Medical Policy

Policy Num:      11.003.139
Policy Name:    Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Ovarian Cancer (BRCA1, BRCA2, Homologous Recombination Deficiency, NTRK)
Policy ID:          [11.003.139] [Ac / B / M+ / P+] [2.04.156]

Last Review:      October 16, 2024
Next Review:      October 20, 2025
 

Related Policies:

11.003.030- Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2)
11.003.028 - Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes
11.003.022 - Genetic Testing for Li-Fraumeni Syndrome
11.003.026 - Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies
11.003.089 - Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)
11.003.134 - Molecular Testing for Germline Variants Associated with Ovarian Cancer (BRIP1, RAD51C, RAD51D, NBN)
11.003.135 - Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer
11.003.140 - Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB)
11.003.009 - Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, HER2, PD-L1, TMB)
11.003.004 - Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, and HER2)
11.003.011 - Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy (BRAF)
11.003.016 - Genetic Testing for PTEN Hamartoma Tumor Syndrome
11.003.064 - Genetic Cancer Susceptibility Panels Using Next Generation Sequencing
05.001.034 - Tropomyosin Receptor Kinase Inhibitors for Locally Advanced or Metastatic Solid Tumors Harboring an NTRK Gene Fusion

Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Ovarian Cancer (BRCA1, BRCA2, Homologous Recombination Deficiency, NTRK)

Summary

Description

Biomarker-targeted therapy has shown a clear survival benefit in patients with ovarian cancer. More recently, testing for microsatellite instability/mismatch repair (MSI/MMR) and tumor mutational burden (TMB) status to select patients for immunotherapy has been proposed. Typically, the evaluation of biomarker status requires tissue biopsy. Circulating tumor DNA testing (also known as a liquid biopsy) is proposed as a non-invasive alternative.

Summary of Evidence

For individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive germline BRCA1/2 variant testing to guide treatment with a poly adenosine diphosphate-ribose polymerase (PARP) inhibitor, the evidence includes FDA-approved therapeutics with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive somatic BRCA1/2 variant testing using tissue biopsy to guide treatment with a PARP inhibitor, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive homologous recombination deficiency (HRD) testing using tumor tissue to guide treatment with a PARP inhibitor, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive somatic BRCA1/2 variant testing using circulating tumor DNA testing (liquid biopsy) to guide treatment with a PARP inhibitor, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether using biomarker testing to select targeted treatment and immunotherapy improves the net health outcome in individuals with ovarian cancer.

Policy Statements

Germline BRCA1/2 variant analysis may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies.

Somatic BRCA1/2 variant analysis using tumor tissue may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies.

All other uses of germline and somatic BRCA1/2 variant analysis to guide targeted therapy for ovarian, fallopian tube, or primary peritoneal cancer are considered investigational.

Homologous recombination deficiency (HRD) analysis of tumor tissue may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies.

All other uses of HRD testing of tumor tissue to guide targeted therapy for ovarian, fallopian tube, or primary peritoneal cancer are considered investigational.

BRCA1/2 variant analysis using circulating tumor DNA (liquid biopsy) may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies when tissue-based analysis is not clinically feasible.

All other uses of circulating tumor DNA testing (liquid biopsy) to guide targeted therapy in individuals with ovarian, fallopian tube, or primary peritoneal cancer are considered investigational.

NTRK1, NTRK2, and NTRK3 gene fusion analysis of tumor tissue may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies.

All other uses of NTRK1, NTRK2, and NTRK3 gene fusion analysis of tumor tissue to guide targeted therapy for ovarian, fallopian tube, or primary peritoneal cancer are considered investigational.

Simultaneous testing using liquid and tumor biopsies (outside of paired or concurrent somatic-germline testing) to guide treatment in individuals with ovarian, fallopian tube, or primary peritoneal cancer is considered investigational (see Policy Guidelines).

Testing for other variants may become available between policy updates.

Policy Guidelines

Plans may need to alter local coverage medical policy to conform to state law regarding coverage of biomarker testing.

Testing for other variants may become available between policy updates.

Testing for individual genes (not gene panels) associated with FDA-approved therapeutics for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher are not subject to extensive evidence review. Note that while the FDA approval of companion diagnostic tests for genes might include tests that are conducted as panels, the FDA approval is for specific genes (such as driver mutations) and not for all of the genes on the test panel.

For expanded panel testing, see evidence review 2.04.115.

For somatic biomarker testing related to use of immune checkpoint inhibitor therapy (BRAF, microsatellite instability/mismatch repair [MSI/MMR], PD-L1, tumor mutational burden [TMB]), see evidence review 2.04.157.

Note that TMB is often included in panel tests and might not have separate coding; Plans with coverage for panels might consider local decision for TMB.

