A Conversation With
A Conversation with Dr. Barry Kramer about Cancer Prevention Research at NCI
Dr. Barry Kramer was appointed director of NCI's Division of Cancer Prevention (DCP) on November 6. Dr. Kramer previously served as director of the NIH Office of Disease Prevention from 2001 to 2010. He has been the editor-in-chief of NCI's Physician Data Query Screening and Prevention Editorial Board since the early 1990s. He is also an investigator with the National Lung Screening Trial and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO).
DCP supports research in cancer prevention and cancer screening. These two often get lumped together, but they're really two different things, aren't they?
Yes. When we talk about prevention, we mean lowering the risk of developing a disease. When we talk about early detection and screening—for most tests in most types of cancer—we're not talking about preventing cancer or lowering the risk of developing cancer, but detecting it early at a treatable stage and changing the outcome.
But there is an overlap in that some screening tests pick up tissue abnormalities before they become cancer—tissue changes that can be treated before they progress to cancer. The classic example, of course, is cervical cancer screening, where we consider it almost a failure of the system if you pick up a cancer, because the true goal is to pick up intraepithelial neoplasia or intraepithelial lesions well before they progress to cancer, treat them, and prevent cancer in the first place.
Another example is screening for colon cancer using endoscopy. We are looking for cancers, so we're not preventing those that are already there. But we're also trying to pick up polyps and neoplasia that could have progressed to cancer but that we can prevent from doing so by removing them.
What do you see as the greatest challenges in cancer prevention and screening?
One of the biggest challenges to prevention is identifying effective agents that prevent cancer but that are also very, very safe. When you're dealing with prevention, you're dealing with healthy people, and it's very difficult to make a healthy person better off than they already are. And that's why you can't accept very much toxicity at all when you are intervening on very large numbers of healthy people. So an active area of research will be to find [chemoprevention] agents that are effective but not toxic.
In screening, one of the big challenges is overdiagnosis, which is when screening tests detect lesions that never would have caused a health problem had they not been detected. The classic example is prostate cancer screening, where there's a large reservoir of silent disease, much of which would never cause a medical problem. If you employ a screening test, you will dip into that reservoir of tumors that wouldn't have caused harm, and you can actually trigger harm [through] some very intensive, but unnecessary, therapy.
So there are three important areas [of research] for DCP in terms of screening. One is figuring out the net benefits and harms of screening tests. The second is that, if someone has chosen to be screened and they have a screen-detected cancer, we have to figure out which people benefit from treatment and which don't. An area of active research for DCP, through the Early Detection Research Network, will be looking for molecular patterns that identify tumors that will not progress.
Third, there are cancers that come up in the interval between screening tests. Those are the cancers you really need to prevent. These cancers tend to be aggressive, because they grow so quickly between screening tests. And so we need to look at the molecular patterns in these tumors as well, to identify pathways that might serve as targets for preventive agents.
What do you think are the most exciting areas for current research in cancer prevention and screening?
We've known for years that obesity is associated with an elevated risk of a variety of cancers. We don't know exactly why, and we need to study why, but we know it's been difficult to have people lose weight or maintain ideal body weight, and, with the increasing prevalence of obesity, we have to figure out the mechanistic links between obesity and cancer.
There's emerging evidence that the gut microbiome—the microorganisms that live in our gut—participates in digestion and energy exchange. And there's at least some evidence in animal models that the gut microbiome helps determine an animal's weight. So it's an exciting area of research, to see if our microbiomes are also linked to energy exchange, food absorption, nutritional balance, and pathways that serve as drivers for cancer.
Then, of course, we have to look for and test new potential screening tests. Some of the screening tests out there are not of proven value, and we need to identify which ones may have value, and identify the ones that are promising enough to put into definitive trials.
Finally, we're excited about immunologic approaches to preventing cancer. Any cancer that is caused by an infectious agent could potentially be a target for primary prevention with a vaccine. We obviously have some very important vaccines already, like the human papillomavirus (HPV) vaccines, which people are now improving to cover a broader spectrum of cancer-causing HPV types. That would be a major breakthrough, if we could prevent most or all of the HPV infections that cause cancer.
Will there likely be more large-scale prevention or screening clinical trials like PLCO?
We need to know what works and doesn't work, and it takes large randomized trials to establish net benefit—or harm. Many assumed that vitamins can't have any harm, and we're learning through large trials like the Selenium and Vitamin E Cancer Prevention Trial (SELECT) that they can. SELECT gave a disappointing result, but it's important to know that vitamin E may be associated with an increased risk and not a decreased risk of prostate cancer. It's equally important to know that beta-carotene increases the risk of death in heavy smokers, which we learned from the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study.
On the plus side, tamoxifen and raloxifene were both proven to decrease the risk of breast cancer, so there have been positive outcomes as well as negative outcomes from large trials—but all are equally important. And the National Lung Screening Trial showed for the first time ever that a screening test can decrease the risk of dying of lung cancer in heavy smokers and former smokers. So there have been notable successes in the area of prevention and screening [trials].
Given the economy, however, it's now hard to launch very large trials, so we have to be selective, and we have to figure out when something is ready for prime time, for definitive testing. We have to get a better handle on what type of evidence it would take to justify a large clinical trial, and that's another area of ongoing investigation in the division.
—Interview by Sharon Reynolds