Personalized Cancer Research Articles

What Do Breast Cancer Previvors Tell Us About Their Stories? To Know or Not to Know?

This study aimed to explore the (1) experiences of breast cancer previvor women during genetic testing; (2) perceptions of the impact of genetic testing on their personal, social, family, and professional lives; and (3) views on breast cancer prevention and follow-up processes. This study focused on the risk of breast cancer in persons with BRCA mutations. Data were collected through individual in-depth semistructured interviews. The data were analyzed using the MAXQDA program based on the method suggested by Graneheim and Lundman. This study was conducted in Istanbul, Turkey, and included 17 participants. Five themes emerged from the data analysis-Acquaintance with BRCA, Living with BRCA, Managing the Legacy, Maternalism, and We Are Here, including a total of 12 categories. The previvors had negative experiences during genetic testing, mainly owing to a lack of information, stigma, and women's roles in society. A structured and individualized process for genetic counseling was identified as the main requirement. National and international policies on breast cancer previvors should be developed to prevent breast cancer and reduce mortality. Adopting a multidisciplinary approach during genetic counseling will favorably contribute to previvors' medical and psychosocial well-being. Follow-up programs before and after genetic testing should be created. Society's cultural and genetic literacy levels should be evaluated, and activities should be planned to raise social awareness.

Fractional order cancer model infection in human with CD8+ T cells and anti-PD-L1 therapy: simulations and control strategy

In order to comprehend the dynamics of disease propagation within a society, mathematical formulations are essential. The purpose of this work is to investigate the diagnosis and treatment of lung cancer in persons with weakened immune systems by introducing cytokines (IL2&IL12\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ IL_{2} \\& IL_{12}$$\\end{document}) and anti-PD-L1 inhibitors. To find the stable position of a recently built system TCDIL2IL12\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$IL_{2} IL_{12}$$\\end{document}Z, a qualitative and quantitative analysis are taken under sensitive parameters. Reliable bounded findings are ensured by examining the generated system’s boundedness, positivity, uniqueness, and local stability analysis, which are the crucial characteristics of epidemic models. The positive solutions with linear growth are shown to be verified by the global derivative, and the rate of impact across every sub-compartment is determined using Lipschitz criteria. Using Lyapunov functions with first derivative, the system’s global stability is examined in order to evaluate the combined effects of cytokines and anti-PD-L1 inhibitors on people with weakened immune systems. Reliability is achieved by employing the Mittag-Leffler kernel in conjunction with a fractal-fractional operator because FFO provide continuous monitoring of lung cancer in multidimensional way. The symptomatic and asymptomatic effects of lung cancer sickness are investigated using simulations in order to validate the relationship between anti-PD-L1 inhibitors, cytokines, and the immune system. Also, identify the actual state of lung cancer control with early diagnosis and therapy by introducing cytokines and anti-PD-L1 inhibitors, which aid in the patients’ production of anti-cancer cells. Investigating the transmission of illness and creating control methods based on our validated results will both benefit from this kind of research.

The complete Kaposi sarcoma-associated herpesvirus genome induces early-onset, metastatic angiosarcoma in transgenic mice

Kaposi sarcoma (KS) is the most common cancer in persons living with HIV. It is caused by KS-associated herpesvirus (KSHV). There exists no animal model for KS. Pronuclear injection of the 170,000-bp viral genome induces early-onset, aggressive angiosarcoma in transgenic mice. The tumors are histopathologically indistinguishable from human KS. As in human KS, all tumor cells express the viral latency-associated nuclear antigen (LANA). The tumors transcribe most viral genes, whereas endothelial cells in other organs only transcribe the viral latent genes. The tumor cells are of endothelial lineage and exhibit the same molecular pattern of pathway activation as KS, namely phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR, interleukin-10 (IL-10), and vascular endothelial growth factor (VEGF). The KSHV-induced tumors are more aggressive than Ha-ras-induced angiosarcomas. Overall survival is increased by prophylactic ganciclovir. Thus, whole-virus KSHV-transgenic mice represent an accurate model for KS and open the door for the genetic dissection of KS pathogenesis and evaluation of therapies, including vaccines.

