Shift to Gene Panels to Assess Hereditary Cancer Risk Forges Ahead; Evidence of Clinical Utility, Cost-Effectiveness Emerges

A virtually unlimited number of genes tied to hereditary cancer risk can be simultaneously assessed in commercially available tests given both advances in technology and the Supreme Court’s two-year old ruling overturning gene patents. By screening multiple genes in parallel, research has shown that diagnostic yields are on the rise and time to results are down, with the added benefit of not adding much incremental cost for delivery of additional information.

As a result of all of these factors, there has been a noticeable uptick in clinical adoption of multigene panels to assess hereditary cancer risk. Yet, despite research heralding the effectiveness of these multigene panels’ appearing in the literature, some clinicians are asking whether adoption is occurring prematurely, before there is a good understanding of the consequences of panel-based testing on clinical management of the patient and other potentially affected relatives.

“Many cancer genetics experts have again urged caution, characterizing the use of multigene testing in the clinical setting as premature. Yet thousands of women and their physicians are ignoring this advice, ordering a wide selection of multiplex tests daily,” writes Elizabeth Swisher, M.D., from University of Washington, Seattle in an editorial in JAMA Oncology on Aug. 13. “The train has left the station and is unlikely to return. It is therefore critical that we assess the clinical utility of such testing.”

Given the relatively mature understanding of the risk posed by BRCA1/2 mutations, many are viewing testing for hereditary breast and ovarian cancer (HBOC) as a “tracer condition” that can demonstrate how “early and rapid” adoption of genetic testing influences treatment decisions. In the case of BRCA1/2 testing, evidence indicates that significantly more women diagnosed with breast cancer are receiving genetic counseling and testing, and among those that complete testing more and more are evaluated using multiplex assays, rather than single gene tests. Even Myriad Genetics (Salt Lake City), the company that was built upon patent protected BRCA testing, has shifted to its myRisk test. The company says that the 25-gene panel identifies more mutation carriers than its BRCAAnalysis or colorectal cancer Colaris tested, combined—an increase in mutation detection by 40 to 50 percent.

“The shift to panels is a mega movement, driven for good reasons,” Robert Nussbaum, M.D., the chief medical officer at molecular testing company Invitae, tells DTET. “Between the wear and tear on the patient and the expense of sequencing single genes, such testing would be completely prohibitive.”

Panels for Hereditary Breast, Ovarian Cancer
Now, emerging evidence is showing that identification of more mutation carriers translates into changes in clinical decision-making behavior. Multigene panel testing to assess HBOC risk is likely to change clinical management for substantially more patients than BRCA1/2 testing alone, according to a study published Aug. 13 in JAMA Oncology.

In the study, more than 1,000 individuals seen at three large academic medical centers were identified as appropriate candidates for HBOC evaluation based on established criteria. The enrolled participants all lacked BRCA1/2 mutations, yet commercially-available multigene panel testing was performed (the 29-gene Hereditary Cancer Syndromes test by Invitae was used at two sites, while the 25-gene MyRisk test from Myriad Genetics was used at the third site). The clinical actionability of detected mutations was assessed using the National Comprehensive Cancer Network (NCCN) established gene-specific management recommendations to measure impact on clinical decision-making.

The researchers found that 40 of 1,046 BRCA1/2-negative patients harbored deleterious mutations, most commonly in moderate-risk breast and ovarian cancer genes (CHEK2, ATM, and PALB2) and Lynch syndrome genes. The authors say that the 3.8 percent prevalence of additional mutations represents a substantial (greater than 40 percent) increase in diagnostic yield of risk-associated mutations compared with BRCA1/2 testing alone. The vast majority of the mutations were deemed clinically significant, driving additional disease-specific screening and/or prevention measures, beyond those decisions based on personal and family history alone. Furthermore, additional changes to familial testing would be considered for almost three-quarters of patients with detected mutations. As expected, the most common mutations were seen in genes associated with low or moderately increased breast cancer risk (40 of 63). Management change (increased screening or preventive surgery) would be recommended for only 10 of 40 of these cases. However, nearly one-third of mutation-positive patients (20 of 63) harbored mutations in high-risk genes tied to NCCN management guidelines and all of these mutations would change case management.