FDA approves tests in between policy review cycles. As such, newly approved tests might need to be considered per local Plan discretion. For guidance on testing criteria between policy updates, refer to the FDA's List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools)(https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools) for an updated list of FDA-approved tumor markers and consult the most current version of NCCN management algorithms.

Note: Extensive evidence review is not included for somatic tests of individual genes (not gene panels) associated with FDA-approved therapies with NCCN recommendations of 2A or higher. The pivotal evidence is included in Table 1 for informational purposes. Additionally, no evidence review is provided for somatic tests of individual genes that do not have associated FDA-approved therapies regardless of NCCN recommendations, as these off-label therapies are deemed investigational per the Blue Cross and Blue Shield Association Medical Policy Program Policies and Procedures.

This policy does not address germline testing for inherited risk of developing cancer.

Repeat Genomic Testing

There may be utility in repeated testing of gene variants for determining targeted therapy or immunotherapy in individuals with ovarian cancer, as a resistance mechanism to platinum-based chemotherapies and poly adenosine diphosphate-ribose polymerase (PARP) inhibitors in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function (Lin et al 2019; PMID 30425037). ASCO currently suggests repeat genomic testing for patients on targeted therapy with suspected acquired resistance, especially if choice of next-line therapy would be guided. The ASCO guidance is not tumor specific, and cautions to consider clinical utility (Chakravarty et. al. 2022; PMID 35175857).

Paired Somatic-Germline Testing

Testing for genetic changes in tumor tissue assesses somatic changes. Some somatic testing involves a paired blood analysis in order to distinguish whether findings in tumor tissue are acquired somatic changes or germline changes. Some laboratories offer paired tumor sequencing and germline sequencing which is done at the same time and in the same laboratory. The goal of this paired testing is to identify truly somatic changes to guide treatment. However, paired testing can also identify potential germline changes that might indicate an inherited cancer syndrome. These results would need to be confirmed through germline testing if personal and family cancer history is consistent with an inherited cancer syndrome (see evidence reviews related to inherited cancer syndromes, 2.04.02, 2.04.08, 2.04.88, 2.04.101).

Paired genetic testing is different than concurrent somatic-germline testing. In concurrent testing, the germline results are not used to filter the somatic results. Rather, the laboratories perform large, separate panels of germline and somatic variants. The goal is to identify options for genome-informed treatment and to identify hereditary cancer risk. For concurrent panel testing, see evidence review 2.04.93 - Genetic Cancer Susceptibility Panels Using Next Generation Sequencing for germline panel, and see evidence review 2.04.115 - Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies for somatic panel.

Concurrent Somatic Liquid-based and Tissue-based Genomic Testing

Liquid biopsy testing uses blood samples and assesses cancer DNA and non-cancer DNA in the same blood sample. The goal is to identify options for genome-informed treatment. Some providers will order a liquid biopsy test and a tissue biopsy test at the same time, not for filtering or for comparison as in the paired genetic testing section above, but to hasten time to treatment. If the intent of concurrent testing is to follow a patient over time for resistance mutations/response to therapy, then consideration could be given to doing liquid biopsy at diagnosis with the tissue biopsy to make sure that whatever mutations are going to be followed longitudinally can be detected by the liquid biopsy. For example, monitoring BRCA mutation evolution (reversion mutations) in individuals with ovarian cancer during PARP inhibitor therapy may be achieved with serial ctDNA sampling, and allow for earlier detection of resistance and selection of alternative therapies to reduce the risk of resistance. This testing strategy has not been fully studied and is not yet discussed in the NCCN guidelines for ovarian cancer.

Genetic Counseling

Genetic counseling is primarily aimed at individuals who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

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

Biomarker Testing and Targeted Treatment in Ovarian Cancer

DNA damage happens daily, and most are repaired to allow normal cell functioning. Double strand breaks (DSB) in the DNA are particularly damaging. Repair of DSB utilizes the homologous recombination repair (HRR) pathway. Many types of cancer, however, are unable to repair DNA damage. This leads to the accumulation of genetic errors, such as loss of DNA, rearrangements in the DNA, and loss of entire genes. The consequence of these errors is genomic instability. The loss of the HRR and associated genomic instability is called homologous recombination deficiency (HRD). HRD is associated with several types of cancer including ovarian cancer.^1,2,Poly adenosine diphosphate-ribose polymerase (PARP) inhibitors are used to target tumor cells with alterations in the HRR genes BRCA1 and BRCA2. Currently, 3 PARP inhibitors are FDA-approved for use in ovarian cancer (Table 1).

