Cancer Screening Strategies Research Articles

Prostate Cancer Screening in Young Men.

Background: Prostate cancer (PCa) screening strategies are being developed and evaluated in several countries. However, most of the evidence regarding PCa screening has been generated in study populations aged 50 and older. Aims: This study summarizes findings of a screening trial in younger men and discuss those findings in the context of other screening trials. Methods: Non-systematic review. Results: Screening of 45-year-old men resulted in a low PCa detection rate. Nonetheless, almost 70% of screen-detected PCa at this age was clinically significant. In young men ISUP GG 1 screen-detected cancers warrant rigorous follow-up. A baseline, midlife prostate-specific antigen (PSA) value at age 45 may safely exclude the vast majority of men from further screening investigations for at least 5 years. At age 45, a confirmatory PSA value reduces the number of subsequent tests almost by half. Sequential magnetic resonance imaging (MRI) as a reflex test subsequent to an elevated PSA ≥ 3 ng/mL needs further investigation in young men. Conclusions: Screening in young men needs to be carefully investigated in order to avoid overscreening and overdiagnosis.

Towards the elimination of cervical cancer in Brazil: A call to the South America region

Brazil, as the largest South American country, accounts for a large proportion of cervical cancer cases and deaths. Even though Brazil leads the implementation of novel strategies for cervical cancer screening and serves as model for other South American countries, several challenges remain. This editorial discusses the challenges associated with eliminating cervical cancer in Brazil.

DNA Methylation Biomarkers in Stool Samples: Enhancing Colorectal Cancer Screening Strategies.

Colorectal cancer (CRC) is a significant global health challenge, ranking among the leading causes of cancer-related mortality worldwide. Despite efforts in prevention and early detection, CRC incidence and mortality rates are expected to rise substantially. Traditional screening methods like gFOBT, FIT, flexible sigmoidoscopy, colonoscopy, CTC, and colon capsule have limitations, including false positives/negatives, limited scope, or invasiveness. Recent developments in CRC screening involve DNA methylation biomarkers, showing promise in detecting early-stage CRC and precancerous lesions. Stool-based DNA testing is emerging as a noninvasive and convenient method for detecting CRC-associated DNA methylation alterations, offering potential for earlier detection compared to traditional methods. Several commercial stool-based DNA methylation tests targeting different genes associated with CRC have demonstrated varying sensitivity and specificity, some surpassing traditional screening methods. Challenges remain in optimizing their performance and accessibility. This review discusses how DNA methylation biomarkers could enhance CRC screening, and stool-based DNA methylation tests could revolutionize CRC screening practices, comparing them to the gold standard.

Physicians’ perception on using a multi-cancer early detection blood test to reduce disparities in cancer screening

IntroductionCancer causes significant morbidity and mortality in the United States. It is the second most common cause of death in the United States, after heart disease. African Americans are disproportionately affected by malignancy, with overall higher death rates compared to other racial and ethnic groups. Screening tests can identify early stage malignancy allowing for timely intervention. However, African Americans less frequently undergo cancer screening. Advancement in genomic technology has led to the identification of signals for cancer in the blood. This has resulted in the development of multi-cancer early detection (MCED) tests which evaluate for circulating cell-free DNA (cfDNA). This study evaluated physicians’ perception of the use of a multi-cancer early detection test (MCED). MethodsAn anonymous, 29 question survey was administered to African American / Black physicians and medical students. Survey participants were identified through the National Medical Association and other professional organizations that included primarily African American physicians. Surveys were excluded from analysis if respondent was non-African American / Black or was not a physician or medical student.The survey collected physician demographics, percentage of African American / Black patients in their practice, patient barriers to screening, potential use of MCED tests and factors influencing decision to recommend testing. Descriptive statistics were generated. Additional analysis was performed using Chi-Square with statistical significance set at p-value <0.05. The survey was pilot tested for reliability and validity. Results1196 (681 female, 515 male) physicians and medical students completed the survey. 95.8 % were physicians who were or had been in clinical practice. Fifty-three percent of physicians reported that >40 % of their patients were African American / Black. Barriers to cancer screening included lack of understanding of the importance (33.8 %), lack of or limited insurance coverage (23.5 %), socioeconomic factors unrelated to insurance coverage (16.2 %), fear of cancer (8.8 %), history of racism and bias in the health care system (7.4 %) with 8.8 % reporting ‘other’ and 1.5 % reporting no perceived barriers. There was a significant difference (p<0.03) in the rate that physicians’ perceived racism and bias in the health care system as barrier for cancer screening in African American / Black patients when compared to other patients.Most physicians and medical students indicated that a MCED test would benefit all patients (86.8 %), would encourage further cancer screening tests (83.8 %), and would be beneficial for minority and under-represented patients regardless of socioeconomics or health care access (83.8 %). Seventy-five percent of survey respondents indicated that a MCED test would be beneficial in promoting further cancer screening and early detection in African American / Black patients. Factors that would impact the ordering of an MCED test included scientific evidence and test validity (63.2 %), efficiency, accessibility, ease of ordering and ease of receiving results (11.8 %), insurance coverage (13.2 %) and ‘other factors’ (11.8 %). DiscussionThis is one of the largest surveys to assess physicians’ perceptions about MCED testing and is the first study to evaluate the perspectives of African American physicians. It offers insight about physician acceptance and potential incorporation of MCED into clinical practice. It is important that a multifaceted approach is employed to improve cancer outcomes and reduce disparities in survival. MCED tests, a relatively new advancement in genomic technology, have the potential to be an important component in cancer screening strategies.

