Cancer Screening Research Articles

Abstract A040: Using mitochondrial abundance in tumor-derived extracellular vesicles for pancreatic cancer screening

Abstract Pancreatic cancer, marked by a high mortality rate and rising incidence, often goes undetected until advanced stages, complicating treatment. Tumor-derived extracellular vesicles (EVs) have emerged as promising cancer biomarkers due to their cargo from parent cells. However, current detection methods are often time-consuming, expensive, and complex. To overcome these challenges, we developed a screening assay for pancreatic cancer that uses the mitochondrial DNA to nuclear DNA ratio in tumor-derived EVs as a distinguishing feature. This assay combines immunoprecipitation with qPCR quantification for direct detection of tumor-derived EVs from serum, utilizing DNA-isolation-free techniques and duplexing probes for qPCR, thus saving at least 3 hours. Clinical sample testing demonstrated the assay's potential as a translational tool for cancer screening, showing a weak correlation with prognosis biomarkers and sufficient discriminatory power between healthy controls, pancreatitis, and pancreatic cancer cases. Citation Format: Dali Sun. Using mitochondrial abundance in tumor-derived extracellular vesicles for pancreatic cancer screening [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A040.

Abstract A064: Lung cancer screening adherence among participants in DETECT-A, the first prospective interventional trial of a multi-cancer early detection (MCED) blood test

Abstract Background: Lung cancer is the leading cause of cancer death in the US. Adherence to guideline- recommended low-dose computed tomography screening is poor and late-stage diagnosis is common. MCED tests may improve early cancer detection if adherence to guideline- recommended single cancer screening is maintained. The DETECT-A study evaluated an MCED test in 9,911 women in Geisinger Health System (GHS), age 65-75, without personal cancer history. This analysis evaluates lung cancer screening adherence among DETECT-A participants to determine if adherence changed significantly following receipt of an MCED test. Methods: Monthly screening eligibility and adherence data (2013 USPSTF criteria) were available from September 2016 - May 2020 for DETECT-A participants and screening-eligible women in GHS who met DETECT-A eligibility criteria but did not participate in DETECT-A. A control group was constructed by randomly selecting GHS non-participants at a 7:1 ratio and assigning index months that matched the distribution of consent months for DETECT-A participants. All analyzed participants had ≥24 consecutive months of adherence data centered around the consent/index month. The proportion adherent at consent/index month and the end of active study participation at 12 months were calculated descriptively. Changes in adherence over time, as well as group comparisons, were assessed using a mixed effects logistic regression model. Results: DETECT-A participants (n=364) and controls (n=2,548) had similar age, race, and ethnicity distributions. The population was predominantly white (>98%) and non-Hispanic (>90%). The odds of adherence at 12 months were significantly higher than at consent/index for both DETECT-A participants (OR: 3.20 [1.04 -9.80], p=0.042) and controls (OR: 2.02 [1.23- 3.33], p=0.006). The increase in odds of adherence between consent/index and 12 months was not significantly different between the groups (OR: 1.58 [0.47-5.31], p=0.461). DETECT-A participant adherence was 28.0% (23.4%-32.6%) in the consent month and increased to 38.5% (33.5-43.5%) at 12 months. Among the 102 DETECT-A participants adherent in the consent month, 70 (68.6%) were also adherent at 12 months. Control adherence was 16.0% (14.6%-17.4%) in the index month and increased to 20.2% (18.7%-21.8%) at 12 months. Among 408 controls adherent in the index month, 257 (63.0%) were also adherent at 12 months. Conclusions: DETECT-A participation did not negatively affect lung cancer screening adherence among this subset of participants. Screening adherence increased over time in both DETECT-A participants and controls; most DETECT-A participants adherent in the study consent month were also adherent 12 months later. Effectiveness of GHS screening programs, DETECT-A participant self-selection, and DETECT-A educational efforts promoting screening may have contributed to these observations. Citation Format: Adam H. Buchanan, Anne Marie Lennon, Paul Z. Elias, Amy M. Lehman, Yongqiang Zhang, Darl D. Flake II, Eric S. Wagner, Seema P. Rego, Omair A. Choudhry, Nickolas Papadopoulos, Tomasz M. Beer. Lung cancer screening adherence among participants in DETECT-A, the first prospective interventional trial of a multi-cancer early detection (MCED) blood test [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A064.