In ovarian cancer targeted therapies, HRD-positive status is generally defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability. Myriad MyChoice^® is an FDA-approved companion diagnostic for the assessment of tumor genomic instability score (GIS) and the detection and classification of variants in the BRCA1 and BRCA2 genes, for the selection of patients who are eligible for targeted treatment. A patient’s Myriad HRD status is determined by detecting single nucleotide variants (SNVs), variants in homopolymer stretches, insertions and deletions (indels), and large rearrangements (LRs) in the BRCA1 and BRCA2 genes, and determining a genomic instability score (GIS) using DNA obtained from ovarian tumor tissue. A positive Myriad HRD Status result is due to either the presence of a pathogenic variant in BRCA1 and/or BRCA2 and/or a GIS above a defined threshold.^3,Approximately 41% to 50% of epithelial ovarian cancers are estimated to exhibit HRD. Germline alterations in BRCA1 and BRCA2 genes have been identified in up to 17% of individuals diagnosed with epithelial ovarian cancer, and somatic mutations are found in an additional 7%.^4,

Circulating Tumor DNA (Liquid Biopsy)

Normal and tumor cells release small fragments of DNA into the blood, which is referred to as cell-free DNA. 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. 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.

Regulatory Status

Table 1 summarizes the targeted treatments approved by the FDA for individuals with ovarian cancer, along with the approved companion diagnostic tests. The information in Table 1 was current as of August 30, 2023. An up-to-date list of FDA cleared or approved companion diagnostics is available at: https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools.

Voluntarily Withdrawn Indications for Maintenance Therapy

In 2022, the manufacturers of all 3 PARP inhibitors used to treat ovarian cancer voluntarily withdrew indications for third-line or greater treatment in ovarian cancer.^5,6,7, The withdrawals were based on updated survival results from the ARIEL4 (NCT02855944), SOLO3 (NCT02282020), and QUADRA (NCT02354586) trials. The withdrawals did not affect other indications in ovarian cancer.

Table 1. Targeted Treatments for Ovarian Cancer and NTRK fusions with FDA-Approved Companion Diagnostic Tests

Sources: Food and Drug Administration (2023)21,; Drugs@FDA22,

Laboratory-Developed Tests

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 under CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.  

Rationale

This evidence review was created in September 2022 with a search of the PubMed database. The most recent literature update was performed through August 1, 2024.

Testing for individual genes (not gene panels) associated with Food and Drug Administration (FDA)-approved therapeutics for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher are not subject to extensive evidence review. The pivotal evidence is included in Table 1 for informational purposes. Note that while the FDA approval of companion diagnostic tests for genes might include tests that are conducted as panels, the FDA approval is for specific genes (such as driver mutations) and not for all of the genes on the test panel.

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.

Population Reference No. 1, 2, 3 

Biomarker Testing Using Tissue Biopsy to Select Targeted Treatment and Immunotherapy (BRCA1, BRCA2, Homologous Repair Deficiency, and Microsatellite Instability/Mismatch Repair)

Clinical Context and Test Purpose

Ovarian cancer treatment selection is informed by tumor type, grade, stage, patient performance status and preference, prior treatments, and the molecular characteristics of the tumor such as the presence of driver mutations. One purpose of biomarker testing of patients who have advanced cancer is to inform a decision regarding treatment selection (eg, whether to select a targeted treatment or standard treatment).

The question addressed in this evidence review is: Does germline testing for BRCA1/2 variants; and, BRCA1/2, HRD, and microsatellite instability/mismatch repair (MSI/MMR) testing using tissue biopsy improve the net health outcome in individuals with ovarian, fallopian tube, or primary peritoneal cancer? Note that this policy does not review NTRK gene fusions; see policy 5.01.31.

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

Populations

The relevant population of interest is individuals with ovarian, fallopian tube, or primary peritoneal cancer for whom the selection of targeted treatment depends on the molecular characterization of the tumor.

Interventions

The technologies being considered are germline testing for BRCA1/2 variants; and, BRCA1/2, HRD, and microsatellite instability/mismatch repair (MSI/MMR) testing using tissue biopsy.

Comparators

Decisions about treatment in ovarian cancer are based on clinical characteristics. The comparator would be no variant testing to guide treatment.

Outcomes

The general outcomes of interest in oncology are overall survival (OS), disease-specific survival, quality of life (QOL), treatment-related mortality and morbidity.

Beneficial outcomes resulting from a true-positive test result are prolonged survival, reduced toxicity, and improved QOL associated with receiving a more effective targeted therapy. Beneficial outcomes from a true negative result are prolonged survival associated with receiving chemotherapy in those without driver mutations.

Harmful outcomes resulting from a false-negative test result include shorter survival from receiving less effective and more cytotoxic chemotherapy in those with driver mutations; possible harmful outcomes resulting from a false-positive test result are a shorter survival from receiving potentially ineffective targeted treatment and delay in initiation of chemotherapy in those without driver mutations.

