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

Abstract

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.

Ras oncogene mutations and survival in patients with lung cancer

“…Aggregating data obtained by univariate analysis in retrospective trials, ras gene alteration appears to be a poor prognostic factor for survival in NSCLC (Mascaux et al, 2005). The authors concluded that ras appears to be a pejorative prognostic factor in terms of survival in NSCLC globally, in adenocarcinomas and when it is studied by polymerase chain reaction.…”

“…The proto-oncogene ras is mutated in 20% of lung cancer (Mascaux et al, 2005). Among 36 patients with primary operable non-small-cell lung cancer (NSCLC), we detected seven (19.4%) with K-ras exon I mutations on tumour samples (Ferretti et al, 2000).…”

Has Cox-2 a prognostic role in non-small-cell lung cancer? A systematic review of the literature with meta-analysis of the survival results

“…The participation of many readers was a guarantee for the correct interpretation of the articles. The methodological evaluation was scored according to the European Lung Cancer Working Party (ELCWP) scale previously published (Steels et al, 2001) and applied in other meta-analyses (Delmotte et al, 2002;Meert et al, 2002aMeert et al, , b, 2003Martin et al, 2003Martin et al, , 2004Mascaux et al, 2005a). Each item was assessed using an ordinal scale (possible values: 2, 1, 0).…”

“…In order to clarify the prognostic impact of other biological factors in lung cancer, our group has performed systematic reviews of the literature with meta-analyses. It allowed us to show that VEGF (Delmotte et al, 2002), microvessel density (Meert et al, 2002b), EGFR (Meert et al, 2002a), HER-2/Neu , Ki-67 (Martin et al, 2004), K-Ras (Mascaux et al, 2005a) and p53 (Steels et al, 2001) have a negative impact on survival, whereas Bcl-2 is associated with a favourable survival effect, at least when studying their impact in univariate analysis.…”

Targetable “Driver” Mutations in Non Small Cell Lung Cancer

“…Overall, KRAS mutations have been reported in 15-20% of all patients with NSCLC and approximately in 30-50% of patients with adenocarcinoma histology [32].…”