Medical Policy

Policy Num:       11.003.142
Policy Name:    Circulating Tumor-Tissue-Modified Viral DNA Testing for Cancer Management

Policy ID:          [11.003.142]  [Ac / B / M- / P-]  [2.04.160]

Last Review:       April 14, 2025
Next Review:      April 20, 2026
 

Related Policies:

11.003.089 - Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)
11.003.136 - Tumor-Informed Circulating Tumor DNA Testing for Cancer Management

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

summary

Description

This evidence review 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.

Summary of Evidence

For individuals who have HPV-related head and neck squamous cell carcinoma (HNSCC) who receive circulating tumor-tissue-modified viral (TTMV) HPV DNA testing with NavDx to guide treatment decisions and monitor for recurrence, the evidence includes 1 systematic review/meta-analysis, 1 nonrandomized clinical trial, 4 retrospective (N = 2,126) studies, and 3 prospective (N = 444) studies. Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measures, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. Studies are limited by an imperfect reference standard, imprecise estimates due to small sample sizes, clinical heterogeneity of study populations, variability in data recording, different conditions under which measurements occurred, and lack of a comparator that prohibit any concrete conclusions regarding clinical utility. No study reported management changes made in response to TTMV-HPV DNA test results and current management algorithms do not substantially differ based on HPV-related pathology. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical utility given the lack of a bona fide reference standard. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have HPV-related anal squamous cell carcinoma (ASCC) who receive circulating tumor-tissue-modified viral (TTMV) HPV DNA testing with NavDx to monitor for reoccurrence, minimal residual disease, and guide treatment decisions, the evidence includes 1 nonrandomized clinical trial and 1 retrospective (N = 117) study. Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measures, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. The retrospective and nonrandomized studies have reported an association between TTMV-HPV DNA positive scores measured at diagnosis, following surgery, during adjuvant therapy, and during surveillance after treatment and poor prognosis. Moreover, individuals whose TTMV-HPV DNA scores improved from baseline measurements were associated with clinical benefit as opposed to individuals whose TTMV-HPV DNA scores did not. However, these studies are limited by an imperfect reference standard, imprecise estimates due to small sample sizes, clinical heterogeneity of study populations, variability in data recording, different conditions under which measurements occurred, and lack of comparators. No study reported management changes made in response to TTMV-HPV DNA test results and current management algorithms do not substantially differ based on HPV-related pathology. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical utility given the lack of a bona fide reference standard. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with cancer of the head and neck or anus that are suspected to be driven by the human papillomavirus (HPV) and receive circulating tumor-tissue-modified viral (TTMV) HPV DNA testing with NavDx to determine if their cancer is HPV-related, the evidence includes 3 observational studies (N = 300) have reported an association of circulating TTMV-HPV DNA with the diagnosis of HPV-related cancer. Relevant outcomes are test validity, overall survival, and disease-specific survival. Studies are limited by an imperfect reference standard, imprecise estimates due to small sample sizes, clinical heterogeneity of study populations, variability in data recording, different conditions under which measurements occurred, and lack of a comparator that prohibit any concrete conclusions regarding clinical utility. No study reported management changes made in response to TTMV-HPV DNA test results and current management algorithms do not substantially differ based on HPV-related pathology. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical utility given the lack of a bona fide reference standard. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether using tumor-informed circulating tumor-tissue-modified viral (TTMV) human papillomavirus (HPV) DNA testing for diagnosis, treatment, or recurrence monitoring of HPV-related head and neck squamous cell carcinoma (HNSCC) and anal squamous cell carcinoma (ASCC) improves the net health outcome.

Policy

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

Policy Guidelines

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

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.^1,2,

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.^3, 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.

Regulatory Status

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 (CILA). 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.

Rationale

This evidence review was created in March 2025 with a search of the PubMed database. The most recent literature update was performed through February 13, 2025.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

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Population Reference No. 1

Circulating Tumor-Tissue-Modified Viral DNA Testing with NavDx in Individuals with Human Papillomavirus-related Head and Neck Cancer

Clinical Context and Test Purpose

The purpose of NavDx testing in patients who have human papillomavirus (HPV)-related head and neck cancer is to inform treatment decisions and to monitor for recurrence following treatment.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are individuals with HPV-related head and neck squamous cell carcinoma.

Interventions

The test being considered is circulating tumor-tissue-modified viral (TTMV) HPV DNA testing with NavDx:

• After treatment to inform decisions about adjuvant treatment, or

• During disease surveillance after treatment, to identify metastatic relapse at an early timepoint, and aid in the selection of individuals who may benefit from early/adjuvant treatment.

