The added value of baseline circulating tumor DNA profiling in patients with molecularly hyperselected, left-sided metastatic colorectal cancer

P. Manca, S. Corallo, A. Busico, S. Lonardi, F. Corti, C. Antoniotti, L. Procaccio, M. Clavarezza, V. Smiroldo, G. Tomasello, R. Murialdo, A. Sartore-Bianchi, P. Racca, F. Pagani, G. Randon, A. Martinetti, E. Sottotetti, F. Palermo, F. Perrone, E. TamboriniM. Prisciandaro, A. Raimondi, M. Di Bartolomeo, F. Morano, F. Pietrantonio

Research output: Contribution to journalArticlepeer-review


Purpose: The routine use of liquid biopsy is not recommended for the choice of initial treatment for patients with metastatic colorectal cancer (mCRC). Experimental Design: We included patients with left-sided, RAS/BRAF wild-type, HER2-negative, and microsatellite stable mCRC, treated with upfront panitumumab/FOLFOX-4 in the Valentino study. We performed amplicon-based genomic profiling of 14 genes in baseline plasma samples and compared these data with tumor tissue ultra-deep sequencing results. Specific gene mutations in circulating tumor DNA (ctDNA) and their clonality were associated with progression-free survival (PFS), overall survival (OS), and radiological dynamics. Results: Ten and 15 of 120 patients had a mutation of RAS and PIK3CA in ctDNA, with a positive concordance with tissue deep sequencing of only 31.3% and 47.1%, respectively. Presence of RAS or PIK3CA mutations in baseline ctDNA was associated with worse median PFS [8 vs. 12.8 months; HR, 2.49; 95% confidence interval (CI), 1.28-4.81; P = 0.007 and 8.5 vs. 12.9 months; HR, 2.86; 95% CI, 1.63-5.04; P < 0.001] and median OS (17.1 vs. 36.5 months; HR, 2.26; 95% CI, 1.03. 4.96; P = 0.042 and 21.1 vs. 38.9 months; HR, 2.18; 95% CI, 1.16-4.07; P = 0.015). RAS mutations in ctDNA were associated with worse RECIST response, early tumor shrinkage, and depth of response, while PIK3CA mutations were not. Patients with higher levels of RAS/PIK3CA variant allele fraction (VAF) in ctDNA had the worst outcomes (VAF ≥ 5% vs. all wild-type: median PFS, 7.7 vs. 13.1 months; HR, 4.02; 95% CI, 2.03-7.95; P < 0.001 and median OS, 18.8 vs. 38.9 months; HR, 4.07; 95% CI, 2.04-8.12; P < 0.001). Conclusions: Baseline ctDNA profiling may add value to tumor tissue testing to refine the molecular hyperselection of patients with mCRC for upfront anti-EGFR.based strategies.

Original languageEnglish
Pages (from-to)2505-2514
Number of pages10
JournalClinical Cancer Research
Issue number9
Publication statusPublished - 2021


  • B Raf kinase
  • circulating tumor DNA
  • epidermal growth factor receptor 2
  • fluorouracil
  • folinic acid
  • oxaliplatin
  • panitumumab
  • phosphatidylinositol 3 kinase
  • Ras protein
  • allele
  • amplicon
  • Article
  • blood sampling
  • cancer prognosis
  • clonal variation
  • gene mutation
  • genetic analysis
  • genetic variability
  • high throughput sequencing
  • human
  • liquid biopsy
  • major clinical study
  • metastatic colorectal cancer
  • microsatellite marker
  • overall survival
  • patient selection
  • priority journal
  • progression free survival
  • sequence analysis
  • treatment response
  • tumor localization
  • wild type


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