Some genomic tests developed to personalize medical decisions about cancer care are beneficial, while for others the evidence is uncertain and reliance on the test might even lead to poorer medical management of cancer in some cases, according new recommendation statements from an expert panel.

The statements appear in the January issue of Genetics in Medicine, the official peer-reviewed journal of The American College of Medical Genetics. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health, a leading provider of information and business intelligence for students, professionals, and institutions in medicine, nursing, allied health, pharmacy and the pharmaceutical industry.

Genetic tests for tumor gene expression in women with early-stage breast cancer to detect those at risk for cancer recurrence, the panel wrote, are based on insufficient evidence to determine whether they offer any improvement in health outcomes. The panel also found insufficient evidence to recommend testing for variants of the gene UGT1A1 in patients undergoing chemotherapy for metastatic colorectal cancer to inform use of the chemotherapy drug irinotecan.

While the test might be useful in identifying patients at risk of side effects from the drug, reducing irinotecan dosage may be more harmful than the side effects, so the clinical utility of the UGT1A1 test is questionable, at best, it said.
On the other hand, genetic testing for Lynch syndrome, a hereditary condition that increases the risk of colorectal cancer, is useful to recommend screening relatives for the mutations that cause the syndrome and encouraging them to have regular colorectal cancer exams, the panel found.

"Our reviews of the evidence found that in some situations genetic testing may be helpful, but that in others, including for some genetic tests currently used in cancer care, there is not enough evidence available to determine the balance of benefits and harms," said Alfred Berg, MD, MPH, chair of the working group that produced the recommendations. These recommendation statements are the most recent analyses from the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.

As the number of available genetic tests continues to increase, so do questions regarding their appropriate use. The EGAPP initiative was developed by the National Office of Public Health Genomics at the Centers for Disease Control and Prevention (CDC), with the goal of supporting evaluation of genetic tests and other genomic applications that are in transition from research to clinical and public health practice. The independent EGAPP Working Group based its recommendations on commissioned, systematic reviews of available studies addressing the validity and utility of specific types of genetic tests. These reviews follow the most up-to-date methods for collecting, analyzing, and grading evidence on analytic and clinical validity and on the clinical utility of genetic and genomic tests. Another article in the January GIM provides more details on the methods used in developing the EGAPP recommendations.


More Evidence Is Needed for Some Breast Cancer, Colorectal Cancer Tests

According to estimates from the American Cancer Society, nearly 150,000 people in the US were diagnosed with colorectal cancer in 2008, whereas over 180,000 new cases of breast cancer were expected among women.

The EGAPP Working Group assessed evidence on genetic tests involving tumor gene expression profiling in women with early-stage breast cancer. Researchers have suggested that these tests might help to identify women at high risk of recurrent cancers, who could then be targeted for more aggressive treatment. However, the EGAPP recommendation found insufficient evidence to recommend for or against use of tumor gene expression profiles to improve health outcomes for certain populations of women with early stage breast cancer. More research will be needed to determine the true value of tumor gene expression profiling in women with breast cancer.

The EGAPP Working Group also evaluated studies of UGT1A1 gene testing in patients undergoing chemotherapy for metastatic colorectal cancer, finding that there was insufficient evidence available at this time to recommend for or against its use in the specific clinical scenario that was evaluated by the panel. The review confirmed previous reports that patients with certain UGT1A1 variants are at increased risk of neutropenia—a serious side effect of treatment with the chemotherapy drug irinotecan.

However, the review questioned the "clinical utility" of UGT1A1 gene testing. Reducing the irinotecan dosage in patients at increased risk of neutropenia may reduce side effects. However, this strategy might also reduce the cancer-killing effectiveness of irinotecan, resulting in increased harm to the patient. No studies were identified that evaluated the benefits of adjusting irinotecan dosage according to the results of UGT1A1 testing.


Evidence Supports Lynch Syndrome Testing for Colorectal Cancer Patients

Lynch syndrome is a genetic condition associated with an increased risk of colorectal and some other types of cancer. Gene mutations associated with Lynch syndrome are found in about 3% of patients with newly diagnosed colorectal cancer. Relatives who have inherited the same mutation are at high risk of colorectal cancer—about 45% will develop the disease by age 70.

In its recommendation statement, the EGAPP Working Group "found sufficient scientific evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer, to reduce morbidity and mortality in relatives." If the patient tests positive for genes linked to Lynch syndrome, then his or her relatives can be offered genetic testing, the panel wrote.

Relatives with positive tests might be offered more frequent screening to detect early colorectal cancer, it recommended. The EGAPP Working Group reported that there is moderate certainty that this type of strategy—involving genetic testing and heightened surveillance where indicated—might be expected to substantially improve individual health outcomes in enough cases to produce a moderate health benefit at the population level.

An important consideration in the corresponding EGAPP-commissioned review, which also appears in the January GIM, is the finding that many affected relatives are willing to undergo the genetic test, and may accept more frequent screening if their test results are positive. More research will be needed to identify the most effective screening strategy, however.
Dr Berg noted that "[t]he EGAPP Working Group recognizes the enormous potential of genetic testing to improve health care, but also recognizes the potential for harm if tests are widely implemented prematurely. Many genetic tests are well suited to examination through the kind of well-constructed randomized controlled trials that would allow us to determine the balance of benefits and harms with confidence. We understand that most research funding now focuses on discovery rather than translation, and that clinical trials can be expensive and lengthy. Nonetheless until better evidence is available the neutral conclusion of ‘insufficient evidence’ is the best we can say for some of these tests right now."

"The history of medicine teaches us again and again that medical practice must be based on a firm foundation of evidence," commented Dr James P. Evans, Editor-in-Chief of Genetics in Medicine. "Good ideas and anecdotes may be a reasonable place to start, but are insufficient to guide proper practice. Genetics is no exception to this basic axiom. As our field of medical genetics increasingly permeates modern medicine it is vital that it be based on a firm evidence base. And make no mistake; such evidence is rarely easily or cheaply acquired. But it is vital if we are to help our patients and avoid harm. In this special issue of GIM we feature a number of evidence based reviews on some of the most active areas of medical genetic research."