Oncological relevance of neuro-urological diseases

Apart from a few exceptions, there is currently little scientific evidence on the oncological relevance of neuro-urological diseases. Most research has been conducted into the association between long-term spinal cord injury with its consequences for the lower urinary tract and the occurrence of bladder cancer. These cancers differ in many ways from bladder cancers in patients without spinal cord injury: patients are 20 years younger on average, tumours are very often already muscle-invasive and poorly differentiated with a high proportion of squamous cell carcinomas, and the prognosis is poor. These characteristics also occur in spinal cord injury patients without permanent catheter drainage of the urinary bladder. Although the pathophysiological association has not been clarified in detail, the presence of a neurogenic bladder appears to be the decisive link between spinal cord injury and the occurrence of bladder cancer. Pathological pressure conditions in the urinary bladder and frequent urinary tract infections or asymptomatic bacteriuria resulting from neurogenic lower urinary tract dysfunction could be the decisive pathophysiological factors. In this respect, urinary bladder cancer in persons with a chronic spinal cord injury represents a model tumour after denervation. The clinically important question of screening requires future interdisciplinary research approaches.

IJCM_151A: Proportion of primary oesophageal cancer in persons with previous head and neck cancer in upper Assam

Background: Head and neck cancer highest amongst Indian states reported from Assam and is the leading cancer in men and third leading cancer in women. Due to advanced disease at the time of diagnosis prognosis of oesophageal cancer is poor. As mass screening for oesophageal cancer is neither feasible nor reasonable, high-risk groups should be identified and surveilled. Objective: To estimate the proportion of primary oesophageal cancer in persons with previous head and neck cancer in upper Assam. Methodology: A match case-control design with equal allocation was conducted in Assam Medical College in 2017. A total of, 232 patients with head and neck squamous cell carcinoma (HNSCC) with age and gender matched controls were evaluated with chromoendoscopy for possible second malignancy in oesophagus. Structured questioning using predesigned pretested schedule was done. Data analysis was done by using rates, ratio and proportion. Results: Men women ratio of the study participants was 79.3%:20.7%(184:48). According to site of primary lesion, majority having hypo-pharyngeal lesions (33%), followed by oral cavity(25%), oropharynx(18%) and nasopharynx(4%), respectively. Out of 232 patients, 64(27.59%) showed presence of varieties of oesophageal abnormalities Conclusion: Counselling all patients and screening of high- risk group specially those with previous head and neck cancer along with health awareness creation and timely intervention may be effective in risk reduction.

Relationship Between Adverse Childhood Experiences, Childhood Obesity And Risk of Colorectal Cancer in Adulthood: A Systematic Review

Background: Adverse childhood experiences are traumatic incidents occurring before the age of 18 years that increases the risk ofadult health problems. Such experiences include various types of abuse; physical and emotional neglect; separation betweenparents; serious household dysfunction; peer violence and community violence.Objective: To determine the risk of colorectal cancer in persons in adult life with exposure to early life trauma. To find relationbetween adverse experiences in childhood and early life obesity.Methods: This systematic review was conducted according to PRISMA guidelines 2020. In this review, 5 independent reviewersextracted the data based on the articles published between 2018 and 2023 with the help of Databases such as PubMed/ Medline andGoogle Scholar. In each database, keywords used were: Adverse Childhood Experiences And Childhood Obesity, Adverse ChildhoodExperiences OR Childhood Obesity AND Colorectal Cancer, Childhood Obesity AND Colorectal Cancer. Studies reported anyrelationship between adverse childhood experiences or childhood obesity and adulthood colorectal cancer were selected..Results: A total of 22 articles were identified. Out of these 13 (59.1%) explained the positive relationship between adverse childhoodexperiences and the development of childhood obesity (increased BMI). The most common childhood adversities related toincreased childhood BMI are Household dysfunction, crime proximity, neglect, bereavement, and abuse. There were 9 (40.9%) ofthe 22 identified articles proved a direct relation between childhood obesity and the development of colorectal carcinoma.Conclusion: Necessary steps must be taken to raise awareness about adverse childhood experiences such as abuse andcommunity-related issues children face and prevent such risk factors from increasing the overall risk of Colorectal Carcinoma, thusalleviating the burden on the health system and provide wellness to the society as a whole.

Skin cancer and HIV

The risk of skin cancer in persons living with HIV (PLWH) is an evolving subject area shaped by the use of antiretroviral therapy. Keratinocyte carcinomas, including basal cell carcinoma and squamous cell carcinoma, have a high incidence in the general population as well as in PLWH. PLWH may have a higher risk of squamous cell carcinoma when compared to the general population. In addition, Merkel cell carcinoma and sebaceous carcinoma exhibit higher incidence rates in PLWH. Data on melanoma risk are varied. Risks of skin cancer may be influenced by vigilant surveillance, photosensitivity, and immune status. Screening for skin cancer is generally recommended, although national guidelines vary in specific recommendations. Treatments range from topical therapies to surgeries to immune checkpoint inhibitors, with Mohs micrographic surgery playing an important role. Data on immune checkpoint inhibitors suggest safe and efficacious use in PLWH, although larger trials are warranted. The dynamic interplay among HIV, antiretroviral use and immunosuppression, and the risk and treatment of skin cancer underscores the importance of rigorous research studies and screening and treatment guidelines specific to this population.

