January 24, 2007

By Heather Maisey

Posted in: risk

Tags: DNA, gene, monograph, multiple, primary, radiation, risk, second

While some cancer survivors are more likely to develop a new tumor than others, little is known about the complex interaction of factors that lead to this increase in risk. The chance of developing a second cancer can be affected by a variety of factors, including shared causal factors, such as lifestyle and environmental exposures, genetic susceptibility, and combinations of risk factors including gene-gene and gene-environment interactions. As more research focuses on the issues faced by cancer survivors, scientists hope to provide answers that will allow for improved therapy and care. Researchers also believe that knowledge gained from these studies will improve the quality of life for all cancer patients.

Margaret A. Tucker, M.D., director of the Human Genetics Program and Chief of the Genetic Epidemiology Branch in NCI’s Division of Cancer Epidemiology and Genetics, is a leading expert on the development of new tumors among cancer survivors. BenchMarks talked with her about some of the causes of second cancers and what is being done to learn more about them. 

Which types of cancer are associated with the development of a second cancer? 

One common type of second cancer is a new cancer in the same organ. For example, the most common cancer after a first breast cancer is a second breast cancer. Researchers postulate that a woman’s right breast has some or all of the same exposures as her left breast; therefore, if one breast has been exposed and the woman develops breast cancer, it’s not unreasonable that a second tumor could develop in the opposite breast. Similar multi-focal origins are also seen with cancers of the colon and lung, as well as melanoma of the skin.

There is a theory called ‘field effect’, which says that different parts of an extended organ system, such as the respiratory and upper aerodigestive system, are exposed to the same carcinogens, so there are primed cells in the same or a neighboring organ system that can develop into a second cancer. It’s important to note, though, that cancer recurrence and metastatic tumors are not considered a second cancer—they are the same cancer reappearing and they arise from the first cancer, either in the same location or distantly.

However, the vast majority of second cancers are those that arise at a different site or within another organ system, separate and independent from the first.

What are the risk factors for developing a second cancer?
There are many risk factors for developing a second cancer, which include environmental and genetic risk factors. Genetic susceptibility is a very broad term because not only does it describe genetic mutations that convey high levels of predisposition affecting a small proportion of the population, like BRCA1/2 mutations for breast cancer, but it also includes the huge number of unidentified genetic variations that are much more common in the population but convey lower levels of risk and often involve interaction with specific exposures in the environment.

How did you become interested in studying therapy-related tumors?

When I came to NCI as a cancer epidemiologist, my work mainly focused on familial cancers and genetic predisposition to cancer. Because of this, I soon became involved in the first-ever case-control study looking at second cancers in survivors of childhood cancer. Many childhood cancers, as you know, are quite rare and often linked to inherited genetic factors, such as mutations in Rb-1, that put these children at high risk for developing certain tumors. I quickly learned that tumors related to cancer therapy presented an interesting paradigm — a unique research opportunity where we know the exact dose of a potent carcinogen that someone receives, usually under very controlled circumstances. We can be fairly accurate in pinpointing and measuring the exposures and the risks. We are able to use that information as a way to understand more about why second cancers happen, and when possible, develop hypotheses about these cancers when they arise in the general population, as well as in cancer survivors.

What are you most concerned about?

Oncologists and other clinicians are dedicated to the successful treatment and survival for those who are diagnosed with cancer. Once someone becomes a cancer survivor, we must do what we can to make sure they maintain their quality of life and good health. We all understand that survivors often fear cancer recurrence or finding a new cancer, so we must ensure that survivors have the appropriate follow-up care, which includes regular check-ups, screening, and, to minimize their risk of a second cancer, encouragement to practice behaviors consistent with a healthy lifestyle — which include no tobacco use, a balanced diet, and physical activity.

Are there gene mutations associated with the risk of developing a therapy-related second cancer?

There do seem to be certain genetic factors that can increase a person’s susceptibility to the harmful effects of anticancer therapies, but we don’t yet know enough to say for sure what they are. For example, the best known case is in individuals diagnosed with hereditary retinoblastoma, who have a specific mutation in the Rb-1 gene. For reasons that aren’t well understood, patients with this mutation, when given radiotherapy, are at higher risk for developing sarcomas either in the bone or connective tissue.

Studies of the genetic mechanisms of second tumor risk in cancer survivors are incredibly complex to carry out. Because these occurrences are rare, the research community doesn’t have big enough studies with a sufficient number of people to definitively identify the susceptibility genes in therapy-related cancers.

An exciting area of research is the identification of variations in genes that are important in activating or detoxifying specific chemotherapy agents. These variations may be useful in predicting efficacy and toxicity of these drugs. It is a promising new avenue of research that a lot of people are investing time and energy in. In the next five to 10 years, we should have much more information than we do now.

What is being done to improve anticancer therapies in order to reduce the risk of long-term effects?

In the last couple of decades, investigators have carried out many clinical trials in efforts to decrease the treatment toxicity but improve long-term survival. They are interested in documenting long-term effects and the difficulties that survivors have. I think that the recent interest in cancer survivorship, quality of life, and long-term toxicity, not only for second cancers, but also for cardiac effects, neurological effects, and fertility effects is important for elucidating risk factors and improving therapy. People are very concerned about mitigating these problems in the future.

What are the current ‘hot topics’ in this area of study?

 In the next few years, I think we’re going to see more work about the impact of behavioral and environmental modifications, such as tobacco cessation, diet modification, weight loss, and physical activity, on the prevention of first and second cancers. Large-scale molecular epidemiology studies will provide unique clues to the genetic factors and biologic pathways involved in tissue repair after radiation and chemotherapy. Also, we have an opportunity, through the NCI’s cancer registries, to continue to monitor survival outcomes in the largest group of cancer survivors ever assembled. By studying risk of second cancer and other long-term health outcomes in clinical trials, especially when the exact treatment regimens are known, we can inform clinical decision-making and management strategies to prevent cancers in the future. Hopefully, new information will allow us to predict not only long-term risk associated with certain drugs and radiation, but also short-term toxicities. This will vastly improve the quality of life for those being treated for cancer.