TY - JOUR
T1 - The Added Value of Baseline Circulating Tumor DNA Profiling in Patients with Molecularly Hyperselected, Left-sided Metastatic Colorectal Cancer
AU - Manca, Paolo
AU - Corallo, Salvatore
AU - Busico, Adele
AU - Lonardi, Sara
AU - Corti, Francesca
AU - Antoniotti, Carlotta
AU - Procaccio, Letizia
AU - Clavarezza, Matteo
AU - Smiroldo, Valeria
AU - Tomasello, Gianluca
AU - Murialdo, Roberto
AU - Sartore-Bianchi, Andrea
AU - Racca, Patrizia
AU - Pagani, Filippo
AU - Randon, Giovanni
AU - Martinetti, Antonia
AU - Sottotetti, Elisa
AU - Palermo, Federica
AU - Perrone, Federica
AU - Tamborini, Elena
AU - Prisciandaro, Michele
AU - Raimondi, Alessandra
AU - Di Bartolomeo, Maria
AU - Morano, Federica
AU - Pietrantonio, Filippo
N1 - ©2021 American Association for Cancer Research.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - 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.
AB - 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.
U2 - 10.1158/1078-0432.CCR-20-4699
DO - 10.1158/1078-0432.CCR-20-4699
M3 - Article
C2 - 33547199
SN - 1078-0432
VL - 27
SP - 2505
EP - 2514
JO - Clin. Cancer Res.
JF - Clin. Cancer Res.
IS - 9
ER -