Biomarker Underutilization Means Missed Opportunities in Cancer

M. Alexander Otto, MMS, PA

October 14, 2020

Patients with cancers who could be treated with targeted drugs are sometimes not being tested for genetic mutations and other biomarkers that would identify them as candidates.

"Testing rates lag behind clinical guidelines and advancements in the field," according to a white paper from the American Cancer Society Cancer Action Network (ACS CAN) and the LUNGevity Foundation, preventing "cancer patients from receiving therapies that could [improve] outcomes," the authors write.

One example is testing for epidermal growth factor receptor (EGFR) mutations in patients with non–small cell lung cancer (NSCLC), which identifies candidates for drugs such as erlotinib. In community oncology practices across the United States, fewer than 50% of eligible patients were tested for EGFR in 2016, several years after such testing became standard of care.

Another example is biomarker testing for patients with metastatic colorectal cancer (CRC), which is recommended in clinical guidelines; from 2013 to 2017, only 40% of patients in academic and community settings were tested.

A larger overview is provided by a survey conducted by the ACS CAN in May/June 2020, which included 933 cancer patients and survivors. Only 39% reported that they had undergone biomarker testing; a further 25% were unsure. Among 13% of respondents who discussed biomarker testing but who were not tested, almost a third declined because insurance would not cover it or their out-of-pocket costs were too high.

Insurance coverage is a major hurdle.

"Without coverage, patients will not have access," the ACS CAN and the LUNGevity Foundation point out.

Coverage has been increasing overall, especially for single analyte companion diagnostics approved with new therapeutics, but it "differs greatly across the multiple public and private payers in the US health care system," the groups comment.

The problem is particularly acute with regard to panels that check hundreds of genes for mutations at a time. Many of the findings from such testing are actionable, but others currently have no known utility. As a result, some payers consider the entire panel to be experimental or investigational, and they don't cover it.

That needs to change, the groups say: "Payers should provide coverage for multi-gene panel testing as indicated by NCCN [National Comprehensive Cancer Network] guidelines, when it is more efficient, when a single analyte test does not exist, or when tissue availability is too limited for use of multiple single analyte testing."

Multigene panels are sometimes the only approved companion diagnostic for a targeted therapy. One example is capmatinib (Tabrecta), recently approved for NSCLC with mutations that lead to mesenchymal-epithelial transition exon 14 skipping. The only FDA-approved companion diagnostic is the Foundation One CDx assay (F1CDx), which tests 324 genes, the findings for many of which are at present inactionable.

Some commercial payers do cover F1CDx; the number of such payers has "increased substantially" since the last review in 2018, the white paper notes. However, numerous payers, including Aetna, United, and most BlueCross BlueShield, still consider large multigene panels as experimental and investigational, "most certainly due to the number of genes included that are felt to be inactionable."

NSCLC "may be a specific case," in that there are enough actionable biomarkers for some payers to agree to cover multigene next-generation sequencing panels. "However, breast cancer, colon cancer, and prostate cancer do not have an adequate number of biomarkers with established utility to warrant coverage of large panels among many payers," the groups say.

ACS CAN and the LUNGevity Foundation also call for commercial payers to cover testing for tumor-agnostic biomarkers, as medically appropriate.

Tumor site agnostic biomarkers include neurotrophic receptor tyrosine kinase (NTRK) gene fusions, for which two targeted drugs are approved ― entrectinib (Rozlytrek) and larotrectinib (Vitrakvi).

Other biomarkers include high tumor mutational burden (TMB-H), high microsatellite instability (MSI-H), and homologous recombination deficiency (HRD).

At present, the immunotherapy pembrolizumab (Keytruda) is approved for use in tumors with MSI-H, mismatch repair deficient (dMMR), or TMB-H indications.

Tumor site agnostic biomarkers are uncommon, but when they are found, targeted treatment can be effective and improve outcomes compared to traditional chemotherapy.

Even so, testing for them is problematic.

NTRK is routinely covered as a specific biomarker by immunohistochemistry, "which is suboptimal," the white paper notes, but NTRK sequencing as well as HRD are generally only available as part of a multigene panel. If the multigene panel test is not covered, then patients with these relatively uncommon disorders are not identified, and they "don't receive the optimal treatment for their malignancy."

"This is even more of an issue" for MSI-H and TMB-H immunotherapy. MSI can be assessed without use of a multigene panel, but in general, TMB cannot.

"Consequently, the pan-tumor approval of the [immuno-oncology] companion difficult in practice if panels are not covered. This paradox requires action," the report states.

