Genetic Testing for Cancer Susceptibility -- ASCO Updates Policy Statement

Zosia Chustecka

February 04, 2010

February 4, 2010 — The American Society of Clinical Oncology (ASCO) has issued an updated policy statement on genetic and genomic testing for cancer susceptibility. The new document, an update of a statement issued in 2003, was published online January 11 in the Journal of Clinical Oncology.

The update was prompted by an increase in the number of such tests, and it raises 2 main concerns — the fact that some tests are of unproven clinical benefit, and the fact that some are now being marketed directly to consumers.

More than 900 genetic tests are now available, although only 5% to 10% of all cancers are considered to be hereditary, according to ASCO.

"The awareness of individual genetic differences within the population has sparked a number of significant developments and an unprecedented level of raw information being made available, not only to health professionals, but also to the public in the form of direct-to-consumer [DTC] tests," said senior author Kenneth Offit, MD, MPH, chief of the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center in New York City, and a member of ASCO's Ethics Committee.

These updated recommendations "attempt to get back to the basics — patient safety and clinical utility — for the individuals considering genetic testing and the doctors who offer testing or may be asked by patients to interpret direct-to-consumer test results," Dr. Offit said in a statement.

Oncologists and other healthcare providers who offer genetic tests should continue to be guided by a recommendation made in 2003, which states that testing should be offered only when the following criteria are met:

  • the individual being tested has a personal or family history suggestive of genetic cancer susceptibility

  • the genetic test can be adequately interpreted

  • the test results have accepted clinical utility.

The updated statement acknowledges that emerging technologies, like genomic profiling for low-penetrance genetic variants (markers of very low disease risk), might be appropriate for patients who do not have a personal or family history suggestive of cancer risk, provided that clinical utility is established and results can be easily interpreted. However, it also points out that the genomic tests for low-penetrance variants currently do not have proven clinical utility.

The premature dissemination of some of these technologies can lead to problems.

"None of us in this field is trying to block or delay the transmissions of useful genetic information to the broadest possible constituency," Dr. Offit emphasized in an interview with Medscape Oncology. "But we want to do this in a responsible way," he added, and there is concern that "the premature dissemination of some of these technologies can lead to problems of false reassurances and false alarms."

There are 2 separate issues, Dr. Offit explained.

There is a clear demarcation between genetic tests for high-prevalence mutations, which have proven clinical utility, and genomic tests for low-prevalence variants, which currently have no proven clinical utility, he said.

He explained that there is also a big difference between using these tests in a traditional medical model, where the test is ordered by and discussed with a healthcare provider who is responsible for the patient's health, and the new situation, where these tests are marketed by commercial companies over the internet and where results are issued in a computer printout without any human interaction.

Tests With Accepted Clinical Utility

Examples of genetic tests for which clinical utility is accepted are testing for high-penetration mutations, such as BRCA1/2 for breast cancer and MLH1/MSH2 for colorectal cancer. These tests inform clinical decision-making and facilitate the prevention or amelioration of adverse health outcomes, the authors explain.

For example, women found to carry the BRCA1 mutation, which increases the relative risk of developing breast cancer 32-fold by the age of 40 to 49 years, can be offered increased screening with mammography or magnetic resonance imaging, or risk-reducing surgery. Individuals found to carry the MSH2 mutation, which increases the risk for colon cancer 13.1-fold by the age of 30 years and 9.3-fold by the age of 50 years, can be offered earlier and more frequent endoscopy and a prophylactic colectomy after a diagnosis of malignancy.

Similar interventions can be offered to individuals found to carry another high-penetrance mutation, APC, which increases the risk for colorectal cancer 19-fold over a lifetime. Another high-penetrance mutation is RET, which increases the risk for medullary thyroid cancer 125-fold over a lifetime; people found to carry this mutation are offered prophylactic thyroidectomy.

However, although these high-penetrance mutations are clinically relevant, they are uncommon, the authors point out.

