Molecular Testing in Lung Cancer: The Time Is Now
- 217 Downloads
In the past few years, we have witnessed a revolution in the molecular understanding of non-small cell lung cancer. Major progress has also been made in the clinic, with the introduction of EGFR-targeted and anti-angiogenic therapies. These advances have led to the development of a multitude of commercially available prognostic and predictive biomarkers. In particular, EGFR mutation and EML4/ALK testing have reached clinical validation and are incorporated into current treatment paradigms. This overview will present the scientific background of the biology of the relevant biomarkers and the studies conducted for their clinical validation. The technical challenges and shortcomings of these assays are also discussed. Furthermore, ongoing biomarker-driven clinical studies and the appropriate clinical use of available tests will be reviewed to assist the clinician with the proper incorporation of molecular testing into the routine care of patients with non-small cell lung cancer.
KeywordsNon-small cell lung cancer Biomarkers Molecular testing EGFR KRAS EML4/ALK translocation
The authors’ work was supported by grants from the Flight Attendant Medical Research Institute and the American Cancer Society (grant number RSG-08-303-01-TBE to BH), as well as the National Institutes of Health/National Cancer Institute “SPORE in Human Lung Cancer” P50 CA90578-04 (BH and DBC).
No potential conflicts of interest relevant to this article were reported.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 15.• Scagliotti GV, Parikh P, von Pawel J, et al.: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008, 26:3543–3551. This phase 3 study demonstrated that in patients with adenocarcinoma and large cell histology, overall survival was superior for cisplatin/pemetrexed versus cisplatin/gemcitabine compared to patients with squamous cell histology, for whom the opposite results were seen.CrossRefPubMedGoogle Scholar
- 35.Eberhard DA, Johnson BE, Amler LC, et al.: Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005, 23:5900–5909.CrossRefPubMedGoogle Scholar
- 38.•• Mok TS, Wu YL, Thongprasert S, et al.: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009, 361:947–957. The I-PASS study showed that gefitinib is superior to carboplatin-paclitaxel as first-line treatment in Asian patients with advanced lung adenocarcinoma and no/limited smoking history. PFS was significantly longer for EGFR-mutant tumors when treated with gefitinib versus chemotherapy, while the opposite held true for EGFR wild-type tumors.CrossRefPubMedGoogle Scholar
- 39.Mitsudomi T, Morita S, Yatabe Y, et al.: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010, 11:121–128.CrossRefPubMedGoogle Scholar
- 40.•Douillard JY, Shepherd FA, Hirsh V, et al.: Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 2010, 28:744–752. The INTEREST trial showed that patients with EGFR-mutated tumors had longer PFS with gefitinib versus docetaxel in the second-line setting.CrossRefPubMedGoogle Scholar
- 41.• Cappuzzo TC, Stelmakh L, Cicenas S, et al.: SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol 2009, 27(15s): abstract 8001. In the phase 3 SATURN trial, erlotinib was shown to produce prolonged PFS and overall survival when compared with placebo in the maintenance setting after first-line chemotherapy. The benefit was modest overall but very striking in patients with EGFR-mutant tumors.Google Scholar
- 54.Taguchi F, Solomon B, Gregorc V, et al.: Mass spectrometry to classify non-small-cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort cross-institutional study. J Natl Cancer Inst 2007, 99:838–846.CrossRefPubMedGoogle Scholar
- 56.Carbone DP, Salmon JS, Billheimer D, et al.: VeriStrat® classifier for survival and time to progression in non-small cell lung cancer (NSCLC) patients treated with erlotinib and bevacizumab. Lung Cancer 2009 Dec 24 (Epub ahead of print).Google Scholar
- 58.Linardou H, Dahabreh IJ, Kanaloupiti D, et al.: Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 2008, 9:962–972.CrossRefPubMedGoogle Scholar
- 70.Shaw AT CD, Iafrate AJ, Dezube BJ, et al.: Clinical activity of the oral ALK and MET inhibitor PF-02341066 in non-small lung cancer (NSCLC) with EML4-ALK translocations. J Thorac Oncol 2009, 4:S305–S306.Google Scholar
- 78.Arqule Joins the Phase III Club. http://seekingalpha.com/article/198568-arqule-joins-the-phase-iii-club. Accessed April 13, 2010.
- 80.Reck M, von Pawel J, Zatloukal P, et al.: Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 2010 Feb 11 (Epub ahead of print).Google Scholar
- 81.Dowlati A, Gray R, Sandler AB, et al.: Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab—an Eastern Cooperative Oncology Group Study. Clin Cancer Res 2008, 14:1407–1412.CrossRefPubMedGoogle Scholar
- 84.BATTLE Trial Personalizes Lung Cancer Therapy [AACR press release]. April 18, 2010.Google Scholar