Authors
Vittorio Studiale, Roberto Moretto, Martina Carullo, Marco M. Germani, Farahnaz Islam, Guglielmo Vetere, Veronica Conca, Victoria Chiou, Christine Lo, Seung Won Hyun, Ada Taravella, Matteo B. Landi, Filippo Ghelardi, Chithra Sangli, Kate Sasser, Sabina Murgioni, Michele Prisciandaro, Riccardo Cerantola, Halla Nimeiri, Chiara Cremolini
Background – Liver-limited disease (LLD) occurs in 20-30% of mCRC patients. While liver resection offers a long-term survival benefit in 20-30% of those patients, most relapse within two years. ctDNA is a promising tool for detecting minimal residual disease (MRD) after surgical resection and may predict recurrence in mCRC patients undergoing liver resection after first-line treatment.
Methods – A cohort of 116 mCRC pts with initially unresectable LLD and R0/R1 resected after first-line therapy were selected from 3 Italian academic medical centers. Prospective blood samples were collected at baseline (T0), pre-surgery (TPrS) and post-surgery (TPoS). T0 samples were evaluable for 82 patients, TPrS for 116 and TPoS for 60. Samples were analyzed with Tempus xM, a tumor-naïve ctDNA-based MRD assay that integrates methylation and genomic variant classifiers to deliver a binary MRD call (+ or -) blinded to clinical outcomes.
Results – Methylation results were available for 60 TPoS pts with a clinical sensitivity of 56.4% and specificity of 100%. TPoS MRD- pts experienced longer median relapse-free survival (mRFS) than MRD+ ones (HR = 6.7, mRFS >24 mos vs 5.5 mos, p<0.001). Pts who were persistently MRD- (n=20) or converted to negative (n=13) from TPrS to TPoS had longer RFS (mRFS 16.3 mos and >24 mos respectively) compared to those who remained persistently MRD+ (n=9) or converted to MRD+ (n=12, mRFS 5.3 mos and 5.9 mos respectively). Pts with variant allele fraction (VAF) reduction of ≥50% from T0 to TPrS (n=53) experienced longer RFS than those with <50% reduction or increase in VAF (n=18, HR 2.21, mRFS 18.8 mos vs 9.8 mos, p=0.012). Lastly, pts that remained MRD+ from T0 to TPrS (n=23) experienced a numerically shorter RFS compared to those who converted to negative (n=47, median RFS 10.4 mos vs 15.1 mos, HR 1.65, p=0.10).
Conclusions -MRD status predicts clinical recurrence and correlates to RFS at TPoS in LLD mCRC pts resected after first-line systemic therapy. Interestingly, pts with a VAF reduction ≥ 50% from T0 to TPrS experience longer RFS following surgery, suggesting a potential role for this tool in the multidisciplinary decision making in this setting.
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