Effects of Medicaid managed care on early detection of cancer: Evidence from mandatory Medicaid managed care program in Pennsylvania.

To examine changes in late- versus early-stage diagnosis of cancer associated with the introduction of mandatory Medicaid managed care (MMC) in Pennsylvania. We analyzed data from the Pennsylvania cancer registry (2010-2018) for adult Medicaid beneficiaries aged 21-64 newly diagnosed with a solid tumor. To ascertain Medicaid and managed care status around diagnosis, we linked the cancer registry to statewide hospital-based facility records collected by an independent state agency (Pennsylvania Health Care Cost Containment Council). We leveraged a natural experiment arising from county-level variation in mandatory MMC in Pennsylvania. Using a stacked difference-in-differences design, we compared changes in the probability of late-stage cancer diagnosis among those residing in counties that newly transitioned to mandatory managed care to contemporaneous changes among those in counties with mature MMC programs. N/A. Mandatory MMC was associated with a reduced probability of late-stage cancer diagnosis (-3.9 percentage points; 95% CI: -7.2, -0.5; p = 0.02), particularly for screening-amenable cancers (-5.5 percentage points; 95% CI: -10.4, -0.6; p = 0.03). We found no significant changes in late-stage diagnosis among non-screening amenable cancers. In Pennsylvania, the implementation of mandatory MMC for adult Medicaid beneficiaries was associated with earlier stage of diagnosis among newly diagnosed cancer patients with Medicaid, especially those diagnosed with screening-amenable cancers. Considering that over half of the sample was diagnosed with late-stage cancer even after the transition to mandatory MMC, Medicaid programs and managed care organizations should continue to carefully monitor receipt of cancer screening and design strategies to reduce barriers to guideline-concordant screening or diagnostic procedures.

Early Detection of Cancer and Precancerous Lesions in Persons with HIV through a Comprehensive Cancer Screening Protocol.

Non-AIDS defining malignancies present a growing challenge for persons with HIV (PWH), yet tailored interventions for timely cancer diagnosis are lacking. The Spanish IMPAC-Neo protocol was designed to compare two comprehensive cancer screening strategies integrated into routine HIV care. This study reports baseline data on the prevalence and types of precancerous lesions and early-stage cancer among participants at enrolment. Acceptability of the procedure was additionally assessed. Cross-sectional analysis of a comprehensive screening protocol to detect precancer and cancer. The readiness of healthcare providers to implement the protocol was evaluated using a validated 4-item survey. Among the 1430 enrolled PWH, 1172 underwent 3181 screening tests, with positive findings in 29.4% of cases, leading to further investigation in 20.7%. Adherence to the protocol was 84%, with HIV providers expressing high acceptability (97.1%), appropriateness (91.4%), and feasibility (77.1%). A total of 145 lesions were identified in 109 participants, including 60 precancerous lesions in 35 patients (3.0%), 9 early-stage cancers in 9 patients (0.8%), and 76 low-risk lesions in 65 subjects (5.5%). Adverse events related to screening occurred in 0.8% of participants, all mild. The overall prevalence of cancer precursors or early-stage cancer was 3.8% (95% CI, 2.74%-5.01%), with highest rates observed in individuals screened for anal and colorectal cancers. The baseline comprehensive cancer screening protocol of the IMPAC-Neo study successfully identified a significant proportion of PWH with precancerous lesions and early-stage cancer. High adherence rates and positive feedback from providers suggest effective implementation potential in real-world healthcare settings.