Abstract 11600: Association Between Obesity and Risk of Total and Obesity-Related Cancer in Persons With Incident Cardiovascular Disease

Introduction: Cardiovascular disease (CVD) and cancer often occur in the same people, in part due to shared risk factors. In a Global Burden of Disease analysis of cohorts from >180 countries, obesity was a top 3 modifiable risk factor for CVD and cancer. Beyond shared risk factors, CVD pathophysiologies may synergize with obesity to influence carcinogenesis. If so, an excess cancer risk in obese persons with CVD has implications for clinical management. Hypothesis: Obesity is positively associated with obesity-related cancer (ObCa) risk in persons with incident CVD independent of shared risk factors. Methods: We used data from the Atherosclerosis Risk in Communities (ARIC) study, a cohort with 28 years of cancer follow-up. The analytic cohort was 5127 participants with incident CVD among whom 1511 were diagnosed with a first primary cancer. Follow up began at incident CVD diagnosis date after visit 1. Obesity was classified by BMI, waist circumference (WC), and waist-to-hip ratio (WHR) measured by trained technicians. We calculated incidence rate differences (RD) between obesity groups adjusted for age, sex, and center. The obesity-cancer association was estimated using Fine-Gray regression adjusted for shared risk factors, including smoking. Results: In people with CVD, cancer incidence was higher in the obese (BMI: RD=226.6/100,000 person-years) than normal weight group. In people with CVD, obesity was suggestively positively associated with ObCa (Table 1). In females with CVD, obesity was associated with increased ObCa risk. Associations were null in males, including after excluding prostate cancer. Conclusion: In this prospective study, obesity is positively associated with ObCa risk in women with incident CVD independent of shared risk factors. More work is needed to investigate why the association appeared in women only, and to identify possible mechanisms by which CVD pathophysiologies may interact with obesity to produce cancer risk.

Assessing cancer in people with profound and multiple disabilities

BackgroundCancers are as common in individuals with intellectual disabilities as in the general population (GP). For the subgroup of people with profound and multiple disabilities (PMD) who present with both severe intellectual disability and major motor disorders, the frequency and distribution of cancers are currently not known, preventing proper cancer surveillance.MethodsWe carried out a systematic and synthetic review of the medical literature, including a focused search of Japanese data.ResultsThe total risk of cancer in individuals with PMD is thought to be lower than in the GP, possibly due to a shorter life expectancy. They have reduced exposure to cancer risk factors, such as alcohol, tobacco, sunlight, human papillomavirus infection, occupational toxins, and being overweight. On the other hand, individuals with PMD present a greater frequency of gastroesophageal reflux disease, Helicobacter pylori gastritis, chronic cystitis, and cryptorchidism, which increase the risk for cancer of the esophagus, stomach, urinary bladder, and testes. In addition, certain genetic disorders underlying compromised motor and cognitive functions are associated with higher risk of childhood cancers. An analysis of 135 cancers in persons with PMD in Japan suggested that they present a particular tumor profile, with certain cancers rarer than in the GP, whereas cancers of the digestive tract are frequent. Cancers of the digestive tract occurred significantly earlier than in the GP (colon: average age 48.3 years vs. 71.3 years in the GP, esophagus: 39 years vs. 72 years in the GP). An increasing number of therapeutic successes in children and adults with PMD have been reported in different countries when cancers are discovered early.ConclusionIndividuals with PMD must be appropriately monitored for cancer. Screenings for breast and colon cancer, as well as regular monitoring of the esophagus, stomach, urinary bladder, and testicles, are necessary. Population-based epidemiological studies are needed to better understand risk factors, frequency, and distribution of cancers in the PMD population.

Skin cancer diagnosis over the lifetime in persons with different disabilities.