Abstract A075: Circulating T-cell receptor repertoire analysis improves cancer early detection

Abstract Introduction: Cancer screening by liquid biopsy promises to detect cancer early when it can be cured. However, current ctDNA-based approaches detect only a minority of early-stage cancers. For liquid biopsy to realize its full potential for cancer early detection, sensitivity for earliest stage disease must be improved. Methods: We set out to improve sensitivity of liquid biopsy by exploiting tumor recognition by T cells through sequencing of the circulating T-cell receptor repertoire. Using gDNA extracted from blood buffy coats, we studied a cohort of 471 lung cancer patients (85% stage I) and 600 subjects without cancer enriched for older individuals with a history of smoking. We performed TCR beta chain sequencing to yield a median of 101,899 TCR clonotypes per sample (median 81,602 cancer / 112,966 controls) and built a TCR sequence similarity graph to cluster clonotypes into TCR repertoire functional units (RFUs). The TCR frequencies of RFUs were tested for association with cancer status and significantly associated RFUs were combined using an SVM model into a cancer score. Cancer RFU levels were also correlated to imputed subject HLA types for 32 HLA Class I and 38 Class II alleles. The model was evaluated by 10-fold cross-validation and compared to a ctDNA panel of 237 mutation hotspots in 154 lung cancer driver genes and to 17 lung cancer related protein biomarkers in 86 subjects. Results: We identified 372 cancer-associated TCR RFUs at FDR≤0.1, including 198 enriched in cancer samples (fold-change range 1.03 to 3.13) and 174 enriched in controls (fold- change 0.96 to 0.30). Levels of 265/372 (71%) RFUs were correlated to presence of an HLA allele at FDR ≤ 0.1. Of the total 2,770 significant HLA-RFU associations, 479 (17%) involved an HLA Class I allele, while 2,291 (83%) involved an HLA Class II allele, highlighting a potential role for CD4 helper or regulatory T cell antigen recognition in the cancer RFUs found. The RFU cancer score achieved a cross-validated test ROC AUC of 0.71 for cancer status prediction (0.71 Stage I / 0.70 Stage II-IV) with 49% of Stage I cancers detected at a specificity of 80%. Importantly, the cancer score was not dependent on sample source site, technical or biological variation in TCR repertoire depth, or lung cancer histology subtype. The TCR RFU score also distinguished lung cancer patients from control subjects with other conditions such as benign lung nodules and COPD. We observed an up to ∼20%-point gain in sensitivity for stage I cancer when TCR RFUs were added to ctDNA and proteins in a potential multi-analyte cancer screening test. By contrast, TCR analysis did not provide additional sensitivity for stage II-IV disease. Conclusion: We demonstrate detection of a significant fraction of early lung cancer cases from blood by analyzing the circulating TCR repertoire and show that this signal is complementary to established analytes such as proteins and ctDNA. A similar study for the detection of early colorectal cancer and advanced adenomas is under way. Citation Format: Yilong Li, Michelle Nahas, Dennis Stephens, Kate Froburg, Emma Hintz, Devin Champagne, Amaneet Lochab, Markus Brown, Jasper Braun, María Antonia Fortuño, María-del-Mar Ocón, Andrea Pasquier, Inés María Luque, Christopher W. Seder, Jeffrey A. Borgia, Luis Miguel Seijo, Luis M Montuenga, Roman Yelensky. Circulating T-cell receptor repertoire analysis improves cancer early detection [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A075.

New strategies for lung cancer diagnosis and treatment: applications and advances in nanotechnology.

Lung cancer leads in causing cancer-related mortality worldwide, continually posing a significant threat to human health. Current imaging diagnostic techniques, while offering non-invasive detection, suffer from issues such as insufficient sensitivity and the risks associated with radiation exposure. Pathological diagnosis, the gold standard for confirmation, also faces challenges like invasiveness and high costs. In treatment, surgery, radiotherapy, and chemotherapy are the main modalities, each encountering challenges related to precision, environmental adaptability, and side effects. Nanotechnology's advancement provides new solutions for the diagnosis and treatment of lung cancer, promising to enhance diagnostic accuracy and reduce side effects during treatment. This article introduces the main types of nanomaterials used in the field of lung cancer, offering a comprehensive overview of current research on the application of nanotechnology in early screening, diagnosis, treatment, and monitoring of lung cancer, and summarizing ongoing clinical research findings.

Cervical cancer screening rates in females living with HIV at three healthcare settings in the United States, 2010-2019.

