reported that cervical cancer could be prevented; however only half (52%; n = 290) knew that vaccination of girls aged 9–13 years could prevent cervical cancer. The majority of participants did not recognize the risk factors for cervical cancer; for example, only 15% (n = 98), 7% (n = 45), and 1.4% (n = 9) recognized early onset of sexual intercourse, infection by the human papillomavirus (HPV), and smoking respectively. On adjusting for age, students’ class, and religion, students in schools with school health programs were twice (aOR = 2.24: 95%CI; 1.24–4.06) more likely to know that cervical cancer is preventable. Conclusion Secondary school girls need information on cervical cancer risk factors and approaches to prevention so that they may avoid exposures to the risk factors and promptly seek and undertake preventive approaches including HPV vaccinations.

Inhibition of non-small cell lung cancer metastasis by knocking down APE1 through regulating myeloid-derived suppressor cells-induced immune disorders.

Non-small cell lung cancer (NSCLC) represents a highly immunogenic malignancy. Immunologic tolerance facilitated by myeloid-derived suppressor cells (MDSCs) is implicated in primary or secondary resistance mechanisms in NSCLC. The potential role of APE1 in regulating NSCLC metastasis by targeting MDSCs remains uncertain. This study utilized a plasmid, Plxpsp-mGM-CSF, to induce elevated granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in A549 cells. Tumor transplantation experiments involved A549, A549+GM-CSF, and A549+GM-CSF-siAPE1 cell lines. Evaluation encompassed MDSCs, Treg cells, IgG, CD3, and CD8 levels. Notably, lung cancer tissues and cells displayed markedly reduced APE1 expression. siAPE1 transfection significantly curtailed tumor growth compared to the A549+GM-CSF group. APE1 knockdown orchestrated immune system modulation in lung tumor mice, characterized by diminished MDSCs but augmented Treg cells, IgG, CD3, and CD8. Additionally, APE1 knockdown led to reduced levels of pro-MDSC cytokines (HGF, CCL5, IL-6, CCL12) and a concurrent upregulation of the anti-MDSC cytokine IL-1ra. Furthermore, APE1 knockdown impeded cell viability in both A549 and H1650 cells. Transplantation of A549-GM-CSF amplified MDSC levels, fostering accelerated tumor growth, while mitigating MDSC levels through APE1 knockdown hindered tumor progression and alleviated inflammatory infiltration in lung cancer tissues. Strategies targeting the APE1/MDSC axis offer a promising approach for lung cancer prevention and treatment, presenting novel insights for NSCLC management.

Risk factors associated with liver cancer in all US participants.

e16276 Background: Liver cancer incidence rates have risen in recent years, more than tripled since 1980, and the liver cancer-caused death rates have more than doubled during the same time. The objective of this research was to identify significant risk factors (both genetic and environmental) that may contribute to the liver cancer development. Methods: The study cohort was obtained from the All of Us (AoU) population with the latest data (data cutoff date 07/01/22) of 413,457 participants. The baseline survey data, genomics data, and electronic medical data have been queried for studying the risk factors to the liver cancer. Baseline demographics, comorbidities, AUDIT-C score (positive score, defined as &gt; = 5 for men and &gt; = 4 for women, was considered as with high risk of alcoholic hepatitis), social determinants of health (SDoH), and genetic variants were evaluated using the logistic regression models respecting the prevalence of liver cancer. Results: The study cohort included total 254,356 participants with their EMR data, genomics data, and AUDIT-C answers (median age 55 years, 61% women, 45% from minority groups, 19% Hispanics). Among them, 1,048 patients were diagnosed liver cancer. Using the logistic regression models, SDoHs showed association with the development of liver cancer. Retired groups demonstrated higher risk (adjusted odds ratio or aOR: 1.34, 95%CI:1.09-1.67) as well as the unemployed groups (aOR: 1.19, 95%CI: 0.98-1.46). C &gt; G variants at 22:43928847 (aOR: 1.18, 95%CI: 1-1.39), G &gt; G variants at 22:43937814 (aOR: 1.35, 95%CI: 0.97-1.82), and G &gt; A variants at 22:43932850 (aOR: 1.18, 95%CI: 0.99-1.39) of gene PNPLA3 were associated with higher risks. C &gt; T variants at 19:19268740 of gene TM6SF2 demonstrated higher risks (aOR: 1.23, 95%CI: 0.97-1.54) as well. The following demographic and comorbidities factors significantly contributed to the development of liver cancer: 45 to 65 age group (aOR: 6.89, 95%CI: 4.05-13), greater than 65 (aOR: 9.99, 95%CI: 5.84-18.91), hepatitis c virus infection (aOR: 12.46, 95%CI: 10.51-14.75), diabetes with chronic complications (aOR: 1.49, 95%CI: 1.25-1.78 ), diabetes without chronic complications (aOR: 1.81, 95%CI: 1.53-1.2.14). Conclusions: This study reveals that multiple risk factors are significantly associated with the liver cancer ranging from common genetic variants, socioeconomic conditions, age, viral infection, and diabetes. Thus, it is very important to take a comprehensive approach for the liver cancer prevention.

