Response to Comments: MolDX: Phenotypic Biomarker Detection from Circulating Tumor Cells

The following comment was submitted to Palmetto GBA:

I appreciate the opportunity to provide comments in support of coverage for Medicare beneficiaries for HER2 + CTC detection.

I am a physician scientist with about 15 years of experience in the treatment of patients with cancer and the corresponding translational research. For the last 10 years I have increasingly utilized circulating tumor cells to identify patients with cancer and to assess the response to antineoplastic therapy. As my clinical practice is dominated by thoracic oncology with a focus on single pathway addicted epithelial malignancies, I am for long familiar with the utilization of CTCs a precision medicine tools and have led multiple clinical and translational efforts leading to the development of liquid biopsy tools.

Especially in breast cancer, the role of molecular biomarkers is for long considered essential for the adequate selection of therapeutic measures. Along with hormonal receptors, Her-2 status is important to select neo-adjuvant, adjuvant and metastatic treatments. Although this assessment is initially conducted on tumor tissue, especially in the case of a relapse, tissue procurement may be cumbersome and associated with procedural risks. Also, although cancer is traditionally considered a clonal disease, significant molecular heterogeneity can be observed even within the same tumor site. In addition, a significant her-2 status discordance between primary and metastatic sites as well as initial tumor presentation and at relapse has been reported. For these reasons, a technology allowing for non-invasive comprehensive evaluation of the patient’s her-2 status is certainly needed. Novel technologies allow now for the assessment of her-2 and hormone receptor status on CTCs. These tools enable us clinicians to conduct multiple assessments of these relevant biomarkers on our patients, without the risk for procedural complications and concerns for molecular heterogeneity. This allows for adequate selection of therapy at any given time in the patient’s treatment history.

In summary, I strongly support the use of non-invasive CTC based her-2 assays and my patients have at multiple occasions experienced benefits from such technology.

In closing, I would like to thank you for the opportunity to provide comments as well as your time and consideration.

Thank you for your thoughtful comments and voice of support for this policy.

The following comment was submitted to Palmetto GBA and Noridian:

We appreciate the opportunity to comment on this important coverage policy. We are a CLIA certified and CAP accredited laboratory with patented and proprietary technology used to develop and perform assays that capture and analyze both circulating tumor cells (CTCs) as well as circulating tumor derived nucleic acids (including ctDNA and ctRNA).

Coverage of assays for the detection of HER2 alternations in CTCs found in peripheral blood will allow physicians to obtain real time biomarker status and make critical treatment decisions for patients diagnosed with breast cancer. We commend the draft LCD providing coverage for the phenotyping of HER2 on CTCs as the clinical utility of this testing is well­ supported by clinical data and guidelines.

Based on the current body of evidence, we respectfully ask you consider a slight modification to the coverage criteria that we believe will have tremendous patient benefit. Specifically, we recommend expanding coverage, when clinically appropriate, to breast cancer patients who have already received prior HER2 testing when the patient shows signs of progression.

Our proposed modification is underlined below.

At least 1 of the following 3 criteria are met:

• The patient’s cancer has not previously been tested for HER2, or
• The patient has newly metastatic cancer, and a metastatic lesion has not been tested for HER2, or
• The patient demonstrates signs of clinical, radiological or pathologic disease progression

Currently, biomarker testing is typically performed at the time of biopsy or surgery and represents only a single time point and specific location within the tumor. This can be problematic because breast cancer tumors are known to be heterogeneous and biomarker status, particularly HER2, can evolve over the course of the disease. This discordance between HER2 status in tumor tissue and progression is well documented and often referred to as receptor conversion.

A 2018 meta-analysis published in the Journal of the National Cancer Institute reviewed receptor conversion in distant breast cancer metastases. For example, Schrijver et al. found that patients with paired primary breast tumors and distant breast cancer metastases demonstrated a pooled percentage HER2 conversion frequency of 10.3% (95% Cl=7.8% to13.6%). Positive to negative conversion occurred in 21.3% of patients (95% Cl= 14.3% to 30.5%) and negative to positive conversion occurred in 9.5% of patients (95% Cl=7.4% to 12.1%) in this meta-analysis. Furthermore, a study of Biocept's CTC technology was conducted at the Dana­Farber/Harvard Cancer Center. The findings demonstrated that 22 percent of 311 breast cancer patients, who were previously HER2 negative in the initial solid tumor biopsy, were found, upon disease progression, to be HER2 positive by CTC analysis.

