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

• Published in: Journal of cancer research and clinical oncology 2015-08, Vol.141 (8), p.1427-1439
• Main Authors: Ying, Min, Zhu, Xiaoxia, Chen, Kexu, Sha, Zhou, Chen, Longhua
• Format: Article
• Language: English
• Subjects: Aged; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Disease Progression; Female; Hematology; Humans; Internal Medicine; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Medicine; Medicine & Public Health; Middle Aged; Mutation, Missense; Oncology; Prognosis; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Review – Clinical Oncology; Treatment Outcome
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-015-1910-9

Purpose Regarding the controversial investigations characterizing the role of KRAS status for predicting patients’ response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small-cell lung cancer (NSCLC), we conducted a meta-analysis in unselected patients and a further subset analysis in EGFR wild-type advanced NSCLC to get a more accurate evaluation. Methods We did systematically searches following the retrieval strategies. The end points were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Results Twelve prospective intervention trials comprised of 1,859 unselected advanced NSCLC patients were identified. KRAS mutation was associated with shorter OS and PFS [hazard ratio (HR) 2.09, 95 % confidence interval (CI) 1.56–2.80; HR 1.82, 95 % CI 1.50–2.20] and lower ORR (relative ratio 0.25, 95 % CI 0.11–0.59) in unselected advanced NSCLC. After subgroup analysis, the association with survival was strengthened in second- or later-line EGFR-TKIs treatment group, with an HR of 2.45 for OS (95 % CI 1.27–4.74) and 1.86 for PFS (95 % CI 1.51–2.29), while the association with response to EGFR-TKIs became nonsignificant ( P  = 0.153). Four retrospective studies on the role of KRAS status in EGFR wild-type advanced NSCLC were deemed eligible and presented that KRAS mutation was associated with none of the outcomes in EGFR wild-type patients treated with EGFR-TKIs. Conclusions 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.