KRASG12D-Mutated Metastatic Colorectal Cancer: Clinical, Molecular, Immunologic, and Prognostic Features of a New Emerging Targeted Alteration.

Autor:	Moretto R; Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy., Rossini D; Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.; Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy., Murgioni S; Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy., Ciracì P; Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy., Nasca V; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Germani MM; Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy., Calegari MA; Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy., Vetere G; Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy., Intini R; Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy., Taravella A; Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy., Studiale V; Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy., Boccaccio C; Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy., Passardi A; Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, Meldola, Italy., Tamburini E; Department of Oncology and Palliative Care, Cardinale G Panico, Tricase City Hospital, Tricase, Italy., Zaniboni A; Oncology Unit, Fondazione Poliambulanza, Brescia, Italy., Salvatore L; Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy.; Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy., Pietrantonio F; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Lonardi S; Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy., Masi G; Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy., Cremolini C; Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
Jazyk:	angličtina
Zdroj:	JCO precision oncology [JCO Precis Oncol] 2024 Nov; Vol. 8, pp. e2400329. Date of Electronic Publication: 2024 Nov 07.
DOI:	10.1200/PO.24.00329
Abstrakt:	Purpose: KRASG12D mutation (mut) occurs in about 10%-12% of metastatic colorectal cancer (mCRC). Recently, novel KRASG12D inhibitors have been developed and are currently under investigation in phase I/II clinical trials in solid tumors including mCRC. We aimed at performing a comprehensive characterization of clinical, molecular, immunologic, and prognostic features of KRASG12D-mutated mCRC to inform the design and the interpretation of future trials. Methods: We performed a pooled analysis of phase III TRIBE and TRIBE2 studies comparing 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/bevacizumab (bev) to doublets (5-fluorouracil, leucovorin, and oxaliplatin or 5-fluorouracil, leucovorin, and irinotecan)/bev. Results: One hundred and thirty-six (16%) of 854 patients with available KRASG12D mutational status were KRASG12D mutated. KRASG12D-mutated patients had more frequently right-sided primary tumor and were less likely to present liver-only metastases with respect to other RAS mutated and all-wild-type (wt) patients. Compared with the BRAFV600E-mutated group, KRASG12D-mutated patients had more frequently left-sided primary tumor, resected primary tumor at the time of diagnosis, and Eastern Cooperative Oncology Group performance status 0. KRASG12D-mutated patients had better prognosis than BRAFV600E-mutated and worse prognosis than all wt patients. No prognostic difference was evident between KRASG12D mut and other RAS mut patients overall or according to other specific KRAS or NRAS hotspot mutations. No interaction effect was observed between KRASG12D mut and the benefit provided by FOLFOXIRI/bev compared with doublets/bev. PIK3CA mut were reported more frequently among KRASG12D-mutated tumors compared with both other RAS mut and all wt. Conclusion: A detail estimation of KRASG12D mut mCRC patients' characteristics and expected outcomes may be useful when planning future studies in this subgroup. The high prevalence of PI3K/PTEN/Akt pathway activating alterations may affect the efficacy of targeted strategies.
Databáze:	MEDLINE
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