The determination of HER2 status on CTCs in a contemporaneous manner will allow physicians to address tumor heterogeneity and receptor conversion changes, thus enabling the most informed treatment decisions for breast cancer patients. The clinical utility of medical decision-making based on HER2 CTCs was recently demonstrated in a publication by Wang et al., which showed improved progression-free survival in advanced-stage breast cancer patients treated with anti-HER2 agents based on their CTC HER2 status.

We appreciate the opportunity to provide our comments.

References were provided for review.

Thank you for your thoughtful comments and voice of support for this policy. We agree and have modified the Criteria for Coverage to include the following “The patient demonstrates signs of clinical, radiological or pathologic disease progression.”

The following comment was submitted to Palmetto GBA and Noridian:

Coverage of HER2 circulating tumor cells (CTC) detection in peripheral blood will allow physicians to obtain real time biomarker status and make critical management and treatment decisions for breast cancer patients based on the most current tumor biomarker status.

While I highly commend the proposed LCD to detect HER2+ CTCs, I respectfully ask you to consider a small edit to the LCD that will have large patient benefit. Specifically, I recommend expanding coverage to breast cancer patients who have already received prior HER2 testing.

At least 1 of the following 3 criteria are met:

• The patient’s cancer has not previously been tested for HER2, OR
• The patient has newly metastatic cancer, and a metastatic lesion has not been tested for HER2, OR
• *The patient demonstrates signs of clinical, radiological or pathologic disease progression   

(*Recommendation)

Biomarker status, particularly HER2, has a multitude of downstream influences which may cause disruption within the biology of the disease over time. HER2 discordance between the primary tumor in metastatic patients is not uncommon; breast cancer tumors are very heterogenous and biomarker status is known to evolve over time with the disease.

Biomarker testing is often performed at time of biopsy or surgery and represents only specific locations at single timepoint. Detecting HER2+ CTCs allows physicians to address tumor heterogeneity and biomarker status changes throughout the continuum of care we provide our patients.

Unfortunately, there is no robust method to predict such potential changes, and without the ability to detect HER2+ CTC, patients may suffer through repeat biopsies. Detection of HER+ CTCs in a non-invasive assay, through a simple peripheral blood draw is critical in making the most informed treatment decision for breast cancer patients.

I stand firmly behind the “bench to bedside” mentality in that the discoveries we produce today will hopefully provide meaningful patient care tomorrow. In closing, I would like to thank you for allowing me to provide comments.

Thank you for your thoughtful comments and voice of support for this policy. We agree and have modified the Criteria for Coverage to include the following “The patient demonstrates signs of clinical, radiological or pathologic disease progression.”

The following comment was submitted to Palmetto GBA:

I would like the opportunity to comment in support of coverage for the Biocept Target Selector HER2 Assay for breast cancer patients.

Breast cancer treatment is based on receptors for estrogen (ER), progesterone (PR) and human epidermal growth factor receptor 2 (HER2). It is well documented in the literature, that at the time of metastasis, receptor status can be discordant from the primary tumor diagnosis. The difficulty of not being able to easily do repeat biopsies for tissue testing for molecular receptor changes highlights the importance and the need for using CTC's in reassessing HER2 receptor status in breast cancer. Receptor discordance between the primary tumor and the brain metastasis may impact survival so from a treatment perspective, I do not want to miss an opportunity to implement effective targeted therapies when receptors are gained.

Having the ability to test patients with a liquid biopsy using circulating tumor cells (CTCs) to find out real time HER2 receptor status provides key clinical information that affects the patient's opportunity for targeted treatment and can impact their survival. This liquid biopsy blood testing allows for rapid sampling and gives me the chance to closely monitor treatment response and disease progression that I would not have otherwise.

Currently, the use of anti-HER2 targeted therapies mostly depends on HER2 status of tumor tissues. Therefore, patients with HER2- usually do not receive therapy. However, some patients with HER2- may benefit from trastuzumab therapy.

Biocept's Target Selector assay will provide a simple non-invasive way for many patients to know their current HERZ receptor status when they are searching for a therapeutic option for their fight with Breast Cancer.

Thank you for your thoughtful comments and voice of support for this policy.

The following comment was submitted to Palmetto GBA and Noridian and was received from multiple stakeholders:

I am writing in full support of coverage for the Phenotypic Biomarker Detection in Circulating Tumor Cells (CTCs) for breast cancer patients.

