Lee, K.N.

Abstract Purpose: Circulating tumor fraction estimate (ctFE) is a machine learning–derived composite metric of circulating tumor DNA (ctDNA) burden. We hypothesized that pre-treatment and early on-treatment ctFE could robustly risk-stratify patients with locally advanced (LA) and oligometastatic non–small cell lung cancer (NSCLC) treated with radiotherapy (RT). Experimental Design: In a prospective phase II clinical trial (NCT03916419), 26 patients with unresectable stage IIB to IIIC NSCLC received magnetic resonance (MR)-guided hypofractionated chemoradiotherapy (chemoRT) followed by immunotherapy. Plasma ctDNA was profiled at baseline and mid-treatment (days 10–14) to derive ctFE and maximum variant allele frequency (Max VAF). A burden-based ctFE threshold derived from baseline samples was applied unchanged to mid-treatment samples and validated in two external cohorts: LA NSCLC treated with chemoRT (LA-RW; n = 94) and oligometastatic NSCLC treated with RT (OM-RW; n = 309). Results: Pre- and mid-treatment ctFE burden strongly stratified overall survival (OS) and progression-free survival (PFS), outperforming Max VAF and ctFE detectability. The baseline ctFE was prognostic for OS (HR 5.93, P = 0.005) and PFS (HR 11.08, P < 0.001) and remained significant at mid-treatment (OS: HR 7.08; PFS: HR 12.06; both P < 0.001). Early ctFE dynamics defined three molecular response groups with OS separation (median OS 60.8 vs. 13.0 vs. 2.9 months; P < 0.001). ctFE remained associated with survival in both validation cohorts. Conclusions: Early ctFE derived from a clinically available, tumor-naïve ctDNA assay enables noninvasive risk stratification in LA and oligometastatic NSCLC treated with RT, supporting its use as a practical biomarker for precision treatment adaptation.

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.

Background: Myxofibrosarcomas are notoriously highly infiltrative soft-tissue sarcomas, making negative surgical margins difficult to obtain. Recently, vacuum-assisted closure (VAC) is used to delay wound closure until a negative margin has been achieved; however, this can delay care and increase costs. Our institution has historically performed single-stage resections with intraoperative frozen margin analysis and reconstruction in these patients. The purpose of this study is to report the outcomes of this technique. Methods: We reviewed 112 patients (62 males, mean age 70 ± 14 years) with superficial myxofibrosarcoma. Eighty-eight patients received preoperative radiation. All patients underwent surgical resection with intraoperative frozen margin analysis, and the planned reconstruction was performed in a single anesthetic. Results: The 10-year local recurrence-free survival was 90%; positive intraoperative frozen section (HR 7.44, p = 0.004) and final permanent margins (HR 8.53, p = 0.007) were associated with local recurrence. Intraoperative margins were negative in 103 (92%) of patients, 1 of which was positive on final permanent section. There were nine cases of microscopically positive margins, of which seven underwent immediate re-excision to a negative margin. The accuracy of frozen margin assessment for myxofibrosarcoma was between 92.92 and 98.23%. All patients underwent reconstruction at the time of resection, with 19% needing an additional procedure, most commonly due to a wound complication (12%). Conclusions: Multidisciplinary single-stage excision with intraoperative frozen margin assessment and soft-tissue reconstruction yields low rates of local recurrence in patients with superficial myxofibrosarcoma.

Importance: Lung cancer and pulmonary metastases remain the leading cause of cancer-related mortality. While surgery is the gold standard, local tissue-ablative therapies are increasingly used in unresectable disease or inoperable patients. Minimally invasive local control presents a safe, repeatable approach to slow disease progression and prolong survival. Observations: Ablative techniques (radiofrequency, microwave, cryoablation, pulsed electric field) utilize extreme heat, cold, or energy to induce cancer cell death. Traditionally, ablation occurred percutaneously with image guidance, but transbronchial approaches are gaining popularity due to a potentially improved complication profile with reduced tumoral seeding. Stereotactic body radiotherapy utilizes non-invasive, precise radiation with a steep dose fall-off to protect peritumoral tissue. Transarterial infusions via transarterial chemoembolization and intraarterial chemoperfusion are emerging approaches that exploit tumor vasculature to provide focal cytotoxicity and ischemia. Intratumoral injectables (chemotherapy, immunotherapy, radiosensitization, oncolytic viruses, adoptive cell therapy, and chimeric antigen receptor T-cell therapy) directly target the tumor microenvironment, potentially increasing efficacy whilst minimizing systemic adverse effects. Conclusions and relevance: In the age of individualized cancer therapy, a multidisciplinary approach with concurrent modalities can achieve local control. This review provides a comprehensive discussion regarding the role and types of local control, safety, efficacy, and survival outcomes in assessing percutaneous, transbronchial, intraarterial, and intratumoral approaches in nonsurgical patients.