KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population

Schirripa, Marta; Nappo, Floriana; Cremolini, Chiara; Salvatore, Lisa; Rossini, Daniele; Bensi, Maria; Businello, Gianluca; Pietrantonio, Filippo; Randon, Giovanni; Fucà, Giovanni; Boccaccino, Alessandra; Bergamo, Francesca; Lonardi, Sara; Tos, Angelo Paolo Dei; Loupakis, Fotios

doi:10.1016/j.clcc.2020.04.009

Cited by 54 publications

(59 citation statements)

References 14 publications

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“…Abbreviations: KRAS, Kirsten rat sarcoma. [21]. The strength of our study lies in validating poor prognosis in the presence of the KRAS G12C mutation with respect to PFS and OS using real-world data obtained outside a clinical trial setting.…”

Section: Discussionmentioning

confidence: 96%

“…Although several reports have described the prognostic impact of KRAS mutation subtypes, most have focused on patients with non-small cell lung cancer and/or nonmetastatic CRC [19,20], and only a few studies have analyzed the prognostic impact of KRAS G12C mutation in mCRC [16,21]. A Figure 2.…”

Section: Discussionmentioning

confidence: 99%

“…Although several reports have described the prognostic impact of KRAS mutation subtypes, most have focused on patients with non‐small cell lung cancer and/or nonmetastatic CRC [19, 20], and only a few studies have analyzed the prognostic impact of KRAS G12C mutation in mCRC [16, 21]. A pooled analysis by the Arbeitsgemeinschaft Internistische Onkologie [AIO] study group revealed that KRAS G12C mutation was significantly associated with lower OS compared with tumors with no KRAS mutations [16]; however, it must be noted here that this pooled analysis also included patients who had received a nonstandard treatment regimen, including FUFIRI, FUFOX, and mIROX as induction chemotherapies and bevacizumab monotherapy or observation alone as maintenance therapies in clinical trials [22, 23].…”

Section: Discussionmentioning

confidence: 99%

“…A pooled analysis by the Arbeitsgemeinschaft Internistische Onkologie [AIO] study group revealed that KRAS G12C mutation was significantly associated with lower OS compared with tumors with no KRAS mutations [16]; however, it must be noted here that this pooled analysis also included patients who had received a nonstandard treatment regimen, including FUFIRI, FUFOX, and mIROX as induction chemotherapies and bevacizumab monotherapy or observation alone as maintenance therapies in clinical trials [22, 23]. Schirripa et al have recently reported poor prognosis in patients with mCRC and KRAS G12C mutation; however, the prevalence of KRAS G12C mutation was relatively high at 17.3%, and favorable outcomes, such as median OS greater than 35 months in patients with KRAS non‐G12C mutations, might not reflect real‐world clinical practice [21]. The strength of our study lies in validating poor prognosis in the presence of the KRAS G12C mutation with respect to PFS and OS using real‐world data obtained outside a clinical trial setting.…”

Section: Discussionmentioning

confidence: 99%

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The Prognostic Impact of KRAS G12C Mutation in Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Observational Study

et al. 2021

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Background. KRAS is one of the most frequently mutated oncogenes in colorectal cancer (CRC). Recently, a novel therapy targeting KRAS G12C mutation has demonstrated promising activities for corresponding advanced solid tumors, including metastatic CRC (mCRC). However, the prognostic impact of the KRAS G12C mutation remains unclear in patients with mCRC. Materials and Methods. We retrospectively reviewed medical records of patients with mCRC who received first-line chemotherapy between January 2005 and December 2017 at four large oncology facilities in Japan. Survival outcomes were compared between patients with KRAS G12C and those with non-G12C mutations. Results. Among 2,457 patients with mCRC, 1,632 met selection criteria, and of these, 696 had KRAS exon 2 mutations, including 45 with KRAS G12C mutation tumors. Patient characteristics were not significantly different between the KRAS G12C and non-G12C groups. At a median follow-up of 64.8 months, patients with the KRAS G12C mutation showed significantly shorter first-line progression-free survival (PFS; median, 9.4 vs. 10.8 months; p = .015) and overall survival (OS; median, 21.1 vs. 27.3 months; p = .015) than those with non-G12C mutations. Multivariate analysis also showed that KRAS G12C mutation was significantly associated with shorter PFS (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.04-1.96, p = .030) and OS (HR, 1.42; 95% CI, 1.01-2.00; p = .044). Conclusion.We demonstrate that, compared with non-G12C mutations, KRAS G12C mutation is significantly correlated with shorter first-line PFS and OS. These findings indicate the relevance of a stratified treatment targeting KRAS G12C mutation in mCRC.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

The Prognostic Impact of KRAS G12C Mutation in Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Observational Study

et al. 2021

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“…29 Luckily, new promise is emerging for patients with the Kirsten RAS (KRAS) p.G12C mutation, comprising 1-4% of colorectal cancers. 30,31 Sotorasib is a novel small molecule that irreversibly inhibits KRAS p.G12C, locking it in the inactive guanosine diphosphate-bound state. 31,32 In the first-in-human phase I CodeBreaK100 trial, sotorasib was studied in 129 patients with the KRAS p.G12C mutation, including 42 patients with advanced colorectal cancer.…”

Section: Sotorasib (Amg 510)mentioning

confidence: 99%

<p>Up-and-Coming Experimental Drug Options for Metastatic Colorectal Cancer</p>

Cimino¹,

Eng²

2020

JEP

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Colorectal cancer is one of the top causes of cancer and cancer-related deaths worldwide. The prognosis of metastatic colorectal cancer is poor and treatment options are limited. Many patients will run out of treatment options before they become medically unfit for therapy. As such, there is a need to expand upon the current understanding of disease biology as well as drug resistance mechanisms in order to create new approaches for therapy. In this review article, we will discuss the mechanistic rationale and clinical data for new drugs and therapeutic combinations under development for metastatic colorectal cancer.

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Colorectal cancer: Review of signaling pathways and associated therapeutic strategies

Leiphrakpam

Rajappa²,

Krishnan

et al. 2023

Journal of Surgical Oncology

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Tumor profiling and targeted therapy revolutionized the treatment strategies of metastatic colorectal cancer (mCRC) in the last decade. The heterogeneity of CRC tumors plays a critical role in the development of treatment resistance, which underscores the need to understand the molecular mechanism involved in CRC to develop novel targeted therapeutic strategies. This review provides an overview of the signaling pathways driving CRC, the existing targeted agents, their limitations, and future trends.

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KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population

Cited by 54 publications

References 14 publications

The Prognostic Impact of KRAS G12C Mutation in Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Observational Study

The Prognostic Impact of KRAS G12C Mutation in Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Observational Study

<p>Up-and-Coming Experimental Drug Options for Metastatic Colorectal Cancer</p>

Colorectal cancer: Review of signaling pathways and associated therapeutic strategies

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