Thomas Reinke
Contributing Editor

One of the most rapidly evolving areas of genetic testing is for germline mutations — changes in the DNA of egg or sperm cells that are passed on to offspring, potentially popping up in a person’s life as a heritable condition.

The test for breast cancer susceptibility in the BRCA1 and BRCA2 genes is probably the most widely recognized germline mutation test. Angelina Jolie’s recent prophylactic double mastectomy as a result of this test gave a real boost to hereditary breast cancer testing.

More testing

“There has been an increase in BRCA testing since the Angelina Jolie news article” last April, says David Finley, MD, Cigna’s national medical officer for enterprise affordability and policy. “We did not anticipate that the interest would be sustained. I thought it would have peaked two or three months after the news, but it has continued,”

“The chances of having a mutation of unknown significance are as high as or even higher than the chances of getting a positive result for the primary indication,” says David Finley, MD, Cigna’s national medical officer for enterprise affordability and policy.

The most visible development in germline testing is for hereditary cancers. Tests involving individual genes have grown to panel tests incorporating multiple genes, in some cases more than 25. Some of these tests provide one-stop shopping, covering multiple hereditary cancers.

The banner on the home page of Myriad Genetics, the commercial lab with the original BRCA test that was the subject of the Supreme Court case on the patentability of genes (decision: no patents), blares “hereditary cancer — know your history, know your risks,” touting its 25-gene test. Other commercial laboratories, such GeneDX and Ambry Genetics, offer similar tests.

The developments with hereditary cancers are one example of the expansion of genetic testing on all fronts as costs fall, new biomarkers are discovered, and the power to accurately detect alterations increases.

While these advances offer hope in personalized medicine, they far outstrip the ability of clinicians to effectively integrate genetics into their practices, posing numerous problems for health plans.

Three challenges

In September 2013 Cigna initiated a clinical management program for genetic testing that addresses three very important challenges: improving consumers’ understanding of genetic testing, ensuring appropriate utilization, and helping physicians incorporate genetics into their practices. Cigna has become the first national health plan to use genetic counseling as an integral part of genetic testing.

Pretest counseling by a certified genetic counselor is required before test precertification for breast, ovarian, and colon cancers and a cardiac condition known as long QT syndrome. Cigna has contracted with Informed DNA to provide genetic counselors to referring physicians and patients, locally or by phone.

The program is a first step in responding to widespread challenges in genetic testing. “About 80% of the tests that go through our review program do not require genetic counseling,” says Finley. “There are many genetic tests that can be done, but most have very limited clinical impact because we do not know what to do with the results. The three cancers that we link to genetic counseling are a minority of our volume, but the biomarkers and tests for them are well established, and there are clear patient management approaches based on the results.”

Commonly misused

“The goal of the program is to provide an opportunity for doctors and patients to become more fully informed about these complex genetic tests,” says Finley. “The reason we focus on those tests is that they are commonly misunderstood and misused, and the volume is high.

“There is no question that the BRCA1 and 2 tests have clinical value if used according to the criteria that would establish a man or woman as having high risk.

“The problem is that the tests and risk criteria are misunderstood by both doctors and patients, and the tests are frequently ordered for people who are not at high risk for the alteration.”

Variability in training

Misuse of the testing partly stems from variability in training and knowledge of genetic testing among the wide range of doctors who order the tests — oncologists, internists and family physicians, obstetricians/gynecologists, breast surgeons, cancer surgeons, and cardiologists.

“Our program is designed to get very accurate information through the use of genetic counselors in collecting and analyzing customers’ personal and family history information,” says Finley. “Based on their risk assessment, the counselors make a positive or negative recommendation for testing.

“Another important part of the counselors’ job is to explain the entire testing process to patients and their doctors, including such things as what to expect from the test results and how that information may affect services after the test. Patients should have a clear understanding of why they are or are not having the test as well as the basis for that recommendation.” The genetic counselors’ services also help physicians understand genetic testing.

Recommendation

If the doctor wants to order a test, the patient must first see a board-certified counselor who will decide whether the patient meets the criteria. Cigna reviews the counselor’s recommendation before certifying the test.

Accurately determining risk is important because of the relative low incidence of confirmatory results from genetic tests for hereditary diseases. The NCI says the BRCA1 and BRCA2 mutations account for about 20%–25% of hereditary breast cancers and about 5%–10% of all breast cancers. Mutations in these genes account for about 15% of ovarian cancers.

Genetic tests like the BRCA1 and 2 test commonly also identify alterations in these genes that are separate from variants that are directly associated with the disease. These additional alterations can cause confusion and concern among patients and thus they reinforce the need for a thorough risk assessment and referral of only appropriate high-risk patients for testing.

“The chances of having a mutation of unknown significance are as high as or even higher than the chances of getting a positive result for the primary indication,” says Finley.

“By using the test for people who are not truly high-risk, you open a can of worms by subjecting them to a test where you get a result that you do not know what do with.”

IOM report

As an example, a 2011 Institute of Medicine report on incorporating genetic information into clinical practice said that at that time, more than 150,000 patients had been tested for BRCA1 variants and tests detected 10 to 20 new missense variants each week.

New alterations

This reflects the current state of the art in genetic testing: While genes like BRCA1 and 2 are associated with a particular disease, new alterations pop up as more people are tested, and geneticists have not identified the cause or causes of disease-producing mutations.

Since testing within specific genes produces a steady stream of new alterations, the recent development of multigene breast cancer tests and gene-panel tests for multiple hereditary cancers increases the possibility of identifying more alterations of unknown significance.

Cigna’s program lays out procedures to ensure that the first steps of genetic testing are properly handled — in this case by conducting thorough risk assessments and ensuring appropriate access to testing by truly high-risk patients. From there, Cigna plans to move ahead carefully.

