gene mutations are divided into germ cell mutations and somatic mutations . Germ cell mutations are genetically brought about by congenital gene mutations; while somatic mutations are acquired mutations, mostly caused by environmental factors. The EGFR gene in lung cancer belongs to the cancer driver gene. Generally, EGFR gene mutation is a somatic mutation.
So, is there any germ cell mutations in the EGFR gene? This situation is rare, but it still exists. Researchers found that acquired somatic EGFR gene mutations are suitable for use with targeted drugs, and the effect of using PD-1 inhibitor immunotherapy for is not ideal. However, patients carrying germ cell EGFR mutations can benefit from the treatment of PD-1 inhibitors. Let’s take a look at the cases below.
congenital EGFR mutation, using PD-1 inhibitors to benefit for a long time
A 61-year-old woman with a history of smoking was diagnosed with hypodifferentiated non-small cell lung cancer . Metastatic lesions were found in bone, adrenal and liver.
By performing a new generation of gene sequencing of the patient's tumor tissue samples, it was found that the patient had relatively complex gene mutations. Specifically, there are: G13D mutations in the KRAS gene, E17K mutations in the AKT1 gene, and V843I mutations in the EGFR gene, with a mutation frequency of up to 49%. Generally speaking, different tumor-driven gene mutations do not appear at the same time, because one is generally enough to drive cancer, so it is unlikely that the KRAS gene and the EGFR gene will appear at the same time, especially in patients who have not yet been treated. G13D of the
KRAS gene is a relatively common mutation, and 8.5% of the KRAS mutations in lung cancer are G13D site mutations. However, V843I mutations in the EGFR gene are less common. This mutation may be a susceptible mutation that is prone to lung cancer, especially 49% of the mutation abundance. Such a high mutation frequency suggests that it may be a germ cell mutation, because somatic mutations rarely show such a high mutation abundance. Later sequencing of the patient's leukocyte also confirmed that the V843I mutation of the EGFR gene is a germ cell mutation.
So, can this mutation benefit from targeted drug treatment? There are no relevant reports for the time being, and there is no targeted drug in the G13D site of the patient's KRAS gene. Since the PD-L1 expression in the patient's cancer cells was 50%, which was highly expressed, the patient directly used PD-1 inhibitors.
Figure: CT examination shows that immunotherapy has significantly reduced the tumor lesions
As shown in the above figure, the treatment effect is amazing. All visible tumor lesions were significantly reduced, manifested as persistent response, and clinically evaluated as partial remission. After using PD-1 inhibitor for 30 months, the patient found progress in the location of the metastatic lesions before, so he started to use pemetrexed combined with carboplatin for second-line treatment. As of June 2022, the patient's overall survival period reached 48 months, that is, 4 years.
reveals
gene detection information in this case shows that the abundance of V843I mutations of the EGFR gene reached 49%, and the researchers evaluated it as a germ cell gene mutation, because the abundance of gene mutations in somatic cells rarely reaches such a value. The driver gene of tumors in
patients is the KRAS gene, not the EGFR gene, so it is logical to benefit from PD-1 inhibitor treatment. As for whether other treatment measures can be interspersed between the treatment intervals to help prolong the drug resistance of PD-1 inhibitors, further research is needed to confirm it.
The current gene sequencing technology is constantly improving, but the overall level is uneven. Some patients can detect gene mutation abundance using tissue samples to reach 88%, which means that 88% of the tissue samples are cancer cells. Some patients also used blood samples to detect 40% of the gene mutation abundance, or detected three driver gene mutations at the same time: EGFR, ALK and RET. The probability of these situations is very low, so the credibility of these gene detection reports is worth considering.
For patients with doubts in genetic testing results, they can consult professionals or cancer medical consultants more frequently, pay attention to the verification of genetic testing reports, so that this emerging diagnosis and treatment technology can truly become a credential for guiding later treatment medication.
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References: 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)
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