“We recognize that our data regarding clinical actionability are based on consensus practice guidelines, rather than actual clinical practice,” writes senior author Leif Ellisen, M.D., Ph.D., from Massachusetts General Hospital (Boston). The authors acknowledge the actual clinical effect of multigene testing could vary depending on the number of patients choosing to be tested, clinician adherence to gene-based management guidelines, and how closely patients follow clinician recommendations. While actionability is a critical driver of genetic test ordering, defining actionability is challenging, Swisher writes in the accompanying editorial. The authors use NCCN guidelines as a standardized measure of actionability, but she notes, NCCN recommendations are incomplete for many genes and therefore may “undervalue” the utility of testing based on current gene-based management guidelines.

Determining Ideal Panel Size
The fact that the technology can interrogate nearly limitless numbers of genes does not necessarily mean that such mega-panels are appropriate or desirable. “There are panels and then there are panels,” Nussbaum says. “If you overdo it with the number of genes, you won’t know the clinical significance of all of the variants and it adds to the burden of the clinician and the genetic counselor.”

While some appreciate the potential future importance of collection of more genetic data (as it can be reanalyzed as genetic understanding evolves), others view mega-panels that include low- to moderate-risk genes mutations as actually complicating clinical decision-making, since the clinical actionability of these results is less defined.

“There is growing concern that clinicians are falling behind in their understanding of fundamental aspects of genetic testing and their confidence in discussing results with patients, writes co-author Steven Katz, M.D., from University of Michigan, Ann Arbor, in a July 23 Viewpoint published in the Journal of the American Medical Association. “An alternative viewpoint is that the use of genetic tests is outpacing the applicability of their findings to cancer treatment decisions.” Katz notes a “widening gap” between the availability of expansive genetic testing and the relative importance of results to treatment decisions.

“There is growing concern that clinicians are falling behind in their understanding of fundamental aspects of genetic testing and their confidence in discussing results with patients, writes co-author Steven Katz, M.D., from University of Michigan, Ann Arbor, in a July 23 Viewpoint published in the Journal of the American Medical Association. “An alternative viewpoint is that the use of genetic tests is outpacing the applicability of their findings to cancer treatment decisions.” Katz notes a “widening gap” between the availability of expansive genetic testing and the relative importance of results to treatment decisions.

Cost Effectiveness
Given the questions over the clinical utility of test results, it is no surprise that insurers often balk at paying for panel-based tests. While the industry is well aware of the need to generate evidence of clinical utility, there remains scant evidence as to the cost effectiveness of panel-based testing. This summer, though, researchers published findings that use of a sequencing panel that includes genes associated with highly penetrant colorectal cancer and polyposis (CRCP) syndromes, in addition to Lynch syndrome genes, is cost effective as a first-line test. According to a study published June 20 in the Journal of Clinical Oncology, the test is likely to provide meaningful clinical benefits using the standard $100,000 per quality-adjusted life years (QALYs) gained threshold.

The researchers developed a decision model to evaluate the cost effectiveness of various sequencing panels in patients with suspected hereditary CRCP syndromes versus the sequential evaluation for Lynch syndrome, as recommended by current guidelines.

The researchers found that evaluation with a sequencing panel that included Lynch syndrome genes plus other genes associated with highly penetrant CRCP syndromes was “highly cost-effective” and led to an average increase of 0.151 year of life, 0.128 QALY, and $4,650 per patient, resulting in an incremental cost-effectiveness ratio of $36,500 per QALY compared with standard care. Sequencing for only Lynch syndrome genes yielded a cost per QALY of $144,200, significantly higher than the accepted $100,000 threshold. The further addition of genes with low colorectal cancer penetrance resulted in an incremental cost-effectiveness ratio of $77,300 per QALY, still cost effective, but less so.

