Evaluation of KRAS Mutations, Angiogenic Biomarkers, and DCE-MRI in Patients with Advanced Non–Small-Cell Lung Cancer Receiving Sorafenib

Abstract Background: KRAS is the most frequently mutated oncogene in cancer, however efforts to develop targeted therapies have been largely unsuccessful. Recently, two small-molecule inhibitors, AMG 510 and MRTX849, have shown promising activity in KRAS G12C-mutant solid tumors. The current study aims to assess the molecular profile of KRAS G12C in colorectal (CRC) and non-small-cell lung cancer (NSCLC) tested in a clinical certified laboratory.Methods: CRC and NSCLC samples submitted for KRAS testing between 2017 and 2019 were reviewed. CRC samples were tested for KRAS and NRAS by pyrosequencing, while NSCLC samples were submitted to next generation sequencing of KRAS, NRAS, EGFR, and BRAF. Results: The dataset comprised 4,897 CRC and 4,686 NSCLC samples. Among CRC samples, KRAS was mutated in 2,354 (48.1%). Most frequent codon 12 mutations were G12D in 731 samples (15.2%) and G12V in 462 (9.6%), followed by G12C in 167 (3.4%). KRAS mutations were more frequent in females than males (p=0.003), however this difference was exclusive of non-G12C mutants (p<0.001). KRAS mutation frequency was lower in the South and North regions (p=0.003), but again KRAS G12C did not differ significantly (p=0.80). In NSCLC, KRAS mutations were found in 1,004 samples (21.4%). As opposed to CRC samples, G12C was the most common mutation in KRAS, in 346 cases (7.4%). The frequency of KRAS G12C was higher in the South and Southeast regions (p=0.012), and lower in patients younger than 50 years (p<0.001). KRAS G12C mutations were largely mutually exclusive with other driver mutations; only 11 NSCLC (3.2%) and 3 CRC (1.8%) cases had relevant co-mutations. Conclusions: KRAS G12C presents in frequencies higher than several other driver mutations, represent a large volume of patients in absolute numbers. KRAS testing should be considered in all CRC and NSCLC patients, independently of clinical or demographic characteristics.

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KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: A meta-analysis of 22 studies

Lung Cancer ◽

10.1016/j.lungcan.2009.11.020 ◽

2010 ◽

Vol 69 (3) ◽

pp. 272-278 ◽

Cited By ~ 195

Author(s):

Chen Mao ◽

Li-Xin Qiu ◽

Ru-Yan Liao ◽

Fang-Bing Du ◽

Hong Ding ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Meta Analysis ◽

Small Cell ◽

Small Cell Lung ◽

Kras Mutations ◽

Egfr Tkis

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Randomized Phase II Study of Erlotinib Plus Tivantinib Versus Erlotinib Plus Placebo in Previously Treated Non–Small-Cell Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2010.34.0570 ◽

2011 ◽

Vol 29 (24) ◽

pp. 3307-3315 ◽

Cited By ~ 277

Author(s):

Lecia V. Sequist ◽

Joachim von Pawel ◽

Edward G. Garmey ◽

Wallace L. Akerley ◽

Wolfram Brugger ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Phase Ii ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Kras Mutations ◽

Randomized Phase Ii ◽

Previously Treated ◽

Met Inhibitor

Purpose c-MET (MET) receptor activation is associated with poor prognosis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non–small-cell lung cancer (NSCLC). This global, randomized phase II trial examined erlotinib plus tivantinib (ARQ 197; ArQule, Woburn, MA), a novel MET inhibitor. Methods Previously treated patients with EGFR TKI–naive advanced NSCLC were randomly assigned to receive oral erlotinib (150 mg daily) plus oral tivantinib (360 mg twice daily) or erlotinib plus placebo (EP). The primary end point was progression-free survival (PFS). At the time of progression, cross-over from EP to erlotinib plus tivantinib (ET) was permitted. Archival tumor tissue specimens were required. Results One hundred sixty-seven patients were randomly assigned to ET (n = 84) and to EP (n = 83). Median PFS was 3.8 months for ET and 2.3 months for EP (hazard ratio [HR], 0.81; 95% CI, 0.57 to 1.16; P = .24). Exploratory analysis revealed that the small cohort with KRAS mutations achieved a PFS HR of 0.18 (95% CI, 0.05 to 0.70; interaction P = .006). Objective responses were seen in 10% of patients on ET, 7% of patients on EP, and in two patients who crossed over from EP to ET, including one with EGFR mutation and MET gene copy number greater than 5. There were no significant differences in adverse events between study arms. Conclusion The combination of the MET inhibitor tivantinib and erlotinib is well-tolerated. Although the study did not meet its primary end point, evidence of activity was demonstrated, especially among patients with KRAS mutations. Additional study of tivantinib and erlotinib in patients with NSCLC is planned.

