Harnessing plasma genotyping for precision therapy against lung cancer

The development of tyrosine kinase inhibitors gefitinib and erlotinib for anti-epidermal growth factor receptor (EGFR) therapy is one of milestones in the history for treatment of lung cancer, a disease that annually causes more than 158,000 deaths in the United States, 610,000 deaths in China, and 1.6 million deaths worldwide (1,2). Activating mutations in the tyrosine kinase domain of the EGFR gene are known to be an oncogenic driver in lung tumorigenesis. It is now clear that non-small cell lung cancer (NSCLC) with EGFR activating mutations represent a distinct biological subtype that is highly sensitive to the treatment with EGFR inhibitors. In fact, the finding that EGFR-mutant lung cancer cells are highly susceptible to the EGFR inhibitors gefitinib (3) and erlotinib (4) has made these two agents the first choice for therapy in patients whose tumors harbor EGFR mutations. Both gefitinib and erlotinib have been reported to significantly improve disease control, objective response rate (ORR), progression-free survival (PFS), and quality of life in patients with EGFR-mutant lung cancer, when compared with conventional chemotherapy (5,6). Approximately 10−17% of lung adenocarcinomas patients in the United States and Europe (7,8) and about 30−65% of lung cancer patients in Asia have EGFR activating mutations (9,10). Deletions in exon 19 and the point mutation L858R in exon 21 are the most common EGFR activating mutations, accounting for about 85% of the EGFR mutations detected in lung cancers (10,11). In the absence of EGFR mutation or gene amplification, there is no significant difference in the responses to the treatment with EGFR inhibitors and conventional chemotherapies (12). Thus, EGFR gene mutation test is mandatory for using EGFR antagonists as the first-line treatment for advanced NSCLC (13). Consequently, genetic profiling of surgical and biopsy samples is routinely performed clinically for lung cancer patients to provide guidance for selection of treatment regimens. A number of DNA sequencing and polymerase chain reaction (PCR) based methods are used clinically to detect EGFR gene mutations in tumor specimens. However, the presence of intratumoral heterogeneity in most cancer patients (14) has imposed a challenge in using the information obtained from analysis of single tiny biopsy samples in clinical practice. Moreover, multiple and serial biopsies are often impractical clinically because of the potential complications of the procedures, including tumor seeding or spreading following percutaneous needle biopsy (15,16).