QALY compared with standard care. Sequencing for only Lynch syndrome genes yielded a cost per QALY of $144,200, significantly higher than the accepted $100,000 threshold. The further addition of genes with low colorectal cancer penetrance resulted in an incremental cost-effectiveness ratio of $77,300 per QALY, still cost effective, but less so.

Insurers, including the Centers for Medicare and Medicaid Services (CMS), are not yet convinced of the benefit of paying for panel-based testing, according to a research note published May 28 by senior research analyst William Quirk at Piper Jaffray & Co. CMS published preliminary gap fill rates for sequencing-based panels well below current reimbursement levels calculated using stacking of Current Procedural Terminology (CPT) codes. Of the 21 next-generation sequencing-related CPT codes, which were designed to improve transparency in reimbursement, only four were priced using preliminary gap fill payment. Of the four priced tests, targeted sequencing panels (of five to 50 genes) were priced by only a single Medicare administrative contractor. Quirk called the pricing for the panel “surprising.” Quirk cites industry sources saying that there is “little reimbursement traction from private payers” as well, with most tests billed under the new codes denied payment.

“One of the major obstacles to adopting the panels is the perception they are exorbitantly costly,” says Nussbaum.

Yet, industry watchers are hopeful that momentum is gaining for reimbursing these multigene panels. In mid-August a multi-stakeholder group convened by the Center for Medical Technology Policy (CMTP, Baltimore, Md.) recommended coverage for sequencing panels of 5-50 genomes if they include a subset of constituent genes that are considered to be standard-of-care and medically necessary for the patient. The groups says such reimbursement is necessary to advance personalized medicine for cancer. CMTP focuses on comparative effectiveness and patient-centered outcomes research. The group, which included

sequencing testing and technology companies, medical professional societies, patient advocacy groups, and leading health plans, also recommended that payers rely on the College of American Pathologists accreditation program and proficiency testing to assure the analytic validity of sequencing tests, as well as a proposal for payers to cover larger, even more comprehensive panels with preauthorization under circumstances of “extenuating medical need.”

In the interim, while payers come up to speed, another strategy is emerging—with companies pricing multigene panels so low they can gain commercial traction through increased access to medically indicated testing with private pay patients. For instance, Invitae (San Francisco), a firm specializing in genetic testing for hereditary disorders, cardiology, hereditary cancer, pediatric genetics, neurology, and hematology, launched a $475 flat fee per indication for its full menu of genetic tests. The patient pay program, the company says, reflects the desire to bring affordable genetic testing “to the masses in a medically responsible way.” The pricing is exclusively for patients who register online, pay up front for genetic services themselves, and whose clinician has ordered the testing online. The company envisions patients ordering the test will be those that do not meet coverage policies for testing, those with high-deductible plans, and those not covered by insurance.

“Most of the conversations about reimbursement for genetic testing have focused on economic issues. However, an under-appreciated dimension in using genetic testing for genetic care is an ethical one,” Nussbaum previously said in a statement. “For years, many people and their families have not had the benefit of clearly indicated genetic testing due to unwillingness of third-party payers to pay the historically high cost. Now that the genetics market is becoming a generic market—and thanks to the ongoing innovations and cost reductions in sample preparation, sequencing and medical interpretation—we are beginning to see the benefits translated into affordable testing for patients.”

Invitae released new pricing for institutional customers and third-party payers, as well. For those payers that include Invitae in their network, the price per indication is $950. For third-party payers with whom Invitae is out of network and non-contracted institutions, the price per indication remains $1,500, the company said in a statement.

Takeaway: Despite awareness of the need to study the effect panel-based testing has on clinical care, panelbased testing for heritable cancer risk will continue to gain momentum, with HBOC testing leading the way.