The overall response rate (ORR) may be used as a surrogate endpoint reasonably likely to predict clinical benefit in patients with refractory solid tumors. ORR can be measured by the proportion of patients with best overall confirmed response of complete response or partial response by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1),^7, or Response Assessment in Neuro-Oncology criteria,^8, as appropriate by a blinded and independent adjudication committee.

There are clearly defined quantitative thresholds for the follow-up of patients in oncology trials. A general rule is a continuation of treatment until disease progression or unacceptable toxicity. Long-term follow-up outside of a study setting is conducted to determine survival status. The duration of follow-up for the outcomes of interest is 6 months and 1 year.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for randomized controlled trials (RCTs);

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Testing for individual genes (not gene panels) associated with FDA-approved therapeutics (ie, as companion diagnostic tests) for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher are not subject to extensive evidence review. Note that while the FDA approval of companion diagnostic tests for genes might include tests that are conducted as panels, the FDA approval is for specific genes (such as driver mutations) and not for all of the genes on the test panel.

Clinically Valid and Clinically Useful

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). 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.

Review of Evidence

Clinical trials have evaluated the effectiveness of poly adenosine diphosphate-ribose polymerase (PARP) inhibitor drugs in individuals with ovarian cancer confirmed to have a BRCA1/2 mutation. Summarized below are the pivotal trials that supported the BRCA variant-related FDA-approved indications in ovarian cancer.

Niraparib

FDA approval for niraparib for treatment of ovarian cancer was based on the QUADRA phase 2 clinical trial.^9, QUADRA evaluated the safety and activity of niraparib in adult patients with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with 3 or more previous chemotherapy regimens. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with HRD-positive tumors (including patients with BRCA and without BRCA pathogenic variants) sensitive to their last platinum-based therapy who had received 3 or 4 previous anticancer therapy regimens (primary efficacy population). Thirteen of 47 patients (28%) in the primary efficacy population achieved an overall response according to RECIST (95% CI, 15.6% to 42.6%; p=.00053).

Olaparib

The effectiveness of olaparib as maintenance therapy in newly diagnosed advanced ovarian cancer was demonstrated in the phase 3 SOLO-1 RCT comparing olaparib to placebo in 391 individuals with newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation.^10, After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo (Kaplan-Meier estimate of the rate of freedom from disease progression and from death at 3 years, 60% vs. 27%; hazard ratio for disease progression or death, 0.30; 95% CI, 0.23 to 0.41; p<.001).

Rucaparib

Several companion diagnostic tests have been FDA-approved to select individuals with BRCA1/2 variants for treatment with rucaparib for ovarian cancer. Subsequently, however, the indication for rucaparib was changed to no longer require BRCA testing for this indication.^4, The indication change was based on results from the ATHENA trial (NCT03522246) which showed improvement in progression-free survival (PFS) regardless of BRCA variant status.^11,

Pembrolizumab

FDA approval of pembrolizumab was supported by the phase 2 KEYNOTE-158 study. The trial included a total of 233 previously treated participants with MSI-H/dMMR solid tumors, 15 of whom had ovarian cancer. In the full cohort, the overall response rate was 34.3% (95% CI, 28.3% to 40.8%). Median PFS was 4.1 months (95% CI, 2.4 to 4.9 months) and median OS was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%).^12,

Section Summary: Biomarker Testing Using Tissue Biopsy to Select Targeted Treatment and Immunotherapy (BRCA1, BRCA2, Homologous Repair Deficiency, and Microsatellite Instability/Mismatch Repair)

Clinical trials have demonstrated clinical benefit when testing was used to identify individuals for treatment with FDA-approved therapies.

For individuals with epithelial ovarian, fallopian tube, or primary peritoneal cancer who receive BRCA1/2 variant testing, homologous recombination deficiency (HRD) testing, or microsatellite instability/mismatch repair (MSI/MMR) testing using tumor tissue to guide targeted treatment or immunotherapy, the evidence includes nonrandomized clinical trials. Relevant outcomes are OS, disease-specific survival, change in disease status, medication use, resource utilization, and treatment-related morbidity. Clinical trials have demonstrated clinical benefit when testing was used to identify individuals for treatment with FDA-approved therapies. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4

Tumor Mutational Burden Testing to Guide Treatment for Ovarian Cancer

Clinical Context and Test Purpose

The purpose of tumor mutational burden (TMB) testing in patients who have ovarian cancer is to inform a decision on whether patients should receive immunotherapy versus another systemic therapy. The goal of immunotherapy is to preferentially kill malignant cells without significant damage to normal cells so that there is improved therapeutic efficacy along with decreased toxicity.

The question addressed in this evidence review is: In individuals with ovarian cancer, does the use of tumor mutational burden testing improve the net health outcome?

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

Populations

The relevant population of interest is individuals with ovarian cancer.

Interventions

Tumor mutational burden, a measure of gene mutations within cancer cells, is proposed as a biomarker for response to immunotherapy.