Significant results from a major multi-year, multi-cancer follow-up study with an enrollment of over 19,000 individuals.

10539 Background: Multi-cancer screening has become a major approach for early stage cancer screening and prevention. However, there has been very few reported multi-year, multi-cancer follow-up studies to validate the effectiveness of multi-cancer screening. We report a number of significant, major findings from what we believe the first large scale, multi-year, multi-cancer follow-up study. Methods: In this study, cancer differentiation analysis (CDA) technology, a bio-physics based detection platform, has been used to screen over 200,000 individuals in a general population. Based on the CDA test values, individuals have been classified into high risk, medium risk and low risk (for cancer) groups. Up to January 31, 2024, a total of 19,141 individuals have been enrolled, with 1,122 in high risk, 15,784 in medium risk, and 2,235 in low risk group. In this follow-up study, enrolled individuals were initially contacted within 6 months (high risk individuals were contacted within 15 days after the test report became available) and subsequently on an annual basis, and their health conditions were recorded. Results: Up to January 31, 2024, 256 individuals have been confirmed with cancer, 1,607 confirmed with pre-cancer diseases and benign tumors, and finally, 1,378 confirmed with diseases. When enrollment is normalized (number of individuals enrolled into each group is equal), for confirmed cancer group, 91.4% is in high risk group, 7.5% in medium risk group and only 1.1% in low risk group. The above result is very significant, indicating that multi-cancer screening using CDA technology is very effective. As shown, there are 23 types of cancer (Table). There are close to 30 types of pre-cancer diseases and benign tumors confirmed. Above results showed that CDA technology is indeed very effective in screening out multiple cancer types (including some cancer types which do not yet have other effective IVD tests such as thyroid cancer and esophageal cancer). The results also show that this approach is very helpful for cancer prevention as it screened out large number of pre-cancer diseases and benign tumor types. Conclusions: A large scale, multi-year, multi-cancer follow-up study has been carried out. Results showed that CDA technology is effective for multi-cancer screening in a general population.[Table: see text]

Oral dysbiosis and risk of gastrointestinal cancers: A systematic review and meta-analysis of longitudinal studies.

Poor oral health and oral dysbiosis were found to be associated with cancers, especially of the gastrointestinal (GI)system. But the cause-and-effect relationship and the effect of the risk are not yet known due to scarcity of literature. Understanding such risk relationship can contribute to an integrated multi-disciplinary approach for GI cancer prevention. The aim of the present systematic review and meta-analysis is to assess the role of oral dysbiosis on increasing the risk of digestive system cancers. To evaluate the effect of poor oral health on increasing the risk of gastrointestinal cancers. We conducted a systematic search following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in databases PubMed, Elsevier, Wiley's online library and Web of Science from inception to February 2023 to include recent cohort studies that assessed the association between poor oral health and the risk of cancer. We assessed bias using the New Castle Ottawa scale. We used inferential statistics to describe the effect of oral dysbiosis on gastrointestinal cancers. We performed a sub-group analysis to assess the effect of oral conditions on individual cancers. We included 10 longitudinal studies in the meta-analysis. The overall effect size of poor oral health and GI cancer risk was hazard's ratio (HR) =1.30 (95% CI: [1.14, 1.46]) (p<0.001) (I2 = 68.78). Sub-group analysis indicated that poor oral health increases the risk of esophageal cancer HR=1.61 (95% CI: [1.37, 1.85]), stomach cancer HR=1.33 (95% CI: [1.08, 1.58]), pancreatic cancer HR=1.90 (95%CI; [1.29, 2.50]) and colorectal and hepatocellular carcinoma HR=1.16 (95% CI: [1.08, 1.23]). The meta-analysis indicated that poor oral health was significantly associated with increasing the risk of GI cancers.

