Appeal type: Medical necessity
Decision: Upheld

Diagnosis: C18.1 - Malignant neoplasm of appendix. C79.51 - Secondary malignant neoplasm of bone.
Treatment: Genetic Testing (Guardant360 CDx) (81479).
The insurer denied the Genetic Testing (Guardant360 CDx) (81479).
The denial is upheld.

The patient is a female with metastatic adenocarcinoma of the appendix.  She initially presented with an adenocarcinoma of the appendix with liver metastases.  She presented with appendicitis and a pT1 invasive, grade II, adenocarcinoma of the appendix was found. 

The patient underwent laparoscopic right hemicolectomy. There was no residual primary tumor and 15 lymph nodes were negative.  She was then treated with FOLFOX times six cycles, followed by right hepatectomy, followed by FOLFOX times five cycles before the treatment ended.

The patient developed progression with metastatic disease in the lungs and bone  and was treated with FOLFIRI plus bevacizumab.  Computed tomographies (CTs) showed a mild increase in size of her pulmonary metastases while on FOLFIRI plus bevacizumab. There was no change in bone lesions. 

A Guardant360CDx liquid biopsy tumor mutation panel test was performed on the blood to determine eligibility for treatment on trial.

No, the proposed Guardant360 testing was not medically necessary.
The Guardant360 test is a next-generation sequencing somatic mutation panel test that interrogates 68 genes including single nucleotide variants (SNVs), copy number variations (CNVs), indels, and rearrangements across more than 150,000 base pairs, aiding in treatment management (see https://www.guardanthealth.com/our-science/#). It is performed on cell free circulating deoxyribonucleic acid (DNA). 

The National Comprehensive Cancer Network (NCCN; URL: www.nccn.org) is an organization whose members are drawn from the nation's National Cancer Institute (NCI) designated comprehensive cancer centers. The National Comprehensive Cancer Network (NCCN) provides detailed practice guidelines for the treatment of individual cancers. Guidelines are written by panels of experts drawn from the member institutions. The National Comprehensive Cancer Network (NCCN) Guidelines for the treatment of colon cancer do not support Guardant360 testing (NCCN Colon Cancer). 

The standard of care in the United States does not yet include selecting chemotherapy for cancer based on the genomic profile of circulating cell free deoxyribonucleic acid (DNA). 

There are no peer-reviewed published clinical studies of the use of the Guardant360 assay to direct therapy of metastatic colorectal cancer (www.pubmed.gov;).

The use of liquid biopsy assays to manage colorectal cancer is considered unproven, "The use of non-standardized methods, the small cohorts of patients analyzed, the lack of demonstration of a clear clinical benefit are the main limitations of the studies with liquid biopsy in [colorectal cancer] reported up to now." (Normanno)

The use of somatic mutation panel test results to select targeted therapies for cancer was studied in a randomized clinical trial that compared the outcomes of treating patients with targeted agents based on panel test results vs conventional treatments (Le Tourneau). The conclusions of this phase III study was that, "The 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 enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy."

The use of next-generation sequencing panels for treatment selection for solid tumors was reviewed (Marrone). This review concludes: "Currently, there is little information available on the post-analytic processes unique to next-generation sequencing platforms used by the companies offering these tests. Additionally, evidence of clinical validity showing an association between the genetic markers curated in these tests with treatment response to approved molecularly targeted therapies is lacking across all solid-tumor types. To date, there is no published data of improved outcomes when using the commercially available tests to guide treatment decisions."

Reviews of liquid biopsies conclude: "We discuss the advantages and limitations of various leading ctDNA (circulating tumor DNA)/CTC (Circulating Tumor Cells) analysis technologies. Finally, guided by the results of clinical trials, we discuss the readiness of cell-free DNA and CTC as routine biomarkers in the context of various common types of neoplastic disease. At this moment, one cannot conclude whether or not liquid biopsy will become a mainstay in oncology practice." (Hench)

As the efficacy of this testing is of unproven benefit, it is not medically necessary.

The testing is not of proven benefit. The National Comprehensive Cancer Network (NCCN) supports solid tumor biopsies when possible as the sensitivity for solid tumor biopsies for detecting mutations is greater than liquid biopsies and the sensitivity for detecting gene fusions is greater still (Wu; Mayo-de-Las-Casas). One issue with liquid biopsies is that some of the mutations found on liquid biopsy do not come from the tumor at all, but rather from clonal hematopoiesis (Bauml; Chan). If tumor mutation panel testing was needed, testing the patient's initial resection or resected liver metastases would have been preferred.