Why many lung cancer patients who have never smoked have worse outcomes?

Researchers at the Francis Crick Institute, UCL and AstraZeneca have discovered the reason why targeted treatment for non-small cell lung cancer fails to work for some patients, particularly those who have never smoked, reported the aforesaid institute.

The study, published today in Nature Communications, shows that lung cancer cells with two particular genetic mutations are more likely to double their genome, which helps them to withstand treatment and develop resistance to it.

Around 85% of patients with lung cancer have non-small cell lung cancer (NSCLC), and this is the most common type found in patients who have never smoked.

The most common genetic mutation found in NSCLC is in the epidermal growth factor receptor gene (EGFR), which enables cancer cells to grow faster. It is found in about 10-15% of NSCLC cases in the UK, particularly in patients who have never smoked.

Lung cancer treatments that target this mutation, known as EGFR inhibitors, have been available for over 15 years. However, while some patients see their cancer tumors shrink with EGFR inhibitors, other patients, particularly those with an additional mutation in the p53 gene—which plays a role in tumor suppression, fail to respond and experience far worse survival rates. But scientists and clinicians have so far been unable to explain why this is the case.

To find the answer, the researchers re-analyzed data from trials of the newest EGFR inhibitor, Osimertinib, developed by AstraZeneca. They looked at baseline scans and first follow-up scans taken a few months into treatment for patients with either EGFR-only or with EGFR and p53 mutations.

The scientists found that, for patients with just the EGFR mutations, all tumors got smaller in response to treatment.

But for patients with both mutations, while some tumors had shrunk, others had grown, providing evidence of rapid drug resistance.

This pattern of response, when some but not all areas of a cancer are shrinking in response to a drug treatment within an individual patient, is known as a “mixed response.”

The scientists found that within five weeks of exposure to the drug, a significantly higher percentage of cells with both the double mutation and double genomes had multiplied into new drug-resistant cells.

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