Prognostic and Predictive Value of KRAS Mutations in Advanced Non-Small Cell Lung Cancer

Sun, Jong‐Mu; Hwang, Deokbi; Ahn, Jin Seok; Ahn, Myung‐Ju; Park, Keunchil

doi:10.1371/journal.pone.0064816

Cited by 71 publications

(107 citation statements)

References 30 publications

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“…Although the issue of KRAS mutations in lung cancer is controversial, a recent study of 484 patients found that they are significantly associated with shorter survival in advanced NSCLC (OS of 7.7 for patients with the G12C mutation vs. 15.0 months for those KRAS wt; ref. 24). In the present study, the prognostic value of TP53 nondisruptive mutations was not dependent on EGFR or KRAS status, and was observed both in chemotherapy-treated, EGFR-wt patients as well as in EGFR-mut patients treated in first line with erlotinib or chemotherapy.…”

Section: Discussionsupporting

confidence: 57%

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Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Molina-Vila

Bertrán-Alamillo

Gasco

et al. 2014

Clinical Cancer Research

134

149

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Purpose: TP53 mutations in early-stage non-small cell lung cancer (NSCLC) may be associated with worse survival but their prognostic role in advanced NSCLC is controversial. In addition, it remains unclear whether mutated patients represent a clinically homogeneous group.Experimental Design: We retrospectively examined TP53 mutations and outcome in a training cohort of 318 patients with stage IIIB-IV NSCLC: 125 epidermal growth factor receptor (EGFR) wild-type (wt) and 193 EGFR mutated (mut). An independent validation cohort of 64 EGFR-mut patients was subsequently analyzed. Mutations were classified as "disruptive" and "nondisruptive" according to their predicted degree of disturbance of the p53 protein structure and function.Results: In the training cohort, TP53 mutations were found in 43 of the 125 EGFR-wt patients (34.4%). Of these, 28 had nondisruptive TP53 mutations and a median overall survival (OS) of 8.5 months, compared with 15.6 months for the remaining 97 patients (P ¼ 0.003). In the EGFR-mut group, TP53 mutations were found in 50 of the 193 patients (25.9%). The OS for the 26 patients with TP53 nondisruptive mutations was 17.8 months versus 28.4 months for the remaining 167 patients (P ¼ 0.04). In the validation cohort, the 11 patients with nondisruptive TP53 mutations had a median OS of 18.1 months compared with 37.8 months for the 53 remaining patients (P ¼ 0.006). In multivariate analyses, nondisruptive TP53 mutations had an independent, significant association with a shorter OS.Conclusions: Nondisruptive mutations in the TP53 gene are an independent prognostic factor of shorter survival in advanced NSCLC.

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Section: Discussionsupporting

confidence: 57%

“…Two recent reports have shown that KRAS mutations are associated with shorter survival in chemotherapy-treated advanced NSCLC (24,25). Therefore, samples were analyzed for KRAS mutations (exons 12-13).…”

Section: Resultsmentioning

confidence: 99%

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Molina-Vila

Bertrán-Alamillo

Gasco

et al. 2014

Clinical Cancer Research

134

149

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“…A recent analysis also demonstrated that the amount of KRAS mutations detected using a sensitive PCR-based assay may correlate with the efficacy of anti-EGFR therapy in patients with human colorectal cancer (31). Similarly, in pancreatic cancer, KRAS mutations (codon 12 or 13) are associated with worse prognosis (32), and in NSCLC, patients with advanced KRAS-mutant cancer have a shorter survival compared with those with EGFR-mutant or EGFR/KRAS wild-type (WT) cancers (33,34). In addition, KRAS mutations predict for resistance to treatment with EGFR tyrosine kinase inhibitors (17,35,36).…”

Section: Clinical-translational Advancesmentioning

confidence: 97%

Molecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers

Okumura¹

2014

Clinical Cancer Research

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Mutations in RAS oncogenes are frequently observed in human cancers, and the mutations result in activation of the RAS-RAF-MEK-ERK pathway, leading to cell proliferation and survival. The pathway is, therefore, a potent therapeutic target in the RAS-mutant cancers. MEK inhibitors can specifically block the pathway and are one of the key types of drugs for the treatment of the RAS-mutant cancers. As RAS proteins activate other downstream signaling proteins in addition to the RAS-RAF-MEK-ERK pathway, combination therapeutic approaches with MEK inhibitors are also being evaluated. Moreover, MEK inhibitors can arrest cancer cells in G 1 phase and repress prosurvival Bcl2 family proteins such as MCL1 and BCL2/BCLXL, and increase expression of Bim, a proapoptotic BH3-only family protein. This mechanism may explain the efficacy of the combination of MEK inhibitors with cytotoxic agents or other targeted inhibitors. A better understanding of the pathway will help us with development of rational combinations for the treatment of the RAS-mutant cancers.

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“…In the LACE-BIO collaborative group study, patients harbouring codon 13 mutations experienced much worse outcomes when allocated to the chemotherapy group compared to the observation arm (HR 5.78, 95% CI 2.06-16.22; p<0.001, interaction=0.002), suggesting a deleterious effect of adjuvant chemotherapy in this subgroup of patients [14]. In KRAS-mutant NSCLC, type of chemotherapy regimen seems to lead to similar clinical outcomes [17,18]. Until 2010, KRAS mutations were considered negative predictive factors in advanced NSCLC patients treated by inhibitors of the tyrosine kinase domain (TKI) of the EGFR, according to the results of two meta-analyses evaluating both erlotinib and gefitinib [5,19,20].…”

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confidence: 99%

KRASoncogene in lung cancer: focus on molecularly driven clinical trials

et al. 2016

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KRAS mutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically for KRAS-mutated NSCLC patients. Direct inhibition of RAS activation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients' clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early-phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclindependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step in KRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens. @ERSpublications MEK inhibition and immunotherapy are very promising therapeutic advances in KRAS-mutated nonsmall cell lung cancer http://ow.ly/U2ohp KRAS mutations in lung cancer: epidemiology and clinical outcomesSince the beginning of the 21st century, the paradigm of precision medicine has shaken up the landscape of lung cancer classification and treatment. The discovery of cancer-related driver molecular abnormalities led to the development of efficient targeted therapies. RAS proteins are GTP kinases, discovered in the 1960s, whose GTP-RAS active isoform stimulates several pathways involved in cellular growth. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations are found in ∼25-35% of newly diagnosed nonsmall cell lung cancer (NSCLC), with a higher proportion in the adenocarcinoma subtype [1,2]. Figure 1 summarises the main amino acid substitutions and genomic features that are associated with KRAS mutations in NSCLC [3,4]. Other molecular abnormalities related to RAS pathway activation are diagnosed in 25% of NSCLC cases, such as epidermal growth factor receptor (EGFR) (10-23%), BRAF mutations (2%), MET amplifications (2%), human epidermal growth factor (HER)2 (1%) and NRAS (0.2%) mutations. Loss of the negative regulator neurofibromin is found in ∼11% of other cases.

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Prognostic and Predictive Value of KRAS Mutations in Advanced Non-Small Cell Lung Cancer

Cited by 71 publications

References 30 publications

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Molecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers

KRASoncogene in lung cancer: focus on molecularly driven clinical trials

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