A new study published on Sept. 17 in Science reported that a rare inherited germline mutation can increase lung cancer risk 62 times in never-smokers and 25 times in smokers. Smoking on its own increases the risk of developing lung cancer 4 times in the general population.
To look for the T790M mutation in the epidermal growth factor receptor (EGFR), researchers evaluated 23andMe genotyping data across 3.37 million individuals and found its prevalence to be 1 in 15,850. Out of the 17 cancers and non-pulmonary conditions screened, this mutation showed a strong association only with lung cancer. The study also traced the origination of the mutation to southern Appalachian populations in the U.S.
“At the moment, screening for lung cancer is based, essentially, solely on tobacco exposure,” said Pasi Jänne, M.D., Ph.D., lung cancer specialist at Dana-Farber Cancer Institute and corresponding author, told Fierce. “Here we've identified a genetic component that is also a risk factor, and maybe these are individuals that would benefit from screening and early detection to identify cancers at an earlier early stage when they're still potentially curable.”
Lung cancer is the second most common cancer in the U.S. and the leading cause of cancer death in both men and women. EGFR is a protein that regulates how cells grow and divide, and when it is mutated, it can cause cancer cells to grow and spread. EGFR mutation-positive lung cancer makes up around 10-15% of lung cancers in the U.S., with a higher incidence in Asian populations.
Tobacco smoking is the leading cause of lung cancer. Interestingly, patients who have an EGFR mutation and develop lung cancer are typically individuals who have never smoked.
Jänne acknowledged that this study does not give the full picture of the lifetime risk of developing lung cancer in someone who has this mutation. “There may be more nuances to the genetics of those individuals that modify the risk," he said. "Even in the presence of this mutation or environmental exposures that modify the risk.”
Therapies targeting EGFR-mutated lung cancer have long been in development, with AstraZeneca’s Tagrisso and Johnson & Johnson’s Rybrevant. Back in 2015, AstraZeneca announced that its therapy showed positive median progression free survival data of 13.5 months in patients harboring the EGFR T790M mutation, data that eventually led to its FDA approval. In August, BlossomHill announced a macrocyclic EGFR-targeting molecule called BH-30643 to challenge Tagrisso.
Other such therapies, however, have hit roadblocks. In 2015, Boehringer Ingelheim handed over as much as $730 million to South Korean drugmaker Hanmi Pharmaceutical in exchange for the rights to olmutinib (BI 1482694), an oral tyrosine kinase inhibitor for EGFR, but the drug caused a life-threatening skin condition. Ingelheim backed out of the deal after a year, and Hamni eventually put olmutinib to bed.