Comprehensive genomic profiling by liquid biopsy captures tumor heterogeneity and identifies cancer vulnerabilities in patients with RAS/BRAFV600E wild-type metastatic colorectal cancer in the CAPRI 2-GOIM trial

D Ciardiello; L Boscolo Bielo; S Napolitano; E Martinelli; T Troiani; A Nicastro; T P Latiano; P Parente; E Maiello; A Avallone; N Normanno; S Pisconti; C Nisi; R Bordonaro; A E Russo; E Tamburini; I Toma; C Lotesoriere; S Vallarelli; M G Zampino; N Fazio; G Curigliano; F De Vita; F Ciardiello; G Martini; CAPRI-2 GOIM study group

doi:10.1016/j.annonc.2024.08.2334

Comprehensive genomic profiling by liquid biopsy captures tumor heterogeneity and identifies cancer vulnerabilities in patients with RAS/BRAF^V600E wild-type metastatic colorectal cancer in the CAPRI 2-GOIM trial

Ann Oncol. 2024 Aug 29:S0923-7534(24)03914-0. doi: 10.1016/j.annonc.2024.08.2334. Online ahead of print.

Authors

D Ciardiello¹, L Boscolo Bielo², S Napolitano³, E Martinelli³, T Troiani³, A Nicastro³, T P Latiano⁴, P Parente⁵, E Maiello⁴, A Avallone⁶, N Normanno⁷, S Pisconti⁸, C Nisi⁸, R Bordonaro⁹, A E Russo⁹, E Tamburini¹⁰, I Toma¹⁰, C Lotesoriere¹¹, S Vallarelli¹¹, M G Zampino¹, N Fazio¹, G Curigliano², F De Vita³, F Ciardiello¹², G Martini³; CAPRI-2 GOIM study group

Collaborators

CAPRI-2 GOIM study group:
Davide Ciardiello, Luca Boscolo Bielo, Stefania Napolitano, Erika Martinelli, Teresa Troiani, Antonella Nicastro, Tiziana Pia Latiano, Paola Parente, Evaristo Maiello, Antonio Avallone, Nicola Normanno, Salvatore Pisconti, Claudia Nisi, Roberto Bordonaro, Alessia Erika Russo, Emiliano Tamburrini, Ilaria Toma, Claudio Lotesoriere, Simona Vallarelli, Maria Giulia Zampino, Nicola Fazio, Giuseppe Curigliano, Fortunato Ciardiello, Giulia Martini, Sara Lonardi, Chiara Cremolini, Carlo Garufi, Pierosandro Tagliaferri, Giampaolo Tortora, Filippo Pietrantonio, Antonio Febbraro, Gerardo Rosati, Silvana Leo, Oronzo Brunetti, Rosanna Berardi, Saverio Cinieri, Mario Scartozzi, Alberto Zaniboni, Giancarlo Paoletti

Affiliations

¹ Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan.
² Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan; Department of Oncology and Hemato-Oncology, University of Milan, Milan.
³ Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples.
⁴ Medical Oncology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo.
⁵ Pathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo.
⁶ Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples.
⁷ IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Mendola.
⁸ Medical Oncology Unit, San Giuseppe Moscati Hospital, Statte.
⁹ Medical Oncology Unit, Azienda Ospedaliera ARNAS Garibaldi, Catania.
¹⁰ Department of Oncology and Palliative Care, Cardinale G Panico, Tricase City Hospital, Tricase.
¹¹ Medical Oncology Unit, National Institute of Gastroenterology, IRCCS de Bellis Research Hospital, Castellana Grotte, Italy.
¹² Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples. Electronic address: fortunato.ciardiello@unicampania.it.

PMID: 39214459
DOI: 10.1016/j.annonc.2024.08.2334

Abstract

Background: Emerging evidence supports tumor tissue-based comprehensive genomic profiling (CGP) in metastatic colorectal cancer (mCRC). Data on liquid biopsy-based circulating tumor DNA (ctDNA) CGP are scarce and mainly retrospective. Prospective comparison between the two tests is not currently available.

Materials and methods: The CAPRI 2-GOIM trial investigates efficacy and safety of ctDNA-driven, cetuximab-based sequence of three treatment lines in patients with RAS/BRAF^V600E wild-type (WT) mCRC, as determined by the local laboratory. Before first-line therapy, CGP is carried out with FoundationOne (F1) CDx and F1 Liquid (F1L) CDx (324 genes) on tumor tissue DNA and plasma ctDNA, respectively.

Results: For 2/207 (0.96%) patients, no ctDNA was detected by F1L CDx. No patient displayed tumor fraction (TF) below 1%, whereas elevated ctDNA (TF ≥ 10%) was detected among 140/205 (68.3%) patients. One thousand and thirteen genomic variants were identified. F1L CDx found KRAS, NRAS, or BRAF^V600E alterations in 19 patients, whose tumors were classified as RAS/BRAF^V600E WT by the local laboratory. Both F1 CDx and F1L CDx were available for 164/205 (80%) patients. A concordance of 61.4% between the two tests was observed. The concordance increased to 72.7% for F1L CDx with TF ≥ 10%. Concordance for genes potentially involved in anti-epidermal growth factor receptor resistance was found in 137/164 (83%) patients, increasing to 91.5% for F1L CDx with TF ≥ 10%. A higher number of genomic alterations was detected by F1L CDx compared with F1 CDx, including six cases with KRAS and NRAS alterations. Overall, 109/205 (53.2%) patients displayed at least one actionable genomic alteration (I to IIIB), according to the European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT).

Conclusion: Baseline liquid biopsy-based CGP is feasible, has high concordance with tumor tissue-based CGP, could better recapitulate tumor heterogeneity, and is clinically informative by identifying additional actionable genomic alterations in approximately half of RAS/BRAF^V600E WT mCRC patients.

Keywords: anti-epidermal growth factor receptor (EGFR) drugs; circulating tumor DNA (ctDNA); colorectal cancer (CRC); comprehensive genomic profiling (CGP); liquid biopsy.