Comparators

The comparator is treatment as usual without TMB testing.

Outcomes

The general outcomes of interest in oncology are OS, disease-specific survival, QOL, treatment-related mortality and morbidity. Beneficial outcomes resulting from a true-positive test result are prolonged survival, reduced toxicity, and improved QOL associated with receiving a more effective targeted therapy. Beneficial outcomes from a true negative result are prolonged survival associated with receiving chemotherapy in those without driver mutations. Harmful outcomes resulting from a false-negative test result include shorter survival from receiving less effective and more cytotoxic chemotherapy in those with driver mutations; possible harmful outcomes resulting from a false-positive test result are a shorter survival from receiving potentially ineffective targeted treatment and delay in initiation of chemotherapy in those without driver mutations.

The ORR may be used as a surrogate endpoint reasonably likely to predict clinical benefit in patients with refractory solid tumors. ORR can be measured by the proportion of patients with best overall confirmed response of complete response or partial response by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1),^7, or Response Assessment in Neuro-Oncology criteria,^8, as appropriate by a blinded and independent adjudication committee.

There are clearly defined quantitative thresholds for the follow-up of patients in oncology trials. A general rule is a continuation of treatment until disease progression or unacceptable toxicity. Long-term follow-up outside of a study setting is conducted to determine survival status. The duration of follow-up for the outcomes of interest is 6 months and 1 year.

Study Selection Criteria

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

• Reported on the accuracy of the marketed version of the technology;

• 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).

Review of Evidence

FDA-Approved Companion Diagnostic Test

FoundationOne CDx is FDA-approved as a companion diagnostic for use with pembrolizumab in patients with TMB-high (≥ 10 mutations per megabase) solid tumors. Approval was based on results of the KEYNOTE-158 study that enrolled patients with solid tumors, but none of the patients evaluated had ovarian cancer.

Clinical Validity

Nonrandomized Trial

Marabelle et al (2020) reported the association of high TMB to response to pembrolizumab in patients with solid tumors enrolled in a prespecified exploratory analysis of the KEYNOTE-158 study.^12, High TMB was defined as >10 mutations per megabase according to the FoundationOne CDx panel. The proportion of patients with an objective response in the TMB-high group was 29%. At a median follow-up of approximately 3 years, the median duration of response was not reached in the TMB-high group and was 33.1 months in the non-TMB-high group. Notably, TMB-high status was associated with improved response irrespective of programmed death-ligand 1 (PD-L1). Median PFS and OS did not differ between the high and non-high TMB groups. Objective responses were observed in 24 (35%; 95% CI, 24% to 48%) of 68 participants who had both TMB-high status and PD-L1-positive tumors (i.e., PD-L1 combined positive score of ≥1) and in 6 (21%; 95% CI, 8% to 40%) of 29 participants who had TMB-high status and PD-L1-negative tumors. Study eligible cancers were limited to anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar. Because no patients with ovarian cancer were included in these analyses, it is not possible to draw conclusions about the clinical validity and utility of TMB in this group of patients.

Clinical Utility

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. There is no direct evidence of clinical utility of TMB testing to guide ovarian cancer treatment.

Chain of Evidence

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

Section Summary: Tumor Mutational Burden Testing to Guide Treatment for Ovarian Cancer

In a prespecified exploratory analysis of a nonrandomized trial of pembrolizumab in patients with various solid tumors, objective responses were observed in 35% of participants who had both TMB-high status and PD-L1-positive tumors and in 21% of participants who had TMB-high status and PD-L1-negative tumors. A TMB-high status was associated with improved response irrespective of PD-L1 status. Median OS and PFS survival were not significantly different between TMB groups. Because no patients with ovarian, fallopian tube, or primary peritoneal cancer were included in these analyses, it is not possible to draw conclusions about the clinical validity and utility of TMB in this group of patients. These results need to be confirmed in well-designed prospective studies enrolling patients in the relevant population.

For individuals with unresectable or metastatic ovarian, fallopian tube, or primary peritoneal cancer who receive TMB testing to select treatment with immunotherapy, the evidence includes a prespecified retrospective subgroup analysis of a nonrandomized phase 2 trial. Relevant outcomes are OS, disease-specific survival, change in disease status, medication use, resource utilization, and treatment-related morbidity. Objective responses were observed in 35% of participants who had both TMB-high status and PD-L1-positive tumors and in 21% of participants who had TMB-high status and PD-L1-negative tumors. High TMB status was associated with improved response irrespective of PD-L1 status. Median OS and progression free survival were not significantly different between TMB groups. Because no patients with ovarian cancer were included in these analyses, it is not possible to draw conclusions about the clinical validity and utility of TMB in this group of patients. Well-designed prospective studies enrolling patients in the population of interest are required. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome

Population Reference No. 5

Circulating Tumor DNA Testing (Liquid Biopsy) to Guide Treatment for Ovarian Cancer

Clinical Context and Test Purpose

One purpose of liquid biopsy testing of patients who have ovarian cancer is to inform a decision regarding treatment selection (eg, whether to select a targeted treatment or standard treatment).