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Abstract 340: Predictive value of KRAS mutations in advanced non-small cell lung cancer (NSCLC) patients (pts) treated with chemotherapy (CT)

10.1158/1538-7445.am2011-340 ◽

2011 ◽

Author(s):

Anne-Marie C. Dingemans ◽

Egbert F. Smit ◽

Jules Derks ◽

Wouter Mellema ◽

Danielle Heideman ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Predictive Value ◽

Small Cell ◽

Small Cell Lung ◽

Kras Mutations ◽

Nsclc Patients

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A Real-World Study in Advanced Non–Small Cell Lung Cancer with KRAS Mutations

Translational Oncology ◽

10.1016/j.tranon.2019.12.004 ◽

2020 ◽

Vol 13 (2) ◽

pp. 329-335 ◽

Cited By ~ 2

Author(s):

Lei Lei ◽

Wen-xian Wang ◽

Zong-yang Yu ◽

Xian-bin Liang ◽

Wei-wei Pan ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Real World ◽

Small Cell ◽

Small Cell Lung ◽

Kras Mutations

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Predictive value of EGFR and KRAS mutations detected in plasma from non-small cell lung cancer (NSCLC) patients treated with docetaxel and intermittent erlotinib

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.8062 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 8062-8062

Author(s):

P. C. Mack ◽

W. S. Holland ◽

R. A. Burich ◽

Y. Li ◽

L. Beckett ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Predictive Value ◽

Small Cell ◽

Small Cell Lung ◽

Kras Mutations ◽

Nsclc Patients

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Clinical significance of the EML4-ALK fusion gene and association with EGFR and KRASgene mutation in 208 Chinese patients with non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e17514 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e17514-e17514 ◽

Cited By ~ 1

Author(s):

JUN Chen ◽

Hongyu Liu ◽

Tong Yang ◽

Sen Wei ◽

Qinghua Zhou

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Fusion Gene ◽

Nsclc Patient ◽

Small Cell ◽

Chinese Patients ◽

Small Cell Lung ◽

Kras Mutations ◽

Female Patients

e17514 Background: EML4-ALK fusion gene is a potentially relevant oncogenic event in lung cancer, which represents a new subgroup of non-small cell lung cancer (NSCLC) patients who respond positively to ALK inhibitors. The characteristics of EML4-ALK fusion gene in Chinese Patients with NSCLC are poorly understood. In this study, we aimed to analyze the prevalence of EML4-ALK fusion gene and their correlation to epidermal growth factor receptor (EGFR) status, KRAS mutation, and clinico-pathological data in Chinese patients with NSCLC. Methods: Genes were detected by nested RT-PCR and confirmed by sequencing. Results: 208 cases of NSCLC were evaluated. There were 24.5% (51/208 cases of mutations in EGFR at exons 18-21, and EGFR mutations occur predominantly (92%) in exons 19 and 21. In concordance with previous reports, these mutations are identified at high frequencies in females (47.5%, 29/61 vs 15.0%, 22/147 in males; P = 0.000); never-smokers (42.3%, 33/78 vs 13.9%, 18/130 in smokers; P = 0.000), and adenocarcinoma patients (44.2%, 42/95 vs 8.0%, 9/113 in non-adenocarcinoma patients; P = 0.000). There were only 6 cases (6/208, 2.88%) of KRAS mutations in our study group. We identified 7 patients who harbored the EML4-ALK fusion gene (3.37%, 7/208) which all confirmed by DNA sequencing. Of these 7 patients, 2 cases displayed the EML4-ALK variant 1 (28.6%), 1 case exhibited variant 2 (14.3%) and 4 cases carried variant 3 (57.1%). All of the positive cases corresponded to female patients (11.5%, 7/61). Six of the positive cases were non-smokers (7.69%, 6/78). The incidence of EML4-ALK translocation in female non-smoking adenocarcinoma patients is as high as 15.2% (5/33). No EGFR/KRAS mutations were detected among EML4-ALK positive patients. The meta-analysis demonstrated that EML4-ALK translocation was 4.71% (125/2652) in unselected patients with NSCLC, and was also predominant in female patients with adenocarcinoma. Conclusions: EML4-ALK translocations are infrequent in the entire NSCLC patient population, but are frequent in the NSCLC patient subgroup of female, nonsmokers, and adenocarcinoma patients.

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