Persons with disabilities globally experience barriers to medical care, preventative screening, and experience disparate health outcomes compared to those without disabilities. The prevalence of skin cancer in persons with different disabilities is not known. The Behavioral Risk Factor Surveillance System (BRFSS) data from 2017 to 2021 was analyzed to study skin cancer across the lifetime in patients with disabilities related to hearing, vision, ambulation, cognition, independent living, and self-care. Of the 10% of BRFSS respondents with a history of skin cancer, the unadjusted prevalence in those with any disability (9.2%) was higher than those without (5.1%). Patients with hearing (adjusted odds ratio (aOR) 1.29, 95% CI 1.26-1.33) and cognitive disabilities (aOR 1.27, 95% CI 1.24-1.31) had higher odds of skin cancer than those with visual, ambulatory, selfcare, and independent living disabilities. Every disability subgroup had an elevated odds of skin cancer and this was maintained in age-stratified analysis. The elevated odds of a skin cancer diagnosis in Americans with different disabilities may be explained by differences in healthcare utilization but further research is needed to understand this association and propose proactive interventions.

Familial Clonal Hematopoiesis in a Long Telomere Syndrome

BackgroundTelomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long telomere length is advantageous is poorly understood.MethodsWe examined the clinical and molecular features of aging and cancer in persons carrying heterozygous loss-of-function mutations in the telomere-related gene POT1 and noncarrier relatives.ResultsA total of 17 POT1 mutation carriers and 21 noncarrier relatives were initially included in the study, and a validation cohort of 6 additional mutation carriers was subsequently recruited. A majority of the POT1 mutation carriers with telomere length evaluated (9 of 13) had long telomeres (>99th percentile). POT1 mutation carriers had a range of benign and malignant neoplasms involving epithelial, mesenchymal, and neuronal tissues in addition to B- and T-cell lymphoma and myeloid cancers. Five of 18 POT1 mutation carriers (28%) had T-cell clonality, and 8 of 12 (67%) had clonal hematopoiesis of indeterminate potential. A predisposition to clonal hematopoiesis had an autosomal dominant pattern of inheritance, as well as penetrance that increased with age; somatic DNMT3A and JAK2 hotspot mutations were common. These and other somatic driver mutations probably arose in the first decades of life, and their lineages secondarily accumulated a higher mutation burden characterized by a clocklike signature. Successive generations showed genetic anticipation (i.e., an increasingly early onset of disease). In contrast to noncarrier relatives, who had the typical telomere shortening with age, POT1 mutation carriers maintained telomere length over the course of 2 years.ConclusionsPOT1 mutations associated with long telomere length conferred a predisposition to a familial clonal hematopoiesis syndrome that was associated with a range of benign and malignant solid neoplasms. The risk of these phenotypes was mediated by extended cellular longevity and by the capacity to maintain telomeres over time. (Funded by the National Institutes of Health and others.)

A Systems Biology Approach for Investigating Significant Biomarkers and Drug Targets Common Among Patients with Gonorrhea, Chlamydia, and Prostate Cancer: A Pilot Study.

Having a previous history of sexually transmitted diseases (STDs) such as gonorrhea and chlamydia increases the chance of developing prostate cancer, the second most frequent malignant cancer among men. However, the molecular functions that cause the development of prostate cancer in persons with gonorrhea and chlamydia are yet unknown. In this study, we studied RNA-seq gene expression profiles using computational biology methods to find out potential biomarkers that could help us in understanding the patho-biological mechanisms of gonorrhea, chlamydia, and prostate cancer. Using statistical methods on the Gene Expression Omnibus (GEO) data sets, it was found that a total of 22 distinct differentially expressed genes were shared among these 3 diseases of which 14 were up-regulated (PGRMC1, TSC22D1, SH3BGRL, NNT, CTSC, FRMD3, CCR2, FAM210B, VCL, PTGS1, SLFN11, SLC40A1, PROS1, and DSE) and the remaining 8 genes were down-regulated (PRNP, HINT3, MARCKSL1, TMED10, SH3KBP1, ENSA, DERL1, and KMT2B). Investigation on these 22 unique dysregulated genes using Gene Ontology, BioCarta, KEGG, and Reactome revealed multiple altered molecular pathways, including regulation of amyloid precursor protein catabolic process, ferroptosis, effects on gene expression of Homo sapiens PPAR pathway, and innate immune system R-HSA-168249. Four significant hub proteins namely VCL, SH3KBP1, PRNP, and PGRMC1 were revealed by protein-protein interaction network analysis. By analyzing gene-transcription factors and gene-miRNAs interactions, significant transcription factors (POU2F2, POU2F1, GATA6, and HIVEP1) and posttranscriptional regulator microRNAs (hsa-miR-7-5p) were also identified. Three potential therapeutic compounds namely INCB3284, CCX915, and MLN-1202 were found to interact with up-regulated protein C-C chemokine receptor type 2 (CCR2) in protein-drug interaction analysis. The proposed biomarkers and therapeutic potential molecules could be investigated for potential pharmacological targets and activity in the fight against in patients with gonorrhea, chlamydia, and prostate cancer.