Cost-effectiveness Analysis of Colorectal Cancer Screening Strategies Using Active Learning and Monte Carlo Simulation.

Detection of colorectal cancer (CRC) in the early stages through available screening tests increases the patient's survival chances. Multimodal screening policies can benefit patients by providing more diverse screening options and balancing the risks and benefits of screening tests. We investigate the cost-effectiveness of a wide variety of multimodal CRC screening policies. We developed a Monte Carlo simulation framework to model CRC dynamics. We proposed an innovative calibration process using machine learning models to estimate age- and size-specific adenomatous polyps' progression and regression rates. The proposed approach significantly expedites the model parameter space search. Two multimodal proposed policies (i.e., 1] colonoscopy at 50 y and fecal occult blood test annually between 60 and 75 y and 2] colonoscopy at 50 and 60 y and fecal immunochemical test annually between 70 and 75 y) are identified as efficient frontier policies. Both policies are cost-effective at a willingness to pay of $50,000. Sensitivity analyses were performed to assess the sensitivity of results to a change in screening test costs as well as adherence behavior. The sensitivity analysis results suggest that the proposed policies are mostly robust to the considered changes in screening test costs, as there is a significant overlap between the efficient frontier policies of the baseline and the sensitivity analysis cases. However, the efficient frontier policies were more sensitive to changes in adherence behavior. Generally, combining stool-based tests with visual tests will benefit patients with higher life expectancy and a lower expected cost compared with unimodal screening policies. Colonoscopy at younger ages (when the colonoscopy complication risk is lower) and stool-based tests at older ages are shown to be more effective. We propose a detailed Markov model to capture the colorectal cancer (CRC) dynamics. The proposed Markov model presents the detailed dynamics of adenomas progression to CRC.We use more than 44,000 colonoscopy reports and available data in the literature to calibrate the proposed Markov model using an innovative approach that leverages machine learning models to expedite the calibration process.We investigate the cost-effectiveness of a wide variety of multimodal CRC screening policies and compare their performances with the current in-practice policies.

Colorectal cancer screening: Modalities and adherence

In the last decade, several studies have explored various modalities and strategies for colorectal cancer (CRC) screening, taking into account epidemiological data, individual characteristics, and socioeconomic factors. In this editorial, we comment further on a retrospective study by Agatsuma et al published in the recent issue of the World Journal of Gastroenterology . Our focus is on screening trends, particularly in relation to efforts to improve the currently suboptimal uptake among the general population worldwide, aiming to enhance early diagnosis rates of CRC. There is a need to raise awareness through health edu-cation programs and to consider the use of readily available, non-invasive screening methods. These strategies are crucial for attracting screen-eligible populations to participate in first-line screening, especially those in high- or average-risk groups and in regions with limited resources. Liquid biopsies and biomarkers represent rapidly evolving trends in screening and diagnosis; however, their clinical relevance has yet to be standardized.

A Linear Relationship between the Number of Cancers among First-Degree Relatives and the Risk of Multiple Primary Cancers.