Positive Nipple Margins in Nipple-Sparing Mastectomy: Management of Nipples Containing Cancer or Atypia.

Nipple-sparing mastectomy (NSM) is an oncologically safe approach for breast cancer treatment and prevention; however, there are little long-term data to guide management for patients whose nipple margins contain tumor or atypia. NSM patients with tumor or atypia in their nipple margin were identified from a prospectively maintained, single-institution database of consecutive NSMs. Patient and tumor characteristics, treatment, recurrence, and survival datawere assessed. A total of 3158 NSMs were performed from June 2007 to August 2019. Nipple margins contained tumor in 117 (3.7%) NSMs and atypia only in 164 (5.2%) NSMs. Among 117 nipple margins that contained tumor, 34 (29%) margins contained invasive cancer, 80 (68%) contained ductal carcinoma in situ only, and 3 (3%) contained lymphatic vessel invasion only. Management included nipple-only excision in 67 (57%) breasts, nipple-areola complex excision in 35 (30%) breasts, and no excision in 15 (13%) breasts. Only 23 (24%) excised nipples contained residual tumor. At 67 months median follow-up, there were 2 (1.8%) recurrences in areolar or peri-areolar skin, both in patients with nipple-only excision. Among 164 nipple margins containing only atypia, 154 (94%) nipples were retained. At 60 months median follow-up, no patient with atypia alonehad a nipple or areola recurrence. Nipple excision is effective management for nipple margins containing tumor. No intervention is required for nipple margins containing only atypia. Our results support broad eligibility for NSM with careful nipple margin assessment.

A contemporary review of breast cancer risk factors and the role of artificial intelligence.

Breast cancer continues to be a significant global health issue, necessitating advancements in prevention and early detection strategies. This review aims to assess and synthesize research conducted from 2020 to the present, focusing on breast cancer risk factors, including genetic, lifestyle, and environmental aspects, as well as the innovative role of artificial intelligence (AI) in prediction and diagnostics. A comprehensive literature search, covering studies from 2020 to the present, was conducted to evaluate the diversity of breast cancer risk factors and the latest advances in Artificial Intelligence (AI) in this field. The review prioritized high-quality peer-reviewed research articles and meta-analyses. Our analysis reveals a complex interplay of genetic, lifestyle, and environmental risk factors for breast cancer, with significant variability across different populations. Furthermore, AI has emerged as a promising tool in enhancing the accuracy of breast cancer risk prediction and the personalization of prevention strategies. The review highlights the necessity for personalized breast cancer prevention and detection approaches that account for individual risk factor profiles. It underscores the potential of AI to revolutionize these strategies, offering clear recommendations for future research directions and clinical practice improvements.

Recent Advances in Machine Learning Methods for LncRNA-Cancer Associations Prediction

Abstract: In recent years, long non-coding RNAs (lncRNAs) have played important roles in various biological processes. Mutations and regulation of lncRNAs are closely associated with many human cancers. Predicting potential lncRNA-cancer associations helps to understand cancer's pathogenesis and provides new ideas and approaches for cancer prevention, treatment and diagnosis. Predicting lncRNA-cancer associations based on computational methods helps systematic biological studies. In particular, machine learning methods have received much attention and are commonly used to solve these problems. Therefore, many machine learning computational models have been proposed to improve the prediction performance and achieve accurate diagnosis and effective treatment of cancer. This review provides an overview of existing models for predicting lncRNA-cancer associations by machine learning methods. The evaluation metrics of each model are briefly described, analyzed the advantages and limitations of these models are analyzed. We also provide a case study summary of the two cancers listed. Finally, the challenges and future trends of predicting lncRNA-cancer associations with machine learning methods are discussed.

The Multiprong Approach in Breast Cancer Prevention: Current Scenario and Future Directions!

