Aunt Wang, 65, discovered advanced lung cancer two years ago, lung aspiration biopsy suggested adenocarcinoma, and genetic testing suggested EGFR mutations, so she began oral targeted drug therapy. However, after more than a year of drug resistance, the lesion gradually increased, in the end what is the resistance gene, the doctor recommended re-puncture biopsy, take the material for genetic testing. However, the pathological results made Aunt Wang very difficult to accept, and the pathological results this time were actually small cell lung cancer. Compared with adenocarcinoma, small cell lung cancer is more malignant and more difficult to treat.
As we all know, one of the biggest problems with targeted therapy is that most patients will develop resistance after taking targeted drugs for a period of time. The problem of small molecule targeted drug resistance has always been a hot topic in clinical research. In the past, for EGFR mutations, a generation of resistance took a second or third generation of targeted drugs, and after three generations of osetinib resistance there was no specialized fourth generation of drugs. Because the mechanism of osetinib resistance is complex, one of the mechanisms of drug resistance is the transition to small cell lung cancer.
Studies have shown that after about 3%-10% of patients are drug-resistant to targeted therapy, the pathological form will be transformed from non-small cell lung cancer to small cell lung cancer. Because re-biopsies are refused or unable to be performed at the time of disease progression, the chances of actually turning into small cell lung cancer may be higher.
Why does non-small cell lung cancer transform into small cell lung cancer?
At present, there are two theories, one of which is the tumor heterogeneity hypothesis, which believes that the tumor tissue itself contains a small amount of small cell lung cancer components, and when the targeted drug kills the sensitive adenocarcinoma cells, the small cell carcinoma becomes the dominant cell and gradually proliferates. Another theory is the tumor stem cell hypothesis, which holds that tumor stem cells carrying sensitive genes and mutated tumor cells have the potential to differentiate into neuroendocrine tumor cells. Under the exposure pressure of targeted therapy, it is easier to transform into small cell lung cancer. Mutated small cell lung cancer still retains EGFR-positive mutations, but EGFR protein expression levels are low and EGFR is also in a state of low amplification, so the use of EGFR TKI targeted drugs is not effective, which also suggests that transformative small cell lung cancer has its own unique genetics. P53 and RB1 deletions are found in most transformed small cell lung cancers. It is believed that inactivation of Rb1 and TP53 may lead to adenocarcinoma eventually turning into small cell lung cancer.
How is transformational small cell lung cancer treated?
For the treatment of transformative small cell lung cancer, the 2021 edition of the CSCO guidelines is recommended separately, and for risk prediction of transformative SCLC, serum NSE and pro-GRP need to be tested. Treatment is divided into three categories: systematic rapid progression, local slow progression, and systematic slow progression.
Systematic rapidly advancing translational SCLC therapy can refer to the standard SCLC chemotherapy regimen;
Locally slow-progressing translational SCLC therapy requires a combination of topical therapy on a standard SCLC chemotherapy regimen (or continuation of the pro-EGFR-TKI);
Systemic slow-progressing translational SCLC therapy should also be judged on the basis of standard SCLC chemotherapy regimens to determine whether pro-EGFR-TKI therapy should be continued.