Most inherited cancer susceptibility arises from a number of DNA sequence variants, each of which, in isolation, confers a limited increase in risk. Genetic tests for intermediate-penetrance mutations and low-penetrance variants (single-nucleotide polymorphisms [SNPs]) are of uncertain clinical utility because the cancer risk associated with the mutation or SNP is too small to form an appropriate basis for clinical decision-making. For all of these intermediate- and low-penetrance variants, there is no proven intervention.

ASCO recommends that genetic tests with uncertain clinical utility, including genomic risk assessment, be administered in the context of clinical trials. However, some of these tests are being directly marketed to the public.

One example of a low-penetrance variant (SNP) is rs10505477 at 8q24, which increases the relative risk for colon cancer 1.27-fold and the relative risk for prostate cancer 1.43-fold.

There are also 2 low-penetrance variants, rs13281615 at 8q24 and rs1219648 at FGFR2, which increase the relative risk for breast cancer 1.21-fold and 1.23-fold, respectively. The authors note that this increase in the relative risk of developing breast cancer is equivalent to that of delaying childbearing from age 30 to age 35. "This level of risk does not warrant changes in recommendations for screening or prevention," they add.

Considerable Concern Over DTC Genetic Testing

Genetic testing for cancer susceptibility has become an accepted part of oncologic care, Dr. Offit and colleagues write. To date, most of this testing is professionally mediated and is of accepted clinical utility, they explain.

However, there is "considerable concern within the medical community about various aspects of direct-to-consumer genetic testing," the authors note. With marketing over the internet, there are concerns about informed consent and inadequate counseling, both before and after testing.

"Not all DTC testing companies offer counseling, and they may only offer counseling to consumers who pay additional fees," the team points out. "Where counseling is provided, there is some concern that the advice offered by testing companies may be biased in favor of testing."

It makes for a tricky situation when individuals who obtain DTC tests then turn to a healthcare professional for help interpreting test results. Such requests can "pose significant challenges," the authors write.

"While most of us look forward to a time when all doctors will offer genome scans to guide preventive care of their patients," Dr. Offit said, he is not as sure that the DTC delivery of these services by for-profit companies is the model to aim for.

Some of these points were raised recently by researchers from the University of Michigan Comprehensive Cancer Center in Ann Arbor.

"While the test is a very easy thing to do — it's a simple blood test — the interpretation of the results can sometimes be very complicated," said Mark Pearlman, MD, professor of obstetrics and gynecology at the University of Michigan Medical School.

It's important to understand that getting the genetic test result is only a piece of the puzzle.

"It's important to understand that getting the genetic test result is only a piece of the puzzle," he continued. "It really takes a professional who understands genetics to work with individual women and men to allow them to understand exactly what the piece of information means to them in terms of their risk, their loved ones' risks, and what can then be done to lower that risk."

These comments appear in a press statement issued by the university in response to a new advertising campaign in the United States that encourages women to be tested for gene mutations related to breast and ovarian cancer (BRCA1/2).

Only 2% of the population should be tested for these mutations, Dr. Pearlman and colleagues point out.

"It's very important that the right women seek out genetic testing for breast and ovarian cancer," said Sofia Merajver, MD, PhD, director of the Breast and Ovarian Risk Evaluation Program at the University of Michigan. "Cancer risk is more complex than a simple yes or no, and the test for genetic mutations is only part of the picture."

Most cases of breast and ovarian cancer are random and are not linked to BRCA gene mutations, the doctors point out. Less than 10% of all women with breast cancer and less than 15% of all women with ovarian cancer carry a BRCA gene mutation.

Only 1 of the 5 authors of the ASCO policy statement update reports a relevant financial relationship: Mark Robson, MD, from Memorial Sloan-Kettering Cancer Center, reports receiving research funding from AstraZeneca and Kudos Pharmaceuticals.

J Clin Oncol. Published online January 11, 2010. Abstract