Targeted therapies offer new hope for patients with “on-target” lung cancer, but a major problem for doctors and patients is “drug resistance” – tumors that are no longer controlled by drugs and are “growing” again. The tumor is no longer controlled by the drug and starts to “grow like crazy”. What’s going on here?
What is tumor resistance?
What is tumor drug resistance?
What is tumor drug resistance?
What is tumor drug resistance?
Drug resistance is when a tumor “resists” a targeted drug and the targeted drug no longer kills the tumor. There are two types of resistance.
The first is when a patient has a genetic variant that is not sensitive to the targeted drug, making it ineffective on the first dose. For example, current targeted drugs can restrain several types of EGFR mutations, but the type “20 exon insertion mutation” is insensitive to the drug; there are also patients who carry a specific mutation in addition to the common EGFR mutation, such as B-lymphoma-2-like protein 11 (BIM) deletion The most important thing is that the patient’s immune system is not sensitive to the drug.
In the second scenario, the patient starts the drug, but after a period of time, the targeted drug is not as effective and the tumor “comes back. This is not uncommon, and the timing varies from person to person. In general, the time to resistance to EGFR-targeted drugs is about 9 to 14 months.
Why does resistance occur?
Why does drug resistance occur
This is because cancer cells are smart and have a “heterogeneity” and “dynamics” that we can’t imagine. What does this mean? Let’s use an analogy.
Historically, emperors often encountered “rebels” and when they found them, they would send troops to suppress them.
I think it’s a good idea to have a good understanding of what you’re talking about.
Similarly, some cells in the tumor may carry a “target gene” that is sensitive to the targeted drug, while others that do not carry this target escape the attack and grow over time, gradually gaining the upper hand and causing the tumor to return. The tumor is then tested again and we see that the type of gene variant the tumor carries may have changed.
To summarize, “heterogeneity” means that tumor cells in different parts of the primary tumor site, or in different metastatic sites throughout the body, have different genetic features and corresponding biological characteristics. Sometimes one feature dominates, sometimes several features constitute the main “force”, and these features lead to differences in tumor growth rate, invasion ability, and sensitivity to drugs. Compared to other cancers, lung cancer is more “heterogeneous” with different subgroups of mutations that have different mechanisms of drug resistance and are in a dynamic evolutionary process.
How is drug resistance detected and monitored?
We suspect drug resistance if, after a period of stabilization, symptoms worsen, or lesions increase, or new metastases develop. So while you are on the targeted drugs, your doctor will recommend that you have a follow-up visit every 6 weeks for a physical exam, chest and abdominal CT, and possibly a head MRI and a whole-body bone scan if brain and bone metastases are suspected.
If your doctor suspects drug resistance, he or she will usually recommend that you take another tissue biopsy for genetic testing to see if there is a new “target” to target. If a tissue biopsy is not available, a genetic test can be taken, but it is only about 70% sensitive and therefore not the first option. In addition, if you are able to do so, blood can be drawn periodically during the course of targeted therapy to monitor the dynamics of genetic variation and to detect drug resistance earlier.
How to deal with drug resistance?
How to deal with drug resistance?
As mentioned above, targeted drugs cannot completely destroy cancer cells, and when one of the “remnants” grows to its strongest, the disease returns or worsens. If there is a new targeted drug that can restrain it, it can “save the day” again. For example, 60% of lung cancer resistance to gefitinib is due to a specific mutation type – T790M, which is currently the third generation targeted drug Ocitinib (trade name Teresza) that has just been launched in China. However, if there are no more applicable targeted drugs at this point, doctors will have to take other approaches, such as chemotherapy, anti-angiogenic drugs, etc.
Of course, whether this force is slowly developing or rapidly expanding, doctors will do a specific analysis. If it is slowly progressing, we catch it early and take the initiative, so we can plan the next step, sometimes continuing targeted therapy and monitoring the disease closely; but if it is rapidly progressing, we have to consider other options.
There is another special case: local progression, which requires a combination of “local armament”. For example, if the lung lesion is not progressing but has metastasized to the brain and bone, local treatment of the brain and bone lesions can be done while maintaining targeted therapy.
The disease is changing, and doctors are figuring out how to deal with it. More and more new drugs are emerging, extending survival time and improving quality of life for many patients. I hope we can fight more of the “forces of evil” in the fight against lung cancer and get better and better.
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Co-reviewed by: Guangdong Provincial People’s Hospital Guangdong Lung Cancer Institute Dr. Qing Zhou, Chief Physician Dr. Xiaoyan Bai Dr. Mei Mei Zheng