|Gregory Otterson, MD, medical oncologist and lung cancer specialist (left); Miguel Villalona, MD, specialist in lung cancer therapy and drug development|
Where There’s No Smoke
By Bob Hecker
Photograph by Roman Sapecki
A greater proportion of lung cancer patients are never-smokers. It’s a different disease and may require different therapy.
If 85 to 90 percent of lung cancer cases in the United States are linked to smoking tobacco, what’s behind the 10 to 15 percent of cases involving people who never smoked?
Medical scientists aren’t sure, but what they do know is that lung cancer in never-smokers is a biologically distinct disease from lung cancer in smokers, and one that sometimes can be treated differently with therapy targeting specific gene mutations.
“In the past decade, researchers have begun studying subtle biological differences in the lung tumors of smokers and of those who have never smoked,” says Gregory Otterson, MD, a medical oncologist and lung cancer specialist at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute (OSUCCC-James). Otterson says carcinogens in cigarette smoke cause gene mutations that are often different from those found in lung tumors of people who have never smoked.
Miguel Villalona, MD, a lung cancer specialist and an expert in drug development at the OSUCCC-James, expects smoking-related lung cancer to remain a difficult disease to treat because tobacco carcinogens cause multiple gene alterations that are hard to target. Scientists have validated two mutations that drive lung tumors in never-smokers, he notes, and an effective frontline treatment is available that targets one of those mutations, although patients eventually relapse.
Some never-smoking patients have neither of the two validated mutations, and a rare few have both, Villalona says, and other mutations may still be found in these tumors. But he believes that ultimately lung cancer in never-smokers will prove easier to treat with targeted therapy because it involves fewer mutations than smoking-related lung cancer.
Lung cancer is the leading cause of cancer death among both men and women in the United States. The National Cancer Institute (NCI) expected 215,000 new cases and nearly 162,000 deaths from this disease in 2008. The Lung Cancer Alliance (LCA), a national non-profit organization dedicated to patient support and advocacy, says the disease kills an average of 439 people a day, or one in three cancer deaths overall. But it wasn’t always this way.
Some 150 years ago, lung cancer was extremely uncommon. For example, it represented only 1 percent of all cancers seen at autopsy at the Institute of Pathology at the University of Dresden in Germany. By 1918, the percentage had risen to almost 10 percent and by 1927 to more than 14 percent.
The growing incidence coincided with a rise in the number of smokers stemming from the mass production of cigarettes beginning in the 1880s. Decades can pass before smokers develop lung cancer, so it wasn’t until the 1930s that physicians began noticing a sizable increase in cases.
Not only has lung cancer in smokers evolved into the top cancer killer, but a consumer health report by Harvard Medical School states that if lung cancer in never-smokers alone were classified as a separate disease, it would still rank among the top 10 most lethal cancers.
An Increasing Proportion
|YOU WIN SOME…|
While the prevalence of smoking has decreased dramatically over the past three decades, the trends in incidences of lung cancer have not been as positive. In 1975, nearly 43 percent of males and 32 percent of females were cigarette smokers. Those numbers dropped to nearly 23 percent for males and 17 percent for females in 2005. During that same time period, 1975 to 2005, the rate of lung cancer incidence in males went from 89 per 100,000 to 74 per 100,000. The incidence of lung cancer in females during that same time period has doubled, increasing from approximately 25 per 100,000 to just over 50 per 100,000.
SOURCES: ABOVE, CENTERS FOR DISEASE CONTROL AND PREVENTION, NATIONAL CENTER FOR HEALTH STATISTICS, NATIONAL HEALTH INTERVIEW SURVEY; RIGHT, Surveillance, Epidemiology, and Ends Results (SEER)-9, SURVEILLANCE RESEARCH PROGRAM, NATIONAL CANCER INSTITUTE
Thanks to highly effective national smoking-cessation efforts, Villalona says, only about 23 percent of American men and 18 percent of women smoke today, compared with an estimated 52 percent of men and 34 percent of women in 1965. Because of this drop in smoking prevalence, a higher percentage of the lung cancer cases seen by physicians today are unrelated to smoking, Villalona says. According to the LCA, more than 60 percent of new cases involve never-smokers or former smokers, many of whom quit decades ago.
Furthermore, non-smoking lung cancer disproportionately affects women. Figures from LCA indicate that one in five women diagnosed with lung cancer are never-smokers compared with only one in 12 men.
“The factors that produce this cancer are not clear,” Villalona says. “We don’t know, for example, whether a virus or something in the environment is responsible.”
Risk factors for lung cancer other than smoking that are listed by the NCI include exposure to radon gas from rocks and soil, asbestos in homes and buildings, secondhand tobacco smoke, and environmental hazards such as nickel, chromium, arsenic, soot, tar and smog. Age and heredity also may be factors.
