Liquid biopsy, molecular testing vs. reimbursement: A personal story

A family member’s liquid biopsy test, gene testing and a journey into coverage decisions and clinical guidelines reveal how difficult the reimbursement path is for these emerging technologies.

As editor and journalist, I am supposed to be objective when it comes to the industry I cover: healthcare

Yet ever since a close family member was diagnosed with Stage 4 renal cell carcinoma back in 2015, it has also been intensely personal. In dealing with docs, nurses, technology, I am routinely flummoxed. Why is it that the medication list in the EHR on the clinic side doesn’t match up with its counterpart on the hospital side? Why is it that hospital discharge papers reflecting the cause for admission contradict the lab work and the conclusion drawn by doctors?

This story about the reimbursement of liquid biopsies and gene testing is also the result of that sense of puzzlement. While novel and gaining in acceptance, liquid biopsies and large-panel testing of genes have a way to go before convincing insurers to reimburse the cost of tests. It will also depend on how clinical guidelines change for managing different types of cancer.

Late last year, the family member’s oncologist recommended that he get the Guardant360 liquid biopsy test. The test concluded that there was no actionable information. In other words, there was no identifiable drug that the oncologist could provide to help his disease based on gene mutations the test unearthed.

A few months ago he got a letter from Cigna, his insurer, saying that even after an appeal from his healthcare provider, the company won’t pay for the Guardant360 test. The claim amount was $6,800. The reason for denial was the following:

After careful consideration of the available clinical information and current scientific data, this request cannot be approved because there is insufficient scientific evidence supporting the validity, clinical utility, and effectiveness of molecular testing for detection of cell-free DNA or circulating tumor cells for any cancer indication.

Guardant Health, for its part, has this on its website:

Guardant360 has undergone extensive analytical and clinical validation and is supported by publications from leading cancer centers globally. It’s been used by thousands of oncologists and helps guide treatment decisions at more than 80% of top US cancer centers.

The two statements could not be more contradictory.

That prompted me to reach out to Cigna with a genuine desire to understand how the insurer evaluates newer technologies like liquid biopsy and broad-panel gene testing. A Cigna spokesman graciously connected me with Dr. Julie Kessel, director of the company’s Coverage Policy unit.

“We don’t always cover liquid biopsy because it depends on the indication it is for and then it depends on what kinds of tests are being requested as part of the liquid biopsy assessment,” she explained in a recent phone interview. “The biggest challenge I think for us right now and for providers and for patients is that those tests give you so much information, what do you with all that information? What is a concern for us is: Do what they measure make a difference in the clinical outcome for the patient? So which of those myriads of targeted mutations actually has the evidence that allows the doctor and a patient to make a decision about their treatment that results in improved clinical outcomes and that’s really what it comes down to.”

In other words, large panel tests are targeting too many genes, in her opinion. Tests like Guardant360 and Foundation One (from Foundation Medicine) subject the tumor fragments in the blood and tumor tissue (from a regular biopsy) respectively to 73 and more than 300 genes respectively.

Based on indication and clinical evidence Cigna will cover a single gene test or two, but it doesn’t cover broad gene testing like those offered by Foundation and Guardant. This is irrespective of whether the sample being interrogated is actual tumor tissue or tumor fragments floating about in the blood and obtained through liquid biopsy. So, no coverage of panel tests no matter what the type of cancer is.

But Kessel did leave room for such decisions to change.

“The tests and the technology are emerging so very rapidly that there is no question that we are rethinking how do we do this, how do we keep up with the science, how do we not interfere with the science, how do we facilitate doctor-patient shared decisionmaking,” she said.

She also pointed out that Cigna looks for guidance from the National Comprehensive Cancer Network (NCCN) while making coverage decisions. NCCN is a nonprofit group comprising top cancer centers that routinely updates clinical practice guidelines in the field of oncology. 

“If the NCCN says we think it’s OK at a level of 1, 2A or 2B [rating] to subject this tissue, however you got it, to these [many] tests, we would approve that,” Kessel declared. “We respect the determination of NCCN and if they were to make a specific recommendation … we have a policy that says we will adhere to that.”