With advances in the early detection and treatment of cancer, the incidence of multiple primary cancers (MPC) or second primary cancers has increased over time. Characterization of etiologic risk factors, including family history of cancer, within the general population is critical for assessing MPC risk in patients. We examined the association between family history of cancer among first-degree relatives and MPC risk in a prospective study of 139,958 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cox proportional hazard models were used to calculate HRs and 95% confidence intervals (95% CI), adjusting for potential confounders. Over a median follow-up of 16 years (IQR: 11-19 years), 6,170 participants were diagnosed with MPC. Having a family history of cancer increased the risk of MPC by 18% (HR, 1.18; 95% CI, 1.12-1.24). A positive linear trend was observed between the reported number of cancers in the family history and MPC risk with HRs (95% CI) of 1.13 (1.07-1.20), 1.23 (1.14-1.33), 1.29 (1.15-1.45), and 1.42 (1.20-1.70) for one, two, three, and four or more cancers among first-degree relatives, respectively (Ptrend = 2.36 × 10-13). No significant differences were observed by cancer histology or specific cancer types reported in the family history. Our study demonstrates that the family history of cancer is an important risk factor for the development of MPCs and that a comprehensive assessment of the number of cancers reported among first-degree relatives may identify those at higher risk who may benefit from targeted cancer prevention and screening strategies. Prevention Relevance: Our study makes a substantial contribution to the understanding of risk factors for MPCs in the general population. It demonstrates that individuals with a strong family history of cancer are at higher risk for MPCs and may benefit from more targeted cancer prevention and screening interventions.

Building Capacity for Cervical Cancer Prevention in U.S.-Affiliated Pacific Islands: The Pacific Against Cervical Cancer Project.

The U.S.-affiliated Pacific Islands (USAPI) have higher cervical cancer incidence and mortality rates and lower screening coverage compared with the United States. This is likely because of economic, geographical, health care delivery, and cultural barriers for women living in these resource-constrained, isolated regions. The most recent U.S. and World Health Organization cervical cancer screening guidelines recommended primary human papillomavirus (HPV) testing as one screening option or the preferred screening modality. Primary HPV screening-based strategies offer several advantages over current screening methods in the USAPI. However, adoption of this newer screening modality has been slow in the United States and not yet incorporated into USAPI screening programs. The U.S. Centers for Disease Control and Prevention and partners initiated the Pacific Against Cervical Cancer (PACe) project in 2019 to evaluate the feasibility, acceptability, and cost-effectiveness of primary HPV testing-based strategies in Guam and in Yap, Federated States of Micronesia. This report provides an overview of the PACe project and outlines the approaches we took in implementing primary HPV testing as a new cervical cancer screening strategy (including the option of self-sampling in Yap), encompassing four core components: (1) community engagement and education, (2) medical and laboratory capacity building, (3) health information and system improvement, and (4) modeling and cost-effectiveness analysis. The PACe project provides examples of systematic implementation and resource appropriate technologies to the USAPI, with broader implications for never screened and under-screened populations in the United States and Pacific as they face similar barriers to accessing cervical cancer screening services.

Patterns of cancer screening practice and mutational status of cancer-predisposing genes among individuals at high risk for cancer.

10557 Background: Research on cancer screening practice and prevention strategies among individuals at high risk for cancer is limited. We explored the patterns of screening practice of seven cancer types in high-risk patients (pts) at a single institution. Methods: Between June-September 2023, we conducted a follow-up survey on pts enrolled in the University of Chicago Cancer Prone Study, a longitudinal cohort of high-risk families initiated in 1992. We assessed breast, cervical, colorectal, prostate (PSA), ovarian, skin (full-body skin exam [FBSE]), and lung cancer screening by mutational status. Results: Of 912 respondents, 80.4% were female. 81.6% were White, followed by 10.6% Black, 4.0% other/multi-racial, and 3.8% Hispanic. Overall, 35.2% reported having cancer-predisposing gene mutations. Mutation carriers were younger than those non-carriers (54.8 [SD 13.7] vs 60.3 [SD 12.8] years). After adjusting for age, carriers were more likely than non-carriers to have had breast MRI ( p&lt;.001), colorectal cancer screening ( p=.039), ovarian cancer screening ( p=.043), and an FBSE ( p=.007) (Table). No statistically significant differences in mammogram (OR=1.50, 95% CI=0.55-2.30; p=.13), cervical cancer (OR=0.92, 95% CI=0.54-1.59; p=.77), PSA (OR=0.70, 95% CI: 0.26-1.88; p=.48), or lung cancer (OR=1.18, 95% CI=0.72-1.92; p=.51) screening between carriers and non-carriers. By race/ethnicity, cervical cancer screening (Hispanic 92%, White 90.6%, other/multiracial 80.7% and Black 76%; p=.002) and colorectal cancer screening (White 83.3%, other/multiracial 71.8%, Black 71.4% and Hispanic 66.6%; p=.004) differed significantly. Conclusions: In this diverse cohort of individuals at high risk for cancer, findings highlight an increased awareness and uptake of cancer screening, though varying by race/ethnicity. Cancer risk assessment clinics can be great avenues to provide comprehensive cancer screening and prevention strategies while addressing racial/ethnic screening disparities. [Table: see text]

Genetic screening of liver cancer: State of the art.

