More than a Cover Up: NCI Research to Prevent Skin Cancer

The words "skin cancer" may conjure up images of potentially deadly melanoma, but nonmelanoma skin cancers are far more common. Though less often lethal, a diagnosis of these cancers is still a cause for concern. Most of these cancers are treated surgically in a doctor's office so incidence estimates are difficult to determine. However, more than 1 million new cases of nonmelanoma skin cancer may occur each year, and there is evidence that the rates are rising.

BenchMarks recently spoke with Kenneth Kraemer, M.D., and John DiGiovanna, M.D., dermatologists researching skin cancer for the National Cancer Institute's (NCI) Center for Cancer Research. Dr. Kraemer has a longstanding interest in human cancer-prone genetic diseases and DNA repair. Dr. DiGiovanna's research has included the basis and treatment of inherited skin disorders; treatment and prevention of skin cancer; retinoids, drugs derived from vitamin A; and other agents. These researchers have collaborated on work with patients who have xeroderma pigmentosum (XP), a disease that increases the risk of skin cancer. An edited transcript of the conversation follows.

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We hear a lot about melanoma, but why is nonmelanoma skin cancer prevention research important?

Dr. DiGiovanna: Skin cancer is increasing in epidemic proportions. There are certain subgroups of the population where the frequency is extremely high, such as post-transplant patients. Because of long-term immunosuppression, patients who have had transplants and also have had substantial sun damage are at risk for developing large numbers of skin cancers. In addition, people with inherited conditions such as the nevoid basal cell carcinoma syndrome and XP are also at risk for developing large numbers of skin cancers.

Dr. Kraemer: The nonmelanoma skin cancers are the most common cancers, although they primarily affect Caucasians. These cancers are so common, they're not actually counted by most surveys of cancer. We're concerned because skin cancer is caused by sunlight exposure. If we teach children to protect themselves at an early age, this might go a long way to protecting children from skin cancer. Prevention is better than treatment.

Since nonmelanoma skin cancer is often handled surgically and not counted in cancer statistics, should people still be concerned?

Dr. Kraemer: No one likes to have cancer, period. Removal of cancer is not fun even if it is not life- threatening. Nonmelanoma cancers are closely related to sun exposure. There are really two kinds: one occurs in basal cells and the other in squamous cells.

Basal cell cancer virtually never spreads or metastasizes throughout the body, but it can be very locally invasive, especially in the face. It can invade and go into the brain. We have had patients that have died after it invaded through the eye, and it could not be treated. This is very rare, but it can happen. Squamous cell cancers also don't metastasize that often, but they can spread anywhere.

Are older or younger people most affected by skin cancers?

Dr. Kraemer: Melanomas more often occur in younger people than do basal and squamous cell carcinomas. The average age of someone with basal cell and squamous cell is 50 years old.

What is xeroderma pigmentosum?

Dr. Kraemer: XP is a genetic condition characterized by a sensitivity to all sources of ultraviolet radiation. XP patients have an increased susceptibility to developing all kinds of skin cancers. Their chances of developing skin cancer is about 1,000 times the normal amount. We discovered that they have defective DNA repair genes. We found that XP can occur in all races-not just people you would generally think of as getting skin cancer.

How do these defective DNA repair genes relate to developing skin cancer?

Dr. Kraemer: Ultraviolet (UV) radiation penetrates the skin and damages the DNA. The DNA repair genes may repair the damaged cells, the damaged cells may die or, in other cases, the cells try to continue working and replicate the DNA, but because of the damage, there is a mutation introduced that can lead to cancers. So XP patients have a defect in their DNA repair system that leads to the 1,000-fold increase in skin cancer. We've been studying XP patients here at NIH, and we have found there are a number of different DNA repair genes that are responsible for this disorder. These findings mean that those genes are protecting the people who don't have XP from getting skin cancers.

What are some of the promising areas of research in nonmelanoma skin cancer prevention?

Dr. DiGiovanna: Isotretinoin (Accutane), a derivative of vitamin A, has been studied as an agent to prevent cancers in patients at high risk, and it has been effective in studies of XP patients, who develop large numbers of skin cancers. T4N5 liposome lotion (Dimericine) has been shown to absorb into skin fairly well and, in one study, to prevent new skin cancers in XP patients. It is another approach to chemoprevention. Clinical trials using Celecoxib in patients with actinic keratoses, a precancerous condition, are also taking place.

Dr. Kraemer: Discovering the basic mechanism that creates skin cancer is the most important research; looking at it from initiation, promotion, precancer to cancer. We are learning about what is happening at each of those stages and want to try to find ways to interrupt the process and prevent cancer.

How successful have retinoids, such as isotretinoin, been in preventing skin cancer?

Dr. Kraemer: We did a study here a few years ago with Accutane, which was very effective in preventing skin cancer in patients with XP. One patient would get 20 separate primary skin cancers each year for many years, and she was just a teenager. We gave her the oral medicine. Within two years, she was getting two or three cancers a year - a really small number. Unfortunately, when we stopped the medicine, she started getting tumors again, and the medicine itself caused a number of side effects. It made the skin very sensitive to sunlight. It causes birth defects, so people on it can't get pregnant. Also, it causes calcifications of tendons and ligaments. Accutane is on the market for acne treatment. The people who are treated for acne are treated for just a short time, but patients with XP would have to be treated for a long time. There are thousands of retinoids, and we hope that someday we can find a different retinoid that is equally as effective but less toxic.

