On the Horizon ­ Genetic Testing Takes Cancer Screening to New Heights

 

Janice Poplack, who underwent genetic testing and learned she carries a faulty gene that predisposes her to ovarian cancer, enjoys a quiet moment with her sons Eric (center) and Gregory.

 

If a blood test could predict cancer risk, would you take one?

 

For Janice Poplack, the answer was a resounding "yes."

 

A breast cancer survivor, Poplack wanted to know if she also was at high risk for developing ovarian cancer. Because if she was, the mother of two was going to take preventive action so "I can be there for my children."

 

Before any blood was drawn, however, Poplack received extensive genetic counseling in the Breast and Ovarian Risk Assessment Clinic at M. D. Anderson's Cancer Prevention Center to understand the risks and benefits associated with testing.

 

"Counseling is critical," says M. D. Anderson genetics counselor Pat Ward, "and should always be offered to anyone considering a genetic evaluation.

 

"Some people, knowing all of the potential positive and negative implications, may actually decide not to go through with the test," Ward explains. "Others, on the other hand, may feel it would be beneficial for them to know their risk."

 

After weighing the pros and cons, Poplack consented to the test, only to learn a short time later that she was more likely than most other women to be diagnosed with ovarian cancer during her life. This is because she carries a faulty gene responsible for causing not only this disease, but also several other cancers, including breast, prostate and possibly colon.

 

Despite the counseling and preparation she received, Poplack wasn't fully ready for the answer she got. "It was overwhelming to realize that this is a genetic condition, which means that it is truly out of my control. I felt powerless."

 

Many people often feel similarly when first hearing they have an altered gene that may lead to cancer, but Poplack's initial reaction only lasted a couple of days. After much thought and discussions with her family and health care team, she has decided to have her ovaries removed in hopes of reducing her chance of getting the disease. Although the degree of protection from surgery is not yet clear, experts say it appears to decrease risk.

 

Identifying faulty genes

 

Poplack is one of a growing number of people electing to undergo genetic testing to learn whether they carry an altered gene that may place them at increased risk of developing cancer.

 

Mutation-based testing has its origins in predicting risk of serious childhood genetic disorders like cystic fibrosis and Duchenne muscular dystrophy. Testing for cancer, however, is still in its infancy as the identification and role of some defective genes only recently have been discovered and understood. Their predictive implications in disease development and management are currently under investigation.

 

As part of its ongoing prevention program, M. D. Anderson has established a Human Clinical Cancer Genetics Clinic to provide risk assessment and counseling as well as testing for heritable genetic mutations that predispose people to breast, ovarian, endometrial, bowel (colon and rectum) and endocrine cancers.

 

Hereditary cancers are believed to account for five to 10 percent of all cancers. The majority of cancers are considered to be sporadic and occur from an accumulation of random mutations that develop over time due to errors in replication and carcinogenic exposures.

 

According to Dr. Gordon B. Mills, chairman of the Department of Molecular Oncology and acting medical director of the Breast and Ovarian Risk Assessment Clinic, understanding inherited genetic changes that can lead to cancer is an important first step in developing new, more effective cancer prevention, diagnostic and treatment strategies.

 

In the Breast and Ovarian Risk Assessment Clinic, testing involves screening for the BRCA1 and BRCA2 genes, also known as Breast Cancer 1 and Breast Cancer 2 genes. About 20-40 percent of women with a mutation of the BRCA1 gene will develop ovarian cancer, and about 40-60 percent will develop breast cancer.

 

Those who have or are suspected of having familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) also can receive genetic counseling and screening for the detection of gene mutations implicated in these diseases, says Dr. Patrick M. Lynch, associate professor of gastrointestinal medical oncology and digestive diseases, and director of the GI Hereditary Colon Cancer Program.

 

Although FAP can be diagnosed using a sigmoidoscope, it often comes at a time when hundreds of polyps have already involved the colon. The goal of genetic testing is to identify carriers before symptoms appear so early detection and curative measures can be started, Dr. Lynch says.

 

A test to screen for several susceptibility genes that account for HNPCC also is available. According to Dr. Lynch, these so-called mismatch repair genes are suspected to cause nearly 90 percent of all inherited colon cancers.

 

Genetic testing for a group of endocrine cancers involves the mutation analysis of the RET gene, says Dr. Robert F. Gagel, chairman of the Department of Medical Specialties and chief of the Section of Endocrine Neoplasia and Hormonal Disorders. This gene is responsible for predisposing carriers to multiple endocrine neoplasia, Type 2 (MEN2) cancers, which includes medullary thyroid carcinoma, pheochromocytoma and parathyroid neoplasia.

 

Individuals with RET mutations will go on to develop these cancer syndromes 90, 50 and 15 percent of the time, respectively.

 

The gene for a second endocrine cancer syndrome, multiple endocrine neoplasia, Type 1 (MEN1), has recently been identified, says Dr. Gagel, endocrine program director. MEN1 is characterized by pituitary, pancreatic and parathyroid tumors. Genetic analysis will make it possible to detect those at risk.