Abstract Breast cancer stands as the most diagnosed cancer among women globally, accounting for one in four cancer cases. Despite this, there is a scarcity of literature addressing prevention strategies and approaches aimed at reducing the risk of breast cancer acquisition, as well as secondary prevention strategies aimed at mitigating morbidity and mortality associated with the disease. The objective of this review is to underscore novel approaches and strategies for the prevention and management of breast cancer. This review is particularly important in the context of resource-poor and developing countries facing challenges in curbing the burden of this disease. This review highlights the importance of addressing multifactorial risk factors with a multiprong approach strategy. This approach encompasses dietary and lifestyle modification, alongside pharmaceutical interventions. Furthermore, recent advances and future directions, including nutrigenomics and early detection strategies, are elucidated. Coordinated and planned efforts at all levels are imperative, encompassing the effective utilization of health education, health promotion, capacity building, and the integration of emerging modalities like precision medicine, targeted approaches, nutrigenomics, and advanced screening tools such as thermography. Exploration of avenues like chemoprevention, precision medicine, and immunoprevention, including targeted approaches, holds promise for further investigation in the future.

Classification of chronic gastritis: historical digression and current state of the issue. A review

For more than a century, physicians have noted the relationship of chronic gastritis with the development of gastric cancer, which prompted great interest in the study and systematization of chronic gastritis in order to better understand the prognosis and develop approaches for cancer prevention. The accumulated knowledge about the etiology, pathogenesis and morphology of gastritis has made it possible to coordinate the general ideas about gastritis in the classifications used by practicing physicians today, and the systems developed and implemented into practice for assessing atrophy/intestinal metaplasia (OLGA/OLGIM) undoubtedly can help the doctor in determining the tactics of curation of the patient.

Regular Use of Aspirin and Statins Reduces the Risk of Cancer in Individuals with Systemic Inflammatory Diseases.

Individuals with systemic inflammatory diseases derive chemoprotective benefits from aspirin and statins, providing a precision cancer prevention approach to address the personal and public challenges posed by cancer.

Abstract 2242: Clinical trials knowledge among Hispanic/Latino gastrointestinal cancer survivors in Puerto Rico

Abstract The discovery of innovative cancer prevention and treatment approaches relies on voluntary participation in clinical trials (CTs); however, participation remains low among minorities/ethnic groups. Knowledge of CTs has been reported as a barrier to CT participation. Yet, there is limited understanding regarding CTs knowledge and participation among gastrointestinal (GI) cancer survivors in Puerto Rico (PR). Colorectal cancer is the second leading cause of death in PR, accounting for 13% among men and women. We aimed to describe the knowledge and factors associated with cancer-related CTs among Hispanic/Latino GI cancer survivors in PR. We analyzed preliminary data from an ongoing cross-sectional study targeting Hispanic/Latino GI cancer survivors aged 21+ years in PR. The study employed an interviewer-administered questionnaire to assess participants' awareness, knowledge, and participation in cancer-related CTs, and the social determinants of health (SDoH) associated with CT participation. Descriptive statistics were used to describe the population. Pearson chi-square test or Fisher's exact test were used accordingly to assess significance. A generalized linear model was used to estimate the odds ratios and 95% confidence intervals (CI) for significant variables. As of November 9, 2023, 59 Hispanic/Latino GI cancer survivors had completed the questionnaire. Women accounted for 56% of the sample, and the median age of study participants was 65 years (IQR: 19). Racial identity among participants was primarily white (63%), followed by other races (18%) and African-American (18%). Most participants were in complete or partial remission from cancer (83%). A significant proportion of the respondents reported having at least 12th grade (81%) and an annual income of $20,000 or higher (67%). Most participants (76%) accurately identified the correct definition of a CT. Participants with 12th grade or more had 1.5 (95% CI:1.1-1.9) times the possibility to correctly identify the CT definition compared to to those with less than 12th grade. Similarly, respondents with an annual income equal or higher than $20,000 had 1.4 (95% CI:1.1-1.8) times the possibility to correctly identify the CT definition compared to their counterpart. Furthermore, 93.2% of respondents had a score of at least 80% of correct responses regarding their knowledge of CTs. Although nearly 100% of the respondents knew about CTs, only 20% had participated. Despite a high level of knowledge regarding CTs in PR, a significant gap remains between knowledge and participation. Factors such as education and income might play a role in understanding the CT definition. However, the barriers preventing participation, including SDoH need further exploration. Enhancing participation among Hispanic/Latino GI cancer survivors in PR is essential for advancing cancer research and improving outcomes for this at-risk population. Citation Format: Hilmaris Centeno-Girona, Marievelisse Soto-Salgado, Mariela Bournigal-Feliciano, Sofia F. Contreras-Fernández, Karina Torres-Mojica, Victoria Williams, Arnethea L. Sutton, Katherine Tossas, Robert Winn, Marcia R. Cruz-Correa. Clinical trials knowledge among Hispanic/Latino gastrointestinal cancer survivors in Puerto Rico [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2242.