Liver cancer, primarily hepatocellular carcinoma, remains a global health challenge with rising incidence and limited therapeutic options. Genetic factors play a pivotal role in the development and progression of liver cancer. This state-of-the-art paper provides a comprehensive review of the current landscape of genetic screening strategies for liver cancer. We discuss the genetic underpinnings of liver cancer, emphasizing the critical role of risk-associated genetic variants, somatic mutations, and epigenetic alterations. We also explore the intricate interplay between environmental factors and genetics, highlighting how genetic screening can aid in risk stratification and early detection via using liquid biopsy, and advancements in high-throughput sequencing technologies. By synthesizing the latest research findings, we aim to provide a comprehensive overview of the state-of-the-art genetic screening methods for liver cancer, shedding light on their potential to revolutionize early detection, risk assessment, and targeted therapies in the fight against this devastating disease.

Successive next-generation sequencing strategy for optimal fusion gene detection in non-small-cell lung cancer in clinical practice

Metastatic non-small-cell lung cancer (NSCLC) displays various molecular alterations in the RAS-MAPK pathway. In particular, NSCLCs show high rates of targetable gene fusion in ALK, RET, ROS1, NRG1 and NTRK, or MET exon 14 skipping. Rapid and accurate detection of gene fusion in EGFR/KRAS/BRAF mutations is important for treatment selection especially for first-line indications. RNA-based next-generation sequencing (NGS) panels appear to be the most appropriate as all targets are multiplexed in a single run. While comprehensive NGS panels remain costly for daily practice, optimal sequencing strategies using targeted DNA/RNA panel approaches need to be validated. Here, we describe our lung cancer screening strategy using DNA and RNA targeted approaches in a real-life cohort of 589 NSCLC patients assessed for molecular testing. Gene fusions were analysed in 174 patients negative for oncogene driver mutations or ALK immunohistochemistry in a two-step strategy. Targetable alterations were identified in 28% of contributive samples. Non-smokers had a 63.7% probability to have a targetable alteration as compared to 21.5% for smokers. Overall survival was significantly higher (p=0.03) for patients who received a molecularly matched therapy. Our study shows the feasibility in routine testing of NSCLC DNA/RNA molecular screening for all samples in a cost- and time-controlled manner. The significant high fusion detection rate in patients with wild-type RAS-MAPK tumours highlights the importance of amending testing strategies in NSCLC.

Sensitive small extracellular vesicles associated circRNAs analysis combined with machine learning for precision identification of gastric cancer

Small extracellular vesicle associated circular RNAs (sEV-circRNAs) are emerging as promising biomarkers for gastric cancer diagnosis. Current research predominantly focuses on identifying these biomarkers through high-throughput sequencing. However, there has been insufficient exploration into the practical application of sEV-circRNAs for early gastric cancer diagnosis. In this study, we developed a sensitive electrochemical platform that leverages tetrahedron-Dox-AuNPs (TDA) tag and DNA tetrahedron-enhanced catalytic hairpin assembly (DT-CHA) to detect sEV-circRNAs. Based on the dual signal amplification of the TDA tag and DT-CHA, the platform can achieve low-concentration detection of the target, with a detection limit of 153.1 aM and a linear range from 1 fM to 1 nM. By profiling four sEV-circRNAs (circNRIP1, circRANGAP1, circCORO1C, and circSHKBP1) in a gastric cancer cohort and combining suitable ML diagnostic model, this platform performed well in distinguishing healthy donors from early GC patients. Thus, this confluence of a multi-biomarker approach with machine learning analysis, applied to plasma sEV-circRNAs, emerges as an important strategy for cancer screening.