Intact circulating breast cancer cells in patients’ peripheral blood provides a simple and cost-effective way of collecting and testing for HER2 amplification. Identifying HER2 amplification for breast cancer allows the choice of the best treatment protocol and provide the best outcomes for patients. Because of heterogeneity and mutations throughout the course of breast cancer, it is well known that phenotypic biomarker status can change from the initial tissue biopsy that was obtained at diagnosis. Liquid biopsies, using CTCs, will allow the determination of the most current biomarker status for that patient, and therefore, administer the most appropriate therapies.

Thank you for your thoughtful comments and voice of support for this policy.

The following comment was submitted to Palmetto GBA:

With over a decade of patient care experience as an attending physician, I appreciate the opportunity to provide comments in support of coverage for Medicare beneficiaries for testing HER2 expression performed on circulating tumor cells (CTCs) in patients with breast cancer.

The discordance between estrogen/progesterone receptor and HER2 between primary tumor and metastases in breast cancer is well documented. Currently, there is not a reliable way of assessing a change in HER2 status given the challenging nature of repeat biopsies for biomarker tissue-based testing. Thus, providers often continue to give HER2-targeted therapies. In instances where a patient's HER2 status has changed, continuing to give ineffective and expensive therapy is detrimental to the patient and wasteful to the healthcare system.

By enabling access to CTC assays for testing HER2 status in Medicare beneficiaries, it will allow providers, like myself, to make personalized treatment decisions for their patients. This would be a significant clinical advance for patients with cancer and health care providers.

Thank you for the opportunity to offer comments and for your time and consideration.

Thank you for your thoughtful comments and voice of support for this policy.

The following comment was submitted to Palmetto GBA:

With 33 years in patient care, I appreciate the opportunity to provide comments in support of coverage for Medicare beneficiaries for testing HER2 expression performed on circulating tumor cells (CTCs) of breast cancer patients.

The discordance between estrogen/progesterone receptor and HER2 between primary tumor and metastases in breast cancer is well documented. Currently, there is not a reliable way of assessing a change in HER2 status given the infeasibility of repeat biopsies for biomarker tissue-based testing. Thus, providers often continue to give anti-HER2 agents such as trastuzumab which may or may not be effective in this circumstance. Conversely it is well documented for a conversion to HER2 positive status documented in both tissue-based assays and in CTCs. In instances where a patient’s HER2 status has changed, continuing to give ineffective therapy can be detrimental to the patient and wasteful to the healthcare system. Patients who have converted to HER2 positive will not have access to life-extending therapy if tissue assays are not available and CTCs are not tested.

By enabling access to CTC assays for testing HER2 status in Medicare beneficiaries, it will allow me to make personalized treatment decisions for my patients. Following clinical practice guidelines and when tissue-based testing is infeasible, I use CTC assays to assess HER2 status for patients in my practice at the time of clinical progression and treatment decision nodes. Patients I have treated based on HER2 positive CTCs appear to have improved outcomes, with documented responses, including to the use of antibody drug conjugates where binding to HER2 molecules on the surface of cancer cells is a prerequisite for activity.

Thank you for the opportunity to offer comments and for your time and consideration.

Thank you for your thoughtful comments and voice of support for this policy.

The following comment was submitted to Palmetto GBA:

Thank you for the opportunity to provide comments in support of coverage for Medicare beneficiaries for testing HER2 FISH on circulating tumor cells (CTCs) of breast cancer patients.

Neoadjuvant chemotherapy (NAC) is considered a standard treatment for locally advanced breast cancer and alteration of biomarker status such as HER2 after NAC is reported up to 15%. The discordance between HER2 status in tumor tissue and metastatic progression is also well documented and often referred to as receptor conversion. It is reasonable to postulate that selection pressure from treatment and intratumoral heterogeneity play a role in HER2 status conversion. Re-evaluation of biomarkers including HER2 after NAC or during metastatic progression is always recommended for proper patient management. Continuing to give ineffective therapy or conversely depriving a patient of potential response to therapy can be detrimental to the patient and considered wasteful to the health care system.

Technology now enables us the ability to evaluate HER2 status in CTCs and offers a reliable way of assessing a change in HER2 status over time without the need for repeat tissue biopsies. Personally, enabling access to CTC assays for testing HER2 status in Medicare beneficiaries, will allow me to make more informed treatment decisions for my patients. Following clinical practice guidelines and when tissue-based testing is not feasible, I frequently use CTC assays to assess HER2 status for patients in my practice. My group has repeatedly demonstrated this phenomenon and, the impact of HER-2 targeted therapies in patients with HR2-, CTCs-HER2 + disease (Wang C, et al. Breast Cancer Research Treat. 2020;181:679-689).