The question addressed in this evidence review is: Does use of circulating tumor DNA (ctDNA) testing to select treatment in patients with ovarian cancer improve the net health outcome?

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

Populations

The relevant population of interest is individuals with ovarian cancer being considered for targeted therapy or immunotherapy.

Interventions

The test being considered is liquid biopsy using ctDNA.

Comparators

In patients who are able to undergo a biopsy, molecular characterization of the tumor is performed using standard tissue biopsy samples. Patients unable to undergo a biopsy generally receive standard therapy.

Outcomes

True-positive liquid biopsy test results lead to the initiation of appropriate treatment (eg, targeted therapy) without a tissue biopsy. False-positive liquid biopsy test results lead to the initiation of inappropriate therapy, which could shorten PFS.

In patients able to undergo a tissue biopsy, negative liquid biopsies reflex to tissue testing. In patients unable to undergo a tissue biopsy, a negative liquid biopsy result would not change empirical treatment. Therefore, health outcomes related to negative test results do not differ between liquid biopsy and tissue biopsy.

The time frame for outcomes measures varies from several months to several years.

Study Selection Criteria

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

• Reported on the accuracy of the marketed version of the technology;

• Included a suitable reference standard;

• Patient/sample clinical characteristics were described;

• Patient/sample selection criteria were described.

Review of Evidence

FDA-Approved Companion Diagnostic Test

In October 2020, FoundationOne Liquid was FDA-approved as a companion diagnostic to identify individuals with BRCA-mutated ovarian cancer to select patients for treatment with rucaparib.^13, Approval was based on analysis of pre-treatment plasma samples from the phase 2 ARIEL2 study. Subsequently, in June 2022 the indication for rucaparib was changed to no longer require BRCA testing.

There are no other FDA -cleared or -approved liquid biopsy companion diagnostic tests for use in selecting targeted treatment or immunotherapy in individuals with ovarian cancer.

Clinical Validity

In 2018, the American Society of Clinical Oncology and College of American Pathologists jointly convened an expert panel to review the current evidence on the use of ctDNA assays.^14, The literature review included a search for publications on the use of ctDNA assays for solid tumors in March 2017 and covers several different indications for the use of liquid biopsy. The search identified 1338 references to which an additional 31 references were supplied by the expert panel. Seventy-seven articles were selected for inclusion. Much of the literature on the use of ctDNA to guide treatment selection was for non-small-cell lung cancer, metastatic colorectal cancer, and breast cancer, The literature review did not specifically address ovarian cancer. The authors concluded that "There is little evidence of clinical validity and clinical utility to support the widespread use of ctDNA assays in most patients with advanced cancer, with the exception of those with demonstrated clinical utility or those with regulatory approval."

Clinical Utility

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. There is no direct evidence of clinical utility of ctDNA testing to guide ovarian cancer treatment.

The clinical utility of FoundationOne liquid was evaluated using plasma samples from participants in the ARIEL2 trial. However, BRCA testing is no longer indicated prior to rucaparib treatment in ovarian cancer and so the relevance of this evidence is uncertain.

Chain of Evidence

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

Section Summary: Circulating Tumor DNA Testing (Liquid Biopsy) to Guide Treatment for Ovarian Cancer

The clinical utility of FoundationOne liquid was evaluated using plasma samples from participants in the ARIEL2 trial. However, BRCA testing is no longer indicated prior to rucaparib treatment in ovarian cancer and so the relevance of this evidence is uncertain. Clinical validity has not been demonstrated in multiple well-designed and conducted studies; therefore, a chain of indirect evidence to show clinical utility cannot be established.

For individuals with ovarian, fallopian tube, or primary peritoneal cancer who receive circulating tumor DNA testing (liquid biopsy) to guide treatment, the evidence includes nonrandomized studies. Relevant outcomes are OS, disease-specific survival, change in disease status, medication use, resource utilization, and treatment-related morbidity. Given the breadth of methodologies available to assess circulating tumor DNA, the clinical validity of each commercially available test must be established independently. The clinical utility of FoundationOne liquid was evaluated using plasma samples from participants in the ARIEL2 trial. However, BRCA testing is no longer indicated prior to rucaparib treatment in ovarian cancer. Clinical validity has not been demonstrated in multiple well-designed and conducted studies; therefore, a chain of indirect evidence to show clinical utility cannot be established. 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 published updated recommendations on poly adenosine diphosphate-ribose polymerase (PARP) inhibitors in the management of ovarian cancer.^4,The recommendations included the following:

