Dynamics of RAS/BRAF Mutations in cfDNA from Metastatic Colorectal Carcinoma Patients Treated with Polychemotherapy and Anti-EGFR Monoclonal Antibodies
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Anna Maria Rachiglio
1, 
Laura Forgione
1,
Raffaella Pasquale
1,
Carlo Antonio Barone
2,
Evaristo Maiello
3,
Lorenzo Antonuzzo
4,
Antonino Cassata
5,
Giuseppe Tonini
6,
Roberto Bordonaro
7,
Gerardo Rosati
8,
Alberto Zaniboni
9, 
Sara Lonardi
10,
Daris Ferrari
11,
Giovanni Luca Frassineti
12,
Stefano Tamberi
13, 
Salvatore Pisconti
14,
Francesca Di Fabio
15,
Cristin Roma
1,
Armando Orlandi
2
,
Tiziana Latiano
3,
Angela Damato
16,17,
Giampaolo Tortora
2, 
Carmine Pinto
16 and
Nicola Normanno
1,*add
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1
Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS, 80131 Naples, Italy
2
Fondazione Policlinico Universitario Agostino Gemelli, 00168 Rome, Italy
3
IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
4
Medical Oncology Unit, Azienda Ospedaliero Universitaria Careggi, 50134 Florence, Italy
5
Medical Oncology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS, 80131 Naples, Italy
6
Medical Oncology Unit, Università Campus Bio-Medico, 00128 Rome, Italy
7
Medical Oncology Unit, ARNAS Garibaldi, 95122 Catania, Italy
8
Medical Oncology Unit, Ospedale San Carlo, 85100 Potenza, Italy
9
Fondazione Poliambulanza, 25124 Brescia, Italy
10
Medical Oncology IOV, 35128 Padua, Italy
11
Ospedale S. Paolo, 20142 Milan, Italy
12
Medical Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy
13
Ospedale per Gli Infermi, 48018 Faenza, Italy
14
Medical Oncology Division, S. Giuseppe Moscati Hospital, 74010 Taranto, Italy
15
Medical Oncology Unit, S. Orsola-Malpighi Hospital, 40138 Bologna, Italy
16
Medical Oncology Unit, Clinical Cancer Center, AUSL-IRCCS Reggio Emilia, 42122 Reggio Emilia, Italy
17
Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
*
Author to whom correspondence should be addressed.
Cancers 2022, 14(4), 1052; https://doi.org/10.3390/cancers14041052
Submission received: 27 December 2021
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Revised: 14 February 2022
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Accepted: 17 February 2022
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Published: 18 February 2022
(This article belongs to the Collection Cancer Biomarkers in Body Fluids)
Simple Summary
Increasing evidence suggests that circulating cell-free DNA (cfDNA) testing might allow for monitoring the response to anti-EGFR monoclonal antibodies in patients with metastatic colorectal carcinoma (mCRC). However, few data are available in treatment-naïve patients. We tested cfDNA samples obtained from mCRC patients enrolled in a phase III trial of the anti-EGFR monoclonal antibody cetuximab plus chemotherapy as first-line treatment. Analysis of serial plasma samples revealed a complex dynamic of RAS/BRAF mutations in response to treatment, with transitory peaks of these mutations that were not associated with resistance to therapy. Overall, our findings suggest that early appearance of RAS/BRAF mutations in the plasma of patients receiving first-line anti-EGFR agents in combination with chemotherapy should not be considered as marker of resistance.
Abstract
Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line treatment of RAS/BRAF wild-type mCRC. Samples were collected at baseline (n = 37), at 8 weeks of treatment (n = 32), progressive disease (PD; n = 36) and 3 months after PD (n = 21). cfDNA testing was performed using the Idylla™ ctKRAS and ctNRAS-BRAF tests and the Oncomine Pan-Cancer Cell-Free Assay. Analysis of basal samples revealed RAS/BRAF mutations in 6/37 cases. A transient RAS positivity not associated with PD was observed at 8 weeks in five cases that showed no mutations at baseline and PD. The frequency of mutant cases increased at PD (33.3%) and decreased again at 3 months after PD (9.5%). The median progression-free survival (mPFS) of patients RAS/BRAF mutant at PD was 7.13 months versus 7.71 months in wild-type patients (p = 0.3892). These data confirm that the occurrence of RAS/BRAF mutations in mCRC patients receiving anti-EGFR agents is relatively frequent. However, the cfDNA dynamics of RAS mutations in patients treated with anti-EGFR agents plus polychemotherapy are complex and might not be directly associated with resistance to treatment.