Comparators

The following practice is currently being used: standard clinical management without NavDx testing. In individuals with HPV-related head and neck cancer, surveillance and follow-up decisions are guided by the individual's tumor staging and other clinicopathological factors.

Individuals with HPV-related head and neck squamous cell carcinoma (HNSCC) lack the traditional risk factors present in HPV-unrelated HNSCC and have been shown to have better prognosis with limited incidences of developing a secondary primary malignancy. Individuals with HPV-related cancer have a longer median time to recurrence than individuals with HPV-unrelated cancer. The median time to recurrence for individuals with HNSCC is approximately 2 years. Surveillance can be challenging because of altered anatomy and/or fibrosis from surgery, radiation, and/or chemotherapy. Surveillance frequency and duration of follow up for HPV-related HNSCC is not well defined and varies amongst physicians in clinical practice. There are no consensus guidelines on the frequency and modality of routine post-treatment imaging in the asymptomatic patient. However, the National Comprehensive Cancer Network (NCCN) guidelines for disease surveillance following head and neck cancer treatment recommend clinical assessments at 4-8 week and regular history and physical exams (including mirror and fiberoptic examination) every 1 to 3 months during year 1, every 2 to 6 months in year 2, every 4 to 8 months in year 3 to 5, and every 12 months thereafter.^2,

Outcomes

The general outcomes of interest are disease-specific survival, test accuracy and validity, and change in disease status. Specific outcomes of interest are recurrence risk, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) at follow-up.

The treatment for HPV-related head and neck squamous cell carcinoma (HNSCC) is highly similar to HPV-unrelated HNSCC as there is currently no evidence to support treatment algorithms that address the distinct biological differences between these cancers. Decisions about neoadjuvant and adjuvant chemotherapy are based on clinicopathological risk factors.^2, If used for risk stratification to rule-out individuals for neoadjuvant chemotherapy at diagnosis or adjuvant treatment following surgery, the performance characteristics of most interest are negative predictive value and sensitivity. If used for risk stratification to rule-in individuals for neoadjuvant chemotherapy at diagnosis or adjuvant treatment following surgery, the performance characteristics of most interest are positive predictive value and specificity.

If used for disease surveillance following primary treatment, beneficial outcomes of a true positive test would be earlier detection of metastasis and initiation of appropriate treatment. Harmful outcomes of a false positive test would be undergoing unnecessary or incorrect treatment and experiencing adverse effects of such treatment. For individuals who are being monitored for relapse following treatment for HPV-related HNSCC, the timepoint of interest to assess recurrence should be between 2 - 5 years following treatment.

Study Selection Criteria

For the evaluation of clinical validity of the NavDx test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Systematic Reviews

Campo et al (2024) published a systematic review of 12 studies (N=1311) investigating the use of circulating tumor human papillomavirus DNA (ctHPVDNA) and tumor-tissue-modified viral (TTMV) HPV DNA as a biomarker for recurrence in patients with HPV-related oropharynx squamous cell carcinoma (OPSCC) post-treatment; only 3 of the included studies used the NavDx TTMV-HPV DNA assay. ^4,; ^5,;^6, The results of this analysis demonstrate that TTMV-HPV DNA testing has high accuracy (Diagnostic Odds Ration [DOR] = 589), sensitivity (89.7% [95% CI 72.2 to 96.7]; p>.05), and specificity (96.4% [95% CI 91.1 to 98.6]; p>.05) for the diagnosis of recurrence in patient with HPV-related OPSCC.

Nonrandomized Studies

Eight nonrandomized studies examined the association of NavDx testing to diagnosis of recurrence, prognosis, or response rates in individuals with head and neck squamous cell carcinoma (HNSCC) (Table 1). They differed in their study designs, populations (e.g., stage of disease), frequency and timing of standard care, outcome measures, and timing of follow up. Four observational studies evaluated the association between positive TTMV-HPV DNA results and diagnosis of recurrence in HNSCC (Table 2). ^7,4,5,6, A fifth retrospective study, set out to determine if TTMV-HPV DNA testing had clinical utility in resolving indeterminate disease status for individuals with HPV-related oropharyngeal cancer and found that TTMV-HPV DNA testing was able to observe faster clinically confirmed recurrence rates with initial clinically indeterminate findings during surveillance. ^8, Three studies monitored the relationship between TTMV-HPV DNA levels and responses to select therapies in patients with recurrent/metastatic HNSCC.^9,10,11, These studies did not provide comparisons of TTMV-HPV DNA testing to standard methods of risk stratification for therapy selection, monitoring response to therapy, or early relapse detection. There are no RCTs, and no studies in which NavDx testing was used to guide treatment decisions.

