Available, FDA-approved drugs may be effective in targeting about 80% of never-smokers’ lung tumors
From: Washington University School of
Medicine [in St. Louis, Missouri]
September 30, 2021 -- Despite smoking's
well-known role in causing lung cancer, a significant number of patients who
develop lung tumors have never smoked. While scientists are still working to
understand what spurs cancer in so-called 'never-smokers,' a study suggests
that 78% to 92% of lung cancers in patients who have never smoked can be
treated with precision drugs already approved by the Food and Drug
Administration to target specific mutations in a patient's tumor.
The new analysis suggests that 78% to
92% of lung cancers in patients who have never smoked can be treated with precision
drugs already approved by the Food and Drug Administration to target specific
mutations in a patient's tumor. The researchers found that most never-smokers'
lung tumors had so-called driver mutations, specific mistakes in the DNA that
fuel tumor growth and that can be blocked with a variety of drugs. In contrast,
only about half of tumors in people who smoke have driver mutations.
The study appears Sept. 30 in the Journal
of Clinical Oncology.
"Most genomic studies of lung
cancer have focused on patients with a history of tobacco smoking," said
senior author Ramaswamy Govindan, MD, a professor of medicine. "And even
studies investigating the disease in patients who have never smoked have not
looked for specific, actionable mutations in these tumors in a systematic way.
We found that the vast majority of these patients have genetic alterations that
physicians can treat today with drugs already approved for use. The patient
must have a high-quality biopsy to make sure there is enough genetic material to
identify key mutations. But testing these patients is critical. There is a high
chance such patients will have an actionable mutation that we can go after with
specific therapies."
In the U.S, about 10% to 15% of lung
cancers are diagnosed in people who have never smoked, and that proportion can
be has high as 40% in parts of Asia.
The researchers analyzed lung tumors
from 160 patients with lung adenocarcinoma but no history of tobacco smoking.
They also compared data from these patients to data in smokers and
never-smokers from The Cancer Genome Atlas and the Clinical Proteomic Tumor
Analysis Consortium, projects led by the National Institutes of Health (NIH) to
characterize different types of cancer. The scientists verified never-smoker
status by examining the mutation patterns in these patients and comparing them
to mutation patterns in lung cancers of patients who had smoked. Past work led
by Govindan and his colleagues found that smokers' lung tumors have about 10
times the number of mutations as the lung tumors of never-smokers.
"Tobacco smoking leads to
characteristic changes in the tumor cells, so we can look for telltale signs of
smoking or signs of heavy exposure to secondhand smoke, for example," said
Govindan, who treats patients at Siteman Cancer Center at Barnes-Jewish
Hospital and Washington University School of Medicine. "But very few of
these patients' tumors showed those signs, so we could verify that this was
truly a sample of lung cancer tumors in patients who had never smoked or had
major exposure to tobacco smoke."
The researchers also found that only
about 7% of these patients showed evidence of having mutations present at birth
that raised the risk of cancer -- either inherited or arising randomly --
furthering the mystery of what causes lung cancer in never-smokers.
"There appears to be something
unique about lung cancer in people who have never smoked," Govindan said.
"We didn't find a major role for inherited mutations, and we don't see
evidence of large numbers of mutations, which would suggest exposure to
secondhand smoke. About 60% of these tumors are found in females and 40% in
males. Cancer in general is more common among men, but lung cancer in
never-smokers, for some unexplained reasons, is more common among women. It is
possible additional genes are involved with predispositions to cancers of this
kind, and we just don't know what those are yet."
The study also shed light on the immune
profiles of these tumors, which could help explain why most of them do not
respond well to a type of immunotherapy called checkpoint inhibitors. Unlike
the smokers' lung tumors studied, very few of the never-smokers' tumors
included immune cells or immune checkpoint molecules that these drugs trigger
to fight the cancer.
"The most important finding is that
we identified actionable mutations in the vast majority of these patients --
between 80% and 90%," Govindan said. "Our study highlights the need
to obtain high-quality tumor biopsies for clinical genomic testing in these
patients, so we can identify the best targeted therapies for their individual
tumors."
This work was supported by the National
Institutes of Health (NIH), grant numbers 2U54HG00307910 and U01CA214195; and
the Mesothelioma Biomarker Discovery Laboratory.
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