Linguistic validation of the Spanish version of the Anal Cancer High-Grade squamous intraepithelial lesions outcomes Research Health-Related Symptom Index (A-HRSI): AMC-A04

ObjectivesThe Anal Cancer High-grade squamous intraepithelial lesions (HSIL) Outcomes Research (ANCHOR) Health-Related Symptom Index (A-HRSI) is a 25-item measure that assesses physical symptoms and impacts, and psychological symptoms. To promote generalizability and equity in the capture of these concepts in Spanish-speaking participants, we linguistically validated a Spanish version of A-HRSI.MethodsFollowing independent forward translation and reconciliation of A-HRSI from English to Spanish, two rounds of cognitive interviews were completed with ANCHOR participants who had been diagnosed with anal HSIL in the prior nine months and preferred delivery of their healthcare in Spanish. Interviews were coded to highlight any items and concepts that were reported as being difficult for any reason by ≥ 3 participants, with such items revised during a research team panel discussion and tested in a second round of interviews if applicable.ResultsSeventeen participants representing 8 nationalities were enrolled (Round 1 n=10, Round 2 n=7); 7 participants reported not completing high school (41.2%). No difficulties were reported with respect to the theoretical concepts measured by A-HRSI. We made modifications to the Spanish translation of eight items and two response option terms in cases where participants had difficulty understanding a term, experienced problems in discriminating between terms, or preferred the use of an alternative term to represent the concept(s).ConclusionThe Spanish version of A-HRSI is a linguistically valid tool that can be used to assess physical symptoms, impacts, and psychological symptoms related to anal HSIL.Plain English SummaryLanguage is a tremendous barrier to enrolling patients to clinical trials. The anal cancer high-grade squamous intraepithelial lesions (HSIL) outcomes research [ANCHOR] trial is a randomized clinical trial that recently established that the treatment of anal HSIL, versus active monitoring, is effective in reducing incidence of anal cancer in persons living with HIV (PLWH). The ANCHOR Health-Related Symptom Index (A-HRSI) is a 25-item patient-reported outcomes measure that was developed to assess physical symptoms, physical impacts, and psychological symptoms related to anal HSIL. As approximately 10% of ANCHOR participants preferred the delivery of their healthcare in Spanish, the purpose of the present study was to linguistically validate a Spanish version of A-HRSI. Based on feedback from interviews with 17 participants from the ANCHOR trial who had been diagnosed with anal HSIL in the prior nine months and preferred delivery of their healthcare in Spanish, we made modifications to the Spanish translation of eight items and two response option terms in cases where participants had difficulty understanding a term, experienced problems in discriminating between terms, or preferred the use of an alternative term to represent the concept(s). The Spanish version of A-HRSI is a linguistically valid tool that can be used to assess physical symptoms, impacts, and psychological symptoms related to anal HSIL as part of clinical trials or routine care.

The Association of Metformin, Other Antidiabetic Medications and Statins on the Prognosis of Rectal Cancer in Patients with Type 2 Diabetes: A Retrospective Cohort Study.

Metformin and statin use have been associated with an improved prognosis for colorectal cancer in persons with type 2 diabetes (T2D). Data regarding rectal cancer (RC) have been inconclusive; therefore, we investigated the issue with high-quality data and a robust study design. We identified 1271 eligible patients with T2D and incident RC between 1998 and 2011 from the Diabetes in Finland (FinDM) database. Cox models were fitted for cause-specific mortality rates to obtain adjusted estimates of the hazard ratios (HR) with 95% confidence intervals (CI) in relation to use of antidiabetic medication (ADM) and statins before the RC diagnosis and for post-diagnostic use in a time-dependent exposure manner. No sufficient evidence was found for either pre- or post-diagnostic metformin use and RC mortality (HR 0.96, 95% CI 0.67–1.38, and 0.70, 95% CI 0.45–1.10, respectively) when compared to other oral ADMs. Both pre- and post-diagnostic statin use appeared to be inversely associated with mortality from RC (HR 0.77 95% CI 0.63–0.94, and 0.57, 95% CI 0.42–0.78, respectively). Our study was inconclusive as to the association of metformin use with the prognosis of RC, but statin use was found to predict reduced mortality, both from RC and from other causes of death in persons with T2D.

