The Deadliest Cancer

With the news last week that former smoker Peter Jennings had succumbed to lung cancer at 67 and Dana Reeve, who never smoked, was diagnosed with the disease at 44, millions of Americans grasped a terrible truth—the deadliest form of cancer doesn't strike just the pack-a-day crowd. Suddenly lung cancer was everyone's concern. And rightly so. Lung cancer may not inspire walkathons or pink-ribbon awareness campaigns, but after three decades of the War on Cancer and four decades of surgeon generals' reports, it remains the most devastating of all malignancies. The disease kills some 160,000 Americans a year—more than breast cancer, colon cancer and prostate cancer combined. The burden has grown steadily in recent decades, thanks to the rising incidence among women, and survival rates have scarcely budged. Nearly 60 percent of patients still die within a year of diagnosis, and 85 percent die within five.

The vast majority of cases are smoking-related, but curbing the use of tobacco isn't the only challenge we face. America's 46 million former smokers still constitute a huge reservoir of risk. And people who smoke don't all suffer the same consequences. Why do some stay healthy, even as nonsmokers are stricken? Are women more susceptible than men? And what are the prospects for earlier detection and more-effective treatment? Can science save other former smokers from Peter Jennings's fate? Researchers are the first to acknowledge the daunting challenges they face. But health officials are making new commitments—the National Cancer Institute unveiled a new research initiative last week—and after decades of discouragement, some researchers are voicing cautious optimism. Geneticists are zeroing in on mutations that may make some people vulnerable. Biologists and radiologists are devising new ways to detect small, localized tumors. And new treatments are beginning to extend survival times, even for advanced-stage patients. "That's not a home run," says Dr. David Johnson of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., "but it's hardly a bunt single."

The causes of lung cancer are no great mystery: some 87 percent of all cases result directly from smoking. Whatever your age, sex, race, occupation or family history, the surest way to protect yourself is to avoid smoking or to quit. Unfortunately, quitting doesn't completely negate the genetic damage that tobacco smoke causes in lung tissue, so former smokers remain more vulnerable than nonsmokers. How much more vulnerable? It depends on how long you smoked, and how heavily. "If you smoke a pack a day for 20 years or more, you have a 50 percent chance of dying from smoke-related disease," says Dr. Norman Edelman, the American Lung Association's chief medical officer. "There is a linear relationship between total smoke exposure and risk for cancer." But the risk declines markedly as healthy cells replace damaged ones in an ex-smoker's lungs. After 10 years of abstinence, a quitter is only half as vulnerable as someone who continues to smoke.

Even among smokers, the risk is not equally distributed. Nelson Mallary took up smoking at the ripe age of 9 and kept at it for more than six decades, burning through 60 butts a day and laughing off generations of friends and relatives who pestered him about quitting. "I was convinced I would never get cancer," he says. At 83, the Atlanta psychotherapist is still cancer-free (he finally gave up cigarettes in his 70s), but he has since learned a few things about the vagaries of the disease. The first blow came in 2000, when lung cancer killed his 43-year-old stepson. Just three years later, his biological son met the same fate. Both men shared their father's addiction. Unfortunately, neither shared his luck.

What, aside from smoking, might shape a person's risk? Environmental pollutants are clearly part of the story. The most important ones are radon, an odorless natural gas that can seep into homes and buildings from the soil, and industrial substances such as asbestos and arsenic. Age is an-other important risk factor (incidence rises sharply after 50). And like most malignancies, lung cancer is strongly linked to family history. People with affected parents or siblings suffer two to three times the usual risk themselves, compared with other people with the same risk factors, and researchers are now homing in on at least two genes that could help explain that phenomenon. In a study completed last year, a team led by geneticist Marshall Anderson of the University of Cincinnati Medical Center analyzed blood and tissue samples from 52 high-risk families, and traced their shared risk to a small region of human chromosome 6. The goal is to pinpoint "susceptibility genes," inherited mutations that make some people especially vulnerable to the cancer-causing agents in cigarettes and the environment. If labs could test for those mutations—as they now do for breast- and colon-cancer genes—high-risk people could be singled out for special precautions, intensive screening and possibly even personalized treatments.

Genes aside, growing evidence suggests that women are uniquely vulnerable to lung cancer. Most of the 600 percent increase they've suffered over the past eight decades can be tied directly to smoking. But when researchers look at the minority of lung cancers involving nonsmokers, a curious disparity emerges. Whereas nonsmokers account for just 10 percent of lung cancer among men, they account for twice that fraction among women. What could explain the discrepancy? Hypotheses abound, but one of the most compelling centers on estrogen, a female reproductive hormone with well-known links to breast and ovarian cancer. Cells taken from lung tumors are covered with estrogen receptors, and the tumor cells proliferate faster when exposed to the hormone in test tubes. Jill Siegfried, a pharmacologist at the University of Pittsburgh Cancer Institute, has documented the same effect in lab mice, and she suspects that something similar is happening in young women's bodies. If she's right, drugs that suppress estrogen could open a new frontier in treatment and even prevention, just as they have in breast cancer.