Chung et al (2022) conducted multi-institutional phase II clinical trial to evaluate overall survival in patients with recurrent and/or metastatic (R/M) HNSCC who have received combination therapy of cetuximab and nivolumab.^10, Analysis of the exploratory endpoints determined that patients with TTMV-HPV DNA levels less than the median at baseline achieved longer median PFS (3.1 months) and OS (8.6 months) compared to those with higher than median levels of TTMV-HPV DNA (p =.02 and p =.05, respectively).

Jhawar et al (2024) evaluated the relationship of TTMV-HPV DNA clearance and its impact on progression-free survival (PFS) in a prospective biomarker study (N = 80) that included patients with non-metastatic HPV-related OPSCC who received definitive radiotherapy (RT)/chemoradiation therapy (CRT).^11, PFS was significantly worse in patients who had persistent TTMV-HPV DNA levels at the end of treatment compared to patients who cleared TTMV-HPV DNA at 2 years (91.7% vs. 71.7%; log rank; p =.042). Moreover, this study included PET/CT surveillance at 3 months post-treatment to determine evidence of disease and found that among patients with complete TTMV-HPV DNA clearance at 3 months but had either a negative, equivocal, or incomplete PET/CT result had a 2-year PFS of 94.3%, 77.8%, and 59.3%, respectively (p =.029).

Hanna et al (2024) assessed the prognostic and surveillance value of TTMV-HPV DNA testing in R/M HPV-related OPSCC in a retrospective fashion. ^9, Patients with detectable TTMV-HPV DNA scores at last follow-up had significantly worse survival compared with those who were undetectable (p <.01).

Rettig et al (2024) enrolled 182 individuals with HPV-related oropharynx cancer in a prospective study to determine if TTMV-HPV DNA testing detects recurrence earlier than standard-of-care imaging techniques. ^7, Individuals with detectable TTMV-HPV DNA during surveillance were significantly associated with a worse RFS (HR = 75, 95% CI = 21 to 273; p <.001). Of note, these estimates were imprecise with wide confidence intervals. TTMV-HPV DNA testing was able to detect many recurrences at earlier intervals than stand-of-care treatment, especially in HPV16 serotypes. However, false-negatives and false-positives were reported in this study and highlight the variability of circulating TTMV-HPV DNA levels in HPV-related cancers. Additionally, due to the small sample size of individuals and the small number of recurrences no definitive conclusions can be drawn on the clinical utility and validity.

Study limitations are shown in Tables 3 and 4. Major limitations include a lack of comparison to tests used for the same purpose, imprecise estimates due to small sample sizes, and clinical heterogeneity of study populations.

Table 1. Nonrandomized Studies of NavDx Testing in HPV-related Head and Neck Cancer - Study Characteristics

  CT = computed tomography; HPV = human papillomavirus; IHC= immunohistochemistry; MRI = Magnetic resonance imaging; NA = not accessible; OPSCC = oropharyngeal squamous cell carcinoma; PET = positron emission tomography; R/M HNSCC = recurrent and/or metastatic head and neck squamous cell carcinoma; SCC = squamous cell carcinoma; TTMV = tumor-tissue-modified viral; *Positive, negative, and indeterminate scores were determined according to the manufacturer's instructions described in the background section of this medical policy.

Table 2. Observational Studies for Diagnosis of Recurrence in HPV-related Head and Neck Cancer

  NA: not assessed; NPV: negative predictive value; PPV: positive predictive value;  a Data was taken from the Campo et al (2024) systematic review as it was not accessible from the original source.

Table 3. Study Relevance Limitations

  The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest. c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose. d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests). e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true positives, true negatives, false positives, false negatives cannot be determined).