Whatever the origin, Otterson says exploring the mechanisms of never-smoking lung cancer is essential. “Our studies of this disease suggest that the proper way to think of lung cancer is not in terms of smoking versus non-smoking forms, but according to the particular molecular and gene defects present in tumor cells. These should define the therapy.”
Lung cancer is broadly classed as either non-small-cell (NSCLC), which constitutes some 80 percent of all cases, and small cell.
NSCLC grows and spreads more slowly and has three subtypes: adenocarcinoma, which starts in the interior lining of the lungs and is the most common of all lung cancers; squamous cell carcinoma, which begins in respiratory tract passages; and large cell carcinoma, characterized by cells that appear large and abnormal under the microscope.
Small-cell lung cancer more quickly reproduces and spreads than NSCLC, and, according to the LCA, it is almost always caused by smoking or secondhand smoke.
Lung cancer in never-smokers is largely adenocarcinoma, Otterson says, whereas lung cancers most associated with smoking are (in order) small cell, squamous cell, large cell and adenocarcinoma. Among all lung cancer cases combined, he says, adenocarcinomas account for about 40 percent, followed by squamous cell at 30 to 35 percent, small cell at 15 percent and large cell at 5 to 10 percent.
Weiqiang Zhao, MD, PhD, co-director of the Pathology Core Facility at Ohio State, leads a team that performs mutation analyses of lung-cancer patients. He has collected data showing that adenocarcinoma occurs in 70 percent of never-smoking lung cancer versus 47 percent of former smoker cases and 40 percent of current smoker lung cancer cases.
Why adenocarcinoma is so common among nonsmoking lung cancers remains unknown.
“We have been fascinated to find that a good proportion of tumors in never-smokers is driven by alterations in the epidermal growth factor receptor (EGFR),” Villalona says. Mutations in this gene are found in 20 to 30 percent of never-smoker lung cancer. “This
is important because it can be targeted by therapy.”
When epidermal growth factor (EGF) binds with EGFR, a receptor tyrosine kinase, it activates a signaling pathway that causes cells to grow and multiply. In some lung cancers, EGFR is present either in abnormally high quantities (i.e., it is amplified) or the receptor tyrosine kinase site is extremely sensitive to EGF stimulation (i.e., the gene is mutated), causing excessive cell division. Drugs called tyrosine kinase inhibitors (TKIs), such as erlotinib, are designed to block EGFR tyrosine kinase activation and thwart this aberrant cell division.
Villalona is principal investigator at Ohio State for a national Cancer and Leukemia Group B (CALGB) clinical trial of erlotinib administered with or without standard chemotherapy for never or previous light-smoker (less than 10 lifetime packs) lung cancer patients. “TKIs cannot cure these tumors, but they can produce dramatic long-lasting responses by shrinking them in a good number of these patients,” Villalona explains. “Resistance eventually develops, but even with the first generation of these agents, we are seeing improvements in the survival time of many patients.”
Zhao and his team in the Pathology Core Facility—accredited by both Clinical Laboratory Improvement Amendments and the College of American Pathology—analyze lung tumors for EGFR mutations. He notes that patients with EGFR-mutant tumors are more likely to be never-smokers and that two types of EGFR mutations are often seen in NSCLC. One, an activating mutation in exons 19 and 21, causes high tyrosine kinase activity and cancer cell proliferation. The other is a mutation in exon 20 that is often found in relapsed patients.
“The exon 19 and 21 mutations enable cancer cells to survive and proliferate in an independent manner even without the presence of EGF because of the intrinsic tyrosine kinase activity of the mutant EGFR,” Zhao says. “When we inhibit the kinase with small molecule drugs, it triggers apoptosis. Hence, tyrosine kinases have become popular targets for drug development.”
|This fluorescent in situ hybridization (FISH) shows the EGFR gene (red dots) is numerous or amplified with fewer CEP17 (green—reference for the chromosome 17, to which EGFR genes belong). The cell nuclei are stained blue.|
The exon 20 mutation, he says, often emerges following the use of TKIs. It changes the structure of the TKI-EGFR binding site to prevent effective TKI interaction, causing patients to relapse. Zhao’s team is working to understand mechanisms of TKI drug resistance.
A second mechanism of TKI resistance involves amplification of c-MET, a tyrosine kinase receptor that is activated by hepatocyte growth factor (HGF). “The binding of HGF to c-MET activates downstream signaling pathways that regulate cancer cell growth, angiogenesis, invasion and metastasis,” Zhao says.
He describes a recent study involving a lung cancer cell line that developed TKI resistance as a result of c-MET amplification. Inhibiting c-MET signaling in these cells restored their sensitivity to the drug. “The status of the c-MET gene can be checked by fluorescent in situ hybridization (FISH) or real-time polymerase chain reaction (PCR) techniques,” Zhao says. “Our laboratory has developed a FISH probe that will soon be placed into clinical practice.”
