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William G. Nelson, MD, PhD Photo by Joe Rubino

AN ANCIENT CHINESE PROVERB PRESENTS a challenge to medical practice that remains relevant today: “The superior doctor prevents sickness, the mediocre doctor attends to impending sickness, and the inferior doctor treats actual sickness.”

Clearly, cancers that have metastasized, or spread, to many different organ sites are difficult to cure. These cancers typically contain thousands of defective genes that drive malignancy and undermine attempts at treatment. Can these cancers be intercepted before they progress to a malignant state?

Many of the most common cancers are heralded by premalignant conditions. Precancerous cells, though unable to invade organs and tissues or spread throughout the body to threaten life, nonetheless share many features with cells in life-threatening cancers, including uncontrolled growth. The premalignant cells also acquire gene defects similar to those seen in full-blown cancers. As these gene defects are better understood, treating premalignancy may prove to be the most promising tactic for cancer interception—intervening early​ to stop cancers before they fully develop.

Most successful cancer pre​vention thus far has focused on minimizing avoidable risks for cancer development. Population research has identified several cancer causes—such as cigarette smoking, viral infections and carcinogens in the diet or workplace—and this has enabled effective cancer prevention. Lung cancer deaths are declining due to smoking cessation. Vaccines against the human papillomavirus and hepatitis B help fend off cancers of the uterine cervix and liver, respectively. Avoiding aflatoxin B1, a contaminant found in some foods, safeguards against liver cancer, and reducing exposure to asbestos in the workplace protects against mesothelioma, a cancer that occurs in the lining of the lungs and chest wall.

Studies of inherited predispositions to cancers have identified further opportunities for cancer prevention using prophylactic surgery. As an example, removal of otherwise healthy but nonetheless cancer-prone tissues from the breasts, ovaries and fallopian tubes can reduce cancer risk for carriers of defective BRCA genes.

Cancer interception, via the systematic targeting of premalignancy, offers a chance to confront an even greater range of cancer types. Already, treatment of premalignant conditions has proven effective in reducing the risk of developing many full-blown cancers. Drugs that treat precancerous conditions of blood-forming cells can limit progression to leukemia or multiple myeloma. At solid organ sites, precancerous lesions (usually referred to as intraepithelial neoplasia or IEN) tend to resemble cancers in many ways. Although they are incapable of growing invasively, these lesions can give rise to invasive cancers. For this reason, if IEN can be removed, the risk for life-threatening cancer is often reduced. Removal of polyps from the colon to prevent colorectal cancer is an example of this approach.

To best tackle premalignancy, research on the gene defects acquired by precancerous cells must be intensified. Just as cataloguing gene defects in established cancers has led to precision treatments guided by the specific gene alterations present in individual cancer cases, taking inventory of gene alterations in premalignant lesions could lead to similar benefits. In addition, the spectacular responses of some metastatic cancers to immunotherapy highlight the need for deeper studies of how the immune system recognizes and responds to premalignancy. Perhaps new immunotherapy approaches could reduce or eliminate IEN and other precancerous conditions.

Ramping up research on premalignancy offers the best response to a challenge issued almost a decade ago by Elizabeth Blackburn, a Nobel laureate and past president of the American Association for Cancer Research, which publishes Cancer Today: “Although treating or even curing cancer is often, understandably, at the forefront of people’s minds, cancer will never be brought under control unless the other side of the equation is addressed: intercepting, or preventing, it.” 

William G. Nelson, MD, PhD, is the director of the Johns Hopkins Kimmel Cancer Center in Baltimore. ​


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