Abstract 5602
Background
Genotyping of ctDNA characterizes the molecular profile and monitors tumor molecular dynamics, but the clinical applicability of next generation sequencing (NGS) DNA sequencing has not been assessed in a large prospective cohort of mCRC patients (pts).
Methods
mCRC pts with RAS wt tumors treated in first line with chemotherapy (CT) + cetuximab in 16 Spanish hospitals were included. Plasma samples were collected baseline (BL) and every 2 cycles until progression. ctDNA was isolated and sequenced with NGS platform Oncomine Colon cfDNA Assay which identifies hotspot mutations (mut) in AKT1, BRAF, CTNNB1, EGFR, ERBB2, FBXW7, GNAS, KRAS, MAP2K1, NRAS, PIK3CA, SMAD4, TP53 and APC. RAS ctDNA mut were also assessed by dPCR (BEAMing) at BL. Detection of any mut in plasma was considered as ctDNA+. Mut in BRAF/RAS/MAP2K1/PIK3CA were considered as anti-EGFR resistance.
Results
101 pts were enrolled (65.3% male; median age 64.5y; 77.6% left colon). RAS mut were detected in 11 pts BL by BEAMing. After quality assessment, 84 samples were sequenced by NGS BL and at least one mut was detected in 65 samples (77.3%; median 1, range 0-5) and 10 RAS mut were detected. Plasma samples from 47 pts were also analyzed after 4 cycles of treatment (C4) and mut were detected in 30 pts (63.8%; median 1, range 0-3). Median mutant allele fraction for paired samples was 24.9 at BL and 0.56 at C4 (p = 0.0045). Treatment clinical benefit (CB: PR, CR and SD ≥ 16weeks) was observed in 72 out of 85 pts. BL ctDNA+ or C4 ctDNA change were not associated with CB (p = 0.722). Assessment of RAS BL mut was not associated with CB (p = 0.243 by NGS and p = 0.712 by BEAMing), while the absence of RAS mut at C4 predicted treatment CB (93.2% vs. 6.8% RAS mut p = 0.02). Median PFS for all pts was 10.13 month. ctDNA+ at BL or C4 were not correlated with PFS (HR 0.8; p = 0.73). No differences in PFS were found in ctDNA RAS mut vs RAS wt BL (BEAMing+ HR = 1.2 p = 0.79 and NGS+ HR = 2.6 p = 0.052). Among all anti-EGFR resistant mut, only ctDNA RAS mut were detected at C4 (N = 4). Persistence or emergence of RAS mut at C4 were strongly associated with PFS (12.9m vs. 4.2. HR 8.8 p = 0.0003).
Conclusions
Early RAS ctDNA dynamics predicts benefit to first line CT+cetuximab in mCRC pts.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Grupo de Tratamiento de los Tumores Digestivos (TTD), Spain.
Funding
Merck-Serono.
Disclosure
J. Vidal Barrull: Honoraria (self), Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Amgen; Honoraria (self): Sysmex-Inostics. E. Elez Fernández: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck-Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Sanofi. F. Losa: Honoraria (self): Amgen; Honoraria (self): Merck-Serono. R. Salazar: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Guardant-Helth; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Ferrer; Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD. J. Tabernero: Honoraria (self), Advisory / Consultancy: Array Biopharma; Honoraria (self), Advisory / Consultancy: Merck-Serono; Honoraria (self), Advisory / Consultancy: Molecular Partners; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Foundation Medicine; Honoraria (self), Advisory / Consultancy: Halio DX SAS. E. Aranda Aguilar: Honoraria (self): Celgene; Honoraria (self): Merck-Serono; Honoraria (self): Roche; Honoraria (self): Sanofi. B. Bellosillo: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Biocartis; Advisory / Consultancy: Novartis; Advisory / Consultancy: Thermofisher. C. Montagut Viladot: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck-Serono; Advisory / Consultancy: Sysmex-Inostics; Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Biocartis; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Guardant-Helth; Advisory / Consultancy: Symphogen. All other authors have declared no conflicts of interest.
Resources from the same session
3353 - Results of the 3rd interim analysis of C-Patrol: A non-interventional study on olaparib in German routine clinical practice
Presenter: Jalid Sehouli
Session: Poster Display session 2
Resources:
Abstract
740 - A real-world analysis of the treatment of advanced ovarian cancer with PARPIs
Presenter: Alejandra Martinez de Pinillos
Session: Poster Display session 2
Resources:
Abstract
5867 - Incidence of tumour BRCA1/2 variants in relapsed, platinum-sensitive ovarian, fallopian tube and primary peritoneal cancer
Presenter: Robert Morgan
Session: Poster Display session 2
Resources:
Abstract
2966 - Frequency of mutations in 21 hereditary breast and ovarian cancer susceptibility genes among 882 high-risk individuals
Presenter: Jihong Liu
Session: Poster Display session 2
Resources:
Abstract
1687 - BRCA testing of 1,284 Brazilian patients for hereditary breast and ovarian cancer in a routine diagnostic setting
Presenter: Fernanda Milanezi
Session: Poster Display session 2
Resources:
Abstract
3162 - A multi-center integrative study on cancer predisposition genes in Chinese patients with epithelial ovarian carcinoma
Presenter: Changbin Zhu
Session: Poster Display session 2
Resources:
Abstract
5993 - Incidental Early Occult Ovarian Cancer after Risk-Reducing Salpingo-Oophorectomy in BRCA1/2 Mutation Carriers followed in a Community Public Hospital
Presenter: Begona Grana Suarez
Session: Poster Display session 2
Resources:
Abstract
5334 - Response to chemotherapy in ovarian cancer (OC) patients with or without prior breast cancer (BC), stratified by BRCA mutation (BRCAm) status
Presenter: Angela George
Session: Poster Display session 2
Resources:
Abstract
4565 - Advanced ovarian cancer: is residual disease after debulking surgery affected by genetics factors involved in angiogenesis and immunity pathways?
Presenter: Michele Bartoletti
Session: Poster Display session 2
Resources:
Abstract
3251 - Surrogate endpoint of progression-free (PFS) and overall survival (OS) for advanced ovarian cancer (AOC) patients (pts) treated with neo-adjuvant chemotherapy (NACT): Results of the CHIVA randomized phase II GINECO study
Presenter: Fabrice Lecuru
Session: Poster Display session 2
Resources:
Abstract