Lung cancer is the deadliest form of cancer worldwide and one of the most common in the Netherlands, with 14,500 new diagnoses per year. The two main types are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC accounting for 85% of cases. In 60-70% of adenocarcinoma cases of NSCLC, a driver gene mutation is found—a genetic alteration that drives tumor growth. This opens up possibilities for targeted therapies that specifically address these mutations.
This dissertation of Fenneke Zwierenga focuses on lung cancer with EGFR exon 20 mutations (EGFRex20+) and ROS1 or ALK fusion genes. Part I explores treatment strategies for EGFRex20+, a rare mutation that affects the function of the EGFR protein. Research shows that the effectiveness of tyrosine kinase inhibitors (TKIs) strongly depends on the specific mutation variant. The POSITION20 study evaluates osimertinib (160 mg) in patients with metastatic NSCLC, revealing a limited clinical response. Additionally, circulating tumor DNA (ctDNA) is investigated as a tool for monitoring and resistance analysis.
Part II focuses on ROS1 and ALK fusion genes. A study on ROS1+ patients indicates that crizotinib has limited efficacy, especially for brain metastases. Experiments with ex vivo cell models explore personalized treatment options. In ALK+ NSCLC, resistance is studied using sensitive techniques such as ddPCR, suggesting that some mutations may already be present before treatment begins.
These findings highlight the need for personalized treatments and further research into resistance mechanisms in lung cancer.