Abstract 4777: A small-molecule SMUG1 activator enhances repair of 5-hydroxymethyl-2’-deoxyuridine-mediated pyrimidine lesions in DNA

Abstract Background: Pharmacological upregulation of DNA repair pathways presents a potentially promising approach for cancer prevention in populations that are genetically high-risk. SMUG1, an enzyme involved in base excision repair, removes uracil and certain oxidized bases from DNA to mitigate adverse genotoxic and mutagenic effects and represents a promising target for cancer therapy. A growing body of evidence suggests that SMUG1 is involved in tumorigenesis, and deficiency of SMUG1 correlates with poor prognosis in several cancers. We hypothesize that upregulation of SMUG1 by a small molecule activator may be a viable strategy for reducing tumorigenesis in at-risk populations. We report on the properties of SU0547 - a SMUG1 activator that was derived from the EGFR inhibitor drug gefitinib - which shows reduced kinase inhibition and potent activation of SMUG1 both in vitro and in human cell lines. Methods: MTT proliferation assays were used to screen for toxicity and to determine the effect of SU0547 on 5-hydroxymethyl-2’-deoxyuridine (5-hmdU)-treated cell lines. The effect of the compound on SMUG1 expression was determined by Western blot and RT-qPCR while its effect on DSBs via γH2AX expression in 5-hmdU-treated cells was determined by immunofluorescence and Western blot. Results: SU0547 activates SMUG1 by 347 ± 50% in vitro at 100 nM, with an AC50 of 2.55 ± 0.62 µM. We examined whether it can modulate SMUG1 activity in a panel of human cell lines by artificially inducing DNA damage with the native SMUG1 substrate 5-hmdU and treating cells with the activator. In all five human cancer cell lines tested, SU0547 caused the cells to become significantly more resistant to 5-hmdU by factors of 2.1 to 5.3-fold. A series of CRISPR-Cas9 generated SMUG1 KO cell lines showed resistance to 5-hmdU and SU0547 had no effect on these treated cells, confirming that this activator acts on endogenous SMUG1. To determine the effect of the activator on double-strand breaks (DSBs), cells were treated with 5-hmdU with or without the compound and DSBs were visualized and quantitated by examining γH2AX foci. 5-hmdU treatment induced γH2AX foci while SU0547 treatment significantly reduced these foci to near or below baseline levels. These results were confirmed using Western blot quantitation of γH2AX. Conclusions: We envision that this activator will serve as a useful tool for further studying the role of SMUG1 in mediating 5-hmdU toxicity and will enable the testing of our hypothesis that enhancing DNA repair processes may serve to inhibit mutagenesis and slow progression of pre-neoplastic lesions to invasive cancers associated with genomic instability. Citation Format: Lisa A. McPherson, Yixuan Gao, Shanthi Adimoolam, Samyuktha Suresh, David L. Wilson, Ishani Das, Elizabeth R. Park, Christine S. Ng, Yong Woong Jun, James M. Ford, Eric T. Kool. A small-molecule SMUG1 activator enhances repair of 5-hydroxymethyl-2’-deoxyuridine-mediated pyrimidine lesions in DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4777.

Abstract 816: Implementation of a community-based multi-component cancer screening intervention supported by a cross-sector community coalition

Abstract It is widely agreed that screening and early detection of cancer saves lives. However, disparities exist in those who received routine screenings and variability in clinic screening protocol. Working with community-based clinics on quality improvement as well as systematically screening all eligible patients can result in increased equity in screening and thus early detection. Be Well Communities™ is MD Anderson’s place-based approach for cancer prevention and control, working with communities to promote wellness and address modifiable risk factors for cancer. The first several years of the initiative in Baytown focused on healthy eating and active living interventions for cancer prevention, over time the community’s trust and appetite increased which allowed for additional and more traditional cancer prevention interventions (e.g., human papilloma virus vaccination, screening). In this project, three evidence-based interventions for cancer screening were implemented in collaboration with Chambers Health, a local FQHC in Baytown, Texas, to work toward addressing the disparities in screening outcomes experienced by community residents. Chambers Health compliance rates have increased since the beginning of the Cancer Screening Navigation program, supported by Be Well Communities. Two full-time patient navigators are supported to facilitate increased screening through patient education, increased clinic compliance and development of standard operating procedures for navigation related operations. In addition, one full-time Outreach Coordinator is supported to engage with patients and provide education on cancer screenings. Compared to 2022, there was a 39% increase in colon cancer screening compliance rates, a 25% increase in cervical cancer screening compliance rates, and a 47% increase in breast cancer screening compliance rates. Compliance refers to any patient who is up-to-date in their cancer screenings. The Be Well Communities team supported Chambers Health through funding, technical assistance, and capacity building. They were then able to provide culturally relevant and high-quality care to enhance community capacity to address low rates of cancer screening in Baytown. Furthermore, Chambers Health has since integrated the patient navigators and Outreach Coordinator into their operational budget, a notable systems change for the organization and demonstration of commitment to the project and continued clinic quality improvement and more so dedication to the patients served. Citation Format: Ruth Rechis, Mayra Aquino, Haley Gardiner, Blanca Puga, Michael T. Walsh. Implementation of a community-based multi-component cancer screening intervention supported by a cross-sector community coalition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 816.