How does the TN45 liposome lotion work to repair DNA damaged skin and prevent skin cancers?

Dr. Kraemer: We've been following that fairly closely. The cream has an enzyme that comes from bacteria that will repair most of the damage done to DNA. The enzyme uses a different method of attacking the damage than the human DNA repair system does. Nevertheless, a study of patients who have XP was done, and the cream reduced the frequency of precancerous lesions and also of skin cancer. I think it's the beginning of an interesting approach of putting proteins into the cells to see if we can alter their repair characteristics.

This is different from gene therapy which involves putting DNA back. This is like giving someone with diabetes a shot of insulin, but instead, we are giving patients the protein they are missing. So, it's an interesting approach, and we've been discussing it with the company that made it. However, this treatment has not been approved by the Food and Drug Administration yet because further study needs to be done. Yet, it is very intriguing.

How can this research benefit the general public in the future?

Dr. Kraemer: Certainly these genetic approaches might identify people who might be at greater risk. DNA repair genes are exceedingly important in protecting against skin cancer. The average age of skin cancer in the general population is 60, but in the XP patients it is 10 years. This means there is a 50-year difference between the average age of onset of skin cancer between XP patients and the general population. If your DNA repair system is working, you get 50 more years of sun exposure before you get your first skin cancer. So, these genes are very important in protection against skin cancer.

Another study we are doing is where we found what are called polymorphisms in these DNA repair genes. Polymorphisms are normal variations in the sequence of genes. These are much more common in the general population. XP itself occurs in maybe one in a million people and the carriers are about 1 in 500. We did one study collaborating with M. D. Anderson Cancer Center in Texas where we had found one repair gene polymorphism occurs in 40 percent of the population. We found that people who have this variation have an increased susceptibility to squamous cell cancer of the head and neck compared to the people who don't.

Are sunscreens really effective in preventing skin cancer?

Dr. DiGiovanna: There is evidence that sunscreens can protect against the development of malignancy both in animal models and in people. Studies have shown that UV radiation can induce tumors in animals and that sunscreen can prevent it.

Dr. Kraemer: Sun protection is more than sunscreens. Sun protection includes avoiding the sun, using clothing to protect yourself, getting shade under a tree if you are going outside, and wearing hats.

It is important for people to understand sun protection factors. The sun protection factor multiplies the number of minutes you can be outside before you burn. For example, if someone can be outside for 10 minutes before they burn, and they use a sunblock with a factor of 10, they can go 100 minutes. The amount of protection begins to level off at 15. What a lot of people do not realize is that although the higher factors do give more protection, it is not as big difference as between 0 to 15. We recommend use of a sunblock of at least SPF (Sun Protection Factor) 15.

Besides sunblock, how else can people protect themselves from skin cancer?

Dr. Kraemer: There is a shadow rule of sun protection. It's called "short shadow seek shade." The reason is that when your shadow is short, the sun is above your head, and you have to protect yourself. As the sun goes down, it goes through more and more of the atmosphere and your shadow gets longer. Eventually the atmosphere itself blocks some of the UV radiation-so it is kind of like a sunblock itself. Meteorologist Leith Holloway made measurements and came up with this shadow rule. It turns out that when your shadow is equal to your height, the SPF of the atmosphere is between 2 and 3 and when the sun goes down even more your shadow will get longer, and you don't need to protect yourself as much. The time you have to protect yourself is when your shadow is shorter than you are. This rule is very important because you don't even need to know how to tell time. Even kindergarteners can know when their shadow is shorter than they are. It works independently of daylight savings time and does not matter what time zone you are in or if it is summer or winter. In fact, it automatically adjusts for that. In the winter, the sun never gets that high. It is an important and very simple way of knowing what to do.

What about vitamin D levels? Don't people need to be in the sun?

Dr. Kraemer: We did a study with XP patients that were protected from sun exposure. All had vitamin D levels in good ranges. Even with sun protection, it is possible to have normal vitamin D levels with a good diet and exercise.

Could certain foods be related to preventing skin cancer?

Dr. DiGiovanna: There has been some research done to study the effect of compounds that work against oxidative damage. These antioxidants may be helpful in preventing damage. There is much work ongoing; green tea is one antioxidant that is being studied to see if it can prevent damage.

What is being done in the area of nonmelanoma skin cancer treatment?

Dr. DiGiovanna: The primary treatment for most nonmelanoma skin cancers is destructive: either surgery or some other destructive method that removes the tumor. There are some topical solutions that can be useful, including a new topical treatment, imiquimod. It is being used in studies with precancerous conditions and skin cancers to stimulate the immune system. It increases the levels of interferon in the body at the site of application. It is not FDA approved yet, but it has been associated with the clearing of nonmelanoma skin cancer.

The National Cancer Institute (NCI) is a component of the National Institutes of Health (NIH), one of eight agencies that compose the Public Health Service (PHS) in the Department of Health and Human Services (DHHS). The NCI, established under the National Cancer Act of 1937, is the Federal Government's principal agency for cancer research and training.