Evolution of RAS Mutations in Cell-Free DNA of Patients with Tissue RAS Wild-Type Metastatic Colorectal Cancer Receiving First-Line Treatment: The PERSEIDA Study

Manuel Valladares-Ayerbes, Pilar Garcia-Alfonso, Jorge Muñoz Luengo, Paola Patricia Pimentel Caceres, Oscar Alfredo Castillo Trujillo, Rosario Vidal-Tocino, Marta Llanos, Beatriz Llorente Ayala, Maria Luisa Limon Miron, Antonieta Salud, Luis Cirera Nogueras, Rocio Garcia-Carbonero, Maria Jose Safont, Esther Falco Ferrer, Jorge Aparicio, Maria Angeles Vicente Conesa, Carmen Guillén-Ponce, Paula Garcia-Teijido, Maria Begoña Medina Magan, Isabel Busquier, Mercedes Salgado, Ariadna Lloansí Vila, PERSEIDA Investigators, Manuel Valladares-Ayerbes, Pilar Garcia-Alfonso, Jorge Muñoz Luengo, Paola Patricia Pimentel Caceres, Oscar Alfredo Castillo Trujillo, Rosario Vidal-Tocino, Marta Llanos, Beatriz Llorente Ayala, Maria Luisa Limon Miron, Antonieta Salud, Luis Cirera Nogueras, Rocio Garcia-Carbonero, Maria Jose Safont, Esther Falco Ferrer, Jorge Aparicio, Maria Angeles Vicente Conesa, Carmen Guillén-Ponce, Paula Garcia-Teijido, Maria Begoña Medina Magan, Isabel Busquier, Mercedes Salgado, Ariadna Lloansí Vila, PERSEIDA Investigators

Abstract

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment-panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA RAS mutations (n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (n = 9; panitumumab subpopulation) presented emergent mutations (RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice.

Keywords: RAS mutations; cell-free DNA; colorectal cancer; solid biopsy.

Conflict of interest statement

M.V-A. has received grants and personal fees from Roche and personal fees from Merck, Amgen, Sanofi, Servier, Celgene, and Bayer. P.G-A. has received honoraria or consultation fees for speaker, consultancy, or advisory roles from Amgen, Bayer, Bristol, Merck Seorono, MSD, Lilly, Roche, Sanofi, Servier, and Pierre Fabre. R.V.-T. has received speaker fees from Amgen, Merck, Sanofi, Servier, Bristol-MS, Bayer, and Roche and educational and scientific activities and travel support from Amgen, Roche, Lilly, Sanofi, Bristol-MS, Pierre-Fabre, and Servier. R.G-C. has received honoraria for speaker/consulting roles from AAA, Advanz Pharma, Bayer, BMS, HMP, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pfizer, Pierre Fabre, Roche, Sanofi, and Servier and research support from ARMO Biosciences, Astrazeneca, Pfizer, Novartis, Ipsen, Roche, Pharmacyclics, Boston Biomedicals, Merck, MSD, Amgen, Sanofi, Bayer, Bristol-Myers-Squibb, Boerhringer, Sysmex, Gilead Sciences, Servier, Adacap, VCN, Lilly, Pharmamar, BMS, and MSD. M-J.S. has received personal fees from Roche, Amgen, Merck, and Sanofi and honoraria for speaker/consulting roles from Amgen, Bayer, BMS, Merck, MSD, Pierre Fabre, Roche, Sanofi, and Servier. JA. has received honoraria for consultancy or advisory roles from Amgen, Merck, Sanofi, Servier, Bayer, and Pierre Fabre. M.S. has received honoraria for speaker and advisory roles for Amgen. A.L.V. is an employee and stakeholder of Amgen S.A. The other authors declare no potential conflicts of interest.

Figures

Figure 1
Figure 1
Percentage of patients with (a) RAS, (b) KRAS, and (c) NRAS mutations in liquid biopsies at baseline, at 20 weeks (±2 weeks), and at disease progression according to mutant allele fraction (MAF) cut-offs. One (n = 1) patient had both KRAS and NRAS mutations (MAF ≥ 0.1% and MAF ≥ 0.02%). n: number of patients with mutations. Percentages calculated based on patients with available samples.
Figure 1
Figure 1
Percentage of patients with (a) RAS, (b) KRAS, and (c) NRAS mutations in liquid biopsies at baseline, at 20 weeks (±2 weeks), and at disease progression according to mutant allele fraction (MAF) cut-offs. One (n = 1) patient had both KRAS and NRAS mutations (MAF ≥ 0.1% and MAF ≥ 0.02%). n: number of patients with mutations. Percentages calculated based on patients with available samples.
Figure 2
Figure 2
Progression free survival according to RAS mutational status in liquid biopsy at any time (panitumumab subpopulation, left tumor location): (a) mutant allele fraction ≥1% cut-off; (b) mutant allele fraction ≥0.1% cut-off; and (c) mutant allele fraction ≥0.02% cut-off.
Figure 2
Figure 2
Progression free survival according to RAS mutational status in liquid biopsy at any time (panitumumab subpopulation, left tumor location): (a) mutant allele fraction ≥1% cut-off; (b) mutant allele fraction ≥0.1% cut-off; and (c) mutant allele fraction ≥0.02% cut-off.

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