Cost-Effectiveness of Population-Based Multigene Testing for Breast and Ovarian Cancer Prevention

The current method of BRCA testing for breast and ovarian cancer prevention, which is based on family history, often fails to identify many carriers of pathogenic variants. Population-based genetic testing offers a transformative approach in cancer prevention by allowing for proactive identification of any high-risk individuals and enabling early interventions. To assess the lifetime incremental effectiveness, costs, and cost-effectiveness of population-based multigene testing vs family history-based testing. This economic evaluation used a microsimulation model to assess the cost-effectiveness of multigene testing (BRCA1, BRCA2, and PALB2) for all women aged 30 to 35 years compared with the current standard of care that is family history based. Carriers of pathogenic variants were offered interventions, such as magnetic resonance imaging with or without mammography, chemoprevention, or risk-reducing mastectomy and salpingo-oophorectomy, to reduce cancer risk. A total of 2000 simulations were run on 1 000 000 women, using a lifetime time horizon and payer perspective, and costs were adjusted to 2022 US dollars. This study was conducted from September 1, 2020, to December 15, 2023. The main outcome measure was the incremental cost-effectiveness ratio (ICER), quantified as cost per quality-adjusted life-year (QALY) gained. Secondary outcomes included incremental cost, additional breast and ovarian cancer cases prevented, and excess deaths due to coronary heart disease (CHD). The study assessed 1 000 000 simulated women aged 30 to 35 years in the US. In the base case, population-based multigene testing was more cost-effective compared with family history-based testing, with an ICER of $55 548 per QALY (95% CI, $47 288-$65 850 per QALY). Population-based multigene testing would be able to prevent an additional 1338 cases of breast cancer and 663 cases of ovarian cancer, but it would also result in 69 cases of excess CHD and 10 excess CHD deaths per million women. The probabilistic sensitivity analyses show that the probability that population-based multigene testing is cost-effective was 100%. When the cost of the multigene test exceeded $825, population-based testing was no longer cost-effective (ICER, $100 005 per QALY; 95% CI, $87 601-$11 6323). In this economic analysis of population-based multigene testing, population-based testing was a more cost-effective strategy for the prevention of breast cancer and ovarian cancer when compared with the current family history-based testing strategy at the $100 000 per QALY willingness-to-pay threshold. These findings support the need for more comprehensive genetic testing strategies to identify pathogenic variant carriers and enable informed decision-making for personalized risk management.

Abstract A035: An analysis of the contribution of the glutathione and thioredoxin antioxidant pathways to triple negative breast cancer development

