Prostate Cancer is Worse in Men Who Smoke

To everything else you know about how smoking cigarettes can hurt you, add this: It contributes to prostate cancer, in ways scientists are just beginning to understand. At the very least, it makes cancer worse, and men who smoke are more likely to die from their prostate cancer than men who don’t smoke. But it may turn out to be far more than this—it may be that cigarettes weaken a man’s ability to fight off daily damage to his DNA, leaving him unprotected, and unable to prevent cancer from developing.

We already knew that each puff of a cigarette injects nicotine and a toxic chemical cocktail into every cell of the body— so even if smoking didn’t cause prostate cancer directly, it probably didn’t help prevent it, either. Now, thanks to a new study of younger men with prostate cancer, done by Johns Hopkins scientists Patrick C. Walsh, M.D., William Roberts, M.D., and Elizabeth Platz, ScD., M.P.H., we know much more: The more a man smokes, the higher his odds of being diagnosed with cancer that is more aggressive, and that has already spread beyond the prostate. The relationship is “dose-dependent” —which means that each cigarette raises the risk just a little bit, like the fabled straws on the camel’s back.

But the opposite is true, too, and this is exciting news: If a man stops smoking before he is diagnosed with prostate cancer, he may slow the development of the disease, or may have a less severe—and more likely curable—form of it.

Why did the scientists focus on younger men for this study? “One reason is that prostate cancer is so rare in these men,” says Walsh. “Only 3 percent of men with prostate cancer are younger than 55, and we have been very interested in finding out why these men get prostate cancer. But we also wanted to see how cigarette smoking affects men who have prostate cancer.”

We know (thanks also to Johns Hopkins research; see Prostate Cancer Update Vol. IV, Spring 1997, and Vol. V, Winter 2000) that men who have a family history of prostate cancer are more likely to develop the disease at a younger age. But until this study, no other risk factors stuck out as obvious red warning flags for cancer in younger men. “Previous studies had shown that although the risk for being diagnosed with prostate cancer appears to be the same in men who smoke cigarettes and men who do not, men who smoke are more likely to develop metastatic disease, and to die from it. We wanted to find out whether men who smoked were more likely to have more aggressive disease.”

For consistency’s sake, the men in this study all underwent radical prostatectomy performed by the same surgeon, Walsh. Between 1992 and 1999, Walsh performed the procedure on 1,544 consecutive men; about one-third of these—498 men—were under age 55 at the time of surgery. The researchers sent a detailed questionnaire to these younger men, asking them about a variety of aspects of their life, and then divided them into two groups: Men with aggressive cancers—high-grade disease, with a Gleason score of 7 or greater, and/or cancer that had spread beyond the prostate—and men who did not have aggressive disease.

In comparing these two groups, the scientists found one risk factor that stuck out like the proverbial sore thumb: Cigarette smoking. Not only were men who smoked cigarettes more likely to have more aggressive disease than nonsmokers, but men who smoked more cigarettes in the 10 years before surgery had an increased risk of high-grade disease, or cancer that quickly spread beyond the prostate. And the men who smoked the most (more than 40 pack-years; this could mean 2 packs a day for 20 years, one pack a day for 40 years, etc.) had greater than three times the risk of highgrade cancer, or more advanced disease. The risks were highest for men who still smoked, and lower for former smokers.

Now, the question is, why? Why are men who smoke at high risk of developing the worst kind of prostate cancer, and of dying from it because they’re diagnosed when the disease has already advanced? One possibility might be that men who smoke are less concerned about their health generally, less likely to have regular check-ups, and thus less likely to have any health problem caught early. But the Brady scientists don’t believe this is the case.

Instead, “we believe that cigarette smoking affects prostate cancer cells directly, resulting in aggressive tumor behavior,” says Walsh. And the key to this is in understanding a concept called oxidative damage. Briefly: In oxidative damage, cells are injured by free radicals—volatile molecules that cause a buildup of toxic byproducts in cells. Normally, free radicals are helpful things—rushing like crime- fighters to a scene of unrest, fighting bacteria and other foreign invaders. And normally, the body makes substances that are able to control free radicals and limit their damage. The most important of these substances is an enzyme with the difficult name of glutathione-S -transferase p, called GS T-p, which provides toxic cleanup in cells. (Note: Brady scientist Bill Nelson, M.D., Ph.D., who also is part of the Kimmel Cancer Center, was the first to figure out GS T-p’s role in prostate cancer. He showed that in all cancers, and even in PIN cells, which are not yet cancerous, but well on their way, GS T-p is knocked out—it is simply not there to prevent oxidative damage.) If cancer is a disastrous chain reaction—one genetic mistake, or mutation, that leads to another, and so on, then what happens to this enzyme is probably among the very earliest events.

Cigarettes are known to contain many carcinogenic (cancer-causing) chemicals. One of the worst is benzopyrene. “And here’s the really interesting thing,” says Walsh: “Benzopyrene is also detoxified by GS T-p. So when a man starts down the pathway to developing prostate cancer and loses GS T-p, not only is he more vulnerable to oxidative damage—he’s also more susceptible to the benzopyrene carcinogens produced by cigarette smoking, and this is a double whammy. He’s in twice as much trouble.”