 

Testing not 100 percent predictive

 

Although testing can determine with a fairly good degree of accuracy if a person has a mutation, it often cannot predict for certain whether that individual will develop cancer.

 

"An inherited abnormality in one or more genes does not automatically mean a cancer diagnosis. It does, however, place that individual at increased risk for getting the disease," says Susan Peterson, project director for cancer genetics studies in the Department of Behavioral Science.

 

In general, testing is not 100 percent predictive, says Paula Rieger, a nurse practitioner in the Breast and Ovarian Risk Assessment Clinic. "Tests currently available may miss certain mutations depending on the gene studied."

 

If a test comes back positive, several options for managing risk are available, Rieger says. Currently, they involve intensive screening, chemoprevention and prophylactic surgeries for removing certain organs or body tissues before cancer occurs.

 

Since testing is new, "these therapeutic interventions in most cases are not well integrated into practice yet or have not been a standard of care," Rieger says.

 

The exceptions are thyroidectomy and colectomy for people predisposed to MEN2 and FAP, respectively. These prophylactic surgeries -- performed at an early age -- are more standard care since they have proven beneficial in preventing these cancers.

 

The benefit of removing a woman's breast or ovaries, however, has not been as clear. While an alternative for women who test positive for BRCA1 or BRCA2 genes, some residual risk of breast and ovarian cancer developing still remains.

 

Despite these limitations, "genetic testing is still an important consideration for individuals who have a strong family history of cancer because hereditary forms of the disease tend to occur at much younger ages than sporadic cancers, often before routine screening is recommended," says Dr. Ellen R. Gritz, chair of the Department of Behavioral Science and holder of the Annie Laurie Howard Research Professorship.

 

"If we know a person is at high risk," she continues, "we can suggest he or she begin early screening examinations to detect any abnormalities before they become cancerous. In some instances, we also can administer chemopreventive agents to keep cancer at bay when appropriate."

 

The Value of Genetic Counseling

 

Aside from the benefits and limitations, there are several other issues surrounding genetic testing people must consider when deciding if testing is right for them.

 

Fortunately, they are not alone -- health care professionals with special training in genetics are there to help. Their role is to educate individuals on the risks, benefits and options of testing, thus helping people make their own informed decisions.

 

"There can be profound psychosocial issues associated with genetic testing," says Dr. Rebecca Pentz, clinical ethicist and associate professor of clinical ethics. "It has incredible symbolic value. There is something very personal about our genetic makeup, and when you find out you have a mutation in a gene, it can affect how you feel about yourself."

 

People who are identified as carriers may experience a change in body image and self-perception, anxiety, depression and guilt over passing the mutation on to a child or for escaping the disease when a sibling has not, Rieger says. Just as a positive test can provoke intense emotions, a negative result can bring feelings of relief and joy.

 

Another issue that ties into testing is that it is not always an individual decision, Rieger says. "It's a decision made in the context of people's immediate and extended family. Any information they receive can potentially impact the whole family. People need to recognize that some family members may want to know, while others may not. It's important they discuss the various implications of testing with their family beforehand to avoid any conflicts."

 

Insurance and confidentiality also are major concerns. At this time, it is still largely undetermined how insurance companies and employers might use this information. "People have real concerns that the information from genetic tests may be used to discriminate against them," Rieger says.

 

"Fortunately, strides have been made in getting laws enacted that protect some from genetic discrimination in several states, including Texas, and at the federal level. While a step in the right direction, more needs to be done to ensure comprehensive protection," Peterson adds.

 

At present, these laws only protect results of genetic testing, but not people's medical history, which can be enough information for insurance companies to suspect a high susceptibility to disease, she says.

 

Even though protective legislation is beginning to be put in place, many people are still reluctant to have their genetic information revealed. In response to this concern, M. D. Anderson has taken steps to assure confidentiality of testing results.

 

"The decision to have genetic testing shouldn't be taken lightly," Dr. Gritz says. "Before going down that path, people need to consider how the results will affect them and their families. That's why genetic counseling is so important. The counseling process needs to be initiated before testing begins and continued when the results are known, and for some time afterwards to ensure that all parties involved are managing well."

 

To better understand the impact of these psychosocial issues, the Department of Behavioral Science is studying -- with the help of a grant from the National Human Genetics Research Institute and the National Cancer Institute -- the implications of genetic testing for HNPCC on individuals and their families. This is one of the first studies in the United States to look at the long-term effects of colon cancer genetic testing. A similar study also is being done with participants undergoing gene-based testing for hereditary breast and ovarian cancer.

 

On the Horizon

 

While genetic testing is new for determining cancer susceptibility, it may one day be used as a routine screening method much like cholesterol tests have been for heart disease. But instead of checking the blood for "good" and "bad" cholesterol, it will look for mutations in the body's genes.

Return to Spring 98