Newly Diagnosed Ovarian Cancer

"Recommendation 2.1. Patients with newly diagnosed stage III-IV EOC [epithelial ovarian cancer] who are in complete or partial response to first-line platinum-based chemotherapy should be offered PARP inhibitor maintenance therapy in high-grade serous or endometrioid ovarian cancer. For those with germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes, options should include olaparib (300 mg orally every 12 hours for 2 years), niraparib (200-300 mg orally daily for 3 years) or rucaparib (600 mg twice a day for 2 years). Longer duration could be considered in selected individuals after discussion of risks. For those who are HRD [homologous recombination deficiency] positive, determined using FDA-approved companion diagnostic tests, rucaparib and niraparib are options. Niraparib or rucaparib may be offered for non-BRCA mutated/HRD negative patients. (Type: Evidence-based, benefits outweigh harms; Evidence quality: High; Strength of recommendation: Strong.)"

Recurrent Ovarian Cancer: Second-Line or Greater Maintenance and Treatment

"Recommendation 3.0. PARP inhibitor monotherapy maintenance (second-line or more) may be offered to patients with EOC who have not already received a PARP inhibitor and who have responded to platinum-based therapy regardless of BRCA mutation status; treatment is continued until progression of disease or toxicity despite dose reductions and best supportive care. Options include olaparib 300 mg every 12 hours, rucaparib 600 mg every 12 hours or niraparib 200-300 mg once daily. (Type: Evidence-based, benefits outweigh harms; Evidence quality: High; Strength of recommendation: Strong.) Maintenance treatment with niraparib for patients without germline or somatic BRCA mutation should weigh potential PFS benefit against possible OS decrement. (Type: Evidence-based, benefits outweigh harms; Evidence quality: Low; Strength of recommendation: Moderate.)"

"Recommendations 3.1/3.2. PARP inhibitor monotherapy should not be routinely offered to patients for the treatment of recurrent platinum sensitive EOC. (Type: Evidence-based, benefits outweigh harms; Evidence quality: Intermediate; Strength of recommendation: Moderate.) Evidence on PARP inhibitor use in this setting is evolving and data are continuing to emerge. Any decision to proceed with PARP inhibitor treatment in select populations (BRCA mutation, No prior PARP inhibitor use, Platinum Sensitive, Advanced Lines of Treatment) should be based on individualized patient and provider assessment of risks, benefits, and preferences."

"Recommendation 3.3. PARP inhibitor monotherapy is not recommended for treatment for patients with either BRCA wild-type or platinum-resistant recurrent EOC. (Type: Evidence-based, benefits outweigh harms; Evidence quality: High; Strength of recommendation: Strong.)"

National Comprehensive Cancer Network

The current NCCN guidelines for ovarian cancer (including fallopian tube cancer and primary peritoneal cancer) are version 2.2023.^11, Guidelines are updated frequently; refer to the source for most current recommendations.

The guidelines include the following relevant recommendations on biomarker testing to guide targeted therapy in ovarian cancer:

• "In the up-front setting, choice of somatic testing should, at a minimum, optimize identification of molecular alterations that can inform use of interventions that have demonstrated benefit in this setting, including BRCA1/2, loss of heterozygosity (LOH), or homologous recombination deficiency (HRD) status in the absence of a germline BRCA mutation.

• In the recurrence setting, tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor-specific or tumor-agnostic benefit including, but not limited to, BRCA1/2, HRD status, MSI, MMR, TMB, FRa, RET,BRAF, and NTRK if prior testing did not include these markers.

• Molecular analyses may be performed on circulating tumor DNA (ctDNA or liquid biopsy) when tissue-based analysis is not clinically feasible.

• Validated molecular testing should be performed in a CLIA-approved facility."

Recommendations on the use of PARP inhibitors for ovarian cancer include the following:

Maintenance Therapy After Recurrence

• "PARP inhibitor options include niraparib, olaparib, or rucaparib.

• For patients with platinum-sensitive disease who have completed two or more lines of platinum based therapy. Olaparib may be used regardless of BRCA status (preferred for those with a BRCA mutation).

• Niraparib is limited to those with a deleterious or suspected deleterious germline BRCA mutation.

• Rucaparib is limited to those with a deleterious or suspected deleterious BRCA mutation.

• Caution should be used when using maintenance PARP inhibitor for longer than 24 months.

• There are limited data on the use of a maintenance PARP inhibitor in patients who previously received a PARP inhibitor or after recurrence therapy with bevacizumab.

• Combination bevacizumab/PARP inhibitor is not recommended at this time for maintenance after recurrence therapy."