Thank you again for the opportunity to comment on this important topic that focuses on advancing a patient-centered, biology-driven model of cancer care.

Thank you for your thoughtful comments and voice of support for this policy.

The following comment was submitted to Palmetto GBA:

The CellSearch^® CTC is an FDA-cleared in vitro diagnostic kit indicated for the enumeration of circulating tumor cells (CTC) of epithelial origin (CD45-, EpCAM+, and cytokeratins 8, 18+, and/or 19+) in whole blood. This FDA-cleared test is intended for use as an aid in the monitoring of patients receiving treatment for with metastatic breast, colorectal or prostate cancer.

We would like to express our support for the current draft coverage policy, but we also respectfully ask for an expansion of the draft LCD to cover the enumeration of circulating tumor cells in metastatic breast cancer and metastatic colorectal cancer as supported by the evidence submitted with our comment letter.

The draft LCD currently covers circulating tumor cell tests when used to identify phenotypic biomarkers, specifically HER2. However, it does not cover the enumeration of circulating tumor cells, which may be reasonable and necessary when HER2 status is already known in patients with breast cancer or when HER2 status is not relevant to treatment decisions in patients with colorectal cancer. While the analytical and clinical validity of CTC enumeration is well established, new evidence over the last four to five years has emerged on the clinical utility of circulating tumor cell enumeration for patients with metastatic breast cancer and metastatic colorectal cancer. Specifically, new evidence demonstrates how the use of CTC enumeration with the CellSearch^® assay can alter management with regard to selection of chemotherapy.

We would also support the retirement of the existing LCD – MolDX: Circulating Tumor Cell Marker Assays– once this draft LCD is finalized.

References were provided for review.

Thank you for your thoughtful comments and voice of support for this policy.

This is a limited coverage policy for assays that detect biomarkers from circulating tumor cells (CTCs). While we agree that CTC enumeration may be a good prognostic indicator for certain cancers, studies do not conclusively suggest a clear effect on outcomes resulting from a change in management. For these reasons, the enumeration of CTCs in metastatic breast cancer is not yet included in the most recent (2021) NCCN guidelines for assessment and monitoring. This is discussed in the Summary of Evidence. Coverage under this policy is restricted to tests that detect biomarkers from CTCs (regardless of whether they also enumerate CTCs).

Additionally, we agree with your comment that CTC-based tests have shown clinical utility beyond breast cancer; as a result, we have expanded the scope of the policy to include biomarker testing from CTCs for additional cancer types.

Given that there are ongoing studies on the use of CTCs (including enumeration), this contractor will continue to monitor the evidence and may modify coverage as needed.

The following comment was submitted to Palmetto GBA, WPS and Noridian:

We appreciate your willingness to provide limited coverage for assays that detect circulating HER2 positive cells and for your continued monitoring of emerging evidence that could impact future coverage of these tests.

Given the limited evidence at this time for the clinical use of these assays, we agree with the coverage limitations that are outlined in the proposed policy.

Regarding the third bullet under coverage criteria, the proposed policy states that, “assays that detect circulating HER2 positive cells are covered when all of the following are met:

• “The clinical validation includes a comparison to tissue HER2 testing”

The use of the term “clinical validation” appears to be inappropriately applied. Clinical validation requires diagnoses to be substantiated by clinical criteria generally accepted by the medical community, typically from authoritative professional guidelines, consensus, or evidence-based sources. Clinical validation involves a clinical review of the case to see if a patient truly possesses the conditions that were documented in the medical record. The HER2 has already been shown to be a clinically valid test that is medically reasonable and necessary, so a test only needs to perform comparable to tissue HER2 testing.

Recommend: Replace the third bullet (“The clinical validation includes a comparison to tissue HER2 testing”) with the following, “the assay performs comparable to tissue HER2 testing.”

Thank you again for the opportunity to review and comment on this proposed policy.

Thank you for your thoughtful comments and voice of support for this policy. As the policy has been broadened beyond HER2 to include additional CTC biomarkers that fulfill the criteria and intended use as established in the policy, we have modified the language to state the following “The clinical validation has demonstrated performance that is equivalent or superior to tissue-based testing or another already-accepted test for the same biomarker for the same intended use.”