33965 Learn2Derm: A community-based pilot program assessing beliefs surrounding skin cancer risk factors, presentation, and prevention strategies

Introduction: Underserved and underrepresented communities exhibit disparities across all spectrums in health. Dermatology is not an exception, as there continues to be disparities in burden of disease, access to healthcare, and patient-provider trust. To address such gaps, a community-based, recurring, interactive and educational program, Learn2Derm, was launched. The first event focused on disparities in education and detection of skin cancer in persons of color in Ward 8 in Washington D.C., an underserved community with a population that is 92% black. Methods: To better understand the needs of this community, an IRB-approved survey was disseminated to participants to investigate familiarity with skin cancer presentation and prevention, and to understand barriers to seeking dermatologic care. Results: 49 attendees completed the survey. Postsurvey results indicated participants learned that skin cancer could present under the fingernail and that sunscreen can prevent skin cancer (P < .05). Participants revealed that cost was the greatest barrier to sunscreen utilization. After the event, 50% of those who responded trusted dermatologists more. Similar culture and comprehensible language were reasons most likely to increase trust (n = 23). All attendees that answered the final item on the survey indicated that they enjoyed the event (n = 47). Conclusions: Our data highlight that community-immersion events can facilitate awareness of dermatologic conditions, foster communication between dermatologists and communities, enhance dermatologic access, and may instill trust placed in providers. Consequently, patients from underserved communities may receive and seek dermatologic care at earlier disease presentation and avoid the long-lasting impacts of untreated skin disease.

Risks of Melanoma and Nonmelanoma Skin Cancers Pre- and Post-Inflammatory Bowel Disease Diagnosis.

We compared risks of nonmelanoma skin cancers (NMSCs) and melanoma preceding and following a diagnosis of inflammatory bowel disease (IBD) and to evaluate the effect of thiopurines and anti-tumor necrosis factor α (anti-TNF-α) on skin cancer risk in IBD. This was a retrospective, historical cohort study using the population-based University of Manitoba IBD Epidemiology Database (11 228 IBD cases and 104 725 matched controls) linked to the Manitoba Cancer Registry. Logistic and Cox regression analyses were performed to calculate skin cancer risks prior to and after IBD diagnosis. Persons with ulcerative colitis (UC) were more likely to have basal cell carcinoma (BCC) predating their UC diagnosis (odds ratio, 1.32; 95% confidence interval [CI], 1.08-1.60). Risks of squamous cell carcinoma (SCC), other NMSCs, or melanoma prior to IBD diagnosis were not significantly increased. Post-IBD diagnosis, risks of BCC (hazard ratio, 1.53; 95% CI, 1.37-1.70) and SCC (hazard ratio, 1.61; 95% CI, 1.29-2.01) were significantly increased across all IBD groups except for SCC in UC. There was no significant association between melanoma and IBD post-IBD diagnosis. The risks of BCC and melanoma were increased in thiopurine and anti-TNF users, and risk of SCC was increased in only thiopurine users. Nested cohort analysis of persons with IBD with censoring at both thiopurines and anti-TNF use confirmed a higher baseline risk of BCC and no effect on SCC, comparable to pre-IBD diagnosis findings. The risk of BCC preceding a diagnosis of UC is higher than in non-UC controls, compared with a generally increased risk of all NMSCs post-IBD diagnosis. Thiopurine and anti-TNF therapy increase the risks for skin cancers in persons with IBD after their diagnoses.

Cancer risk in persons with new-onset anaemia: a population-based cohort study in Denmark

BackgroundThe time interval from first symptom and sign until a cancer diagnosis significantly affects the prognosis. Therefore, recognising and acting on signs of cancer, such as anaemia, is essential. Evidence is sparse on the overall risk of cancer and the risk of specific cancer types in persons with new-onset anaemia detected in an unselected general practice population. We aimed to assess the risk of cancer in persons with new-onset anaemia detected in general practice, both overall and for selected cancer types.MethodsThis observational population-based cohort study used individually linked electronic data from laboratory information systems and nationwide healthcare registries in Denmark. We included persons aged 40–90 years without a prior history of cancer and with new-onset anaemia (no anaemia during the previous 15 months) detected in general practice in 2014–2018. We measured the incidence proportion and standardised incidence ratios of a new cancer diagnosis (all cancers except for non-melanoma skin cancers) during 12 months follow-up.ResultsA total of 48,925 persons (median [interquartile interval] age, 69 [55–78] years; 55.5% men) were included in the study. In total, 7.9% (95% confidence interval (CI): 7.6 to 8.2) of men and 5.2% (CI: 4.9 to 5.5) of women were diagnosed with cancer during 12 months. Across selected anaemia types, the highest cancer incidence proportion was seen in women with ‘anaemia of inflammation’ (15.3%, CI: 13.1 to 17.5) (ferritin > 100 ng/mL and increased C-reactive protein (CRP)) and in men with ‘combined inflammatory iron deficiency anaemia’ (19.3%, CI: 14.5 to 24.1) (ferritin < 100 ng/mL and increased CRP). For these two anaemia types, the cancer incidence across cancer types was 10- to 30-fold higher compared to the general population.ConclusionsPersons with new-onset anaemia detected in general practice have a high cancer risk; and markedly high for ‘combined inflammatory iron deficiency anaemia’ and ‘anaemia of inflammation’. Anaemia is a sign of cancer that calls for increased awareness and action. There is a need for research on how to improve the initial pathway for new-onset anaemia in general practice.

