Circulating Tumor-Tissue-Modified Viral DNA Testing for Cancer Management

POLICY NUMBER

A.2.04.160

DESCRIPTION

This policy addresses the use of circulating tumor-tissue-viral modified (TTMV) human papillomavirus (HPV) DNA testing for cancer management. The purpose of tumor-informed TTMV-HPV DNA testing in individuals with HPV-related cancer is to predict disease outcomes to inform treatment decisions and to monitor for recurrence following treatment.

Human Papillomavirus Related Cancers

Human papillomavirus (HPV) infections are the predominant cause of squamous cell carcinoma (SCC) of the oropharynx and constitute 50% of head and neck cancers. Additionally, HPV infections are highly associated with invasive anal carcinomas with over 85% of anal cancer being attributed to an HPV infection. Individuals with locally advanced HPV-related HNSCC as compared to HPV-unrelated individuals have improved response to treatment and survival (overall survival [OS] and progression-free survival [PFS]). Individuals with HPV-related anal carcinoma also demonstrate a favorable prognosis in regard to OS in comparison to HPV-unrelated tumors. Despite the favorable prognosis for HPV-related cancers, the treatment is highly similar to HPV-unrelated cancer as there is currently no evidence to support treatment algorithms that address the distinct biological differences between these malignancies. Decisions about neoadjuvant and adjuvant chemotherapy are currently based on clinicopathological risk factors.

Circulating Tumor Human Papillomavirus DNA

Normal and tumor cells release small fragments of DNA into the blood, which is referred to as cell-free DNA (cfDNA). Cell-free DNA from nonmalignant cells is released by apoptosis. Most cell-free tumor DNA is derived from apoptotic and/or necrotic tumor cells, either from the primary tumor, metastases, or circulating tumor cells. Circulating tumor DNA (ctDNA) is released by dying cancer cells and represents an accessible source for detecting tumor genetic biomarkers in many cancer types. Unlike apoptosis, necrosis is considered a pathologic process and generates larger DNA fragments due to incomplete and random digestion of genomic DNA. The length or integrity of the circulating DNA can potentially distinguish between apoptotic and necrotic origin. Circulating tumor DNA can be used for genomic characterization of the tumor. In human papillomavirus (HPV)-related cancer, HPV viral genomes are usually integrated into the tumor cell genome or episomal DNA and release circulating tumor HPV DNA (ctHPVDNA).

Circulating Tumor-Tissue-Modified Viral DNA

NavDx is a tumor-tissue-modified viral (TTMV) HPV DNA test for HPV-related cancers of the head and neck or anus. TTMV-HPV DNA is a unique cancer biomarker that tumor cells of cancers driven by human papillomavirus shed into the blood. The TTMV-HPV DNA biomarker is unique to HPV-related cancers such as head and neck squamous cell carcinoma (HNSCC) or anal squamous cell carcinoma (ASCC) and is specific to the implicated HPV-genotype. HPV-16 is the most common pathogenic genotype; however, other high-risk HPV genotypes include HPV-18, HPV-31, HPV-33, and HPV-35. These genotypes are distinguishable from noncancerous genotypes by using droplet digital polymerase chain reaction (ddPCR) and paired with an algorithmic analysis of fragmentation patterns used to generate a TTMV-HPV DNA score. This approach detects tumor-derived HPV DNA from the 5 high-risk HPV subtypes (16, 18, 31, 33, and 35). Results are reported as a TTMV-HPV DNA score, which reflects the normalized number of TTMV-HPV DNA fragments per milliliter of plasma. Scores are categorized as positive, indeterminate, or negative. Scores >7 (for HPV subtype 16) or >12 (for HPV subtypes 18, 31, 33, or 35) are considered positive, scores between 5 and 7 (HPV 16) or 5 and 12 (HPV 18, 31, 33, or 35) are considered indeterminate, while scores <5 are considered negative, regardless of HPV subtype.

In publicly available literature, ctHPVDNA and TTMV-HPV DNA are used synonymously as they both refer to circulating DNA derived from HPV-related tumors. However, TTMV-HPV DNA refers directly to DNA that is detected using the commercially available NavDx test.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing.

NavDx® (Naveris) is the first commercially available tumor-tissue-modified (TTMV™) human papillomavirus (HPV) DNA blood test regulated under CLIA marketed for the detection of HPV-related cancer. The test has not been cleared or approved by the United States Food and Drug Administration.

Related medical policies –

• Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)

• Tumor-Informed Circulating Tumor DNA Testing for Cancer Management

POLICY

Circulating tumor-tissue-modified viral (TTMV) human papillomavirus (HPV) DNA testing (e.g., NavDx) is considered investigational.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

08/15/2025: New policy added. Approved by the Medical Policy Advisory Committee.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.160

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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