Samson, Pamela

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.

AbstractBackgroundPrognosis among patients with differentiated thyroid cancer is widely variable. Better understanding of biologic subtypes is necessary to stratify patients and improve outcomes.MethodsIn patients diagnosed with classic histology papillary thyroid cancer treated from 1973 to 2009, BRAF V600E mutation status was determined on surgical tumor specimens by restriction fragment length polymorphism analysis. A tissue microarray (TMA) was constructed from tumor specimens in triplicate and stained by immunohistochemistry for RET, phospho‐MEK, MAPK(dpERK), PPARγ, and phospho‐AKT(pAKT). Stained slides were scored independently and blindly by two investigators and compared to tumor and patient characteristics and outcomes.ResultsA total of 231 patients had archived formalin‐fixed, paraffin‐embedded tumor tissue available and were included on the TMA. Mean age at diagnosis was 44 years (range 6‐82 years); proportion of patients with female sex was (72%); 2015 American Thyroid Association (ATA) risk stratification was low (26%), intermediate (32%), and high (42%). BRAF V600E mutation was found in 74% of specimens, and IHC was scored as positive for RET (61%), MAPK (dpERK) (14%), PPARγ (27%), and pAKT (39%). Positive RET staining was associated with a lower risk of recurrence (HR = 0.46, 95% CI 0.22‐0.96). No other molecular biomarkers were independent predictors of recurrence on univariable analysis. On RPA, patients with RET‐negative and either MAPK(dpERK)‐positive or pAKT‐positive tumors were identified to have a high risk of recurrence (HR = 5.4, 95%CI 2.5‐11.7). This profile remained associated with recurrence in a multivariable model including ATA risk stratification (HR = 2.8, 95% CI 1.3‐6.0).ConclusionCharacterization of molecular pathways involved in cPTC tumorigenesis may add further risk stratification for recurrence beyond the 2015 ATA risk categories alone.