The Challenges of Incorporating Gene Panels Into Clinical Practice

Kate M. O'Rourke


June 22, 2015

In the past several years, an increasing number of gene panel tests have become available for use in the clinic. At the recent annual meeting of the American Society of Clinical Oncology (ASCO), speakers discussed some of the controversies and clinical dilemmas surrounding these tests.

Mark Robson, MD, clinical director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center in New York City, described gene panels as incredibly powerful and potentially disruptive tools. One of the biggest controversies is when to use a multigene test for cancer susceptibility.

"We don't have a standard way of deciding when these types of technologies should become standard of care," said Dr Robson. He pointed out that there is a standard, rigorous way that new drugs are evaluated and adopted into practice. Drugs go through phase 1, phase 2, and phase 3 clinical trials and are then approved by the US Food and Drug Administration (FDA). "Clinical adoption of the drug follows and then, generally, there is a standard of care developed through a consensus process," said Dr Robson. "We don't have anything like this [process] for devices."

Gene panel tests, similar to radiographic scans, are classified by the FDA as devices. The FDA evaluates devices, but not from an efficacy standpoint. "When you think of genomic testing and germline testing, there is no agency like the FDA saying, 'Yes, this device does what it says it does,'" said Dr Robson. "Things move to clinical adoption through an organic process, and then a similar organic process takes place to make them standard of care. The evolution toward standard of care is not usually driven by some sort of consensus mechanism."

The Centers for Disease Control and Prevention's Office of Public Health Genomics has established a process for evaluating scientific data on emerging genetic tests, called ACCE.[1] ACCE takes its name from the four main criteria for evaluating a genetic test: analytic validity; clinical validity; clinical utility; and associated ethical, legal, and social implications.[2] Analytic validity is how well a test measures the property or characteristics it is intended to measure. Clinical validity is the accuracy of a test in diagnosing or predicting the risk for a health condition. Clinical utility is the usefulness and added value that a test brings to patient management.

"Value is part of the clinical utility equation," said Dr Robson. "You have to think about how much you are paying in terms of toxicity or economically to make a decision about whether something has enough clinical utility to move into standard of care."

Actionability is another term that is bandied about when discussing genetic testing. "There is no universally accepted definition, but one suggestion is that an actionable finding is one that could plausibly lead to a specific medical recommendation or intervention, but there is no implication that the action is going to be beneficial," said Dr Robson.

There is a slew of data showing that clinicians change their practice based upon results of genetic testing. A recent study showed that Oncotype DX® and MammaPrint® influenced a change in treatment recommendations in 21%-74% of patients with breast cancer.[3] Retrospective analyses of the National Surgical Adjuvant Breast and Bowel Project B20 and Southwest Oncology Group SWOG-8814 trials revealed a large benefit of chemotherapy in patients with estrogen receptor–positive tumors and high Oncotype DX Recurrence Score (RS ≥ 31).[4] In another study of women testing negative for BRCA1/2 mutations, multigene sequencing identified 16 potentially pathogenic mutations in other genes, of which 15 prompted consideration of a change in care, enabling early detection of a precancerous colon polyp.[5] While it's clear that genetic tests are influencing treatment decisions, there are no prospective, randomized trials demonstrating that the changes improve outcomes.

Two of the first prospective trials expected to report on the benefits of changing therapy after a genomic test are TAILORx and RxPONDER. TAILORx is examining whether genes that are frequently associated with risk for recurrence in women with early-stage breast cancer can be used to assign patients to the most appropriate and effective treatment. The RxPONDER trial is aiming to determine the benefits, if any, from adding chemotherapy to hormonal therapy after surgery for patients with node-positive, hormone receptor–positive, HER2-negative breast cancer who also have low to intermediate Oncotype DX recurrence scores.

According to Dr Robson, analytic validity is a hurdle for gene panel tests. "Next-generation sequencing is not uniformly perfect. The technology is widely available, and many laboratories have not published their validation systems. The validation requirements are not standardized, and even within laboratories, the extent of the analysis might differ," said Dr Robson. "Different labs may go further or less far into the introns. There may be different approaches to dealing with the issues of pseudogenes that might compromise things. There are a lot of technical factors that can make different laboratories have different results, and that information is not necessarily transparent. It is potentially an argument for increased regulatory oversight by the FDA."

