Mutated K-ras gene analysis in a randomized trial of preoperative chemotherapy plus surgery versus surgery in Stage IIIA non-small cell lung cancer

Rosell, Rafael; Molina, Francisco; Moreno, Isabel; Martínez, Eva; Pifarré, Alex; Font, Albert; Li, Shanrong; Skácel, Z; Gómez-Codina, José; Camps, Carlos; Monzó, Mariano; Anta, Javier

doi:10.1016/0169-5002(95)00421-v

Cited by 25 publications

(14 citation statements)

References 15 publications

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“…Rosell et al (16) only presented a survival curve for patients with stage III disease without data on the remaining patients. Mitsudomi et al (19) was excluded since only NSCLC cell lines were analyzed, whereas data from Rosell et al (20,23) were included in Rosell et al (22). Therefore, as specified previously, only data from Rosell et al (22) were included in the meta-analysis.…”

Section: Resultsmentioning

confidence: 99%

K-ras oncogene mutation as a prognostic marker in non-small cell lung cancer: a combined analysis of 881 cases

1999

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The treatment of non-small cell lung cancer (NSCLC) remains unsatisfactory, with most patients succumbing to metastatic disease within 5 years of diagnosis. Improved selection of patients for aggressive adjuvant therapy may contribute to improved survival. Mutation of the k-ras oncogene is considered a potentially clinically useful prognostic biomarker for this purpose. This report presents the results of a meta-analysis performed to determine whether the existing data support such a role for k-ras mutations in NSCLC. Two year survival data derived from 881 NSCLC patients in eight published studies were analyzed using a general variance-based meta-analytical method employing confidence intervals. The outcome of interest was a summary relative risk (RR s ) reflecting the risk of death at 2 years associated with k-ras mutation-positive versus k-ras mutation-negative disease. Prior to calculation of RR s , analysis for heterogeneity showed Q to equal 15.52 (7 df, P ⍧ 0.03). This indicated heterogeneity across the analyzed studies in terms of their estimate of effect. Possible sources of heterogeneity were identified and included selection bias and various other sources of uncontrolled confounding. Although a RR s of 2.35 (95% CI ⍧ 1.61-3.22) was found when all eight studies were combined (favoring a negative prognostic role for k-ras mutation), it is unclear whether the magnitude of the RR s would persist after adjusting for other wellestablished prognostic indicators (e.g. stage). The existing data suggest that k-ras mutation may be associated with shortened survival in NSCLC, although this finding awaits confirmation in well-designed multivariate analyses which adjust for the effect of known prognostic indicators.

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Section: Resultsmentioning

confidence: 99%

K-ras oncogene mutation as a prognostic marker in non-small cell lung cancer: a combined analysis of 881 cases

1999

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“…Another meta-analysis based on a review of the literature on the role of KRAS2 as prognostic factor in lung cancer was previously published (Huncharek et al, 1999). Only eight trials Kern et al, 1994;Silini et al, 1994;Rosell et al, 1995a;Cho et al, 1997;Fukuyama et al, 1997;Rodenhuis et al, 1997;Siegfried et al, 1997) Figure 1 Meta-analysis of studies assessing RAS with IHC in NSCLC.…”

Section: Discussionmentioning

confidence: 99%

“…In all, 10 of these articles were excluded because an identical patient cohort had been used in other selected publications (Rodenhuis et al, 1988;Miyamoto et al, 1991;Fujino et al, 1995;Rosell et al, 1995aRosell et al, , b, 1996Dosaka et al, 1997;Keohavong et al, 1997;Hommura et al, 2000;Konishi et al, 2000;Volm et al, 2002). One of the 43 remaining studies (Volm et al, 1993) assessed separately by immunohistochemistry (IHC) KRAS2, NRAS and HRAS p21.…”