Abstract 5941: A simulation modeling study to support personalized breast cancer prevention and early detection in high-risk women

Abstract Purpose: To evaluate the impact of early detection with screening and primary prevention with risk-reducing medication to provide personalized data that will help identify women who are more likely to benefit from various interventions or combinations of interventions with the least harms. Methods: We adapted the CISNET microsimulation model G-E of breast cancer natural history to evaluate the harms and benefits of annual mammography and risk reducing medication among high-risk women (i.e., 5-year risk greater than or equal to 3%). Model G-E is a discrete event microsimulation model that follows millions of women from birth to death and captures the variability in distributions of each event. Each simulated woman is assigned a cohort-specific life expectancy which is used to select a date of breast cancer death. For this study, we dynamically updated the risk of developing breast cancer for each simulated woman based on her family history, breast density, age and history of biopsy. We used large observational and clinical trial data to derive input parameters for cohort-specific birth rates, incidence and stage without screening, other cause mortality by age, screening performance (sensitivity/specificity), survival by age, stage, and subtype without treatment, treatment efficacy, and other cause mortality. We compared model outcomes for screening alone vs. screening with a 5-year course of risk reducing medication. We modeled various screening strategies including annual or biennial screening starting at ages 35, 40, 45 and stopping at ages 65 and 74 years. Model outcomes for each strategy included, the benefits of risk-reducing drugs (avoiding breast cancer) and screening (breast cancer stage, breast cancer-specific survival), and harms of screening (false positives, overdiagnosis). We also conducted sensitivity analysis to estimate the effects of uncertainty in model inputs or assumptions on results. Results: We found that risk reducing medication could result in an additional 28% decrease in invasive breast cancer incidence, 20% decrease in stage IV diagnosis, and a 30% decrease in breast cancer death if screening started at age 35 in a high-risk woman. However, potential breast density changes due to risk reducing medication among high-risk women could result in a 19% increase in false positive screening results compared to screening alone. The results varied by the starting age of screening. Conclusions: Simulation modeling is useful in assessing the relative benefits and harms of screening and risk reducing medication in high-risk women. Citation Format: Jinani Jayasekera, Amy Zhao. A simulation modeling study to support personalized breast cancer prevention and early detection in high-risk women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5941.

Abstract 1387: High-dimensional analysis of T cell responses to mutant neoantigens and nonmutant antigens in mouse models of melanoma