Determining the clinical validity of a gene panel test has its own set of challenges. Often, gene panels include many different genes that are not associated with the phenotype that a clinician is testing for, and the risks associated with mutations in those genes are not entirely clear. The risks associated with functionally significant mutations are poorly defined for many genes in some commercial panels, such as BARD1 and NBN.[2,6] There is also a high rate of missense mutations, and there has been disagreement about the classification of these variants.

"It is important to think of multigene testing as a strategy, not a test," said Dr Robson. "The threshold for actionability tends to be subjective."

Another huge stumbling block for clinicians in integrating gene panels into their practice is how to communicate test results. In a recent study, BRCA1/2-negative and untested patients were asked to complete pre- and posttest counseling, as well as surveys evaluating testing experiences and cognitive and affective responses to multiplex testing.[7] Of the 73 patients, 67% completed the pretest counseling. BRCA1/2-negative patients were more likely to proceed with multiplex testing than those not tested for BRCA1/2 (86% vs 43%; P < .01). Many patients who declined testing reported concern over uncertainty and distress. The majority of patients would not change anything about their pretest counseling (76%) or posttest counseling (89%), and roughly three quarters of patients were classified as making an informed choice, including 81% of those who proceeded with multiplex testing.

"Women who had previous BRCA1/2 testing that was negative had a high interest in having testing with a multigene test for their cancer risk. Women who had not had prior testing chose to just have BRCA1/2 testing," said Wendy Kohlmann, MA, a genetic counselor at University of Utah Health Care, Salt Lake City, Utah. This latter group of women were only interested in the test that was most relevant to them and did not want to be overwhelmed with other information.

"This study also demonstrated that the process of pretest counseling helped set expectations, preparing people to make a choice and understand their results," said Ms Kohlmann. "The best time to deal with complex test results is during pretest counseling."

For example: A 40-year-old healthy woman inquires about BRCA1/2 genetic testing due to her family history (her mother) of ovarian cancer. The clinician orders a multigene panel including BRCA1/2 testing and identifies a mutation in CDH1, which is associated with hereditary diffuse gastric cancer. The patient does not react well to the news. She feels angry and scared. "This is the classic example of the pros and cons of this new technology," said Ms Kohlmann. "We have the technology to find life-saving mutations that we wouldn't have otherwise identified, but on the other hand, we really don't know whether the finding of this type of mutation, out of the context that we normally study it in, has the same meaning and should come with the same recommendations."

After delving further into the mother's medical history, the clinician determines that she didn't present with the typical ovarian cancer symptoms and may have had gastric cancer. "Panels are great. They let us look for things that we maybe wouldn't have thought of. But on the other hand, taking a family history is still important," said Ms Kohlmann. Had this woman been told about the possibility of her mom having gastric cancer and the existence of genes that predispose individuals to gastric cancer, she may have processed the test results in a different way.

"The whole process of returning complex information starts before testing has been done," said Ms Kohlmann. "Pretest counseling is incredibly important for both determining patient goals and setting expectations."

ASCO has developed an expert statement on how and what to collect for a cancer family history and how to interpret the family history in the context of other information.[8] "ASCO has developed elements of informed consent that should be considered for every genetic test that is done, but particularly with preparing patients for possible outcomes," said Ms Kohlmann.

Another crucial element in communicating genetic testing results is that follow-up does not end with the disclosure of results. If a practice is not able to help carry out some of the other aspects of testing, such as long-term screening or dealing with unaffected family members, having systems in place for referral to other providers or genetic specialists who can take on those goals is very important.

"How well we are able to all come together as a team and help families implement this information into their care is really going to be a key component of determining whether genetic tests have clinical utility," said Ms Kohlmann.

Dr Robson disclosed a consulting/advisory role with AstraZeneca, Bayer, BioMarin, McKesson, and Pfizer. Ms Kohlmann disclosed receiving honoraria from and a consulting/advisory role with Myriad.


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