People who have never smoked may be less likely to respond to standard treatment for non-small cell lung cancer (NSCLC) due to a combination of two genetic mutations. Researchers at University College London and the Francis Crick Institute, along with AstraZeneca, found that a mutation in the epidermal growth factor receptor gene (EGFR) combined with a mutation in the p53 gene can make cancer cells in non-smokers more resistant to treatment. This can result in the development of drug-resistant tumors, leading to worse survival rates in patients with non-smoking related lung cancer.
NSCLC is typically treated with EGFR inhibitors, but the study found that tumors in individuals with both the EGFR and p53 mutations did not respond well to treatment. Some tumors actually grew after treatment in these cases. Lab and animal studies revealed that these drug-resistant tumors had more cancer cells that had doubled their genome, causing them to develop extra copies of all their chromosomes. This genome doubling can contribute to cancer growth and disease progression.
While non-small cell lung cancer patients are currently tested for EGFR and p53 mutations, there is currently no available test to detect the dangerous genome doubling that may occur in some cases. However, researchers are working on developing such a test. Once this test is available, patients with both EGFR and p53 mutations that display whole genome doubling can be treated in a more selective way. This may involve more intensive follow-up, early radiotherapy, or the early use of combination therapies to target resistant tumors.
Drugs such as osimertinib, a targeted therapy, are being studied in combination with other treatments to prevent the emergence of resistance. Combination therapies may offer better outcomes for NSCLC patients when single targeted therapies are ineffective. However, there is a concern about potential toxicity in patients receiving combination therapies. It can be challenging to determine which patients will benefit more from one therapy versus another.
New therapies are being developed to address cases where EGFR inhibitors are ineffective in non-small cell lung cancer. For example, when targeted treatments stop working, molecular testing can be done to identify new mutations in the tumor. This information helps in designing appropriate interventions to overcome resistance mechanisms. Experimental drugs are being tested in clinical trials to target specific resistance mechanisms, such as the C797S mutation in patients with EGFR mutations.
The proportion of lung cancers in individuals who have never smoked has been increasing in recent decades, particularly among women and younger age groups. Approximately two-thirds of cases among non-smokers occur in women, making them more than twice as likely to develop lung cancer than men who have never smoked. These findings highlight the importance of developing targeted therapies and diagnostic tests to improve the treatment outcomes for non-smokers with non-small cell lung cancer.