The performance of single and combination test strategies using visual inspection, cytology, high-risk HPV DNA and HPV16/18 to screen South African women with and without HIV-infection

BackgroundCervical cancer screening strategies should ideally be informed by population-specific data. Strategies recommended for secondary prevention, are often inadequately studied in populations with high cervical disease burdens. This report describes the test performance measured against CIN2 + /CIN3 + histology in HIV-positive women (HPW) and HIV-negative women (HNW) with the aim to determine the most effective strategies to identify South African women at risk.MethodsPrimary screening using visual inspection, cytology and HPV DNA (cobas®) was performed in two South African provinces on 456 HPW and 639 HNW participating in the multicentric DiaVACCS trial. Histology was obtained for 91.7% screen-positive and 42.7% screen-negative participants, and unavailable histology was determined by multiple imputation to adjust for verification bias. Cross-sectional test performance was calculated for single and combination test strategies with and without intermediate risk categories using different cut-offs. Minimum acceptability for sensitivity and specificity, treatment and follow-up numbers were considered to evaluate strategies.ResultsThe only single test to reach acceptability in HPW was cytology (LSIL) [sensitivity 71.2%; specificity 90.5%; treatment 33.4%]; in HNW only HPV (hr) qualified [sensitivity 68.2%; specificity 85.2%; treatment 23.5%]. The universally best performing strategy which also resulted in smaller treatment numbers without intermediate risk group was primary HPV(hr), with treatment of both HPV(16/18) and cytology (ASCUS +) [HPW: sensitivity 73.6%; specificity 89.7%; treatment 34.7%. HNW: sensitivity 59.1%; specificity 93.6%; treatment 13.9%].DNA testing for hrHPV (any) and hrHPV (16/18) was the best universally acceptable strategy with an intermediate risk category (early follow-up) in HPW [sensitivity 82.1%; specificity 96.4%; treatment 17.1%; follow-up 31.4%] and HNW [sensitivity 68.2%; specificity 96.7%; treatment 7.6%; follow-up 15.9%]. In comparison, using both HPV (16/18) and cytology (ASCUS +) as secondary tests in hrHPV positive women, decreased follow-up [HPW 13.8%, HNW 9.6%], but increased treatment [HPW 34.7%, HNW 13.9%].ConclusionUsing hrHPV (any) as primary and both HPV16/18 and cytology as secondary tests, was universally acceptable without an intermediate risk group. Strategies with follow-up groups improved screening performance with smaller treatment numbers, but with effective management of the intermediate risk group as prerequisite.

External validation of the RIETE and SOME scores for occult cancer in patients with venous thromboembolism: a multicentre cohort study.

Venous thromboembolism (VTE) may be the first sign of an undiagnosed cancer. The RIETE and SOME scores aim to identify patients with acute VTE at high risk of occult cancer. In the present study, we evaluated the performance of both scores. The scores were evaluated in a retrospective cohort from two centers. The area under the receiver-operating characteristics curve (AUC) evaluated the discriminatory performance. The RIETE score was applied to 815 patients with provoked and unprovoked VTE, of whom 56 (6.9%) were diagnosed with cancer. Of the 203 patients classified as high-risk, 18 were diagnosed with cancer, representing 32.1% (18/56) of the total cancer diagnoses. In the group of 612 low-risk patients, 67.9% of the cancer cases were diagnosed (38/56). Sensitivity, specificity, negative and positive predictive values, and AUC were 32%, 76%, 94%, 9%, and 0.430 (95% confidence interval [CI], 0.38‒0.47), respectively. The SOME score could be calculated in 418 patients with unprovoked VTE, of whom 33 (7.9%) were diagnosed with cancer. Of the 45 patients classified as high-risk, three were diagnosed with cancer, representing 9.1% (3/33) of the total cancer diagnoses. In the group of 373 low-risk patients, 90.9% of the cancer cases were diagnosed (30/33). Sensitivity, specificity, negative and positive predictive values, and AUC were 33%, 88%, 94%, 20%, and 0.351 (95% CI, 0.27‒0.43), respectively. The performance of both scores was poor. Our results highlight the need to develop new models to identify high-risk patients who may benefit from an extensive cancer screening strategy.

Risk of Subsequent Primary Cancers Among Adult-Onset 5-Year Cancer Survivors in South Korea: Retrospective Cohort Study.