Abstract Effective cancer immunotherapy, such as immune checkpoint therapy (ICT) [e.g., anti-CTLA-4 and anti-PD-1/PD-L1], is dependent on T cell recognition of tumor antigens presented on major histocompatibility complex (MHC) and leads to durable responses in certain cancer patients. Recent advances have facilitated identification of tumor mutant neoantigens and led to efforts to develop effective personalized neoantigen cancer vaccines. However, little is known about how expression of multiple neoantigens with variable peptide-MHC (pMHC) binding or TCR affinity/avidity affects T cell responses to both discrete neoantigens and shared non-mutant antigens, and if the localization of T cells with distinctive pMHC specificity differs within the tumor. To address this, we genetically introduced multiple combinations of MHC-I and MHC-II neoantigens in the poorly immunogenic Brafv600e Pten-/- Cdkn2a-/- YUMM1.7 (Y1.7) mouse melanoma line that contains a paucity of neoantigens. We expressed neoantigens previously found in a mouse sarcoma line of the same MHC haplotype as Y1.7. The MHC-I neoantigens used were formed by G1254V mutation in Laminin alpha subunit-4 (Lama4) and A506T mutation in the Asparagine-linked glycosylation 8 (Alg8) and the MHC-II neoantigen was formed by A710T mutation in Integrin beta-1 (Itgb1). We generated Y1.7 lines expressing minigenes for mLama4, mAlg8, or mLama4 + mAlg8 MHC-I neoantigens. All three lines also expressed the mItgb1 MHC-II neoantigen. Whereas ICT-treated mice bearing the parental Y1.7 melanoma line showed rapid tumor growth, modified Y1.7 lines expressing mLama4 and/or mAlg8 plus mItgb1 were rendered sensitive to ICT. Tumors expressing mLama4 and/or mAlg8 contained mLama4- and/or mAlg8-specific CD8+ T cells, respectively. Preliminary analysis revealed expression of either MHC-I neoantigen alters the frequency of CD8+ T cells specific for non-mutant endogenous antigens in Y1.7. Interestingly, therapeutic synthetic long-peptide (SLP) vaccines incorporating mLama4 and/or mAlg8 neoantigens plus poly I:C induced tumor rejection comparable to ICT. Moreover, SLP vaccines amplified intratumoral mLama4- and mAlg8-specific CD8+ T cells, as well as in tumor-draining lymph nodes, where these neoantigen-specific CD8+ T cells were found to express IFN-γ. During either vaccination or ICT, CD8+ T cell response to mLama4 was higher than that to mAlg8 when both neoantigens were co-expressed. Altogether, these melanoma models will enable us to determine whether expression of one or more MHC-I neoantigens influences CD8+ T cell responses to both distinct neoantigens and non-mutant antigens (e.g., gp100, Trp2) during ICT and SLP vaccination. Furthermore, high-dimensional analyses approaches including scRNA-seq. and CODEX imaging are ongoing and will facilitate development of improved immunotherapies and may help uncover novel biomarkers of response. Citation Format: Sunita Keshari, Charmelle D. Williams, Elizabeth D. Sanchez, Alexander S. Shavkunov, Matthew M. Gubin. High-dimensional analysis of T cell responses to mutant neoantigens and nonmutant antigens in mouse models of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1387.

Implementing systematized patient-facing Lynch syndrome (LS) risk assessment in oncology using the electronic health record (EHR) system.

10503 Background: Lynch syndrome (LS) is the most common inherited cause of colorectal (CRC) and endometrial cancers. Significant provider and institutional level barriers limit LS detection, even in oncology patients with LS-associated cancers. PREMM5 is a validated tool based on personal and family cancer history that is recommended by national professional societies for LS risk assessment. This project’s goal was to study the feasibility of patient-facing LS risk assessment using a PREMM5 screener embedded in an electronic health record (EHR) system, as a means of improving LS identification. Methods: The PREMM5 LS screener intake questions were adapted to be completed by patients rather than healthcare providers. Screener adaptation and implementation involved iterative review by multidisciplinary experts and multilevel stakeholder engagement. The patient-facing PREMM5 LS screener was embedded in the EHR (Epic) at the Dana-Farber Cancer Institute (DFCI) to enable remote (via the EHR patient portal) and on-site completion (in clinic waiting rooms). All new gastrointestinal (GI) cancer patients seen at DFCI for initial oncology consultation from 6/2020-12/2021 were invited through the portal to complete the screener. PREMM5 scores ≥2.5% were considered “positive”, with genetics referral recommended. Beginning 2/2021, the EHR generated an automated provider-facing alert for positive screens. Results: 35% (1504/4262) of new GI cancer patients completed the screener. 367/1504 (24%) had a positive PREMM5 screen (mean age 53 years), of whom 66% were male, and 62%, 12% and 10% had CRC, neuroendocrine and pancreas cancer respectively. 97% (357/367) of screen positives completed the PREMM5 screener remotely through the portal. 102/367 (28%) received a genetics referral as a result of their positive PREMM5 screen (not including 75 genetics referrals outside this workflow), 13 of whom had a pathogenic variant (PV) on germline testing, including 4 with LS ( MSH2, MSH6, PMS2), and others with PVs in ATM, BRCA2, CHEK2, NTHL1, RAD50 and RECQL4. Conclusions: A practice-wide patient-facing EHR-integrated PREMM5 risk assessment workflow is feasible and identified nearly 1 in 4 general GI oncology patients as warranting genetic evaluation, resulting in the identification of numerous actionable germline PVs. This method of deployment could make genetic risk assessment more accessible to non-genetics providers. The suboptimal screener completion rate and 28% genetics referral rate among positive screens suggest the need for additional refinements, including patient and provider engagement and outreach to positive screens who do not follow up with appointments for genetic evaluation.