Females living with human immunodeficiency virus (FLWHIV) are at increased risk of cervical cancer and U.S. guidelines, first published in 2009 and updated since then, recommend more frequent screening in this population. We examined screening rates among FLWHIV in the U.S. during 2010-2019. This cohort study included 18-89-year-old FLWHIV during 2010-2019 at three U.S. healthcare settings. Sociodemographics, comorbidities, and cervical cancer screening tests were ascertained from administrative and clinical databases. We reported cervical cancer screening rates overall and by modality. Generalized estimating equations with Poisson distribution were used to estimate screening rate ratios (SRRs) and 95% confidence intervals (CIs) for the associations between screening rates and calendar year, age, race and ethnicity, and comorbidity. Among 3,556 FLWHIV, a total of 7,704 cervical cancer screening tests were received over 18,605 person-years during 2010-2019 (screening rate = 41.4 per 100 person-years). Relatively lower screening rates were associated with later calendar years (SRR = 0.71 [95% CI 0.68-0.75] for 2017-2019 versus 2010-2013), older age (SRR = 0.82 [95% CI 0.74-0.89] for 50-65-year-olds versus 18-29-year-olds), non-Hispanic white race versus non-Hispanic Black race (SRR = 0.89 [95% CI 0.81-0.98]) and greater comorbidity burden (SRR = 0.89 [95% CI 0.82-0.98] for ≥ 9 versus 0-6 comorbidity score). The decrease in cervical cancer screening rates during 2010-2019 in this large cohort of FLWHIV may be explained at least partly by guideline changes during the study period recommending longer screening intervals. Our findings of relatively lower screening rates in FLWHIV who were non-Hispanic white, older, and with greater comorbidity burden should be confirmed in other U.S.

Evaluating the use of environmental and polygenic risk scores to inform colorectal cancer risk-based surveillance intervals

Objective: U.S. Multi-Society Task Force colonoscopy surveillance intervals are based solely on adenoma characteristics, without accounting for other risk factors. We investigated whether a risk model including demographic, environmental and genetic risk factors could individualize surveillance intervals under an “equal management of equal risks” framework. Methods: Using 14,069 individuals from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnostic colonoscopy following an abnormal flexible sigmoidoscopy, we modeled the risk of colorectal cancer (CRC), considering the diagnostic colonoscopy finding, baseline risk factors (e.g., age and sex), 19 lifestyle and environmental risk factors, and a polygenic risk score (PRS) for CRC. Ten-year absolute cancer risks for each diagnostic colonoscopy finding [advanced adenoma (N=2446), ≥3 non-advanced adenomas (N=483), 1-2 non-advanced adenomas (N=4400) and no adenoma (N=7183)] were used as implicit risk thresholds for recommended surveillance intervals. Results: The area-under-the-curve (AUC) for the model including colonoscopy findings, baseline characteristics, and PRS was 0.658. Applying the “equal management of equal risks” framework, 28.2% of individuals with no adenoma and 42.7% of those with 1-2 non-advanced adenomas would be considered high risk and assigned a significantly shorter surveillance interval than currently recommended. Among individuals who developed cancer within 10 years, 52.4% with no adenoma and 48.3% with 1-2 non-advanced adenomas would have been considered high risk and assigned a shorter surveillance interval. Conclusion: Using a personalized risk-based model has the potential to identify individuals with no adenoma or 1-2 non-advanced adenomas, who are higher risk and may benefit from shorter surveillance intervals.

Does free cancer screening make a difference? Evidence from the effects of a free-coupon program in Japan

Does free cancer screening make a difference? Evidence from the effects of a free-coupon program in Japan

Functional Immunoaffinity 3D Magnetic Core-Shell Nanometallic Structure for High-Efficiency Separation and Label-Free SERS Detection of Exosomes.

Tumor exosomes, known as maternal cell messengers, play an important role in cancer occurrence, proliferation, metastasis, immune escape, drug resistance, and other processes and are an entry point for cancer research. However, there is still a lack of an efficient detection technology for exosomes. In this study, the ultrahigh sensitivity SERS nanoprobe with a three dimensional (3D) magnetic core/Au nanocolumn/Au nanoparticles shell strongly coupling multistage structure (Fe3O4@NR-NPs) was constructed by crystal growth of nanocrystals in the confined space of a central radiating single particle mesoporous molecular sieve channel and strong coupling secondary growth of gold particles. The exosomes were confined onto the "hot spot" of plasmonic nanoparticles and rapidly enriched by CD63 antibody functional-Fe3O4@NR-NPs to achieve high sensitivity detection, with the limit of detection of 1 × 103 particles/mL (S/N = 3). The spectral data set of different exosomes is applied to train for multivariate classification of cell types and to estimate how the normal exosome data resemble cancer cell exosomes by principal component analysis (PCA). Finally, this detection method has also been successfully employed for the detection of exosomes in complex samples; this proves that the proposed SERS-based method is a promising tool for clinical cancer screening.

Comparison of AI software tools for automated detection, quantification and categorization of pulmonary nodules in the HANSE LCS trial.