Section: Study Selection and Characteristicsmentioning

confidence: 99%

The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis

et al. 2004

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The proto-oncogene RAS, coding for a 21 kDa protein (p21), is mutated in 20% of lung cancer. However, the literature remains controversial on its prognostic significance for survival in lung cancer. We performed a systematic review of the literature with metaanalysis to assess its possible prognostic value on survival. Published studies on lung cancer assessing prognostic value of RAS mutation or p21 overexpression on survival were identified by an electronic search. After a methodological assessment, we estimated individual hazard ratios (HR) estimating RAS protein alteration or RAS mutation effect on survival and combined them using metaanalytic methods. In total, 53 studies were found eligible, with 10 concerning the same cohorts of patients. Among the 43 remaining studies, the revelation method was immunohistochemistry (IHC) in nine and polymerase chain reaction (PCR) in 34. Results in terms of survival were significantly pejorative, significantly favourable, not significant and not conclusive in 9, 1, 31, 2, respectively. In total, 29 studies were evaluable for meta-analysis but we aggregated only the 28 dealing with non-small-cell lung cancer (NSCLC) and not the only one dealing with small-cell-lung cancer (SCLC). The quality scores were not statistically significantly different between studies with or without significant results in terms of survival, allowing us to perform a quantitative aggregation. The combined HR was 1.35 (95% CI: 1.16 -1.56), showing a worse survival for NSCLC with KRAS2 mutations or p21 overexpression and, particularly, in adenocarcinomas (ADC) (HR 1.59; 95% CI 1.26 -2.02) and in studies using PCR (HR 1.40; 95% CI 1.18 -1.65) but not in studies using IHC (HR 1.08; 95% CI 0.86 -1.34). RAS appears to be a pejorative prognostic factor in terms of survival in NSCLC globally, in ADC and when it is studied by PCR.

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“…29,30 Although some data are controversial, 38 KRAS mutations have also been associated with poor prognosis in resected typical NSCLC. [39][40][41] The high rate of KRAS mutations in lung SC may therefore contribute to the aggressive outcome of these tumors.…”

Section: Discussionmentioning

confidence: 99%

EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: Implications for anti‐EGFR treatment of a rare lung malignancy

Italiano

Cortot

Ilié

et al. 2009

Intl Journal of Cancer

103

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Sarcomatoid carcinomas (SC) of the lung are uncommon malignant tumors composed of carcinomatous and sarcomatous cell components and characterized by a more aggressive outcome than other histological subtypes of nonsmall cell lung cancer (NSCLC). Although epidermal growth factor receptor (EGFR)‐targeted therapies have emerged as a promising therapeutic approach in patients with advanced typical NSCLC such as adenocarcinoma, the potential clinical activity of these drugs in lung SC is still unknown. To investigate this point, we have analyzed the status of 4 EGFR pathways biomarkers in a series of lung SC. EGFR protein expression, EGFR gene copy number, EGFR mutational status and KRAS mutational status were assessed in a series of 22 consecutive cases of primary lung SC. EGFR protein overexpression was observed in all the cases. High level of polysomy (≥4 copies of the gene in >40% of cells) was detected in 5 cases (23%). No EGFR mutation was detected. KRAS mutations were found in 8 patients (38%; Gly12Cys in 6 cases and Gly12Val in 2 cases). The consistent EGFR protein overexpression and the high rate of KRAS mutation may contribute to the poorer outcome of lung SC in comparison with typical NSCLC. The rare incidence of increased EGFR gene copy number, the lack of EGFR mutation and the high rate of KRAS mutation observed in our series also suggest that most patients with lung SC are not likely to benefit from anti‐EGFR therapies. © 2009 UICC

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Mutated K-ras gene analysis in a randomized trial of preoperative chemotherapy plus surgery versus surgery in Stage IIIA non-small cell lung cancer

Cited by 25 publications

References 15 publications

K-ras oncogene mutation as a prognostic marker in non-small cell lung cancer: a combined analysis of 881 cases

K-ras oncogene mutation as a prognostic marker in non-small cell lung cancer: a combined analysis of 881 cases

The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis

EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: Implications for anti‐EGFR treatment of a rare lung malignancy

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