The number of cancer survivors who develop subsequent primary cancers (SPCs) is expected to increase. We evaluated the overall and cancer type-specific risks of SPCs among adult-onset cancer survivors by first primary cancer (FPC) types considering sex and age. We conducted a retrospective cohort study using the Health Insurance Review and Assessment database of South Korea including 5-year cancer survivors diagnosed with an FPC in 2009 to 2010 and followed them until December 31, 2019. We measured the SPC incidence per 10,000 person-years and the standardized incidence ratio (SIR) compared with the incidence expected in the general population. Among 266,241 survivors (mean age at FPC: 55.7 years; 149,352/266,241, 56.1% women), 7348 SPCs occurred during 1,003,008 person-years of follow-up (median 4.3 years), representing a 26% lower risk of developing SPCs (SIR 0.74, 95% CI 0.72-0.76). Overall, men with 14 of the 20 FPC types had a significantly lower risk of developing any SPCs; women with 7 of the 21 FPC types had a significantly lower risk of developing any SPCs. The risk of developing any SPC type differed by age; the risk was 28% higher in young (<40 years) cancer survivors (SIR 1.28, 95% CI 1.16-1.42; incidence: 30 per 10,000 person-years) and 27% lower in middle-aged and older (≥40 years) cancer survivors (SIR 0.73, 95% CI 0.71-0.74; incidence: 80 per 10,000 person-years) compared with the age-corresponding general population. The most common types of FPCs were mainly observed as SPCs in cancer survivors, with lung (21.6%) and prostate (15.2%) cancers in men and breast (18.9%) and lung (12.2%) cancers in women. The risks of brain cancer in colorectal cancer survivors, lung cancer in laryngeal cancer survivors, and both kidney cancer and leukemia in thyroid cancer survivors were significantly higher for both sexes. Other high-risk SPCs varied by FPC type and sex. Strong positive associations among smoking-related cancers, such as laryngeal, head and neck, lung, and esophageal cancers, were observed. Substantial variation existed in the associations between specific types of FPC and specific types of SPC risk, which may be linked to hereditary cancer syndrome: for women, the risks of ovarian cancer for breast cancer survivors and uterus cancers for colorectal cancer survivors, and for men, the risk of pancreas cancer for kidney cancer survivors. The varying risk for SPCs by age, sex, and FPC types in cancer survivors implies the necessity for tailored prevention and screening programs targeting cancer survivors. Lifestyle modifications, such as smoking cessation, are essential to reduce the risk of SPCs in cancer survivors. In addition, genetic testing, along with proactive cancer screening and prevention strategies, should be implemented for young cancer survivors because of their elevated risk of developing SPCs.

Abstract PO4-19-02: Genetic risk estimation in breast cancer and assessing health disparities

