Appeal type: Experimental/Investigational
Decision: Upheld

Diagnosis: Breast Cancer
Treatment: Guardant 360
The insurer denied the Guardant 360.
The determination is upheld.

This is a patient with progressive metastatic hormone receptor positive, HER2- breast cancer. The Guardant360 assay was obtained for phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) testing and is under review as to whether it is likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease.

No. It is not likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease.
The use of next generation sequencing gene panels to guide the treatment of patients with breast cancer has not been demonstrated to be of benefit. The assay is question is Food and Drug Administration (FDA) approved. Several ongoing trials (eg, the National Cancer Institute [NCI] Molecular Analysis for Therapy Choice [MATCH] and the American Society of Clinical Oncology (ASCO) Targeted Agent and Profiling Utilization Registry [TAPUR] trails) are using next-generation sequencing of multiple genes (gene panel tests) to identify molecular abnormalities in the tumors of patients with refractory cancers that may potentially match molecularly targeted therapies that are either in clinical trials or approved for treatment of other cancer types (National Clinical Trial (NCT) 02465060 and NCT02693535).
To date, the SHIVA trial is the only large, randomized trial to evaluate off-label use of molecularly targeted agents on the basis of identified molecular alterations for which results have been published in the peer-reviewed literature. 741 patients were enrolled in this multi-institutional trial that included adult patients with any kind of metastatic solid tumor refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumor was established with a mandatory biopsy of a metastatic tumor and large-scale genomic testing. Patients with an actionable mutation were randomized these (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomization (blocks of size six). Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population. Median follow-up was 11.3 months (Interquartile Range (IQR) 5.8-11.6) in the experimental group and 11.3 months (8.1-11.6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2.3 months (95% confidence interval (CI) 1.7-3.8) in the experimental group versus 2.0 months (1.8-2.1). The conclusion of the authors was "...he use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrollment in clinical trials should be encouraged to assess predictive biomarkers of efficacy....
Further complicating the role of liquid biopsies if that their results are limited in sensitivity to between 60 and 80 percent. The limited sensitivity of liquid biopsies is thought to reflect the biology that some cancers do not shed deoxyribonucleic acid (DNA) into the bloodstream rather than a feature of any given assay. However, mutation detection in blood has been associated with more advanced disease characteristics, including worsened performance status and prognosis and the presence of more metastatic sites. A second limitation of liquid biopsies is that the types of studies have a higher chance of being falsely negative compared with traditional biopsies, given the minuscule and variable amounts of DNA that tumors may shed into circulation. Finally, tests for programmed death-ligand 1 (PD-L1) expression cannot be conducted on liquid biopsies.
Another important point is that simply having a potentially targetable mutation does not guarantee that the patient will benefit from a therapy that presumably targets that mutation. Another potential pitfall is if targeted testing identifies a potentially actionable genetic abnormality for which a molecularly targeted treatment is available but not yet approved.
Based on the paucity of supporting data, neither the peer-reviewed literature nor authors of UpToDate recommend the use of the Guardant360 assay in this clinical scenario. The FDA-approved companion diagnostic test for PIK3CA mutation testing is the Qiagen therascreen PIK3CA rotator gene Q (RGQ) polymerase chain reaction (PCR) Kit, which was used in the pivotal trial evaluating apelisib, SOLAR-1 (NCT02437318).