Table 4. Study Design and Conduct Limitations

  CT = computed tomography; MRI = Magnetic resonance imaging; PET = positron emission tomography The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience). b Blinding key: 1. Not blinded to results of reference or other comparator tests. c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described. d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data. f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison to other tests not reported.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials. No studies have directly assessed health outcomes in individuals prospectively managed with and without TTMV-HPV DNA testing.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: Circulating Tumor-Tissue-Modified Viral DNA Testing for Human Papillomavirus-related Head and Neck Cancer

For individuals who have HPV-related head and neck squamous cell carcinoma (HNSCC) who receive circulating tumor-tissue-modified viral (TTMV) HPV DNA testing with NavDx to guide treatment decisions and monitor for recurrence, the evidence includes 1 systematic review/meta-analysis, 1 nonrandomized clinical trial, 4 retrospective (N = 2,126) studies, and 3 prospective (N = 444) studies. Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measures, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. The systematic review, nonrandomized, and observational studies have reported positive TTMV-HPV DNA scores measured at diagnosis, following surgery, during adjuvant therapy, and during surveillance after treatment that underscore the potential clinical utility of NavDx testing in determining recurrence at earlier stages with potential to make better treatment decisions. However, these studies are limited by an imperfect reference standard, imprecise estimates due to small sample sizes, clinical heterogeneity of study populations, variability in data recording, different conditions under which measurements occurred, and lack of a comparator that prohibit any concrete conclusions regarding clinical utility. No study reported management changes made in response to TTMV-HPV DNA test results and current management algorithms do not substantially differ based on HPV-related pathology. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical utility given the lack of a bona fide reference standard. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Circulating Tumor-Tissue-Modified Viral DNA Testing for Human Papillomavirus-related Anal Cancer

Clinical Context and Test Purpose

The purpose of NavDx testing in patients who have human papillomavirus (HPV)-related anal cancer is to predict disease course (e.g., aggressiveness, risk of recurrence, death) and inform treatment decisions, and to monitor for recurrence following treatment.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are individuals with HPV-related anal squamous cell carcinoma (ASCC).

Interventions

The test being considered is circulating tumor-tissue-modified viral (TTMV) HPV DNA testing with NavDx:

• After treatment to inform decisions about adjuvant treatment, or

• During disease surveillance after treatment, to identify metastatic relapse at an early timepoint, and aid in the selection of individuals who may benefit from early/adjuvant treatment.

Comparators

The following practice is currently being used: standard clinical management without NavDx testing. In individuals with HPV-related anal cancer, surveillance and follow-up decisions are guided by the individual's tumor staging and other clinicopathological factors.

Individuals with HPV-related anal squamous cell carcinoma (ASCC) lack the traditional risk factors present in HPV-unrelated ASCC and have been shown to have better prognosis with limited incidences of developing a secondary primary malignancy. However, studies have shown that approximately 30% of individuals with ASCC will experience recurrence after receiving chemoradiation therapy.^12, Individuals with HPV-related cancer have a longer median time to recurrence than individuals with HPV-unrelated cancer with the median time to recurrence of 2 years. Surveillance according to the National Comprehensive Cancer Netowrk (NCCN) guidelines includes re-evaluation using digital anorectal examination (DRE/DARE) between 8 and 12 weeks after completion of chemoradiation therapy. Based on the clinicopathological factors, patients are classified into 3 groups, complete remission of disease, persistent disease, or progressive disease and will undergo follow-up accordingly.^2,

Outcomes

The general outcomes of interest are disease-specific survival, test accuracy and validity, and change in disease status. Specific outcomes of interest are recurrence risk, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) at follow-up.

The treatment for HPV-related ASCC is highly similar to HPV-unrelated ASCC as there is currently no evidence to support treatment algorithms that address the distinct biological differences between these cancers. Decisions about neoadjuvant and adjuvant chemotherapy are based on clinicopathological risk factors.^2, If used for risk stratification to rule-out individuals for neoadjuvant chemotherapy at diagnosis or adjuvant treatment following surgery, the performance characteristics of most interest are negative predictive value and sensitivity. If used for risk stratification to rule-in individuals for neoadjuvant chemotherapy at diagnosis or adjuvant treatment following surgery, the performance characteristics of most interest are positive predictive value and specificity.

If used for disease surveillance following primary treatment, beneficial outcomes of a true positive test would be earlier detection of metastasis and initiation of treatment. Harmful outcomes of a false positive test would be undergoing unnecessary or incorrect treatment and experiencing adverse effects of such treatment. For individuals who are being monitored for relapse following treatment for HPV-related ASCC, the timepoint of interest to assess recurrence should be between 2 - 5 years following treatment.

Study Selection Criteria

For the evaluation of clinical validity of the NavDx test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Nonrandomized Studies

Two noncomparative studies reported the association of NavDx testing with survival outcomes in anal squamous cell carcinoma (ASCC) (Table 5).

