Owen, Dawn

Abstract Background: Personalizing chemoradiotherapy (chemoRT) for locally advanced non-small cell lung cancer (LA-NSCLC) is limited by the lack of early biomarkers that inform response during treatment. Current circulating tumor DNA (ctDNA) molecular residual disease assays predict post-treatment outcomes but lack mid-treatment utility. ctDNA burden estimation has traditionally relied on variant-centric metrics such as maximum variant allele fraction (Max VAF), which rely on mutation-specific signals and may be confounded by histology-dependent shedding variability, allelic imbalance, and clonal hematopoiesis. Here we present circulating tumor fraction estimate (ctFE), a machine-learning composite score that integrates VAF distributions, copy-number alterations, and germline B-allele frequency deviations to approximate global tumor burden using a widely available, tumor-naïve clinical platform. Methods: A burden-based ctFE threshold was derived using pre-treatment plasma from a prospective phase II clinical trial of MR-guided hypofractionated chemoRT (LA-WU, n=26), locked, and applied unchanged to early mid-treatment samples (day 10-14). To test scalability and generalizability, its prognostic performance was validated in two real-world cohorts: 94 LA-NSCLC patients receiving definitive chemoRT (LA-RW) and 309 oligometastatic NSCLC patients receiving consolidative RT (OM-RW). ctFE and Max VAF were compared as continuous predictors across cohorts. Results: ctFE consistently outperformed Max VAF. In LA-WU, pre-treatment ctFE was associated with overall survival (OS HR=1.15, p=0.04) and progression-free survival (PFS HR=1.84, p=0.009), whereas Max VAF was not. Mid-treatment ctFE remained prognostic for PFS (HR=1.14, p=0.026). Early ctFE dynamics defined three molecular response groups with marked OS separation: consistently low, responder, and nonresponder groups (median OS 60.8 vs 13.0 vs 2.9 months, respectively; p<0.001). In multivariable models including both biomarkers, higher ctFE remained independently associated with worse survival in LA-RW (OS HR=1.88, p=0.010) and OM-RW (OS HR=1.37, p=0.040; PFS HR=1.45, p=0.008), whereas Max VAF did not. The locked ctFE threshold stratified OS across all cohorts (LA-WU HR=5.93; LA-RW HR=9.08; OM-RW HR=2.26; all p<0.001). Conclusion: ctFE provides clinically meaningful pre- and mid-treatment risk stratification and consistently outperforms Max VAF across locally advanced and oligometastatic NSCLC cohorts. We show that ctFE is a biologically informative, clinically generalizable and scalable ctDNA burden metric measurable using a tumor-naïve, off-the-shelf assay, supporting its practical utility in biomarker-adapted radiotherapy strategies. Citation Format: Ayesha Hashmi, Jessica Linford, Pradeep S. Chauhan, Kaushal Parikh, Rotem Ben-Shachar, John Guittar, Malvika Pillai, Jyoti Patel, Matteo Bergsagel, Nicholas P. Semenkovich, Kenneth R. Olivier, Sean S. Park, Dawn Owen, David M. Routman, Katie N. Lee, Alex D. Sherry, Aaron S. Mansfield, Daniel Morgensztern, Ramaswamy Govindan, Clifford G. Robinson, Carmen Bergom, Saiama N. Waqar, Bruna Pellini Ferreira, Gregory R. Vlacich, Aadel A. Chaudhuri. Early ctDNA quantification by ctFE outperforms Max VAF for survival stratification across locally advanced and oligometastatic NSCLC treated with radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1183.

Abstract Aims Radiation therapy (RT) is an integral component of cancer therapy but associated with adverse events. Our goal was to establish risk prediction models for major adverse cardiovascular and cerebrovascular events (MACCE) after chest RT. Methods and results A retrospective study of lung/breast cancer patients who had chest RT with planning CT at Mayo Clinic between 01/2010 and 01/2014. Predictive models were developed based on weighted independent predictors using a derivation (406 lung and 711 breast cancer) and validation cohort (179 lung and 234 breast cancer). Patient characteristics, pre-RT CT for coronary artery calcification (CAC), and post-RT MACCE data were reviewed. Post-RT MACCE occurred in 6.1 and 5.6% in the derivation and validation cohort over a mean follow-up of 42 ± 13 months. Post-therapy model (C2AD2) included CAC (two points), MACCE history (two points), age ≥74 (three points), DM (two points), and mean heart radiation dose ≥ 850 mGy (two points), and pre-therapy model (C2AD) included post-therapy model parameters minus mean heart radiation dose. Both models stratified patients into three risk groups: low (0–2), intermediate (3–5), and high (≥6). Post-RT MACCE across these groups were 2.7, 8.9, and 19.8% in the derivation, and 3.9, 6.6, and 16.4% in the validation cohort for post-therapy model (C2AD2) and 2.8, 9.2, and 20.4% in the derivation and 3.7, 9.2, and 13.2% in the validation cohort for pre-therapy model. Both models showed statistically significant graded survival outcome. Conclusion Post-therapy (C2AD2) and pre-therapy (C2AD) models are simple, easy to use and effective tools to stratify breast and lung cancer patients undergoing chest radiation for post-RT MACCE.

e20554 Background: The paradigm for locally advanced non-small cell lung cancer has been markedly altered to include maintenance durvalumab (D) post completion of definitive chemoradiation (CRT) following the publication of the Pacific trial in 2018. The toxicity of this treatment has not been well evaluated in the real-world setting. Methods: We identified 42 patients (pts) with Stage IIB-IIIC NSCLC treated at Mayo Clinic Rochester between 6/1/2018 and 10/1/2020 who received definitive CRT followed by maintenance D. Data were abstracted by retrospective chart review under an IRB approved protocol. Results: Median age was 66 yrs (range 47-90) and 62% were women. Primary lung cancer histology included 19 adenocarcinoma, 20 squamous cell, and 3 adenosquamous. The distribution of stages was: IIB (4/42), IIIA (15/42), IIIB (19/42), IIIC (4/42). Approximately half of patients had PDL1 expression > 25% (20/42). With a median follow up of 12.2 months (calculated from first cycle of D; range 4.2-30.5 months), 14 had completed one year of maintenance D, 16 were receiving ongoing D, and 10 stopped D early with 6/12 discontinuing due to disease progression (4/6 local progression, 2/6 distant progression). Other reasons for discontinuation (5/10) included grade 3 colitis, grade 2 hepatitis, aspergillus lung infection, and flare of autoimmune disorders. One quarter of patients experienced grade 2 radiation pneumonitis (RP; 10/42) with median time to development of RP 78 days from end of CRT and 45 days from start of D. RP was determined by multidisciplinary review of imaging and treatment fields. 17/42 patients developed immune related adverse events (see Table for details). There was minimal overlap between the patients who experienced pneumonitis and immune related toxicity; 2/17 had both pneumonitis and immune related toxicity (hepatitis, thyroiditis). Conclusions: In our early experience with the Pacific regimen, 29% of patients did not complete D due to either toxicity or progression during D administration. Pneumonitis was common (10/42 patients) although there were no grade 3 events. Nearly half of the patients developed an immune-related adverse event. Further analysis is needed to evaluate the real-world toxicity of this treatment as well as oncologic outcomes.[Table: see text]