Reasons why targeted therapy for lung cancer is ineffective

  In addition to the three classical methods of lung cancer treatment: surgery, radiotherapy and chemotherapy, targeted therapy is another new and relatively effective treatment measure, which has been explicitly written into the “Treatment Specification for Primary Lung Cancer” by the Medical Secretary of the Ministry of Health of the People’s Republic of China and recommended as the first-line drug for patients with advanced lung cancer.  Currently, a variety of EGFR (epidermal growth factor receptor) targeting drugs have been developed. Depending on the mechanism of action of the drugs, there are five types of targeted drugs, and EGFR-TKI (tyrosine kinase inhibitors) is one of them. The most commonly used EGFR-TKI are gefitinib and erlotinib. Although EGFR-TKIs are effective in the treatment of non-small cell lung cancer, they are not effective in all patients.  Studies have shown that gefitinib can be as effective as 80% in patients with mutations in exons 18, 19 or 21 of EGFR, while it is largely ineffective in wild-type patients. In addition, some patients with effective initial treatment and late development of drug resistance are closely related to exon 20 mutations in EGFR. In non-small cell lung cancer, the incidence of EGFR exon 20 mutations is about 1.6%, accounting for about 9% of EGFR mutations, and 50% of EGFR-TKI resistance is associated with p.T790M point mutations in EGFR exon 20.  The results of the above literature data show two reasons for the ineffectiveness and partial ineffectiveness of targeted therapy in non-small cell lung cancer, one is the wild type of EGFR genotype; the other is the point mutation of p.T790M in EGFR exon 20.  Recently, Professor Victor Velculescu and others from Johns Hopkins University compared the genome sequencing results of tumor tissues and normal tissues of 815 people who suffered from 15 different malignancies such as lung cancer, breast cancer, leukemia, etc. In their study, the results showed that 2/3 of the genetic mutations detected were false positives and not related to malignancy, because they were also present in normal tissues. The researchers further analyzed genes for cancer drug targets and found that about 50% of these mutations were false positives.  The results of this study suggest that when we do target gene testing, both tumor tissue and normal tissue are tested and their results are compared. This biphasic testing increases the financial burden of patients to some extent, but only accurate genomic test results can guide clinicians to develop precise and standardized treatment plans, which are still of greater benefit to patients. Therefore, biphasic genetic testing has its relevance in clinical work.