Clinical efficacy of sequential treatments in KRASG12C-mutant metastatic colorectal cancer: findings from a real-life multicenter Italian study (CRC-KR GOIM)

Ciardiello, Davide; Chiarazzo, Cinzia; Famiglietti, Vincenzo; Damato, Angela; Pinto, Carmine; Zampino, Maria Giulia; Castellano, Grazia; Zaniboni, Alberto; Oneda, Ester; Rapisardi, Stefania; Zichi, Clizia; Maïo, Massimo Di; Parisi, Alessandro; Berardi, Rossana; Lavacchi, Daniele; Antonuzzo, Lorenzo; Tamburini, Emiliano; Maiorano, Brigida Anna; Parrella, Paola; Latiano, T.; Normanno, Nicola; Stefano, Alfonso De; Avallone, Antonio; Martini, Giulia; Napolitano, Stefania; Troiani, Teresa; Martinelli, Erika; Vita, Ferdinando De; Maiello, Evaristo

doi:10.1016/j.esmoop.2022.100567

Cited by 10 publications

(7 citation statements)

References 38 publications

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“…Similar results were (27). Consistent with this, in a large Italian case series the incidence of peritoneal metastases in RAS G12C metastatic CRC patients was 18.9% and lung metastases 41.4% (28). Intriguingly, despite the low number of patients detected, the 4 patients with CNS metastasis were all G12 mutated, observation not described in literature.…”

Section: Discussionsupporting

confidence: 87%

“…Similar results were obtained from a large retrospective analysis conducted by Osterlund et al., where peritoneal metastases were reported in 15% of patients with G12C tumor vs 19% of patients with other KRAS mutations (p=0.63) and lung metastases were reported in 39% vs 36%, respectively (p=0.26) ( 27 ). Consistent with this, in a large Italian case series the incidence of peritoneal metastases in RAS G12C metastatic CRC patients was 18.9% and lung metastases 41.4% ( 28 ).…”

Section: Discussionsupporting

confidence: 67%

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Mutations matter: An observational study of the prognostic and predictive value of KRAS mutations in metastatic colorectal cancer

et al. 2022

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BackgroundAbout half of metastatic colorectal cancers (CRCs) harbor Rat Sarcoma (RAS) activating mutations as oncogenic driver, but the prognostic role of RAS mutations is not fully elucidated. Interestingly, specific hotspot mutations have been identified as potential candidates for novel targeted therapies in several malignancies as per G12C. This study aims at evaluating the association between KRAS hotspot mutations and patient characteristics, prognosis and response to antiangiogenic drugs.MethodsData from RAS-mutated CRC patients referred to Careggi University Hospital, between January 2017 and April 2022 were retrospectively and prospectively collected. Tumor samples were assessed for RAS mutation status using MALDI-TOF Mass Spectrometry, Myriapod NGS-56G Onco Panel, or Myriapod NGS Cancer Panel DNA.ResultsAmong 1047 patients with available RAS mutational status, 183 KRAS-mutated patients with advanced CRC had adequate data for clinicopathological and survival analysis. KRAS mutations occurred at codon 12 in 67.2% of cases, codon 13 in 23.5%, codon 61 in 2.2%, and other codons in 8.2%. G12C mutation was identified in 7.1% of patients and exon 4 mutations in 7.1%. KRAS G12D mutation, as compared to other mutations, was significantly associated with liver metastases (1-sided p=0.005) and male sex (1-sided p=0.039), KRAS G12C mutation with peritoneal metastases (1-sided p=0.035), KRAS G12V mutation with female sex (1-sided p=0.025) and no surgery for primary tumor (1-sided p=0.005). No associations were observed between specific KRAS variants and age, ECOG PS, site of primary tumor, pattern of recurrence for resected patients, and lung, distant lymph node, bone, or brain metastases.Overall survival (OS) was significantly longer in patients with KRAS exon 4 mutations than in those with other KRAS mutations (mOS 43.6 months vs 20.6 months; HR 0.45 [0.21-0.99], p=0.04). No difference in survival was observed for mutations at codon 12/13/61 (p=0.1). Treatment with bevacizumab (BV) increased significatively mPFS (p=0.036) and mOS (p=0.019) of the entire population with a substantial benefit in mOS for G12V mutation (p=0.031).ConclusionsPatterns of presentation and prognosis among patients with specific RAS hotspot mutations deserve to be extensively studied in large datasets, with a specific attention to the uncommon isoforms and the role of anti-angiogenic drugs.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 67%