Participant management in a lung cancer screening (LCS) depends on the assigned Lung Imaging Reporting and Data System (Lung-RADS) category, which is based on reliable detection and measurement of pulmonary nodules. The aim of this study was to compare the agreement of two AI-based software tools for detection, quantification and categorization of pulmonary nodules in an LCS program in Northern Germany (HANSE-trial). 946 low-dose baseline CT-examinations were analyzed by two AI software tools regarding lung nodule detection, quantification and categorization and compared to the final radiologist read. The relationship between detected nodule volumes by both software tools was assessed by Pearson correlation (r) and tested for significance using Wilcoxon signed-rank test. The consistency of Lung-RADS classifications between Software tool 1 (S1, Aview v2.5, Coreline Soft, Seoul, Korea) and Software tool 2 (S2, Prototype ''ChestCTExplore'', software version ToDo, Siemens Healthineers, Forchheim, Germany) was evaluated by Cohen's kappa (κ) and percentual agreement (PA).The derived volumes of true positive nodules were strongly correlated (r > 0.95), the volume derived by S2 was significantly higher than by S1 (P < 0.0001, mean difference: 6mm3). Moderate PA (62%) between S1 and S2 was found in the assignment of Lung-RADS classification (κ = 0.45). The PA of Lung-RADS classification to final read was 75% and 55% for S1 and S2, but the incorporation of S1 into the initial nodule detection and segmentation must be considered here. Significant nodule volume differences between AI software tools lead to different Lung-RADS scores in 38% of cases, which may result in altered participant management. Therefore, high performance and agreement of accredited AI software tools are necessary for a future national LCS program.

Participation in the National Bowel Cancer Screening Program by people with severe mental illness, Australia, 2006-2019: a national data linkage study.

To compare rates of participation in the National Bowel Cancer Screening Program (NBCSP) and follow-up for people with severe mental illness with those for people without severe mental illness or not prescribed antidepressants. Retrospective cohort study; analysis of de-identified linked NBCSP, Pharmaceutical Benefits Scheme (PBS), and Medicare Benefits Schedule (MBS) data. Australia, 2006-2019. People aged 50-74 years (NBCSP-eligible) with severe mental illness, defined as those dispensed two or more prescriptions for second generation antipsychotics or for lithium (PBS data), and a random sample of people aged 50-74 years eligible for Medicare-subsidised services but never prescribed psychotropic medications (antipsychotics, lithium, antidepressants). NBCSP participation (returned faecal occult blood test sample), valid test result, positive test result, and follow-up colonoscopy rates. A total of 119 475 people with severe mental illness and 1 090 574 control group people were included in our analyses. The proportion of women was larger in the severe mental illness group (51.3%) than the control group (48.7%), as were the proportions who lived in inner regional areas (23.5% v 19.1%) or in areas in the lowest socio-economic quintile (21.8% v 14.7%). The NBCSP participation rate was lower among people with severe mental illness (adjusted incidence rate ratio [IRR], 0.70; 95% confidence interval [CI], 0.69-0.84). The proportion of valid test results was smaller for people with severe mental illness (95.9% v 98.7%; adjusted IRR, 0.97; 95% CI, 0.96-0.99), and the positive test result proportion larger (12.3% v 6.6%; adjusted IRR, 2.01; 95%CI, 1.94-2.09). The proportion of positive test results followed by colonoscopy was smaller for people with severe mental illness (71.7% v 82.6%; adjusted IRR, 0.88; 95% CI, 0.85-0.92). People with severe mental illness were less likely to participate in the NBCSP or to undergo colonoscopy after a positive test result than other Australians. These differences may contribute to higher colorectal cancer mortality among people with severe mental illness. The contributions of differences in cancer stage at diagnosis and subsequent treatment to higher colorectal cancer mortality require further study.

Efficacy of Interventions Intended to Increase Lung Cancer Screening Rates: A Systematic Review and Meta-analysis.

Few eligible patients in the United States participate in lung cancer screening (LCS) with low-dose computed tomography (LDCT). What is the efficacy of interventions to increase LCS participation? We performed a systematic review following a prespecified protocol registered in PROSPERO (CRD42021283984). In June/July of 2021, we searched Ovid MEDLINE, Embase, Cochrane, CENTRAL, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and Epistemonikos from 1946 to October 2021 to identify studies evaluating interventions to increase LCS participation. Thirteen of 2761 studies met inclusion criteria for data extraction. Of these, six had results available (five RCTs and one prospective observational study). The studies had predominantly White and non-Hispanic participants. An intention-to-treat analysis was used to calculate each study's relative risk (RR) to increase LCS. Effect sizes were pooled using a random-effects model with a subgroup analysis for multi- versus single-step interventions. Risk of bias was evaluated with the revised Cochrane risk-of-bias tool (RoB 2) and risk of bias in non-randomized studies of interventions (ROBINS-I). Overall, the proportion of screening LDCTs performed did not improve in the intervention group relative to the comparator group (RR [95% CI] of 1.30 [0.74, 2.29]), and meta-analysis indicated high heterogeneity of studies (I2 = 91%). Subgroup analysis suggests that interventions targeting multiple barriers may increase LCS participation (RR [95% CI] for multistep vs single-step; 2.68 [1.77, 4.05] vs 0.99 [0.89, 1.10], P < 0.01). Quality assessment revealed that three of five RCTs showed some concerns or high risk of bias. Evidence on efficacy of interventions to increase LCS participation is limited due to a small number of prospective studies performed in non-diverse populations with critical risk of bias. Further, overall, studied interventions did not improve lung cancer screening participation, though interventions targeting multiple barriers may have some benefit.