Turns out NCCN, at least in nonsmall-cell lung cancer, has approved broad-based gene testing at a 2A rating, according to a spokeswoman. Here’s the specific language published in July representing the eighth version of the 2017 guidelines.

Testing should be conducted as part of broad molecular profiling.

Footnote: The NCCN NSCLC Guidelines Panel strongly advises broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials. Broad molecular profiling is a key component of the improvement of care of patients with NSCLC.

Dr. Rogerio Lilenbaum, a board member of NCCN and Chief Medical Officer of Smilow Cancer Hospital at the Yale Cancer Center said that for nonsmall-cell lung cancer, both panel testing and liquid biopsies are appropriate. 

“In lung cancer, for example, we do have data that liquid biopsies are clinically useful and are accurate,” explained Lilenbaum, who is a medical oncologist and sits on the NCCN’s NSCLC panel. “In lung cancer, there are clinical trials and other guidelines that suggest that there is a good level of accuracy between the liquid biopsy and the tumor biopsy, which would serve as the gold standard. In certain circumstances, you can use a liquid biopsy to guide treatment without having to resort to a tumor biopsy.”

When it comes to broad molecular profiling and testing, insurance coverage  is, “at best erratic,” Lilenbaum said. He added that some insurers may cover individual genes but that is probably not the best way forward.

“We have a large insurance company like Anthem here in Connecticut and they don’t seem to be paying for any panels,” Lilenbaum said. “They may cover individual genes but that’s probably not a cost-effective way to do molecular profiling.”

He said insurers will argue that there are six to eight actionable genes that we know of and so why should we cover a large panel of 300 genes.

“There is no simple answer to this,” Lilenbaum said. “From a clinical practice, they are correct. You can argue that in an academic center like ours we still want to test because we want to pursue other less known mutations or molecular alterations because 1) it can guide clinical trials and 2) it allows us to create a database that perhaps in the future will change how we approach patients with those mutations. We are looking at the future. But for a clinical practice guideline – what you do with your patient tomorrow – there are only a few of those genetic alterations [that are actionable.]”

Priority Health, which is listed on Guardant Health’s website as an insurer that covers the test, declined comment as did a representative from Guardant, which is based in Redwood City, California.

Lilenbaum said that his understanding of the way Medicare looks at molecular profiling is that as long as a panel test includes the handful actionable genes, the Centers for Medicare and Medicaid may be willing to cover it.

However, “it’s not a policy that’s well known or consistent across states ….” he said. “Docs continue to order the tests without knowing who’s going to pay for them.”

CMS coverage is, of course, the benchmark for commercial insurers. And at a recent medical technology conference, a CMS official hinted that the agency is very close to making a National Coverage Decision (NCD) as it pertains to Foundation Medicine.

“One of our Parallel Review projects is with Foundation Medicine next-generation sequencing,” explained Tamara Syrek Jensen, director of the Coverage and Analysis group, at CMS. “We’re actually working on the decision and I had a briefing with Carol (Blackford, director, Hospital & Ambulatory Policy Group at CMS) on what we think the decision is and going to meet Demetrios (Kouzoukas, CMS Principal, Deputy Admin and Director, CMS) next week to bring him up to the date on that decision. I also briefed Jeff Shuren (director, Center for Devices and Radiological Health, FDA) at the back of the room on that decision [given that FDA and CMS are simultaneously reviewing Foundation Medicine’s data].

If Foundation Medicine wins a positive NCD from Medicare, broad panel testing is likely to take a big leap in the field of oncology. And hopefully, fewer patients will be left holding the bag.

Liquid biopsy companies, like Guardant and many others, will likely have to wait a bit longer to change hearts and minds.

That is true even of clinical practice guidelines for kidney cancer, the disease that the close family member is battling. For now, an expert who sits on NCCN’s clinical guidelines panel for kidney cancer, recommends a handful of genes be tested.

“Large panel somatic mutation tests can be performed on tumors from patients with refractory disease but at this point in time there are no specific algorithms in place as there are relatively few actionable mutations in kidney cancer.” said Dr Eric Jonasch, with the MD Anderson Cancer Center in an email forwarded by a NCCN spokeswoman. “This will undoubtedly change as our understanding of kidney cancer biology evolves.”

Photo: jxfzsy, Getty Images