Mutations matter: An observational study of the prognostic and predictive value of KRAS mutations in metastatic colorectal cancer

et al. 2022

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“…The study of the molecular profile, in fact, allows for the documenting of mutations involved in tumor oncogenesis and determining a response predictive factor for targeted treatments. KRAS mutation is documented in colorectal cancer in a very large number of patients, close to half of the cases, and it is considered a predictor of poor outcome [ 88 , 89 ]. Despite this fact, knowledge about the mutation had never been translated before into a therapeutic possibility with drugs directed against the mutation itself, which, in fact, was considered for many years to be untargetable.…”

Section: Discussionmentioning

confidence: 99%

Integrated Decision-Making in the Treatment of Colon-Rectal Cancer: The Case of KRAS-Mutated Tumors

Cherri

Melocchi

Gandolfi

et al. 2023

Life

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In recent years, precision medicine has taken an increasing place in various branches of medical oncology, including colorectal cancer. Among the potentially relevant mutations for this cancer is the KRAS mutation, initially defined as “untargetable”; today, we see the birth of new molecules that target one of the variants of the KRAS mutation, KRAS G12C, having a significant impact on the therapeutic options for other malignancies, such as metastatic lung cancer. This fundamental step forward has stimulated scientific research on other potential targets of KRAS, both indirect and direct, and combination treatments aiming to overcome the mechanisms of resistance to these drugs that decrease in efficacy in colorectal cancer. What was once a negative predictive marker of response to anti-EGFR drugs today has become a potential target for targeted treatments. In turn, the prognostic role of the mutation has become extremely interesting, making it a potentially useful element in therapeutic decision-making, not only regarding oncological treatments but also in a more complex and complete manner within a global vision of the patient, involving other figures on the multidisciplinary team, such as surgeons, radiotherapists, and interventional radiologists.

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“…In colorectal cancer, the KRAS glycine-to-cysteine mutation at codon 12 ( KRAS G12C) occurs in up to 4% of patients and is associated with poorer overall survival (OS) in the first and second line when treated with chemotherapy. In addition, in the refractory setting among patients treated with TAS-102, KRAS G12C mutations were biomarkers for reduced OS benefit from TAS-102 [ 11 , 12 , 13 ]. Indeed, median overall survival (mOS) among patients with KRAS G12C tumors was 16.1 and 9.7 months in the first and second line, whereas mOS for those patients with non-G12C KRAS -mutated tumors was 18.3 and 11.4 months in the first and second line, respectively [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver

Ros,

Vaghi,

Baraibar

et al. 2024

IJMS

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Kirsten rat sarcoma virus oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancer. In colorectal cancer (CRC), KRAS mutations are present in more than 50% of cases, and the KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in up to 4% of patients. This mutation is associated with short responses to standard chemotherapy and worse overall survival compared to non-G12C mutations. In recent years, several KRAS G12C inhibitors have demonstrated clinical activity, although all patients eventually progressed. The identification of negative feedback through the EGFR receptor has led to the development of KRAS inhibitors plus an anti-EGFR combination, thus boosting antitumor activity. Currently, several KRAS G12C inhibitors are under development, and results from phase I and phase II clinical trials are promising. Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring KRAS G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation. Nonetheless, most of these patients will eventually relapse. In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance.

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Clinical efficacy of sequential treatments in KRASG12C-mutant metastatic colorectal cancer: findings from a real-life multicenter Italian study (CRC-KR GOIM)

Cited by 10 publications

References 38 publications

Mutations matter: An observational study of the prognostic and predictive value of KRAS mutations in metastatic colorectal cancer

Mutations matter: An observational study of the prognostic and predictive value of KRAS mutations in metastatic colorectal cancer

Integrated Decision-Making in the Treatment of Colon-Rectal Cancer: The Case of KRAS-Mutated Tumors

Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver

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