Kabarriti et al (2025) evaluated NavDx for disease surveillance in 117 individuals who had HPV-related ASCC and received at least one TTMV-HPV DNA test during the course of the disease.^13, TTMV-HPV DNA testing with NavDx demonstrated high diagnostic accuracy, sensitivity, and specificity that result in meaningful positive and negative predictive values. Individuals with at least one positive NavDx score post-treatment had significantly worse recurrence-free survival and those whose test scores resolved to a negative score had significantly better recurrence-free survival (Table 6).

Huffman et al (2024) evaluated TTMV-HPV DNA levels as an exploratory endpoint in patients with advanced ASCC who have received pembrolizumab during a multi-institutional phase II clinical trial.^14, Analysis of the exploratory endpoint determined that patients with lower baseline TTMV-HPV DNA scores were associated with clinical benefit (CR, PR, or SD ≥ 6 months; p =.003). Moreover, patients received an associated benefit in cycle 2 and cycle 3 when their TTMV-HPV DNA scores improved from baseline at these time intervals in response to pembrolizumab (p =.008 and p =.01, respectively). Patients whose TTMV-HPV DNA scores increased from baseline had significantly worse PFS compared to those whose TTMV-HPV DNA scores decreased from baseline in response to pembrolizumab at cycle 3 (HR: 0.37; 95%CI: 0.14 to 0.99, log-rank p=.04).

Study limitations are shown in Tables 7 and 8. Major limitations of both studies include a lack of comparison to standard methods of monitoring, and heterogeneity in the study populations.

Table 5. Nonrandomized Studies of NavDx Testing in Anal Cancer - Study Characteristics

  ASCC = anal squamous cell carcinoma; CT = computed tomography; HPV = human papillomavirus; MRI = Magnetic resonance imaging; PET = positron emission tomography; RECIST V.1.1 = response evaluation criteria in solid tumors version 1.1; TTMV = tumor-tissue-modified viral; *Positive, negative, and indeterminate scores were determined according to the manufacturer's instructions described in the background section of this medical policy.

Table 6. Nonrandomized Studies of NavDx Testing in Anal Cancer - Study Results

  CI = confidence interval; RFS = recurrence-free survival; HR = hazard ratio; PPV = positive predictive value; NPV = negative predictive value

Table 7. Study Relevance Limitations

  HPV = human papillomavirus The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest. c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose. d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests). e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true positives, true negatives, false positives, false negatives cannot be determined).

Table 8. Study Design and Conduct Limitations

  HPV = human papillomavirus; TTMV = tumor-tissue-modified viral The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience). b Blinding key: 1. Not blinded to results of reference or other comparator tests. c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described. d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data. f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison to other tests not reported.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials. There are no randomized controlled studies (RCTs), and no studies in which NavDx testing was used to prospectively guide treatment decisions.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: Circulating Tumor-Tissue-Modified Viral DNA Testing for Human Papillomavirus-related Anal Cancer

For individuals who have HPV-related anal squamous cell carcinoma (ASCC) who receive circulating tumor-tissue-modified viral (TTMV) HPV DNA testing with NavDx to monitor for reoccurrence, minimal residual disease, and guide treatment decisions, the evidence includes 1 nonrandomized clinical trial and 1 retrospective (N = 117) study. Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measures, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. The retrospective and nonrandomized studies have reported an association between TTMV-HPV DNA positive scores measured at diagnosis, following surgery, during adjuvant therapy, and during surveillance after treatment and poor prognosis. Moreover, individuals whose TTMV-HPV DNA scores improved from baseline measurements were associated with clinical benefit as opposed to individuals whose TTMV-HPV DNA scores did not. However, these studies are limited by an imperfect reference standard, imprecise estimates due to small sample sizes, clinical heterogeneity of study populations, variability in data recording, different conditions under which measurements occurred, and lack of comparators. No study reported management changes made in response to TTMV-HPV DNA test results and current management algorithms do not substantially differ based on HPV-related pathology. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical utility given the lack of a bona fide reference standard. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3

Circulating Tumor-Tissue-Modified Viral DNA Testing for Diagnosis of Human Papillomavirus-related Cancer of the Head and Neck or Anus

Clinical Context and Test Purpose

The purpose of NavDx testing in patients who have suspected human papillomavirus (HPV)-related cancer of the head and neck or anus is to diagnosis and confirm their HPV status.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are individuals with suspected HPV-related cancer of the head and neck or anus.