First-Line Maintenance Therapy

• "After first-line therapy with bevacizumab, data are limited on maintenance therapy with a single-agent PARP inhibitor (olaparib, niraparib, or rucaparib) for patients with a germline or somatic BRCA1/2 mutation. However, based on the magnitude of benefit of PARP inhibitor maintenance therapy for other subgroups, single-agent PARP inhibitors can be considered."

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

T

The Centers for Medicare & Medicaid Services (CMS) National Coverage Determination on Next Generation Sequencing (90.2) states:

"Effective for services performed on or after March 16, 2018, [CMS] has determined that Next Generation Sequencing (NGS) as a diagnostic laboratory test is reasonable and necessary and covered nationally, when performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, when ordered by a treating physician, and when all of the following requirements are met:

a. Patient has:

1. either recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer; and

2. not been previously tested with the same test using NGS for the same cancer genetic content, and

3. decided to seek further cancer treatment (e.g., therapeutic chemotherapy).

b. The diagnostic laboratory test using NGS must have:

1. Food & Drug Administration (FDA) approval or clearance as a companion in vitro diagnostic; and,

2. an FDA-approved or -cleared indication for use in that patient’s cancer; and,

3. results provided to the treating physician for management of the patient using a report template to specify treatment options." ^23,

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in August 2023 did not identify any trials that would likely influence this review.

References

1. National Cancer Institute. NCI Dictionaries: Homologous Recombination Repair Pathway. n.d. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/homologous-recombination-repair-pathway. Accessed August 1, 2024.
2. Mateo J, Boysen G, Barbieri CE, et al. DNA Repair in Prostate Cancer: Biology and Clinical Implications. Eur Urol. Mar 2017; 71(3): 417-425. PMID 27590317
3. Myriad Genetics. MyChoice CDX Myriad HRD Companion Diagnostic Test. 2024. https://myriad.com/genetic-tests/mychoicecdx-tumor-test/. Accessed August 1, 2024
4. Tew WP, Lacchetti C, Kohn EC. Poly(ADP-Ribose) Polymerase Inhibitors in the Management of Ovarian Cancer: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. Nov 20 2022; 40(33): 3878-3881. PMID 36150092
5. AstraZeneca. Dear Healthcare Professional (Lynparza). 2023. https://www.lynparzahcp.com/content/dam/physician-services/us/590-lynparza-hcp-branded/hcp-global/pdf/solo3-dhcp-final-signed.pdf. Accessed August 1, 2024.
6. Clovis Oncology, Inc. United States Securities and Exchange Commission Report (Rubraca). 2022. https://d18rn0p25nwr6d.cloudfront.net/CIK-0001466301/017377a8-ad55-47da-ac40-91c5f2a5f69f.pdf. Accessed August 1, 2024.
7. GSK. Dear Health Care Provider Letter (Niraparib). 2022. https://www.zejulahcp.com/content/dam/cf-pharma/hcp-zejulahcp-v2/en_US/pdf/ZEJULA%20(niraparib)%20Dear%20HCP%20Letter%20November%202022.pdf. Accessed August 1, 2024.
8. Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. Apr 2020; 21(4): 531-540. PMID 32105622
9. National Comprehensive Cancer Network. Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 3.2024. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed August 1, 2024.
10. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. Feb 2020; 21(2): 271-282. PMID 31838007
11. González-Martín A, Pothuri B, Vergote I, et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. Dec 19 2019; 381(25): 2391-2402. PMID 31562799
12. González-Martín A, Pothuri B, Vergote I, et al. Progression-free survival and safety at 3.5years of follow-up: results from the randomised phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib maintenance treatment in patients with newly diagnosed ovarian cancer. Eur J Cancer. Aug 2023; 189: 112908. PMID 37263896
13. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. Dec 01 2016; 375(22): 2154-2164. PMID 27717299
14. Moore K, Colombo N, Scambia G, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. Dec 27 2018; 379(26): 2495-2505. PMID 30345884
15. DiSilvestro P, Banerjee S, Colombo N, et al. Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial. J Clin Oncol. Jan 20 2023; 41(3): 609-617. PMID 36082969
16. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med. Dec 19 2019; 381(25): 2416-2428. PMID 31851799
17. Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. Sep 2017; 18(9): 1274-1284. PMID 28754483
18. Poveda A, Floquet A, Ledermann JA, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. May 2021; 22(5): 620-631. PMID 33743851
19. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. Apr 12 2012; 366(15): 1382-92. PMID 22452356
20. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. Oct 28 2017; 390(10106): 1949-1961. PMID 28916367
21. Food and Drug Administration. 2024. List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools. Accessed August 2, 2024.
22. Food and Drug Administration. 2024. Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed August 1, 2024.
23. Centers for Medicare & Medicaid Services. 2020. National Coverage Determination: Next Generation Sequencing (90.2). https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=372. Accessed August 1, 2024.

Codes

Applicable Modifiers

N/A

Policy History