The groups anticipate expanded coverage of multigene liquid biopsy tests following recent FDA approval of two.

One of the liquid biopsies is Guardant360 CDx, a companion diagnostic for osimertinib (Tagrisso) for identifying patients with NSCLC with targeted EGFR mutations. The other is FoundationOne Liquid CDx, approved for use with rucaparib (Rubraca) for identifying metastatic castration-resistant prostate cancer patients with appropriate BRCA1 and BRCA2 mutations.

Already, "the maturation of the evidence base for liquid biopsy coupled with challenges of biopsy tissue stewardship has resulted in some payer coverage," the report notes.

Biomarker Coverage: The Lay of the Land

Insurance coverage of biomarkers for targeted therapies has increased for some cancers but has remained flat for others, according a report from the American Cancer Society Cancer Action Network and the LUNGevity Foundation.

Non–Small Cell Lung Cancer

At present, for patients with NSCLC, most commercial payers cover select individual biomarkers, including EGFR, ALK, ROS1, BRAF, and NTRK. Some payers also cover KRAS. However, emerging biomarkers, such as HER2, RET, and MET, are covered by fewer payers.

Since the last review in 2018, tissue-based multigene panels for NSCLC are more widely covered, though there are still large gaps in coverage. There seems to be growing recognition by payers that sequential testing of individual biomarkers is not practical when the amount of available tissue is limited and because the results of these tests can inform urgent treatment decisions. Because of the increase in the number of individual actionable analytes in NSCLC, insurance companies are considering covering panels as the most expeditious and potentially most cost-effective approach.

Commercial payers recognize the value of liquid biopsies in NSCLC in certain clinical settings, most notably, in cases involving a patient who is medically unfit for invasive tissue sampling of a metastatic focus or in cases in which there is insufficient material for molecular analysis following pathologic confirmation of a NSCLC diagnosis.

Colorectal Cancer

All payers cover select individual biomarkers in CRC, and they are fairly consistent across plans. Generally, NRAS, KRAS, and BRAF are considered medically necessary. Few payers cover MSI and NTRK testing.

With rare exceptions, payers consider tissue-based multigene panels in CRC to be experimental and investigational, owing to the relative lack of actionable targets. Since the 2018 review, there has been little change in coverage of panels for CRC. Emerging evidence supporting the role of immuno-oncology therapy early in the treatment of metastatic colon cancer will increase the pressure on payers to cover panels.

Breast Cancer

Biomarkers indicated in breast cancer, including ER, PR, HER2, PD-L1, BRCA1, and BRCA2, are widely covered, as is PIK3CA via tumor tissue and liquid biopsy for its companion therapeutic, alpelisib (Piqray).

There has been little change in coverage of panels for breast cancer since 2018. Testing for NTRK fusions and mismatch repair is covered sparingly. Well-established prognostic breast cancer gene expression assays are covered by most payers. Consistent with National Comprehensive Cancer Network guidelines, some payers preferentially cover Oncotype DX Breast.

Prostate Cancer

Coverage of prognostic prostate cancer biomarkers, including AR-V7, and tumor-based molecular assays, including Decipher, OncotypeDx Prostate, Prolaris, and Promark, is inconsistent across payers. Although there is a new companion diagnostic paradigm for BRCA testing in prostate cancer, many payers have yet to update their policies.

Given the rapid expansion in knowledge of the significance of biomarkers in prostate cancer, it is likely that prostate cancer will be an area of increased clinical focus for panel testing. BRACAnalysis CDx and FoundationOne CDx are indicated for patients with metastatic castration-resistant prostate cancer (mCRPC) who may benefit from treatment with olaparib (Lynparza). FoundationOne Liquid CDx is indicated for mCRPC patients who may benefit from treatment with rucaparib (Rubraca).

Source: ACS CAN, LUNGevity Foundation: Payer Coverage Policies of Tumor Biomarker Testing. Full text

The white paper was commissioned by the American Cancer Society Cancer Action Network and the LUNGevity Foundation. LUNGevity's funders include Bristol-Myers Squibb, which manufactures several immunotherapies, and Genentech/Roche, manufacturer of entrectinib and owner of Foundation One Medicine. ACS funders include Merck, manufacturer of pemproblizumab, and Lilly, which has several targeted therapies..

ACS CAN and LUNGevity Foundation. Improving Access to Biomarker Testing. Full text

M. Alexander Otto is a physician assistant and award-winning medical journalist who has previously worked for several major news outlets, including McClatchy and Bloomberg BNA. He is a former MIT Knight Science Journalism fellow. Email:

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