Rego, Seema P.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in the United States and worldwide. HCC screening among patients at elevated risk is associated with improved early detection and overall survival, but current ultrasound-based screening strategies are challenged by low adherence and suboptimal sensitivity. Blood-based screening tests have the potential to enhance adherence and improve early-stage HCC detection if they can demonstrate favorable performance compared with ultrasound-based screening. Here we present the design and rationale for ALTUS (A lternative to Ultrasound), a prospective, longitudinal, multicenter study in the United States to investigate the performance of the multi-target HCC blood test (mt-HBT) for the detection of HCC in a screening population. Methods: Adults with liver cirrhosis or chronic hepatitis B infection will be enrolled to undergo standard-of-care screening imaging and concurrent blood collection for the mt-HBT. All participants will undergo contrast-enhanced CT or MRI imaging with central radiology LI-RADS assessment as the reference method to determine HCC status. Participants without an identified malignancy will undergo a second screening visit and blood collection, and longitudinal clinical and imaging data will be collected up to 18 months from enrollment. The primary study objectives are to demonstrate that the mt-HBT is non-inferior to ultrasound for early-stage HCC sensitivity and to assess mt-HBT HCC specificity. The secondary objective is to assess mt-HBT overall sensitivity. Results: ALTUS is in progress with readout of the primary analysis expected in 2025. Conclusions: This prospective head-to-head comparison of the mt-HBT versus ultrasound will provide novel data regarding the performance and utility of the mt-HBT for HCC screening.

Guideline-recommended screening programs exist for only a few cancer types. Although all these programs are understood to lead to reductions in cancer-related mortality, standard-of-care screening tests vary in accuracy, adherence and effectiveness. Recent advances in high-throughput technologies and machine learning have facilitated the development of blood-based multi-cancer cancer early detection (MCED) tests. MCED tests are positioned to be complementary to standard-of-care screening and they may broaden screening availability, especially for individuals who are not adherent with current screening programs and for individuals who may harbor cancers with no available screening options. In this article, we outline some key features that should be considered for study design and MCED test development, provide an example of the developmental pathway undertaken for an emerging multi-biomarker class MCED test and propose a clinical algorithm for an imaging-based diagnostic resolution strategy following MCED testing.

11135 Background: Cancer screening programs can improve outcomes and may reduce treatment cost and utilization by shifting cancers to earlier, more curable stages at diagnosis (Dx). Few studies have evaluated the impact of screening on outcomes prior to diagnosis. Such information is needed to better understand the potential impact of newer blood-based multicancer early detection technologies. Methods: We conducted a retrospective cohort study using SEER cancer registry data linked with Medicare claims. Patients with a breast cancer (BC) or colorectal cancer (CRC) Dx between 2010-2019 were included if they were 65-74 years old at Dx, continuously enrolled in Medicare Parts A&B, had a Charlson Comorbidity Index of ≤2, and no cancer for ≥12 months prior to Dx. Those enrolled in an HMO or with high genetic risk for BC (in BC cohort) were excluded. Patients were assigned to screening groups prior to Dx; screening was defined as ≥1 screening procedure in the 6 months prior to Dx using CPT/HCPCS codes. Screening included FIT/FOBT, sigmoidoscopy, colonoscopy, CT colonography, mt-sDNA (CRC), and mammography (BC). Screened and not screened groups were compared for statistical significance using chi-squared for categorical variables, Wilcoxon rank-sum test for continuous variables. Results: Screening procedures were more prevalent in the BC cohort (68%) than the CRC cohort (44%) (table). Both screened subgroups (vs non-screened subgroups) had significantly lower proportions of patients diagnosed at stage 4 (2% vs 10% BC, 16% vs 27% CRC) and shorter times from first screening or imaging procedure to confirmed diagnosis (BC: 33 vs 227 days, CRC: 14 vs 29 days). Screened patients in both cancer cohorts had a similar number of average procedures prior to treatment initiation as non-screened (BC: 4.8 vs 4.2, CRC: 3.3 vs 3.3 respectively, including screening procedures). Conclusions: Individuals diagnosed with BC and CRC through screening exhibit earlier stage diagnoses and shorter intervals to diagnosis. Novel screening technologies such as MCED tests can potentially improve peri-diagnostic outcomes in cancers lacking existing or widely adopted screening methods. [Table: see text]