Interventions

The test being considered is circulating tumor-tissue-modified viral (TTMV) HPV DNA testing with NavDx for the diagnosis of HPV-related cancer of the head and neck or anus.

Comparators

There are currently no diagnostic tests with regulatory approval for HPV status. However, the National Comprehensive Cancer Network (NCCN) recommends that head and neck cancers undergo surrogate evaluation of tumor HPV status via p16 immunohistochemistry for all patients diagnosed with an oropharyngeal cancer. Furthermore, confirmatory HPV testing is recommended for clinical trials of HPV-targeted therapeutics or designed test deintensification strategies, which include polymerase chain reaction (PCR) and RNA and DNA in situ hybridization (ISH).^2,

Outcomes

The general outcomes of interest are test validity and accuracy, more specifically, the association between test results and the diagnosis of HPV-related cancer of the head and neck or anus.

Study Selection Criteria

For the evaluation of clinical validity of the NavDx test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

One study was excluded from the evaluation of the clinical validity of the NavDx test because they did not have a sufficient sample size to report on the accuracy of test due to the limited data collected. ^15,

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Nonrandomized Studies

Three nonrandomized studies reported the association of a positive NavDx test and the diagnosis of HPV-related cancer of the head and neck (Table 9). Relevant outcomes such as test validity, accuracy, and other test performance measures are reported in Table 10.

Rettig et al (2022) conducted a retrospective matched case-control study in 12 individuals with head and neck squamous cell carcinoma (HNSCC [case]) that had plasma samples collected at least 6 months prior to their diagnosis and were matched to individuals without HNSCC (control) that had similar patient characteristics (age, calendar year at time of plasma collection, race, and sex).^16, 10 out of the 12 patients with HNSCC were confirmed to have HPV-related cancer using archival tumor samples and of those 10 patients, tumor-tissue-modified viral (TTMV) HPV DNA testing with NavDx was able to confirm HPV status in 30 percent of patients (3/10, 95% CI = 7 to 65%) prior to their diagnosis with a median time of 30.5 months.

Ferrandino et al (2023) evaluated NavDx testing for diagnosis and disease surveillance in 399 individuals with oropharyngeal squamous cell carcinoma (OPSCC) who had at least one TTMV-HPV DNA test and stratified individuals into 2 cohorts: diagnostic cohort (n = 163) and surveillance cohort (n = 290).^5, Out of the 163 individuals within the diagnostic cohort, 152 were confirmed to have HPV-related OPSCC with 139 of patients being detected via NavDx testing. The per-test sensitivity and specificity for diagnosis of HPV-related OPSCC was reported as 91.5% (95% CI, 85.8% to 95.4% [139 of 152 tests]) and 100% (95% CI, 71.5% to 100% [11 of 11 tests]), respectively.

Ferrandino et al (2024) enrolled 138 individuals into a prospective diagnostic study in which they were evaluated for a lateral neck mass suspected of malignancy. Individuals were only evaluated if they were able to obtain a definitive TTMV-HPV DNA test result and a tissue biopsy of the mass.^17, The study included an analysis of the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of NavDx testing in comparison with a tissue biopsy, but not to current methods to identify HPV status, such as p16 ICH, PCR, and ISH. The results demonstrated improved diagnostic accuracy with high sensitivity (95.7% [95% CI, 85.5% to 99.5%]) and specificity (97.8% [95% CI, 92.3% to 99.7%]) with favorable predictive values, but ultimately there was no significant difference.

Study limitations are shown in Tables 11 and 12. Major limitations of both studies include a lack of comparison to standard methods of monitoring, and heterogeneity in the study populations.

Table 9. Nonrandomized Studies of NavDx Testing for Diagnosis of HPV-related Cancer - Study Characteristics

  HPV = human papillomavirus; TTMV = tumor-tissue-modified viral; *Positive, negative, and indeterminate scores were determined according to the manufacturer's instructions described in the background section of this medical policy.

Table 10. Observational Studies for Diagnosis of HPV-related Cancer

  NA = not assessed; NPV = negative predictive value; PPV = positive predictive value   

Table 11. Study Relevance Limitations

  The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest. c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose. d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests). e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true positives, true negatives, false positives, false negatives cannot be determined).

