American Association for Cancer Research

Precancers: Opening a New Front in the War on Cancer

A Position Statement from the American Association for Cancer Research

February 2002

More than three decades ago, the nation declared war on cancer with the signing of the National Cancer Act. The hope, if not the expectation, was that by now mortality rates from the most common forms of cancer would be greatly reduced. Though tremendous strides have been made in our understanding of how normal cells turn cancerous, and new drugs and technologies have been added to the war chest, victory over this medical enemy is far from complete.

It is now time to take the war on cancer to a new front, featuring the rapid development and deployment of a new arsenal of drugs capable of attacking cancer cells during their formative - precancerous - stage.

A special task force report of the American Association for Cancer Research (AACR), published in the February 2002 issue of the journal Clinical Cancer Research, spelled out a landmark set of recommendations on how to speed the development of drugs that target common precancers.

The task force and the AACR now urge the federal Food and Drug Administration (FDA) to speed approval of drugs that prevent and treat precancerous lesions when the link between these lesions and cancer is shown to exist. It's hoped that such an effort will encourage researchers in academia, the government and pharmaceutical companies to begin scientific inquiries into "chemopreventive" agents that would launch preemptive strikes against precancerous cells and tissue.

Changes in attitude and advances in technology have converged to make this approach possible.

Historically, doctors have long believed that precancers should be treated. Their eradication - usually by surgery Ð as soon as they are discerned through a test like a Pap smear, colonoscopy, mammography, or biopsy substantially reduces a patient's risk of developing invasive cancer later.

Surgery has drawbacks, though. Surgical removal of a lesion, for instance, may leave the rest of the organ or tissue area at risk. Some small lesion may escape detection leaving the rest of the tissue susceptible to precancerous growth. In some cases, standard surgical treatment requires radical procedures that leave permanent disfigurement or disruption in normal function.

Aside from surgery, doctors have limited options to treat precancers. Currently, only five agents have been approved by the FDA to combat specific precancers in patients with high-risk of developing cancers: topical 5-FU for actinic kerotoses, a precancer of the skin; topical diclofenic, also for actinic kerotoses; intravescial BCG, for bladder cancer; tamoxifen, for ductal carcinoma that leads to invasive breast cancer; and celecoxib, for adenomous polyps of the colon.

The pursuit of drugs to treat precancers has been slowed by several factors. First, there were technical limitations. Simply, science had not advanced far enough to allow clinicians to visualize early cancers or to monitor the results of treatment on a molecular level.

Today, however, emerging technologies for noninvasive imaging are increasing the numbers of lesions that can be detected and identified at an early stage.

The development of the gene chip, for example, is allowing scientists and clinicians to measure specific cancer-related genomic changes in patients undergoing treatment. Imaging devices such as confocal microscopes and the magnifying endoscope for colorectal monitoring also present clearer and earlier pictures of cells and how they change following drug therapy. Such technologies also can be used for precancers.

Second, many worried about the risks of giving medicine to seemingly healthy people - including those with precancers Ð to prevent them from getting sick. However, this attitude clearly has changed with the treatment of other life-threatening conditions such as cardiovascular disease.

About 15 years ago, a debate raged about whether to treat high cholesterol simply because of its association with increased risk of heart attack and stroke. Scientifically, there was a link, but not a direct cause. The debate led the FDA to approve the first statin drugs for lowering high cholesterol levels; drug companies did not have to prove that lowering cholesterol meant fewer heart attacks, only that cholesterol levels reduced heart attack risk.

The AACR now believes that reducing precancers lowers cancer risk, and that the FDA should take a similar stance regarding drugs for the approval of this condition. AACR believes the link between some precancers and invasive cancers Ð particularly in certain high-risk populations - is so clear that drug developers should only be required to prove their proposed medicines are safe and effective in treating or preventing the evolution of precancer to cancer.

For instance, strong evidence links the presence of colorectal adenomatous polyps with the later presence of colon cancer, particularly when polyps are large and composed of more abnormal tissue. With prostate cancer, studies have shown that 40 percent of all patients with high-grade prostatic intraepithelial neoplasia (HGPIN) - and no detectable cancer - develop cancer three years later, with cancer incidence growing to 80 percent in 10 years. Other high-risk populations include people with severe Barrett's esophagus and women with abnormal breast cells who have been previously treated for breast cancer or have a family history of breast cancer.

The AACR contends that a revolution in how scientists and the public think about preventing and curing cancer is needed. This revolution has begun in the laboratory and is already well accepted by a public seeking ways - through lifestyle modification as well as medical screening and intervention - to reduce their personal risks of developing cancer.

To complete the revolution, we need new investments in research. Only then can we develop the weapons, the chemopreventive drugs, that can stop or reverse a deadly process that starts with the diagnosis of a precancer.