Lung Cancer Susceptibility Runs in Families

Researchers at The University of Texas M. D. Anderson Cancer Center have documented a 25% increased risk of developing one of a number of cancers in first-degree relatives (parents, siblings, offspring) of lung cancer patients who have never smoked compared with families of people who neither smoke nor have lung cancer.

Researchers say their study, one of the largest ever done and the only one to include both men and women never smokers and to inquire about the smoking history of their relatives, strongly suggests that these lung cancer patients and their affected relatives share an inherited genetic susceptibility to cancer.

“This study demonstrates the importance of familial factors in the general development of cancer,” said the study’s first author, Olga Gorlova, Ph.D., an assistant professor in the Department of Epidemiology. “These susceptibility factors can be environmental but are more likely to be influenced by genetic factors, because genes control pathways common to a number of cancers.”

Such marked cancer susceptibility also likely explains why patients in this study, who never smoked but might have been exposed to secondhand smoke, developed lung cancer in the first place, she said.

The research team, headed by Margaret Spitz, M.D., professor and chair of the Department of Epidemiology, looked at whether 2,465 first-degree relatives of 316 lung cancer patients who never smoked developed cancer. They also established a matched comparison group of 2,442 first-degree relatives of 318 “controls”—individuals who also never smoked but did not have lung cancer. They discovered the following:

First-degree relatives of lung cancer patients had a 25% increased risk of developing any type of cancer.

• Relatives of these patients had a 68% higher risk of developing lung cancer.
• Relatives of patients were about 10 years younger than relatives in the control group when they were diagnosed with cancer.
• Family members of patients had a 44% excess risk of young-onset cancers—those diagnosed before age 50.
• There was more than a six-fold risk of developing young-onset lung cancer in these families.
• Mothers of patients had more than a two-fold risk of developing breast cancer.

“It has long been observed that cancer seems to aggregate in some families more than in others, and with the help of this unique group of lung cancer patients and their relatives, we can begin to understand why that might be the case,” said Dr. Spitz.

Should Low-Risk Prostate Cancer Be Treated?

A new study will follow eligible low-risk prostate cancer patients with “watchful waiting” to determine if they can avoid or postpone therapy and related side effects but still live as long as patients who immediately receive invasive therapy.

Some men diagnosed with low-grade prostate cancer throughout the country will undergo active surveillance at M. D. Anderson Cancer Center for their disease, having changes monitored through regular prostate specific antigen (PSA) tests, biopsies, and check-ups.

The study will provide key information for the future development of clinical guidelines for watchful waiting and will also try to identify molecular markers that will better predict a person’s risk of developing aggressive disease that requires treatment.

“With the advent of the PSA test, we now see prostate cancer detected much earlier. But because of the sensitivity of the test, clinically insignificant tumors sometimes are over-diagnosed and patients may, as a consequence, be over-treated with radiation and surgery,” said Jeri Kim, M.D., principal investigator of the study and associate professor in the Department of Genitourinary Medical Oncology at M. D. Anderson. Researchers suspect that managing low-risk disease through surveillance may outweigh the risks and side effects of treatment. This study, and similar ones around the country, will seek to determine which patients are the best candidates for the watchful waiting approach.

“Prostate cancer is one of only a few cancers that can be latent in the body for some time and not require immediate treatment,” said Dr. Kim. “Many researchers have documented over the years that many men die with their disease rather than from it. While we need to intervene early, we also need to intervene appropriately with respect to the stage of disease, the man’s age, his health in general, and quality of life.”

For more information on the watchful waiting study for men with early-stage prostate cancer, call (713) 563-1602.

Assessing Lung Cancer Risk

Physicians have little to help them predict the development of lung cancer in their patients—even a history of heavy smoking doesn’t really help, since only a small fraction of lifetime smokers develops the cancer.

Now, however, researchers at M. D. Anderson Cancer Center are developing a risk assessment model that they hope will promote earlier detection of lung cancer in those smokers identified to be most at risk.

“Our goal is to develop an instrument that can help physicians estimate risk for developing lung cancer, like the Gail model does for breast cancer, or the Framingham model used to predict heart disease,” said the study’s first author, Matthew Schabath, Ph.D., a postdoctoral researcher in the Department of Epidemiology.

The analysis is based on research that compared the medical history and DNA repair capacity profiles of 2,134 lung cancer patients with the same data from 2,295 matched healthy individuals.

The prototype model is designed to first evaluate risk using only medical history and lifestyle factors, if that is all that is available, or a combination of medical history and genetic factors. For example, DNA repair capacity can increase or reduce a person’s risk of developing cancer. To the model, researchers added data from a laboratory test that measures how efficiently subjects’ lymphocytes drawn into a test tube repair damage from a carcinogen in tobacco smoke.

This model showed, for example, that:

• Heavy smokers who have been diagnosed with emphysema exhibit nearly a four times higher risk of lung cancer than light smokers without emphysema.
• This risk increases to nearly 11-fold if a person with the same history of emphysema and heavy smoking also has inefficient DNA repair capacity.

Clinical variables that appear to protect against lung cancer development are also being incorporated into the model, Dr. Schabath said. For example, they have estimated that:

• Individuals with a history of allergies (defined by a history of hay fever) have a 29% reduced risk of lung cancer.
• Such individuals who also exhibit efficient DNA repair capacity have a 56% reduced risk of developing lung cancer, compared with people who do not have allergies but have poor DNA repair capacity.

The model is a work in progress, said senior author Margaret Spitz, M.D., professor and chair of the Department of Epidemiology. The next steps in building the model are to add to it variations in important genetic pathways that control cellular functions and additional environmental and dietary factors.

“Early detection is key to successful treatment of any cancer, and this model is designed to help physicians identify and screen those smokers at highest risk for lung cancer,” Dr. Spitz added.

Promising Option for Herceptin Resistance

Breast cancer patients with HER2-positive tumors that don’t respond to Herceptin (trastuzumab) may benefit from a cocktail therapy that includes Herceptin along with one or more PI3K-inhibiting agents, say researchers at M. D. Anderson.

Their findings were made in cell culture and mouse studies but are so promising that a phase I/II clinical trial will start at M. D. Anderson in HER2-positive breast cancer patients whose disease has progressed despite Herceptin treatment.

“More than half of patients with HER2-positive tumors don’t respond to Herceptin as a single agent, and our research found that the presence of the protein PTEN is a powerful predictor of response,” said the study’s lead author, Dihua Yu, M.D., Ph.D., a professor in the Department of Surgical Oncology.

PTEN is known to block the effect of a growth-promoting protein known as PI3K, which itself controls an oncogenic pathway. Dr. Yu decided to test what would happen if she administered an experimental drug that blocks PI3K and thus mimics PTEN’s tumor suppressor activity.

In this study, the research group tested seven different PI3K inhibitors that are either used or under development for clinical trials. They found that one, RAD001 (everolimus), had better antitumor activity when combined with Herceptin than did Herceptin or RAD001 alone.

Another PI3K inhibitor, TCN-P (triciribine), showed significant benefit when used in combination with Herceptin, Dr. Yu said.

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

Other articles in OncoLog, May 2006 issue:

• A Better Kind of Brain Surgery
• Raloxifene Effective for Breast Cancer Prevention: Osteoporosis Drug Edges Past Tamoxifen in National STAR Trial
• House Call: The Many Benefits of Massage
• DiaLog: Cancer Vaccines and Immunotherapy

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