Lung cancer: Not just for smokers
“Did he smoke?”
That’s often the first response to news that someone has lung
cancer. It’s an understandable reaction: Cancer epidemiologists
estimate that 85%–90% of those who die from lung cancer in the
United States were smokers.
But what of the remaining 10%–15%? Some experts estimate that
as many as 15,000 Americans die each year from lung cancer even though
they have never smoked. If never-smokers’ lung cancer were a separate
category, it would be among the top 10 most lethal cancers in the country,
ranking somewhere near ovarian cancer.
Secondhand smoke is undoubtedly a factor in many cases. According to
one estimate, every year about 3,000 Americans get lung cancer from breathing
in secondhand smoke, although evidence suggests that exposure is declining
as workplace and restaurant smoking bans become more common.
Even when you factor in secondhand smoke, there’s a sizable group
of lung cancer patients whose disease can’t be easily traced to
Its own disease
Until recently, doctors had little reason to view lung cancer affecting
never-smokers as a separate entity. Diagnosis and treatment are the same,
regardless if patients smoked or not. Never-smokers may have responded
slightly better to treatment than smokers, but doctors had no way of
determining whether there were inherent differences in the cancers of
smokers and never-smokers.
Now, however, there’s growing recognition that in certain key
respects, never-smokers’ lung cancer may be a distinct disease.
Two cancer medicines — gefitinib (Iressa) and erlotinib (Tarceva) — are
more effective in people who never smoked, and researchers have identified
genetic differences that may explain why.
As part of a clinical trial, doctors at the Harvard-affiliated Dana-Farber
Cancer Institute in Boston are testing the lung cancer tumors of never-smokers
and former smokers with relatively light habits. Dr. Pasi A. Jänne,
a researcher at Dana-Farber, says these trials are the “first example
of personalized medicine in lung cancer.” Personalized medicine
is the catchphrase for efforts to tailor medical treatment to a patient’s
individual genetic profile.
Who is affected?
Epidemiologists have had some difficulty getting a handle on nonsmokers’ lung
cancer. In 2005, though, a number of studies of never-smokers were published.
Epidemiologists at the American Cancer Society (ACS) reported results
from one of the largest studies so far.
The ACS researchers’ conclusions challenged some commonly held
beliefs about never-smokers’ lung cancer. They found that the lung
cancer mortality rate is actually higher for male never-smokers, although
there are more female patients because there are so many more women age
60 or over in the never-smoker category. They also found that the mortality
rate is higher for African American women than for white women. And while
some studies have found that the number of cases of never-smokers’ lung
cancer is going up, the ACS researchers’ analysis found no evidence
of such an increase.
Lung cancer runs in families, but so does smoking, so it doesn’t
jump out as an inherited, genetic condition. But Japanese researchers
reported in the October 2006 issue of the journal Chest that
family history was a stronger risk factor among never-smokers than among
smokers, suggesting perhaps that never-smokers’ lung cancer may
indeed have a significant inherited component.
Drugs get smarter
FDA approval of imatinib (Gleevec) in May 2001 was heralded as the beginning
of a new era in cancer treatment that would feature “smart” drugs
designed to zero in on aberrant proteins found only in cancer cells.
Their selectivity would not only make them more effective, but also produce
fewer side effects because noncancerous cells would be largely unaffected.
What sometimes got lost in the excitement was that Gleevec worked against
relatively rare cancers (chronic myelogenous leukemia and gastrointestinal
stromal tumors). In contrast, gefitinib (Iressa) targeted epidermal growth
factor receptors (EGFRs), which are found in many cancers. They raised
hopes for Gleevec-like drugs for more common forms of cancer.
But there was a major snag: Iressa shrank tumors in only about 10% of
the lung cancer patients who took the drug. That was the clinical paradox:
If the receptor is there, why doesn’t everyone benefit?”
When researchers examined study results in more detail, they found that
the lung cancers of certain types of people were more likely to respond
to Iressa and Tarceva. Women’s tumors had a noticeably better response
rate than men’s, for example.
The favorable results in Japanese and other East Asian patients have
led to a flurry of Iressa and Tarceva studies in Asia. Researchers also
began searching for variations in the genes of lung cancer cells that
might explain the divergent responses.
Some of the bloom came off Gleevec’s rose when doctors found that
patients developed resistance to the drug. Fortunately, a second generation
of drugs has been developed that can be used after resistance occurs.
In 2005, the FDA approved two of them, sunitinib (Sutent) and dasatinib
(Sprycel). These drugs are not quite as “single-minded” as
Gleevec and target multiple proteins, not just one.
Resistance is also a major limitation for both Iressa and Tarceva. Virtually
all patients who respond to the drugs develop resistance within 14 months
or so. In about half of these patients, researchers have identified a
genetic mutation that appears to be responsible. But the hope is that
drug developers will find an agent that can deactivate such resistance-causing
genes and that testing for them will become a routine part of personalized
Redrawing the boundaries
For the foreseeable future, smoking will continue to be the main cause
of lung cancer, so smoking cessation programs and getting young people
not to smoke remain priorities. At the same time, the large group of
lung cancer patients who never smoked should remind us that we need to
look beyond the usual risk factors and disease categories. With the advent
of genetic testing, as well as some old-fashioned epidemiology, traditional
diagnostic and treatment boundaries are in flux and new entities — like
never-smokers’ lung cancer — are getting added to the map.
March 2007 update
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