Beatson West of Scotland Cancer Centre

The CALYPSO study demonstrated activity of savolitinib and durvalumab in MET-driven papillary renal cancer (PRC). We report final efficacy outcomes and exploratory circulating tumor DNA (ctDNA) biomarker analysis. This single-arm phase II study evaluated savolitinib and durvalumab in treatment-naïve or pretreated PRC. End points included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). FoundationOne CDx assessed DNA alterations and MET/PD-L1 or MET/tumor mutational burden (TMB) copositivity. ctDNA collected at baseline and on treatment was correlated with outcomes. At 41-months median follow-up, ORR was 34% (95% CI, 20.0 to 51.0) in the intention-to-treat (ITT) population (N = 41) and 53% (95% CI, 28.0 to 77.0) in MET-driven patients (n = 17). Median PFS was 6.5 (95% CI, 2.7 to 12.0) versus 13.9 months (95% CI, 2.9 to 23.8), and OS was 18.3 (95% CI, 7.3 to 30.7) versus 27.4 months (95% CI, 9.3 to 37.4), in the ITT population and the MET-driven population, respectively. PD-L1 (66% positive) and TMB (median 2.5 mut/Mb) status did not correlate with response. Baseline ctDNA positivity (10/21) correlated with shorter OS (median 7.3 v 33.3 months), while ctDNA clearance and mean variant allele frequency reduction correlated with improved OS (median 31.3 v 7.2 and 31.3 v 15.5 months, respectively). Savolitinib plus durvalumab shows OS in MET-driven PRC, supporting the ongoing SAMETA RIII trial (ClinicalTrials.gov identifier: NCT05043090). ctDNA may be a useful predictive biomarker.

Abstract Background: Detection of circulating tumour DNA (ctDNA) in plasma predicts future recurrence in early breast cancer (EBC). Previous studies have relied on tumour-informed approaches with personalised assays. In this study, we performed orthogonal testing on plasma samples collected prospectively in the c-TRAK-TN study to compare a tissue-free assay with digital droplet PCR (ddPCR) for ctDNA analysis. Methods: c-TRAK-TN recruited 161 patients with early triple negative breast cancer (TNBC) deemed clinically high risk of relapse. Patients underwent ctDNA analysis by ddPCR starting within 4 weeks of completion of treatment and continuing every 3 months for up to 2 years. ddPCR tracked 1 or 2 patient specific variants as previously described. We further analysed 1062 timepoints from a total of 159 patients (median 7 per patient, range 1-11) using Guardant Reveal assay, a tissue-free approach that exploits differential methylation patterns in breast cancer compared with normal tissue. Results: Samples were successfully analysed from 95.3% (1012/1062) timepoints from 159 patients with the tissue-free Reveal assay. CtDNA was detected in 34.0% (54/159) of patients in at least 1 timepoint, with a median methylation tumour fraction of 0.266% (range 0.002 to 51.0%). Detection of ctDNA with the tumour agnostic assay strongly associated with future risk of relapse (HR 20.62, p<0.0001; logrank). Of patients who relapsed by 24 months follow up, 89.5% (34/38) of relapses were detected by prior ctDNA analysis. There were 159 patients available for comparison between ddPCR and the tissue-free assay (Reveal), in 1005 timepoints (median 7 per patient, range 1-11). Concordant test results were observed in 950/1005 timepoints with an overall agreement rate of 94.5%. In this cohort, 63.5% (101/159) of patients did not have ctDNA detected by either assay; 26.4% (42/159) had ctDNA detected by both assays and 10.1% (16/159) had discordant results. Of those detected, 44.8% (26/58) were detected by the tissue-free assay first and 6.9% (4/58) by ddPCR (p<0.0001, Fisher exact test). The median time from first detection of ctDNA to relapse for the tissue-free assay was 7.9 months (95% confidence interval (CI): 5.7-10.5 months) compared to ddPCR assay with 5.7 months (95% CI: 2.9-9.7 months) (HR = 0.6, p=0.0574; mixed effects cox model). Conclusion: Detection of ctDNA with a tissue-free assay anticipated relapse with high accuracy, in patients with early TNBC. The tissue-free assay frequently detected ctDNA at an earlier timepoint than ddPCR, trending towards a longer lead time from detection of ctDNA to relapse. Tissue-free approaches might offer simpler workflows for ctDNA analysis than tumour-informed approaches, and further assessment in clinical trials is warranted. Citation Format: N. Cunningham, R. J. Cutts, C. Swift, K. Dunne, M. Dewan, L. Kilburn, K. Goddard, P. Hall, C. Harper-Wynne, T. Hickish, I. Macpherson, A. Okines, A. Wardley, S. Waters, C. Palmieri, M. Winter, J. Bliss, D. Dustin, M. Ellis, I. Garcia- Murillas, N. C. Turner. Tissue-free circulating tumour DNA detection in patients with early triple negative breast cancer from the c-TRAK-TN trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF3-05.

