Prevalence of<i>KRAS</i>G12C Mutation and Co-mutations and Associated Clinical Outcomes in Patients With Colorectal Cancer: A Systematic Literature Review

Strickler, John H.; Yoshino, Takayuki; Stevinson, Kendall; Eichinger, C.; Giannopoulou, Christina; Rehn, Marko; Modest, Dominik Paul

doi:10.1093/oncolo/oyad138

Cited by 11 publications

(2 citation statements)

References 75 publications

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“…Almost half of patients with CRC exhibit KRAS mutations, but the KRAS G12C mutation appears in only 3%. Novel insights into the structure and biochemical properties of mutant KRAS G12C have led to the development of inhibitors like sotorasib and adagrasib [ 47 ]. Pre-clinical studies have shown that inhibition of KRAS G12C rapidly reactivates the EGFR-mediated MAPK pathway, but inhibition of EGFR increased efficacy and maintained response for a longer period.…”

Section: Patients With Kras G12c Mutationsmentioning

confidence: 99%

Treatment Options in Late-Line Colorectal Cancer: Lessons Learned from Recent Randomized Studies

Tarpgaard,

Winther,

Pfeiffer

2023

Cancers

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Systemic treatment of metastatic colorectal cancer (mCRC) has improved considerably over the past 20 years. First- and second-line combinations of 5FU, oxaliplatin, and irinotecan, with or without anti-angiogenic and/or anti-EGFR antibodies, were approved shortly after the turn of the millennium. Further triumphs were not seen for almost 10 years, until the approval of initially regorafenib and shortly after trifluridine/tipiracil. A growing understanding of tumor biology through molecular profiling has led to further treatment options. Here, we review the most recent clinical data for late-line treatment options in mCRC, focusing on randomized trials if available. We include recommendations for options in unselected patients and therapies that should only be offered in patients with distinct tumor profiles (e.g., BRAF mutations, KRAS G12C mutations, HER2 amplification, deficient MMR, or NTRK gene fusions).

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Section: Patients With Kras G12c Mutationsmentioning

confidence: 99%

Treatment Options in Late-Line Colorectal Cancer: Lessons Learned from Recent Randomized Studies

Tarpgaard,

Winther,

Pfeiffer

2023

Cancers

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“…In CRC, KRAS is mutated in around 40% of cases [ 13 ]. The global median prevalence of the KRAS p.G12C mutation in CRC is 3.1% [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Concurrent KRAS p.G12C mutation and ANK3::RET fusion in a patient with metastatic colorectal cancer: a case report

Bedau,

Heydt,

Siebolts

et al. 2024

Diagn Pathol

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Background Colorectal cancer (CRC) frequently involves mutations in the KRAS gene, impacting therapeutic strategies and prognosis. The occurrence of KRAS mutations typically precludes the presence of RET fusions, with current medical literature suggesting a mutual exclusivity between these two genetic alterations. We present a unique case that challenges this notion. Case Presentation An 85-year-old female with metastatic CRC was found to have a combination of genetic anomalies that is to the best of our knowledge not yet described in the medical literature: a KRAS p.G12C mutation, associated with oncogenesis and treatment resistance, and an ANK3::RET fusion, an infrequent but targetable mutation in CRC. This molecular profile was uncovered through comprehensive genomic sequencing after the patient experienced metachronous tumor dissemination. The presence of both genetic events complicates the treatment approach. Conclusions The identification of both a KRAS p.G12C mutation and an ANK3::RET fusion in the same CRC patient adds a new layer to the oncogenic landscape and treatment considerations for CRC. It highlights the intricate decision-making required in the era of precision medicine, where targeted therapies must be carefully chosen and potentially combined to combat complex genetic profiles. The case emphasizes the urgency of investigating the clinical effects of concurrent or sequential use of KRAS p.G12C and RET inhibitors to inform future therapeutic guidelines and improve patient outcomes in similar cases.

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Metabolic Response to Small Molecule Therapy in Colorectal Cancer Tracked with Raman Spectroscopy and Metabolomics

Cutshaw,

Joshi,

Wen

et al. 2024

Angewandte Chemie

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Despite numerous screening tools for colorectal cancer (CRC), 25% of patients are diagnosed with advanced disease. Novel diagnostic technologies that are early, accurate, and rapid are imperative to assess the therapeutic efficacy of clinical drugs and identify new biomarkers of treatment response. Here Raman spectroscopy (RS) was used to track metabolic reprogramming in KRAS‐mutant HCT116 and SW837 cells, and KRAS wild‐type CC cells. RS combined with multivariate analysis methods distinguished nonresponsive, partially responsive, and responsive cells treated with cetuximab, a monoclonal antibody for EGFR inhibition, sotorasib, a clinically approved KRAS inhibitor, and various doses of trametinib, an inhibitor of the MAPK pathway. Cells treated with a combination of subtoxic doses of trametinib and BKM120, an inhibitor of the PI3K pathway, showed a synergistic response between the two pathways. Using a supervised machine learning regression model, we established a scoring methodology trained to a priori predict therapeutic response to new treatment combinations. RS metabolites were verified with mass spectrometry, and enrichment pathways were identified, including amino acid, purine, and nicotinate and nicotinamide metabolism that differentiated monotherapy from combination therapy. Our approach may ultimately be applicable to patient‐derived primary cells and cultures of patient tumors to predict effective drugs for individualized care.

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Prevalence ofKRASG12C Mutation and Co-mutations and Associated Clinical Outcomes in Patients With Colorectal Cancer: A Systematic Literature Review

Cited by 11 publications

References 75 publications

Treatment Options in Late-Line Colorectal Cancer: Lessons Learned from Recent Randomized Studies

Treatment Options in Late-Line Colorectal Cancer: Lessons Learned from Recent Randomized Studies

Concurrent KRAS p.G12C mutation and ANK3::RET fusion in a patient with metastatic colorectal cancer: a case report

Metabolic Response to Small Molecule Therapy in Colorectal Cancer Tracked with Raman Spectroscopy and Metabolomics

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