Some Non-Smokers With Lung Cancer Don’t Respond to Treatment
Recent research finds the surprising reasons
When you think of lung cancer, smoking is probably the first risk factor that comes to mind. After all, tobacco use is the leading cause of lung cancer, but a significant number of people who develop this deadly disease have never puffed on a cigarette in their lives. In fact I have two relatives who died of this though they never smoked, and lived in a smoke-free household.
Up to 20% of lung cancer cases in the U.S. occur in those who have never smoked, according to the Centers for Disease Control and Prevention, and the reasons behind these cases aren’t totally clear, but factors like second-hand smoke, radon exposure, air pollution, and genetics are thought to play a role.
What is clear from new research is that some never-smokers with a common form of lung cancer called non-small cell lung cancer (NSCLC) don’t respond as well to standard treatments as others.
And scientists say they may have uncovered why.
A Potent Combination of Gene Mutations
The key seems to lie in two specific gene mutations that, when combined, make cancer cells incredibly resistant to drugs designed to treat them. The first mutation impacts the EGFR gene, which controls cell growth and division.
Up to half of never-smokers with NSCLC have a mutation in this gene that causes cancer cells to multiply rapidly.
The second mutation disrupts the famous TP53 tumour suppressor gene, which normally helps prevent cancer by repairing damaged DNA and causing cancerous cells to self-destruct, but when mutated, it loses this protective ability.
Researchers from University College London, the Francis Crick Institute, and AstraZeneca found that lung tumors in never-smokers with just the EGFR mutation tended to shrink nicely when treated with EGFR inhibitor drugs like osimertinib.
These targeted therapies work by blocking the effects of the mutated EGFR gene.
However, in patients who also carried the TP53 mutation alongside the EGFR one, some tumors actually grew larger on these drugs rather than shrinking. Lab experiments revealed the dangerous combination was fuelling genomic instability within the cancer cells.
A Recipe for Drug Resistance
With both mutations at play, the researchers observed high rates of “whole genome doubling” — where cancer cells made complete duplicates of their entire genome, essentially doubling up on all their chromosomes.
This genomic chaos provided a fertile breeding ground for new drug-resistant cancer cell variants to emerge and thrive despite treatment. In essence, the combination of mutations enabled faster evolution of tumour cell populations that could shrug off the effects of the EGFR inhibitors.
“We’ve shown why having a p53 mutation is associated with worse survival in patients with non-smoking related lung cancer,” said study co-author Dr. Charles Swanton. “The combination of EGFR and p53 mutations enables genome doubling, which increases the risk of drug-resistant cells developing.”
As a result, never-smokers with both mutations tended to have much shorter periods of progression-free survival on EGFR inhibitors compared to those with just the EGFR mutation. Their treatment often failed within a couple years as resistant tumours emerged.
Better Tests and Treatments Needed
So what’s the solution? For starters, the researchers say better diagnostic tests are needed to identify never-smoker NSCLC patients with both the EGFR and TP53 mutations, as well as signs of genome doubling in their tumours.
Once identified, these high-risk patients could potentially receive more aggressive upfront treatment approaches. “This might mean more intensive follow-up, early radiotherapy or ablation to target resistant tumours, or early use of combinations of EGFR inhibitors with other drugs including chemotherapy,” said study co-author Dr. Crispin Hiley.
The goal would be to hit the cancer harder from the start with multiple therapies, reducing the chance for any resistant cells to survive and flourish during treatment. Clinical trials testing such combination regimens are underway.
“Treatment strategies such as combination therapies have begun to emerge, aimed at preventing the emergence of resistance,” noted Dr. Eric Singhi from the University of Texas MD Anderson Cancer Center. “These trials are looking to prove whether two types of treatments together offer better outcomes for patients than one targeted therapy alone.”
Of course, combining multiple cancer drugs also increases the risk of side effects. So a fine balance must be struck between efficacy and tolerability. But for some never-smoker lung cancer patients, more aggressive upfront treatment may end up being the best chance at survival.
While advances are still needed, this research provides valuable insight into why some never-smokers don’t fare as well on standard lung cancer treatment, and what biology is driving drug resistance in these cases.
Perhaps with that understanding, oncologists can start developing smarter, more personalized therapies to overcome these genetic hurdles.
References:
Lung cancer: Why non-smokers don’t respond to treatments (medicalnewstoday.com)
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