Biomarkers for personalized management of advanced stage lung cancer

Abstract

Non-small cell lung cancer (NSCLC), mainly adenocarcinoma subtype, can carry different types of oncogenic mutations. EGFR mutations are present in up to 50% of lung adenocarcinomas from the Asian population. EGFR-tyrosine kinase inhibitor (EGFR-TKI) should be used as primary treatment of lung cancer bearing sensitising EGFR mutations, namely 15-base pair deletion at exon 19, or L858R or L861Q mutations at exon 21. First- and second-generation EGFR-TKIs have greatly improved the treatment of EGFR mutant lung cancer. However, the majority of patients who respond initially will eventually experience treatment failure with disease progression. In patients who develop acquired resistance to EGFR-TKI, up to 50% showed a second EGFR T790M mutation at exon 20. Third-generation EGFRTKI targeting EGFR T790M mutation has been recently approved for treatment of lung tumors bearing EGFR T790M mutation. Demonstration of EGFR T790M mutation through repeat tumor biopsy after treatment is, however, not always feasible at disease progression. Liquid biopsy may help in such situation. ALK gene rearrangement is present in up to 7% of non-small cell lung cancer, but once detected, upfront use of first generation ALK-inhibitors is associated with good therapeutic efficacy. ALK mutations have been found to be involved with acquired resistance to ALK inhibitors. Second-generation ALK-inhibitors have become available for treatment failure with first-generation ALK-inhibitors. Immune checkpoint inhibitors, or one specific form known as anti-PD1 monoclonal antibodies, have gained recent approval from US FDA as second line therapy for NSCLC. Whether Programmed Death-1 (PD1) expression could be a potential biomarker for guiding therapy is not certain yet. Molecular testing for lung cancer biomarkers is not limited to testing in tumor tissues. Liquid biopsy for detection of cell free tumor DNA in plasma, and hence detection of EGFR mutations in plasma using different molecular diagnostic techniques, is a rapidly developing field. The identification of biomarkers will support the practice of personalised medicine and this will be closely tied to the understanding of biology and molecular progression of lung neoplasms. Reference 1. Cooper WA, Lam DC, O'Toole SA, Minna JD. Molecular biology of lung cancer. J Thorac Dis. 2013;5 Suppl 5:S479-90. 2. Lam DC, Tam TC, Lau KM, Wong WM, Hui CK, Lam JC, Wang JK, Lui MM, Ho JC, Ip MS. Plasma EGFR Mutation Detection Associated With Survival Outcomes in Advanced-Stage Lung Cancer. Clin Lung Cancer. 2015;16(6):507-13. 3. Sundar R, Soong R, Cho BC, Brahmer JR, Soo RA. Immunotherapy in the treatment of non-small cell lung cancer. Lung Cancer. 2014;85(2):101-9.