Communicating Probabilities of Cervical Cancer Screening Results with Icon Arrays or Tree Diagrams: A Longitudinal Experiment

ABSTRACT Simple graphical displays such as icon arrays and tree diagrams have been proposed for communicating health risks and supporting informed decisions. The UK’s National Health Service (NHS) uses tree diagrams to communicate the chances of different cervical cancer screening results, but their effectiveness has not been compared to icon arrays. We conducted a well-powered longitudinal experiment involving 3,100 UK women eligible for cervical screening (25–64 years) to examine the effectiveness of icon arrays to communicate possible cervical screening results, relative to the UK NHS’s tree diagram and to a numerical-only format. We also examined whether the presence (vs. absence) of explanatory text referring to different types of results (i.e. distinguishing between HPV positive results with vs. without abnormal cervical cells) moderated effects of presentation format. Presentation format did not affect verbatim or gist knowledge of probabilities at initial assessment (i.e. immediately after participants viewed the displays), but icon arrays were associated with better gist knowledge of absolute magnitudes than tree diagrams and numerical-only formats at 1-month follow-up. Participants exposed to icon arrays also perceived lower likelihood of adverse screening results and reported stronger screening intentions at initial assessment. For displays without explanatory text, icon arrays were also associated with more positive user evaluations and less negative affective reactions than tree diagrams at initial assessment. Overall, our findings suggest that icon arrays support enduring knowledge of approximate magnitudes of probabilities and are better suited than tree diagrams for communicating possible screening results.

Centering intersectional breast cancer screening experiences among black, Latina, and white women: a qualitative analysis

ObjectiveMammography screening guidelines in the United States highlight the importance of informing and involving women when making their breast cancer screening decisions. However, the complexity of interpreting and applying these population-level guidelines can contribute to patient burden. Patient-centered communication strategies can alleviate patient burden, but few consider perspectives from racially and ethnically marginalized populations. We examine diverse women’s perspectives on screening to characterize patient-centered experiences.MethodsWe conducted 28 focus groups with 134 non-Latina Black (n = 51), non-Latina White (n = 39), and Latina (n = 44) participants. We coded participants’ discussion of their screening influences. We used deductive and inductive qualitative methods to identify common themes.ResultsWe identified three themes: (1) personal relationships with primary care providers, (2) potential impacts of cancer on families, and (3) interactions with medical systems. Most White participants described trusting physician relationships in contrast to perfunctory, surface-level relationships experienced by many Black participants; high costs of care prevented many Latina participants from accessing care (Theme 1). Diagnosis was a concern for most Black participants as it could burden family and most Latina participants as it could prevent them from maintaining family well-being (Theme 2). While many White participants had general ease in accessing and navigating healthcare, Latina participants were often held back by embarrassment—and Black participants frequently described disrespectful providers, false negatives, and unnecessary pain (Theme 3).ConclusionCultural and structural factors appeared to influence participants’ approaches to breast cancer screening. Structural barriers may counteract culturally salient beliefs, especially among Black and Latina participants. We suggest patient-centered communication interventions be culturally adjusted and paired with structural changes (e.g., policy, insurance coverage, material resources) to reflect women’s nuanced values and intersectional social contexts.

Abstract A061: A cost-effective two-step approach for multi-cancer early detection in general population

Abstract In population-wide cancer screening, three key issues need to be focused on: number of cancer cases identified, the issue of false positives, and cost. A high false positive rate can result in a significant waste of healthcare resources. Large-scale screening inevitably leads to significant financial burdens on the healthcare system which is a key factor constraining nationwide screening. OncoSeek is a multi-cancer early detection (MCED) test using a panel of seven plasma protein tumor markers (PTMs) and artificial intelligence (AI). SeekInCare is a MCED test that integrates the seven PTMs and four cancer genomic features (aneuploidy, fragment size, end motifs, and oncogenic viruses) from cell-free DNA (cfDNA) by shallow whole-genome sequencing (sWGS). In a two-step approach, the initial screening is conducted using OncoSeek and SeekInCare is then used as the secondary test for those individuals who tested positive by OncoSeek. In a case-control study (n = 1197) including both OncoSeek and SeekInCare testing results, OncoSeek showed 49.9% sensitivity at 91.0% specificity, while SeekInCare demonstrated 60.0% sensitivity at 98.3% specificity. In the two-step process, specificity significantly increased from 91.0% to 99.3%, while sensitivity decreased from 49.9% to 39.9%. We modeled a screening in five million adults aged ≥ 50 years with a cancer incidence rate of 1.9%. The simulated real-world sensitivities of OncoSeek and two-step were adjusted downward proportionally to 28.0% and 22.4% based on the sensitivity differences observed between GRAIL’s CCGA study (case-control, 51.5%) and PATHFINDER study (prospective, 28.9%). While at 91.0% specificity OncoSeek had 441,450 cases of false positives, using the two-step approach significantly reduced false positives to 34,335 (0.7%). Although Galleri ($949 per test) identified more cancer cases than the two-step MCED, with 27,455 and 21,280 cases respectively, its total cost for the former reached $4,745 million. As the positive predictive value (PPV) of two-step (38.3%) was the same as Galleri (38.3%), it reduced cost 6.6-fold, amounting to a total cost of $713.6 million and a cost of $143 per individual screened. The cost of per cancer case detected using Galleri is $172,828 compared to $33,534 using the two-step MCED, which represents a 5.2-fold difference. In conclusion, the two-step approach not only significantly reduces false positives, but also cuts the screening cost down substantially, making it a cost-effective strategy for population-wide cancer screening. Citation Format: Mao Mao, Geng shuai peng, Li shi yong, Wu Wei, Chang Yin Yin. A cost-effective two-step approach for multi-cancer early detection in general population [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A061.