“This is a new program and it’s complicated.” says Finley. “Because there are many moving pieces and constant developments in genetics, we decided to start with a small number of tests and get the wrinkles ironed out. The two major pieces of this program are very different from other clinical management programs and we want to make sure that we are doing it absolutely correctly and that our customers are satisfied.” (The two major pieces are using counselors to obtain a detailed and complete family history and then allowing people who might have questions to meet with counselors.)

Growing recognition

Use of genetic counselors to conduct better risk assessments and provide a recommendation for tests ordered by physicians is a novel approach to precertification. It reflects the growing recognition of the role that genetic counselors can play in this very complex area of medicine, and it helps physicians integrate genetics into their practices. But it also injects a new precertification procedure that some physicians may object to.

What to do about incidental findings?

The genetic tests for some hereditary conditions are rapidly expanding from tests of individual genes into tests of panels of genes, driven by the power of next-generation sequencing and rapidly decreasing costs.

Development of multigene tests is a trend that experts say in many cases will lead to even broader tests — exome and genome sequencing. Genome sequencing analyzes all of the genes in an individual’s complete DNA of 23 pairs of chromosomes.

Exome sequencing is an analysis of all exons, which constitute about 1% of the genome. Exons are components of DNA that cause gene mutations by altering the function of essential proteins in tissues and organs. Exome sequencing is much more efficient and thorough than genome sequencing, with a faster turnaround time.

The American College of Medical Genetics and Genomics (ACMG) says exome and genome sequencing play a key role in several clinical areas: understanding rare diseases, personalized cancer treatment, pharmacogenomics, and preconception screening. Currently exome and genome sequencing are used in limited clinical situations, such as in children who have been through a diagnostic odyssey for a rare condition.

Because of their very broad analytical approach, exome and genome sequencing are likely to identify clinically significant alterations which are not directly related to the primary reason or indication for the test. These incidental findings pose many problems in terms of what should be reported to patients.

Reporting incidental findings is of growing concern as exome and genome sequencing become more common. In response, the ACMG working group on incidental findings has developed a policy statement to serve as a guide in reporting these results.

Opinions about what should be reported range from including all disease-associated alterations that could be medically useful to reporting only results where there is strong evidence of benefit. In response to the varied opinions, the working group developed three categories of results that determine what is to be reported: known pathogenic results, expected pathogenic results, and genetic variants of unknown significance. Known and expected pathogenic results are to be included in test results and genetic alterations of unknown significance are not.

The statement recommends that labs sequence a set of 57 genes that may indicate the presence of 24 disorders for which early intervention is likely to reduce or prevent morbidity or mortality.

Including expected pathogenic results creates a gray area for clinicians and patients. Test results will become part of a patient’s medical record, and the idea of an expected pathogenic result sitting in a patient record creates an obligation for future follow-up by the lab performing the test and the patient’s physician.

The ACMG policy covers other aspects of results reporting: respecting patient preferences about receiving test results and handling of test results in children or informing their family members about inherited traits.

The ACMG recommended that patients not be allowed to opt out of receiving the results for incidental findings. It acknowledged that this may seem to violate existing ethical norms regarding the patient’s autonomy and right not to receive genetic risk information. It said, however, that the rationale for reporting all results is that the list of incidental findings is weighted toward conditions for which pathogenic alterations may be high and intervention may be possible. The ACMG says clinicians and laboratory personnel have a fiduciary duty to prevent harm by warning patients and their families about incidental findings and this principle supersedes concern about autonomy.

To pave the way for this reporting, the ACMG recommends that pretest counseling include a discussion of possible incidental findings and specifically the fact that patients may not opt out of the laboratory’s reporting of incidental findings.

The ACMG’s recommendation also addresses reporting of incidental findings for children. The ACMG and the American Academy of Pediatrics jointly say that diagnostic genetic testing should be “driven by the best interests of the child” and that carrier screening and presymptomatic testing of children at risk for adult-onset diseases should be deferred until the child reaches maturity.

The policy statement on incidental findings creates an exception to that recommendation. The rationale here begins with the idea that genome sequencing in children should be ordered and performed only if there are clear clinical indications for a particular condition. Incidental findings could include a mutation that predicts risk of another childhood disease.

Finding a variant that predicts an adult-onset condition, such as a BRCA1 gene mutation, however, would seem to violate the principle of testing children only for their immediate medical benefit.

The ACMG said, however, that the disclosure of incidental findings such as a BRCA1 gene mutation is justified for three reasons. First, if a child carries a pathogenic mutation, there is a high probability that one parent does as well and, since the alteration is an incidental finding, it is possible that the presence of the variant in the family has not been previously identified. The ACMG says the child benefits by potentially preventing a severe adverse health outcome in a parent.

Second, the recommendation for not testing children for an adult-onset disorder often occurs when the family risk is already known, and it is expected that the child will be offered testing at the appropriate time. However, if there are no other clinical or family history indications, as might be the case for an incidental finding, that future testing may not occur until the child is affected.

The third reason is that there is some concern that the nurturing of the child might be adversely affected by the parent’s knowledge of the child’s future risk and the need to decide when to reveal that to the child.

The ACMG says that the ability to identify a significant medical risk for the child that could avoid future morbidity takes precedence over this possible risk.

The ACMG says this policy statement is a starting point for a dialogue about reporting results. It provides insight regarding some of the many issues that need to be considered as genetic testing and genomics begin to be used more widely.

Cigna has become the first national health plan to use genetic counseling as an integral part of genetic testing.

Thomas Reinke writes on pharmaceuticals and other topics for Managed Care.

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