Abstract Background: Breast Cancer (BC) incidence and the distribution of BC risk factors vary between racial and ethnic groups within the United States. It has been demonstrated that providing education on individualized breast cancer risk will improve patient uptake to recommended BC screening and prevention strategies. Most clinical risk assessment tools, including the validated IBIS model were derived from data using non-Hispanic white women. Consortia have also now identified over 300 common genetic susceptibility loci for BC, summarized by the polygenic risk score (PRS). When combined with clinical risk assessment tools, such as the IBIS or BCRAT models, the PRS can further refine risk estimation for patients. To date, most studies on the use of PRS have been done in non-Hispanic white women. While these PRS still perform well in racial minorities, there has been a recognized need to improve racial and ethnic diversity in genomic research cohorts. Herein, we aim to combine clinical risk assessment models that are already used in routine clinical practice with information derived from PRS testing in women of racial minorities to determine if this can improve risk estimation, patient understanding, and uptake to recommended breast cancer screening and prevention strategies. Design: This is a minimal risk prospective study with a single arm incorporating the PRS into a standard breast cancer risk reduction consultation, followed by annual surveys over 10 years to determine if and how the information provided by the PRS influenced patient decisions regarding recommended BC screening and prevention. Patients will have IBIS and BCRAT risks calculated at baseline visit. A survey of patient perceptions/understanding of risk, intention to undergo screening, and use of preventive medicine is completed after baseline visit prior to receiving the PRS results. Blood sample is obtained at baseline and DNA samples are analyzed for approximately 300 SNPs on a custom-designed, targeted SNP panel from ThermoFisher Scientific by the Mayo Clinic Genomics Laboratory. This PRS result is then combined with the clinical risk assessments (IBIS and BCRAT scores) using the R package Individualized Coherent Absolute Risk Estimators (iCare) tool to provide a new estimate of breast cancer risk for 5year, 10year, and lifetime risk. Patients are seen for follow-up to review results and then complete a second survey to assess their understanding of the results, BC risk, and how the PRS impacted their decision to undergo screening/prevention strategies. Eligibility Criteria: Women who self-identify as African American/Black or Hispanic/Latinx between 30-75 years old with any of the following: 1.)IBIS score of ≥5% for the 10 year risk OR BCRAT score of ≥ 3 % for the 5 year risk. 2.) History of biopsy proven atypical hyperplasia 3.) History of biopsy proven lobular carcinoma in situ. Specific Aims: Aim 1: The primary aim of this study is to explore if the addition of PRS to the BCRAT and IBIS score will improve intentions to undergo recommended breast cancer screening strategies such as mammography, MRI, or molecular breast imaging in women of underserved racial minorities Aim 2: To explore if the addition of the PRS to the BCRAT and IBIS risk score will aid women of racial minorities in deciding whether to take preventative endocrine therapy. Aim 3: To understand how individualized risk assessment and information on PRS may alter perceived risk of breast cancer. Statistical Methods Analysis will be mostly descriptive. Continuous variables will be summarized as mean (standard deviation) or median (range) and categorical variables will be reported as frequency (percentage). Kaplan-Meier method will be used to estimate the long-term cumulative risk of cancer. Current Accrual: 3. Target Accrual: 50 Citation Format: Lauren Cornell, Sandhya Pruthi, Linda Hasadsri, Sarah McLaughlin. Genetic risk estimation in breast cancer and assessing health disparities [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-02.

Toward a Unified Theory of Why Young People Develop Cancer.

Epidemiologic and genetic studies have now defined specific patterns of incidence and distinct molecular features of cancers in young versus aging people. Here, I review a general framework for the causes of cancer in children and young adults by relating somatic genetic mosaicism and developmental tissue mutagenesis. This framework suggests how aging-associated cancers such as carcinomas, glioblastomas, and myelodysplastic leukemias are causally distinct from cancers that predominantly affect children and young adults, including lymphoblastic and myeloid leukemias, sarcomas, neuroblastomas, medulloblastomas, and other developmental cancers. I discuss the oncogenic activities of known developmental mutators RAG1/2, AID, and PGBD5, and describe strategies needed to define missing developmental causes of young-onset cancers. Thus, a precise understanding of the mechanisms of tissue-specific somatic mosaicism, developmental mutators, and their control by human genetic variation and environmental exposures is needed for improved strategies for cancer screening, prevention, and treatment.

Cholangiocarcinoma and Occupational Exposure to Asbestos: Insights From the Italian Pooled Cohort Study.

Recent studies supported the association between occupational exposure to asbestos and risk of cholangiocarcinoma (CC). Aim of the present study is to investigate this association using an update of mortality data from the Italian pooled asbestos cohort study and to test record linkage to Cancer Registries to distinguish between hepatocellular carcinoma (HCC) and intrahepatic/extrahepatic forms of CC. The update of a large cohort study pooling 52 Italian industrial cohorts of workers formerly exposed to asbestos was carried out. Causes of death were coded according to ICD. Linkage was carried out for those subjects who died for liver or bile duct cancer with data on histological subtype provided by Cancer Registries. 47 cohorts took part in the study (57,227 subjects). We identified 639 causes of death for liver and bile duct cancer in the 44 cohorts covered by Cancer Registry. Of these 639, 240 cases were linked to Cancer Registry, namely 14 CC, 83 HCC, 117 cases with unspecified histology, 25 other carcinomas, and one case of cirrhosis (likely precancerous condition). Of the 14 CC, 12 occurred in 2010-2019, two in 2000-2009, and none before 2000. Further studies are needed to explore the association between occupational exposure to asbestos and CC. Record linkage was hampered due to incomplete coverage of the study areas and periods by Cancer Registries. The identification of CC among unspecific histology cases is fundamental to establish more effective and targeted liver cancer screening strategies.