Table 12. Study Design and Conduct Limitations

  HPV = human papillomavirus; TTMV = tumor-tissue-modified viral The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience). b Blinding key: 1. Not blinded to results of reference or other comparator tests. c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described. d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data. f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison to other tests not reported.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials. There are no RCTs, and no studies in which NavDx testing was used to guide treatment decisions, including potential therapy de-escalation. Current treatment algorithms for HPV-related cancers do not substantially differ from HPV-unrelated cancers, underscoring uncertain clinical utility for testing.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: Circulating Tumor-Tissue-Modified Viral DNA Testing for Diagnosis of Human Papillomavirus-related Cancer

For individuals with cancer of the head and neck or anus that are suspected to be driven by the human papillomavirus (HPV) and receive circulating tumor-tissue-modified viral (TTMV) HPV DNA testing with NavDx to determine if their cancer is HPV-related, the evidence includes 3 observational studies (N = 300) have reported an association of circulating TTMV-HPV DNA with the diagnosis of HPV-related cancer. Relevant outcomes are test validity, overall survival, and disease-specific survival. The nonrandomized studies have reported positive TTMV-HPV DNA scores measured at diagnosis that underscore the potential clinical utility of NavDx testing in determining HPV status at earlier stages with the potential to make better treatment decisions. However, these studies are limited by an imperfect reference standard, imprecise estimates due to small sample sizes, clinical heterogeneity of study populations, variability in data recording, different conditions under which measurements occurred, and lack of a comparator that prohibit any concrete conclusions regarding clinical utility. No study reported management changes made in response to TTMV-HPV DNA test results and current management algorithms do not substantially differ based on HPV-related pathology. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical utility given the lack of a bona fide reference standard. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society of Clinical Oncology

In 2022, the American Society of Clinical Oncology (ASCO) published a provisional clinical opinion on somatic genetic testing in individuals with metastatic or advanced cancer.^18, The opinion addressed circulating tumor DNA (ctDNA) testing under additional topics but did not include a specific statement with a strength of recommendation rating. The panel noted, "There is a growing body of evidence on the clinical utility of genomic testing on cell-free DNA (cfDNA) in the plasma," citing the systematic review conducted by Merker et al (2018).^19, The panel also noted that ASCO will update that systematic review over the next few years.

The discussion also included the following points:

• "In patients without tissue-based genomic test results, treatment may be based on actionable alterations identified in cfDNA."

• "Testing is most helpful when genomic testing is indicated, archival tissue is unavailable, and new tumor biopsies are not feasible."

• "cfDNA levels themselves may be prognostic and early cfDNA dynamics may serve as an early predictor of therapy response or resistance."

• "Ongoing studies are expected to better delineate the clinical utility of serial liquid biopsies.

Of note, neither of these reviews explicitly address circulating tumor-tissue-modified viral (TTMV) DNA.

National Comprehensive Cancer Network

There is no general National Comprehensive Cancer Network (NCCN) guideline on the use of circulating tumor-tissue-modified viral DNA. However, the NCCN guidelines for head and neck cancer (v.2.2025) state there is currently no diagnostic test with regulatory approval for HPV status and recommends that head and neck cancers undergo evaluation of tumor HPV status by use of a surrogate of p16 immunohistochemistry for all patients diagnosed with an oropharyngeal cancer.^1, Furthermore, confirmatory HPV testing is recommended for clinical trials of HPV-targeted therapeutics or designed test deintensification strategies, which include polymerase chain reaction (PCR) and RNA and DNA in situ hybridization (ISH). Lastly, the guideline notes: "At this time, persistent cell-free oncogenic HPV DNA detection in plasma (among those positive and quantifiable at diagnosis) may identify patients at increased risk for progression after completion of curative intent therapy. However, without concurrent clinical, radiographic or pathological correlates represents an outcome without actionable therapeutic implications outside of clinical trials."

Despite publishing unique staging criteria for head and neck cancer that is HPV-related and noting that it is biologically distinct from head and neck cancer that is HPV-unrelated, the treatment algorithms for both are highly similar. Further research is needed to explore the precise nature of HPV-related pathology that can be exploited by therapeutic intervention. Refer to treatment recommendations by cancer type for specific recommendations.

NCCN guidelines for anal cancer (2.2025) note that the optimal approach to screening for high-grade anal intraepithelial neoplasia (AIN) "remains an area of uncertainty, but it is likely that future approaches will include additional tests such as HPV."^2, Current NCCN treatment algorithms for anal cancer do not stratify by HPV status.

U.S. Preventive Services Task Force Recommendations

Not applicable

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 13.

Table 13. Summary of Key Trials

 NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.