Abstract The accumulation of reactive oxygen species (ROS), also known as oxidative stress, occurs during tumorigenesis, for example because of changes in cell metabolism or in a cell’s microenvironment. Since elevated ROS can cause senescence or cell death, cells with increased ROS-buffering capacity are selected for during tumor initiation and progression. It is unknown, however, at which stage during carcinogenesis oxidative stress develops, which oxidative response programs are engaged, and whether there is a spatial distribution of oxidative stress within the tissue. Our lab developed a murineTrp53loxp/loxp Brca1loxp/loxp model of triple negative breast cancer (TNBC) that histologically recapitulates the disease progression of human, progressing from normal epithelium, to abnormal proliferation, before advancing to adenocarcinoma. We are applying cyclic immunofluorescence and spatial transcriptomics to study relevant antioxidant pathways in situ. These studies are complemented by analyses of previously published scRNAseq datasets from similar models. Our initial observations have shown that antioxidant expression peaks at a stage of tumorigenesis prior to frank tumor formation, suggesting that nascent tumor cells must overcome oxidative stress to progress. Inhibition of a key antioxidant pathway, the glutathione pathway, did not significantly decrease the Trp53-/- Brca1-/- cell population, and preliminary spatial transcriptomics data do not support an induction of the major players of this pathway during tumorigenesis. A closer examination of the expression patterns of these genes within the mammary gland demonstrates that they are not expressed in the cell of origin of TNBC. In contrast, members of the thioredoxin (TXN) pathway are expressed in the precursor cells of TNBC. One member of the TXN pathway, Txnrd1, is upregulated in Trp53-/- Brca1-/- glands, but not contralateral control glands. This upregulation occurs around the time of epithelial cell expansion post tumor suppressor loss. Furthermore, glutathione pathway inhibition drives Txnrd1 protein expression up in the mutant, but not wildtype glands. Together, our data support an important role for the thioredoxin pathway in reducing oxidative stress during tumorigenesis. Ongoing work aims to assess whether the thioredoxin pathway may represent a viable treatment option to prevent or slow the development of breast cancer in the Trp53/Brca1-deficient background. Insights into vulnerabilities of Brca1-deficient cells may provide BRCA1 germline mutation carriers new approaches for cancer prevention that have otherwise been limited to mastectomy and oophorectomy. Citation Format: Nomeda Girnius, Aylin Z Henstridge, Francesca Silvestri, Carman Man Chung Li, Joan S Brugge. An analysis of the contribution of the glutathione and thioredoxin antioxidant pathways to triple negative breast cancer development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A035.

Inherited blood cancer predisposition through altered transcription elongation

Despite advances in defining diverse somatic mutations that cause myeloid malignancies, a significant heritable component for these cancers remains largely unexplained. Here, we perform rare variant association studies in a large population cohort to identify inherited predisposition genes for these blood cancers. CTR9, which encodes a key component of the PAF1 transcription elongation complex, is among the significant genes identified. The risk variants found in the cases cause loss of function and result in a ∼10-fold increased odds of acquiring a myeloid malignancy. Partial CTR9 loss of function expands human hematopoietic stem cells (HSCs) by increased super elongation complex-mediated transcriptional activity, which thereby increases the expression of key regulators of HSC self-renewal. By following up on insights from a human genetic study examining inherited predisposition to the myeloid malignancies, we define a previously unknown antagonistic interaction between the PAF1 and super elongation complexes. These insights could enable targeted approaches for blood cancer prevention.

Genome-wide functional integration identified MAZ-controlled RPS14 dysregulation in hepatocellular carcinoma.

Chronic infection with Hepatitis B virus (HBV) significantly increases the risk of hepatocellular carcinoma (HCC), particularly in Eastern Asia. However, only a subset of individuals with chronic HBV infection develop HCC, suggesting the role for genetic factors in HCC etiology. Despite genome-wide association studies (GWASs) identifying multiple single nucleotide polymorphisms (SNPs) associated with HBV-related HCC susceptibility, the underlying mechanisms and causal genetic polymorphisms remain largely unclear. To address this, we developed The Updated Integrative Functional Genomics Approach (TUIFGA), an methodology that combines data from transcription factor (TF) cistromics, ATAC-seq, DNAase-seq, and the 1000 Genomes Project to identify cancer susceptibility SNPs within TF-binding sites across human genome. Using TUIFGA, we discovered SNP rs13170300 which located in the TF MAZ binding motif of RPS14. The RPS14 rs13170300 was significantly associated with HCC risk in two case-control sets, with the T allele as the protective allele (Shandong discovery set: TT OR = 0.60, 95% CI = 0.49-0.74, P = 1.0 × 10-6; CT OR = 0.69, 95% CI = 0.55-0.86, P = 0.001; Jiangsu validation set: TT OR = 0.70, 95% CI = 0.56-0.87, P = 0.001; CT OR = 0.65, 95% CI = 0.53-0.82, P = 1.6 × 10-4). SNP rs13170300 affected MAZ binding in the RPS14 promoter, resulting in allele-specific changes in gene expression. RPS14 functions as a novel oncogene in HCC, specifically via activating the AKT signaling. Our findings present important insights into the functional genetics underlying HBV-related HCC development and may contribute to personalized approaches for cancer prevention and novel therapeutics.