Another gene alteration that has been validated as a tumor driver in never-smoking lung tumors is a mutated KRAS. “These mutations once were thought to occur only in lung cancer patients who smoke, but they also occur in about 15 percent of patients who never smoked,” Villalona says. “Lung tumors with KRAS mutations tend to be resistant to EGFR TKIs, rendering the agents ineffective against this type of tumor.
“We have no targeted therapy for patients with KRAS mutations; we can offer them only standard chemotherapy,” Villalona says. However, he is working with Roger Briesewitz, PhD, of the OSUCCC’s Experimental Therapeutics Program, to develop a series of agents that targets KRAS.
“The challenge with KRAS is in finding ways to disrupt the protein-protein interactions that this mutated oncogene establishes,” Briesewitz says. “Mutated KRAS provides a strong signaling pathway that gets ‘stuck’ in an ‘on’ position and leads to proliferation of cancer cells. We are trying to develop a drug that disrupts interactions between KRAS and the signaling proteins that bind to it.”
Their idea, he explains, is to generalize the mechanism of two small natural molecules, FK206 and rapamycin, to thwart interactions between the KRAS oncogene and KRAS effector proteins, thus stopping cell proliferation and inducing cell death. Briesewitz and his lab are collaborating with Dehua Pei, PhD, professor of Chemistry at Ohio State, who synthesizes the molecules and does the initial testing. Pei’s lab studies the catalytic mechanisms of enzymes and designs inhibitors as research tools and potential therapeutic agents.
Villalona is also the principal investigator for an Ohio State trial for never-smoker lung cancer patients with recurrent disease who receive oral applications of another TKI, sorafenib, as a second-line therapy that indirectly targets KRAS mutations.
A clinical trial opened in spring 2009 to examine the effects of an oncovirus called reolysin, plus chemotherapy, in lung cancer patients with EGFR or KRAS mutations. The study holds promise, especially for patients with the KRAS mutation, Briesewitz says.
Other important treatment-related questions also remain, Zhao says. “For example, how do we treat patients who are non-smokers but have no activating mutations in EGFR, or patients who have neither or both the EGFR and KRAS mutations? What about patients who have relapsed and for whom TKIs are no longer effective? To face these challenges, we hope that a large-scale, randomized clinical trial will help modernize our view of this disease.”
Although much work remains, the investigators are excited about global progress in developing targeted cancer therapies.
“In the past decade there has been an explosion of targeted therapeutics based on our improved understanding of the molecular defects that give rise to cancer,” Briesewitz says, noting the discovery of imatinib against chronic myelogenous leukemia and erlotinib against lung cancer. “Erlotinib is a breakthrough drug in lung cancer; patients with EGFR mutations often respond dramatically to it. My hope is that many more imatinibs and erlotinibs will arise from our research to better understand the genetic defects that cause lung cancer.”
The work of these investigators also has important implications for personalized health care. “The term ‘lung cancer’ is not meaningful unless we think of each case in terms of its molecular and genetic distinctions,” Otterson says. “Only then can we best apply all of our resources for treating it.”
One in five women and one in 12 men diagnosed with lung cancer are never-smokers, according to data from the lung cancer alliance.
Run for Your Life
The diagnosis was a deadly surprise for Jack Roth and his family. Roth, 56, was a runner who had never been seriously ill and who routinely received six-month physical exams that confirmed his good health. What’s more, he had never been a smoker. And now—what?—his doctor said he had lung cancer?
“He was one of the healthiest people I knew,” says his daughter, Maren Roth. “But he had been feeling a little run down and thought he might have a virus. He was trying to diagnose himself by doing research on the Internet. Eventually my mother found him unresponsive on the floor. He’d had a seizure from a brain tumor.”
Tests showed that the tumor was a metastasis of stage four lung cancer. Doctors told Roth he probably had two years to live.
Roth, of Bexley, Ohio, survived for nine months. “He was sick for such a short time, but in that time he had so many friends and visitors around him,” Maren says. “It was inspiring to see such amazing friendship.”
Noted author Bob Greene, who had known Roth since kindergarten and graduated with him in the Bexley High School Class of 1964, was among Roth’s many visitors. In 2006 Greene published a book titled And You Know You Should Be Glad—A True Story of Lifelong Friendship.
“Bob Greene’s book was a fitting tribute to the kind of man my dad was—a kind, gentle, selfless person who was always helping others,” Maren says.
Roth’s death prompted his wife and daughter to take action by establishing the Jack Roth 5-K Rock N’ Run/Walk, an annual fundraiser for lung cancer research at the OSUCCC.
To date, the event has raised $106,000, including $71,000 for the Jack Roth Memorial Fund at the OSUCCC-James and $35,000 to support research by James medical oncologist Miguel Villalona, MD, into genetic mechanisms of this disease.
The fourth annual Rock ‘N Run/Walk will be Sunday, May 31, starting at 9 a.m. at Bexley High School. For information, visit the race Web site at jackrothfund.org or premierraces.com