References

1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancer (Version 2.2025). https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed February 12, 2025.
2. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Anal Carcinoma (Version 2.2025). https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf. Accessed February 13, 2025.
3. Alix-Panabières C, Pantel K. Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy. Cancer Discov. May 2016; 6(5): 479-91. PMID 26969689
4. Berger BM, Hanna GJ, Posner MR, et al. Detection of Occult Recurrence Using Circulating Tumor Tissue Modified Viral HPV DNA among Patients Treated for HPV-Driven Oropharyngeal Carcinoma. Clin Cancer Res. Oct 03 2022; 28(19): 4292-4301. PMID 35576437
5. Ferrandino RM, Chen S, Kappauf C, et al. Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus-Associated Oropharyngeal Cancer. JAMA Otolaryngol Head Neck Surg. Nov 01 2023; 149(11): 971-977. PMID 37422913
6. Hanna GJ, Roof SA, Jabalee J, et al. Negative Predictive Value of Circulating Tumor Tissue Modified Viral (TTMV)-HPV DNA for HPV-driven Oropharyngeal Cancer Surveillance. Clin Cancer Res. Oct 13 2023; 29(20): 4306-4313. PMID 37566241
7. Rettig EM, Schoenfeld JD, Miller J, et al. Prospective Trial of Biomarker-Guided Surveillance for HPV-positive Oropharynx Cancer Using Plasma Tumor Tissue Modified Viral HPV DNA. Clin Cancer Res. Dec 26 2024. PMID 39715483
8. Roof SA, Jabalee J, Rettig EM, et al. Utility of TTMV-HPV DNA in resolving indeterminate findings during oropharyngeal cancer surveillance. Oral Oncol. Aug 2024; 155: 106874. PMID 38878355
9. Hanna GJ, Jabalee J, Lukens JN, et al. Circulating tumor tissue modified viral (TTMV)-HPV DNA in Recurrent, metastatic HPV-driven oropharyngeal cancer. Oral Oncol. Nov 2024; 158: 107002. PMID 39159525
10. Chung CH, Li J, Steuer CE, et al. Phase II Multi-institutional Clinical Trial Result of Concurrent Cetuximab and Nivolumab in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. Jun 01 2022; 28(11): 2329-2338. PMID 35344035
11. Jhawar SR, Haring C, Pan X, et al. Impact of circulating tumor human papillomavirus DNA kinetics on disease outcomes in HPV-associated oropharyngeal cancer. Int J Cancer. Dec 16 2024. PMID 39679923
12. Tang S, Wang K, Hein D, et al. Recurrence-free survival prediction for anal squamous cell carcinoma after chemoradiotherapy using planning CT-based radiomics model. Br J Radiol. Feb 01 2025; 98(1166): 296-304. PMID 39535872
13. Kabarriti R, Lloyd S, Jabalee J, et al. Evaluating Tumor Tissue Modified Viral (TTMV)-HPV DNA for the Early Detection of Anal Squamous Cell Carcinoma Recurrence. Cancers (Basel). Jan 08 2025; 17(2). PMID 39857955
14. Huffman BM, Singh H, Ali LR, et al. Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders. J Immunother Cancer. Jan 25 2024; 12(1). PMID 38272561
15. Batool S, Sethi RKV, Wang A, et al. Circulating tumor-tissue modified HPV DNA testing in the clinical evaluation of patients at risk for HPV-positive oropharynx cancer: The IDEA-HPV study. Oral Oncol. Dec 2023; 147: 106584. PMID 37837735
16. Rettig EM, Faden DL, Sandhu S, et al. Detection of circulating tumor human papillomavirus DNA before diagnosis of HPV-positive head and neck cancer. Int J Cancer. Oct 01 2022; 151(7): 1081-1085. PMID 35262203
17. Ferrandino RM, Barlow J, Gold B, et al. Diagnostic Accuracy of Circulating Tumor HPV DNA Testing in Patients With a Lateral Neck Mass. JAMA Otolaryngol Head Neck Surg. Sep 19 2024; 150(12): 1089-96. PMID 39298177
18. Chakravarty D, Johnson A, Sklar J, et al. Somatic Genomic Testing in Patients With Metastatic or Advanced Cancer: ASCO Provisional Clinical Opinion. J Clin Oncol. Apr 10 2022; 40(11): 1231-1258. PMID 35175857
19. Merker JD, Oxnard GR, Compton C, et al. Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. J Clin Oncol. Jun 01 2018; 36(16): 1631-1641. PMID 29504847

Codes

Policy History