Abstract A041: Detection of early-stage gastrointestinal cancers using micronuclei DNA from erythrocytes

Abstract Background: Gastrointestinal (GI) cancers account for over a third of cancer deaths. However, their early detection remains a challenge. Micronuclei (MN) are cytoplasm-resident subcellular structures, containing damaged chromosome segments that indicative of genomic instability. Increased MN frequency in hematopoietic cells is observed in patients with solid tumors. Our developed technique (WO2021/228246 A1) enables the purification and characterization of micronuclei DNA in erythrocytes from peripheral blood. By comparing MN-DNA from healthy donors (HDs) and GI cancer patients, we identified significant changes in read densities at specific genomic locations in patients, which were termed as tumor-associated MN-DNA (taMN- DNA) features. Here, we evaluated the potential of these features for early-stage GI cancer detection, including colorectal (CC), gastric (GC) and esophageal (EC) cancers. Methods: Peripheral blood (1-2 mL) was collected from healthy donors (HD) and cancer patients MN-DNA isolation and purification from erythrocytes. Participants were randomly divided into training, validation and independent test cohorts in a 7:2:1 ratio, maintaining similar cancer types, gender and age distribution. Distinct MN-DNA features between cancer patients and HDs were identified using sequencing data. Machine learning algorithms were applied using these features for cancer detection. Results: The study enrolled 1753 participants, including 987 HDs, 420 CC, 282 GC and 64 EC cases. Of these, over half were diagnosed with early-stage diseases; TNM stage 0-I accounted for 40.57%, stage II for 23.32%, stage III for 29.25% and stage IV for 6.87%. The pan-cancer model achieved 88.2% sensitivity with an overall specificity of 95.4%. Patients in individual caner types were detected from the tissue of origin classification with an overall accuracy of 91.9% based on pan-cancer at 95.4% specificity. Sensitivity was 90.8% for CC, 91.7% for GC and 100% for EC. For early- stage (stage 0-II) CC, GC and EC, the model demonstrated sensitivities of 97.4%, 94.7% and 100.00%, respectively, at 95.4% specificity. Conclusions: Unlike cell-free DNA, MN-DNA are chromosomal fragments in the cytoplasm. The abundance of erythrocytes in peripheral blood provides an easily accessible source for MN-DNA enrichment. This pilot study illustrates the potential of MN-DNA as a tool for early GI cancer detection, contributing to large-scale efforts towards developing an effective GI cancer screening test. Research sponsor: Timing Biotech. Citation Format: Haobo Sun, Xingyun Yao, Yuehua Han, Yurong Jiao, Xiangxing Kong, Chengcheng Liu, Qingqu Guo, Fei Meng, Honghao Liang, Hongbo Li, Xiuqin Fan, Jun Li, Xiaofei Gao. Detection of early-stage gastrointestinal cancers using micronuclei DNA from erythrocytes [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A041.

Abstract A050: Early detection of liver cancer from diverse populations using cfDNA fragmentome and protein biomarkers

Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer death world-wide. In the US, liver cancer has increased in incidence and mortality due to a growing population from South and Central America, which faces higher risk of disease in part due to aflatoxin exposure. Recently, we showed that the DELFI (DNA evaluation of fragments for early interception) approach using genome-wide cell free DNA (cfDNA) fragmentation profiles and machine learning can be used for detection of liver and other cancers. Having previously demonstrated that a DELFI classifier accurately detects HCC in populations from the US and Hong Kong, we evaluated the classifier in other clinically relevant cohorts worldwide. Here we show that approach generalizes to diverse populations, and that including other genomic and protein features from the same blood draw improves performance. We examined plasma samples from 377 individuals, including 244 individuals with HCC and 133 without cancer, including 85 with cirrhosis. Plasma samples were collected from individuals with or without HCC in a case-control study in Guatemala (n=203) and from a prospective collection in Romania (n=174) and cfDNA was analyzed by whole- genome sequencing at ∼10x coverage. The median DELFI scores using a locked classifier (Foda et al., Cancer Discovery, 2023) were higher in both cohorts for patients with cancer across all stages compared to individuals without cancer, regardless of the presence of cirrhosis. Using the locked model with a threshold that corresponded to 80% specificity in prior work, DELFI detected individuals with HCC with sensitivities of 90% and 69% in the two cohorts at specificities of 92% and 86%, respectively. For early-stage HCC within Milan Criteria for liver transplantation, sensitivities were 85% in the case-control cohort and 64% in the prospective cohort. In these cohorts, the fixed DELFI model outperformed AFP at the clinically used threshold of 20 ng/mL with a sensitivity in the combined cohorts of 78% at 91% specificity, compared to 63% sensitivity at 91% specificity for AFP. A combined approach using either DELFI at a threshold that corresponded to a 90% specificity in our previous study or AFP at the clinical threshold resulted in 82% sensitivity (74% in early stage) at 92% specificity and was superior to estimates of AFP and ultrasound for early-stage disease (63% sensitivity at 84% specificity). Individuals who tested positive with DELFI had a significantly shorter overall survival (p=0.002, log rank test), even amongst individuals at the earliest stage, while AFP alone did not stratify survival for patients with early-stage disease. Single-molecule analyses from low coverage WGS of cfDNA revealed genome-wide mutational profiles that were similar to those of HCC and in individuals from Guatemala that were characteristic of aflatoxin exposure. Overall, this work provides insight into the origins of cfDNA in populations at risk for HCC and validates our genome-wide fragmentome approach for non-invasive cancer detection that may facilitate liver cancer screening. Citation Format: Zachariah H Foda, Daniel Bruhm C Bruhm, Akshaya V Annapragada, Shashikant Koul, Sarah Short, Keerti Boyapati, Adrianna Bartolomucci, Vilmos Adleff, Nicholas A Vulpescu, Hope Orjuela, Andrei Sorop, Razvan Iacob, Liana Gheorghe, Simona Dima, Katherine A McGlynn, Manuel Ramírez-Zea, Jillian Phallen, John Groopman, Robert B Sharpf, Victor E Velculescu. Early detection of liver cancer from diverse populations using cfDNA fragmentome and protein biomarkers [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A050.

Cancer Risk Among Patients With Multiple Sclerosis: A 10-Year Nationwide Retrospective Cohort Study.

Previous literature has been diverging on cancer risk in people with multiple sclerosis (PwMS). Therefore, this study compared the risk of cancer in PwMS and a matched sample from the French general population. This 10-year nationwide retrospective matched cohort study (2012-2021) used data from the national French administrative health care database (99% coverage of the French population) to determine the time to the first incident cancer. PwMS were identified using their long-term disease (LTD) status, hospitalizations, and multiple sclerosis (MS)-specific drug reimbursements. The control population was matched 4:1 on age, sex, residence, insurance scheme, and cohort entry date. Participants were included if they had no history of cancer in the 3 years before inclusion. Patients with cancer were identified through LTD status, hospitalizations, chemotherapy, radiotherapy, or prostate cancer-specific drug reimbursements. Overall and cancer location-specific hazard ratios (HRs) for the first incident cancer were obtained from Fine and Gray models, and age- and sex-stratified estimates were reported. Participation in cancer screening through the 3 national programs (breast, colorectal, and cervical) were compared between groups. Cancer incidence was 799 per 100,000 person-years (PYs) (n = 8,368) among the 140,649 PwMS and 736 per 100,000 PYs (n = 31,796) among the 562,596 matched controls (70.8% of women; follow-up: 7.6 ± 3.2 years). A small overall risk increase was observed for PwMS (HR 1.06, 95% CI 1.03-1.08), mostly in women (HR 1.08, 95% CI 1.05-1.11). Risk varied by cancer types and was lower for prostate (HR 0.80, 95% CI 0.73-0.88), breast (HR 0.91, 95% CI 0.86-0.95), and colorectal (HR 0.90, 95% CI 0.84-0.97) cancer and higher for bladder (HR 1.71, 95% CI 1.54-1.89), brain (HR 1.68, 95% CI 1.42-1.98), and cervical (HR 1.24, 95% CI 1.12-1.38) cancer in PwMS. Cancer risk was higher in PwMS younger than 55 years (HR 1.20, 95% CI 1.15-1.24) but decreased in PwMS aged 65 years and older (HR 0.89, 95% CI 0.85-0.94). This trend was found in all cancer locations. There were fewer PwMS getting screened than controls (all programs), with a particularly pronounced difference among those aged 65 years and older. Cancer risk was slightly increased in PwMS, particularly for urogenital cancers, possibly due to surveillance bias. Risk fluctuated depending on age, perhaps due to varying generational screening practices (i.e., diagnosis neglect in the older PwMS) and risk factors.

