Should KRAS mutation still be used as a routine predictor of response to EGFR-TKIs in advanced non-small-cell lung cancer? A revaluation based on meta-analysis

Ying, Min; Zhu, Xiaoxia; Chen, Kexu; Zhou, Sha; Chen, Longhua

doi:10.1007/s00432-015-1910-9

Cited by 12 publications

(9 citation statements)

References 53 publications

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“…Resistance to EGFR-TKIs treatment for KRAS mutant NSCLC was also reported in other two meta-analysis conducted by Chen et al [ 56 ] and Min et al [ 57 ]. The reported pooled RR for ORR was 0.29 (95% CI 0.18-0.47) in Chen's study and 0.21 (95% CI 0.12-0.39) in ours while the reported pooled HR for PFS was 1.86 (95% CI 1.51-2.29) in Min's study and 1.46 (95% CI 1.23-1.74) in ours, showing highly consistent results among studies.…”

Section: Discussionsupporting

confidence: 68%

KRAS mutation is a weak, but valid predictor for poor prognosis and treatment outcomes in NSCLC: A meta-analysis of 41 studies

et al. 2016

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Mutation of oncogene KRAS is common in non-small cell lung cancer (NSCLC), however, its clinical significance is still controversial. Independent studies evaluating its prognostic and predictive value usually drew inconsistent conclusions. Hence, We performed a meta-analysis with 41 relative publications, retrieved from multi-databases, to reconcile these controversial results and to give an overall impression of KRAS mutation in NSCLC. According to our findings, KRAS mutation was significantly associated with worse overall survival (OS) and disease-free survival (DFS) in early stage resected NSCLC (hazard ratio or HR=1.56 and 1.57, 95% CI 1.39-1.76 and 1.17-2.09 respectively), and with inferior outcomes of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment and chemotherapy (relative risk or RR=0.21 and 0.66 for objective response rate or ORR, 95% CI 0.12-0.39 and 0.54-0.81 respectively; HR=1.46 and 1.30 for progression-free survival or PFS, 95%CI 1.23-1.74 and 1.14-1.50 respectively) in advanced NSCLC. When EGFR mutant patients were excluded, KRAS mutation was still significantly associated with worse OS and PFS of EGFR-TKIs (HR=1.40 and 1.35, 95 % CI 1.21-1.61 and 1.11-1.64). Although KRAS mutant patients presented worse DFS and PFS of chemotherapy (HR=1.33 and 1.11, 95% CI 0.97-1.84 and 0.95-1.30), and lower response rate to EGFR-TKIs or chemotherapy (RR=0.55 and 0.88, 95 % CI 0.27-1.11 and 0.76-1.02), statistical differences were not met. In conclusion, KRAS mutation is a weak, but valid predictor for poor prognosis and treatment outcomes in NSCLC. There's a need for developing target therapies for KRAS mutant lung cancer and other tumors.

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Section: Discussionsupporting

confidence: 68%

KRAS mutation is a weak, but valid predictor for poor prognosis and treatment outcomes in NSCLC: A meta-analysis of 41 studies

et al. 2016

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“…In the last two decades, many studies have been published analysing the prognostic and predictive roles of KRAS mutations in sustaining resistance to different types of treatment such as EGFR Tyrosine-Kinase Inhibitors (TKIs) and chemotherapy 15 16 17 . KRAS mutated patients were indicated to have a worse prognosis and resistance to treatment in different types of cancer but no clear conclusions have been stated for NSCLC 18 .…”

Section: Discussionmentioning

confidence: 99%

Role of KRAS-LCS6 polymorphism in advanced NSCLC patients treated with erlotinib or docetaxel in second line treatment (TAILOR)

Ganzinelli

Rulli

Caiola

et al. 2015

Sci Rep

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MicroRNAs were described to target mRNA and regulate the transcription of genes involved in processes de-regulated in tumorigenesis, such as proliferation, differentiation and survival. In particular, the miRNA let-7 has been suggested to regulate the expression of the KRAS gene, a common mutated gene in non-small cell lung cancer (NSCLC), through a let-7 complementary site (LCS) in 3′UTR of KRAS mRNA. We have reported the analysis performed on the role of the polymorphism located in the KRAS-LCS (rs61764370) which is involved in the disruption of the let-7 complementary site in NSCLC patients enrolled within the TAILOR trial, a randomised trial comparing erlotinib versus docetaxel in second line treatment. In our cohort of patients, KRAS-LCS6 polymorphism did not have any impact on both overall survival (OS) and progression free survival (PFS) and was not associated with any patient’s baseline characteristics included in the study. Overall, patients had a better prognosis when treated with docetaxel instead of erlotinib for both OS and PFS. Considering KRAS-LCS6 status, the TG/GG patients had a benefit from docetaxel treatment (HR(docetaxel vs erlotinib) = 0.35, 95% CI 0.15–0.79, p = 0.011) compared with the TT patients (HR(docetaxel vs erlotinib) = 0.72, 95% CI 0.52–1.01, p = 0.056) in terms of PFS.

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“…32,33 Several prospective studies have shown that KRAS mutations predict poor survival and efficacy of EGFR-TKIs. 34 In addition, particular KRAS mutation subtypes may lead to different prognosis. Zer et al conducted a pooled analysis of 275 patients with KRAS mutation treated with EGFR-TKIs, which showed that patients with G12C/G12V mutation had a poor prognosis, while G12D/G12S positive patients could benefit from EGFR-TKIs.…”

Section: Kras Mutation As a Predictive Factormentioning

confidence: 99%

KRAS oncogene may be another target conquered in non‐small cell lung cancer (NSCLC)

Chen

Zhao

2020

Thoracic Cancer

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Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most common mutant oncogenes in non-small cell lung cancer (NSCLC). The survival of patients with KRAS mutations may be much lower than patients without KRAS mutations. However, due to the complex structure and diverse biological properties, it is difficult to achieve specific inhibitors for the direct elimination of KRAS activity, making KRAS a challenging therapeutic target. At present, with the tireless efforts of medical research, including KRAS G12C inhibitors, immunotherapy and other combination strategies, this dilemma is expected to an end. In addition, inhibition of the downstream signaling pathways of KRAS may be a promising combination strategy. Given the rapid development of treatments, understanding the details will be important to determine the individualized treatment options, including combination therapy and potential resistance mechanisms.

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Should KRAS mutation still be used as a routine predictor of response to EGFR-TKIs in advanced non-small-cell lung cancer? A revaluation based on meta-analysis

Abstract: In unselected advanced NSCLC patients, KRAS mutations could be used as a potential negative predictor of clinical benefit from EGFR-TKIs. However, KRAS testing is of limited value to identify patients for EGFR-TKIs when EGFR status is considered.

Cited by 12 publications

References 53 publications

KRAS mutation is a weak, but valid predictor for poor prognosis and treatment outcomes in NSCLC: A meta-analysis of 41 studies

KRAS mutation is a weak, but valid predictor for poor prognosis and treatment outcomes in NSCLC: A meta-analysis of 41 studies

Role of KRAS-LCS6 polymorphism in advanced NSCLC patients treated with erlotinib or docetaxel in second line treatment (TAILOR)

KRAS oncogene may be another target conquered in non‐small cell lung cancer (NSCLC)

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