Gene mutation is divided into germ cell mutation and somatic mutation. Germ cell mutation is a congenital gene mutation brought about by inheritance; while somatic mutation is an acquired mutation, which is mostly caused by the environment. caused by factors. The EGFR gene in lung cancer is a cancer driver gene, and the general EGFR gene mutation is a somatic mutation.
So, is it possible that there is a germline mutation of the EGFR gene? This is rare, but it still exists. The researchers found that acquired somatic EGFR gene mutations are suitable for targeted drug therapy, and immunotherapy with PD-1 inhibitors is less effective. However, patients with germline EGFR gene mutations can benefit from PD-1 inhibitor therapy. Let’s take a look at the following cases.
Congenital EGFR mutation, long-term benefit with PD-1 inhibitors
A 61-year-old woman with a history of smoking was diagnosed with poorly differentiated non-small cell lung cancer with metastatic lesions in the bone, adrenal gland, and liver.
Next-generation genetic sequencing of tumor tissue samples from patients revealed complex genetic mutations in patients. Specifically: G13D mutation of KRAS gene, E17K mutation of AKT1 gene, and V843I mutation of EGFR gene, the mutation frequency is as high as 49%. In general, different tumor driver gene mutations are unlikely to appear at the same time, because generally one is enough to drive cancer, so the KRAS gene and the EGFR gene are unlikely to appear at the same time, especially in patients who have not yet been treated.
G13D of KRAS gene is a relatively common mutation, and 8.5% of KRAS mutations in lung cancer are G13D site mutations. But the V843I mutation of the EGFR gene is less common. This mutation may be a susceptibility mutation that leads to lung cancer, especially the mutation abundance of 49%. Such a high mutation frequency suggests that it may be a germline mutation, because somatic mutations rarely have such a high mutation abundance. Later sequencing of the patient’s leukocytes also confirmed that the V843I mutation of the EGFR gene was a germline mutation.
So, could this mutation benefit from targeted drug therapy? There is no relevant report for now, and there is no targeted drug for the G13D locus of the KRAS gene in the patient. Since the PD-L1 expression in the patient’s cancer cells is 50%, which is a high expression, the patient directly uses a PD-1 inhibitor.
Picture: CT scan showed that immunotherapy significantly reduced tumor lesions
As shown in the picture above, the results of the treatment are amazing. All visible tumor lesions had shrunk significantly, demonstrating a sustained response, clinically assessed as a partial response. After 30 months of PD-1 inhibitor use, the patient was found to have progressed in the location of the previous metastases, so he started second-line treatment with pemetrexed and carboplatin. As of June 2022, the overall survival of patients reached 48 months, or 4 years.
The genetic testing information of the patient in this case indicated that the abundance of V843I mutation in EGFR gene reached 49%, and the researchers evaluated it as a germline mutation because the abundance of somatic gene mutation is very high. Rarely can such a value be achieved.
The driver of the patient’s tumor is the KRAS gene, not the EGFR gene, so it is logical to benefit from PD-1 inhibitor therapy. As for whether other treatment measures can be interspersed in the treatment interval to help prolong the resistance time of PD-1 inhibitors, further research is needed to confirm.
Current gene sequencing technology continues to improve, but the overall level is mixed. The abundance of gene mutations detected by some patients using tissue samples can reach 88%, that is, 88% of the tissue samples are cancer cells. There are also patients who use blood samples to detect 40% gene mutation abundance, or detect three driver gene mutations at the same time: EGFR, ALK and RET. The probability of these cases is very low, so this part of the genetic test report can be Reliability is worth considering.
For patients who have doubts about the results of genetic testing, they can consult with professionals or cancer medical consultants, and pay attention to the verification of genetic testing reports, so that this emerging diagnosis and treatment technology can truly serve as a guide. Credentials for later treatment medication.
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Reference: O. Trabelsi Grati, L. et al., Long response to Immune Checkpoint Inhibitors in metastatic NSCLC despite EGFR germline mutation. A Case Report, Lung Cancer (2022)