Enhancing Lung and Breast Cancer Screening with Advanced AI and Image Processing Techniques

This research investigates the application of CNNs for diagnostics improvements in lung and breast cancers based on AI image classification approaches. Using the datasets with 15,000 images describing lung cancer and 10,000 images describing cases of breast cancer, the models showed high performance: 90% for lung cancer and 99% for breast cancer classification. The descriptive analysis pointed out different features in imaging, such as dense tissue structure and irregular cell patterns; the models successfully identified these. The findings underlined the vital role that AI could play in assisting radiologists by delivering preliminary analysis, triaging high-risk cases, and leading to early cancer detection. Essential challenges were highlighted: ethical considerations concerning patients' privacy and AI algorithms' transparency. The limitation of the dataset diversity resulted in the conclusion that only broader data can ensure good generalization in various clinical settings. They recommended integrating the AI tool with clinical workflow and also called for training radiologists for effectiveness. Future research directions include real-time imaging and patient data integration for comprehensive diagnostic support and multi-modal approaches that combine imaging with genomics for more precise predictions. This leads to a more personalized cancer diagnosis and treatment plan, thus ultimately improving the results of the patients. This research, therefore, underlines the transformative capabilities of AI and image processing in modernizing cancer screening and diagnostics toward more accurate and efficient healthcare practices.

Annual Survey of State and Territorial Chronic Disease Prevention and Health Promotion Capacity and Organizational Development Needs—United States, 2023

Objective: The National Association of Chronic Disease Directors (NACDD) is a nonprofit organization that supports state and territorial chronic disease prevention and health promotion efforts through capacity building and technical assistance. Each year, NACDD surveys health department leaders who oversee chronic disease prevention and health promotion (hereafter, Chronic Disease Directors). We have previously used the annual survey results to inform strategic planning and resource allocation but have not historically published key findings in the peer-reviewed literature. In this paper, we report on NACDD’s 2023 survey outcomes and place those findings into the broader public health policy context. Design: State Chronic Disease Directors completed a survey about their organizational capacity and development needs. Responses were summarized in aggregate and by jurisdiction size. Results: State chronic disease units have varied staffing and responsibilities, but most address diabetes, cardiovascular diseases, and cancer screening and prevention. Chronic Disease Directors generally reported strong or improving capacity in most practice areas but ranked workforce development lower. Staffing increased slightly during 2023 compared with the 2020 baseline (median of 1.3 and 1.1 employees per 100 000 jurisdiction population, respectively). However, Chronic Disease Directors expressed ongoing concerns about turnover, hiring, and training of inexperienced staff, as well as about funding limitations and uncertainty. Looking forward to 2024, many Chronic Disease Directors expressed intentions to focus on supporting their workforce with training and development opportunities and addressing health equity. Conclusions: During this period of pandemic recovery, turnover, hiring, and training—particularly of the many new public health staff—remain key areas of concern for many chronic disease units. Continued stabilization of public health funding and increased prioritization of organizational capacity development—particularly workforce development, chronic disease data systems, and tools for addressing health equity—could help ensure chronic disease units can better address current and emerging challenges in chronic disease prevention and health promotion.

Using a behaviour-change approach to support uptake of population genomic screening and management options for breast or prostate cancer.

As the possibility of implementing population genomic screening programs for the risk of developing hereditary cancers in health systems increases, understanding how to support individuals who wish to have genomic screening is essential. This qualitative study aimed to link public perceived barriers to a) taking up the offer of population genomic screening for breast or prostate cancer risk and b) taking up risk-management options following their result, with possible theory-informed behaviour-change approaches that may support implementation. Ten focus groups were conducted with a total of 25 members of the Australian public to identify and then categorise barriers within the behaviour-change Capability, Opportunity, Motivation - Behaviour (COM-B) model. Ten COM-B categorised barriers were identified as perceived influences on an individual's intentions to take-up the offer, including Capability (e.g., low public awareness), Opportunity (e.g., inconvenient sample collection procedure) and Motivation (e.g., genomic screening not perceived as relevant to an individual). Ten barriers for taking up risk-management options included Motivation (e.g., concerns about adverse health impact) and Opportunity (e.g., social opportunity and cost incurred to the individual). Our findings demonstrate that a nuanced approach is required to support people to take-up the offer of population genomic screening and, where appropriate, to adopt risk-management options. Even amongst participants who were enthusiastic about a population genomic screening program, needs were varied, demanding a range of implementation strategies. Promulgating equitable uptake of genomic screening and management options for breast and prostate cancer risk will require a needs-based approach.