Combination chemotherapy provides significant survival advantage in patients with advanced gastro-oesophageal adenocarcinoma compared with best supportive care. Peri-operative chemotherapy is standard of care for patients with operable disease. We hypothesised that biomarkers of genomic instability and inflammation may have clinical utility in these patients. We initiated open-label, non-randomised biomarker studies in patients with advanced disease due to receive Epirubicin, Cisplatin and Capecitabine (ECX)/Epirubicin, Cisplatin and Fluorouracil (ECF) or Epirubicin, Oxaliplatin and Capecitabine (EOX)/Epirubicin, Oxaliplatin and Fluorouracil (EOF) regimens (advanced study, n = 375), and in patients planned to receive perioperative chemotherapy with the same regimen (peri-operative study, n = 306). Relative telomere length (RTL) in peripheral blood mononuclear cells (PBMCs) and plasma levels of 10 inflammatory cytokines were analysed to determine association with progression-free and overall survival, and response. Blood samples were collected prior to treatment and on each treatment cycle. Both studies comprised biomarker discovery and validation cohorts. Here we report analysis of the discovery cohorts. In advanced disease, high pre-treatment levels of IL8 and IL10 associated with poor Progression Free Survival (PFS) and Overall Survival (OS) in univariate analysis, and IL6 with poor OS. In multivariate analysis, IL6 and IL8 remained associated with OS, and IL8 with PFS. In the perioperative study, cytokine levels were significantly lower and no relationships were observed. There was no association between RTL and any endpoint in either study. Pre-treatment RTL was not prognostic, although IL6/IL8 were negative prognostic factors in advanced disease. Levels of these were lower in patients with localised disease, suggesting an association with disease progression. Further analysis of systemic inflammatory status in gastro-oesophageal adenocarcinoma may be promising for development of future predictive biomarker signatures.

The aim of radioactive iodine (RAI) in differentiated thyroid cancer (DTC) is ablation of thyroid remnant and/or treatment of residual disease. This review compares guidelines recommending the use of RAI (or not) in DTC, with a focus on randomized trials in low-risk DTC. Molecular genotyping offers therapeutic options in advanced RAI-refractory DTC. The ESTIMABL2 and IoN trials suggest that thyroidectomy (with or without central compartment lymph node dissection) followed by surveillance is sufficient in low-risk DTC, despite key differences in inclusion criteria, recurrence-definition, and monitoring protocols. RAI practice is tailored in many aspects: selection of intermediate-risk DTC for RAI and activity based on individual factors, including early dynamic risk assessment; lesional dosimetry in advanced DTC; restrictions following RAI; and choice of systemic therapy in the RAI-refractory setting. RAI in DTC is evolving towards a risk-adapted model. Escalating evidence indicates that RAI may be safely withheld in a large proportion of low-risk DTC. Optimal management of intermediate-risk DTC remains controversial, due to heterogeneity in clinical and pathological characteristics and conflicting data over survival advantage. Well designed studies incorporating molecular genotype may be key in identifying those most likely to benefit from RAI and in elucidating mechanisms of RAI-resistance.