Ziding, Feng

Abstract Background: Early detection is the most potent strategy to improve survival in PDA, but its success hinges on an unresolved question: does radiologically invisible disease represent biologically early or indolent disease, or established malignancy beneath the threshold of detection? We leveraged prediagnostic CTs—incidental scans obtained 3-36 months prior to diagnosis without a focal mass—to define the relationship between imaging phenotype and tumor biology. Methods: From a multi-institutional pool of 5,046 biopsy-confirmed PDAs, we assembled a cohort of 346 prediagnostic CTs, which were independently evaluated by three radiologists using a standardized protocol. Based on majority vote, CTs were dichotomized into imaging-occult (IO) (normal pancreas) and imaging-apparent (IA) (abnormal pancreas with indirect signs such as focal atrophy, duct dilatation, etc.) groups. Tumor size and metastases (M) at diagnosis, and overall survival (OS) were compared using multivariable linear (size), logistic (M1), and Cox proportional hazards (OS) models, adjusting for lead time to diagnosis, age, sex, diabetes, CA 19-9, and surgical resection status, to isolate the independent biological relevance of the imaging phenotype. Results: IO phenotype was seen in 150 patients (mean age 66.7±11.2; 37.3% females) while 196 had IA phenotype (mean age 69.9±10.6; 49.5% females). Median lead time was 396 days (range: 90-1088) with the IA group being enriched in 3-12-month lead time (57.7% vs 33.3%; p<0.001). Both groups had comparable diabetes rates (IA 33.2% vs IO 32.7%; p=1.0), median CA 19-9 (IA 193 vs IO 322 U/mL; p=0.41), and surgical resection (IA 38.3% vs IO 38.0%; p = 1.0). While unadjusted mean tumor size at diagnosis was larger in IA group (3.8 cm vs 3.2 cm), there was no difference after adjusting for clinical factors (-7.1% difference; 95% CI: -17.2, 4.2; p=0.21). Metastases were also comparable (M rate: IA 22.4% vs IO 27.3%; adjusted OR 0.97; 95% CI: 0.50, 1.88; p=0.93). Adjusted Cox models demonstrated equivalent OS (median: 18.7 vs 17.6 months; HR 1.06; p=0.66), which persisted even when stratified by surgical status (HR 1.07; 95% CI: 0.83, 1.38; p=0.61). Even in the critical 3-12 months lead time (n=163), OS remained equivalent (HR 0.89; p=0.62), and groups did not differ in either tumor size (-6.4%; 95% CI: -22.4, 12.9; p=0.49) or metastases (OR 0.48; 95% CI 0.14, 1.59; p=0.23). Conclusions: A normal-appearing pancreas on prediagnostic imaging is common yet signifies neither early nor indolent disease—it harbors PDA biologically equivalent to the imaging-apparent pancreatic phenotype. Because the disease at this stage lies beyond human perceptual capacity, AI augmentation represents the only potential path to realizing the survival benefit of early detection. Citation Format: Khurram Khaliq Bhinder, Sovanlal Mukherjee, Armin Zarrintan, Angela Ammirabile, Ahmed Khan Jadoon, Ziding Feng, Suresh T. Chari, Ajit H. Goenka. Dissociation between prediagnostic imaging phenotype and tumor biology defines the early detection challenge in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB205.

Background: Blood-based biomarker panels, including GALAD, have been proposed as an alternative to abdominal ultrasound for hepatocellular carcinoma (HCC) surveillance. Studies suggest longitudinal evaluation of biomarkers can improve test performance; however, no large studies have validated these findings. Methods: We leveraged the HCC Early Detection Strategy (HEDS) study (n=1019 patients with cirrhosis; 99 incident HCC) and Texas HCC Consortium (THCCC) (n=2345 patients with cirrhosis; 126 incident HCC) to compare the performance of fixed-threshold GALAD (cutoff of −1.36), and 4 longitudinal algorithms: longitudinal GALAD, PALAD, mFB-ALAD, and mPEB-ALAD. The HEDS cohort was used to derive longitudinal algorithms, and external validation was performed in THCCC. Patient-level sensitivity and test-level false-positive rate (FPR) were examined overall and across subgroups by age, sex, and cirrhosis etiology. Results: In THCCC, fixed-threshold GALAD had higher sensitivity in the 6 months before HCC diagnosis (71.4%, 95% CI: 62.9%–81.7%) than longitudinal GALAD (55.1%, 95% CI: 49.3–66.4), PALAD (55.1%, 95% CI: 50.0%–70.5%), mPEB-ALAD (53.1%, 95% CI: 43.6%–62.0%), and mFB-ALAD (42.9%, 95% CI: 32.3–48.5). However, fixed-threshold GALAD had a higher FPR (25.4%, 95% CI: 23.7%–26.9%) compared with longitudinal GALAD (15.0%, 95% CI: 12.8%–15.8%), PALAD (13.0%, 95% CI: 10.2%–14.6%), and mFB-ALAD (11.2%, 95% CI: 9.6%–12.1%) but comparable to mPEB-ALAD (22.9%, 95% CI: 21.2%–23.8%). In subgroup analyses, fixed-threshold GALAD had the highest FPR in males (35.6%) and those aged ≥65 (43.5%); longitudinal algorithms had significantly lower FPRs in subgroups but with lower sensitivity for HCC. Conclusions: Improvements in FPRs with longitudinal GALAD algorithms, as compared with fixed-threshold GALAD, are offset by significantly decreased sensitivity for HCC detection.