Thursday, November 11, 2021

Dramatic Day for Precision Oncology: MolDx Releases "Minimal Residual Disease" LCD

On November 11, 2021, three MolDx MACs released final LCDs for Minimal Residual Disease testing in cancer, coverage that will be effective on December 25, 2021.  The decision had been awaited since the release of a draft policy back in September 2020.

Here are the links.  I also provide all the files in one Cloud Zip File - here.  

I've also made a three minute video that explains the LCD - here.

  • Final LCD here.
  • Final billing article here.
  • Final Q&A on public comments here.
  • (Original draft LCD online here).
  • See a rapid press release from Natera - here.
  • See Adaptive Technologies press release here.
  • See coverage at Genomeweb/Precision Oncology, here.
In the Zip file, find also a Redline comparison of the draft and final documents.   The LCD has almost doubled in length, from 4026 words to 7708 words (and from 40 references to 89).   The public comments article is probably the longest I've ever seen, at  68 PDF pages, and the billing article (mostly ICD10 codes) runs to 91 pages.

Both Recurrence and Therapeutic Response

The LCD covers BOTH testing for minimal residual disease recurrence (e.g. relapse after colon cancer surgery) as well as changes in circulating tumor DNA reflective of response-or-failure of chemotherapy.

click to enlarge

MolDx Plans a Consistently Updated Coverage Article Naming Tests

The billing article includes instructions, at this time, for the Natera SIGNATERA test and the Adaptive technologies CLONOSEQ test.  MolDx has not always regularly updated its billing articles to reflect the most current coverage.  However, THIS billing article A58376 states that "Tests not listed in this table have not been established that they meet the coverage criteria...This table will be updated to reflect revisions or additions of newly covered tests."

Natera Signatera Coverage for Immune Checkpoint Therapeutic Monitoring

On page 50 of the Billing Article A38779 (my PDF version) there is coverage for "Signatera tests used to monitor response to immune checkpoint inhibitor therapy for use with any solid tumor cancer."  This type of molecular test coverage should help compensate for the difficulty of predicting ICI response in advance (e.g. via PDL1 staining) or early in therapy (due to the lag time for imaging response or due to ICI pseudoprogression.)

Tech Assessment Forms

The Billing Article states that MolDx may, to implement the LCD, issue special tech assessment forms specific to this MRD LCD.   When you apply for coverage, check for the most recent version of the MRD LCD (if in fact there is one).


Noridian Lags

Three of four MolDx MACs released the LCD concurrently and effective on 12/25 (L38779 Palmetto, L38835 WPS, L38822 CGS).  The Noridian MAC did not release an LCD today, as far as I saw, but this lag for Noridian is not uncommon in the MolDx MAC system.   To see all CMS LCDs in the "notice of final" period, go to this link and for the dropdown box "all statuses" select "in  notice."

Quoting the MolDx Coverage in Full

Since it is fairly lengthy and defies a simple summary, I am quoting the "coverage rules" in full below.  I have provided some underscoring and a single comment to aid the reader of this blog.  There is no highlighting in the original LCD.  

The LCD covers both hematopoeitic cancers (e.g. leukemia relapse) and solid cancers.


This Medicare contractor will provide limited coverage for minimally invasive molecular deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) tests that detect minimal residual disease (MRD) in patients with a personal history of cancer.

This Contractor provides limited coverage for MRD testing in cancer when ALL of the following are true:

1. If Next-Generation Sequencing (NGS) methodology is used in testing, the conditions set by NCD 90.2 are fulfilled (summarized: the patient has advanced cancer; plans on being treated for said cancer, and has not been previously tested with the same test for the same genetic content) or are not applicable (the patient does not have cancer as defined below);

2. The patient has a personal history of cancer, the type and staging of which is within the intended use of the MRD test;

3. The identification of recurrence or progression of disease within the intended use population of the test is identified in the National Comprehensive Cancer Network (NCCN) or other established guidelines as a condition that requires a definitive change in patient management;

4. The test is demonstrated to identify molecular recurrence or progression before there is clinical, biological or radiographical evidence of recurrence or progression AND demonstrates sensitivity and specificity of subsequent recurrence or progression comparable with or superior to radiographical or other evidence (as per the standard-of-care for monitoring a given cancer type) of recurrence or progression;

5. To be reasonable and necessary, it must also be medically acceptable that the test being utilized precludes other surveillance or monitoring tests intended to provide the same or similar information, unless they either (a) are required to follow-up or confirm the findings of this test or (b) are medically required for further assessment and management of the patient;

6. If the test is to be used for monitoring a specific therapeutic response, it must demonstrate the clinical validity of its results in published literature for the explicit management or therapy indication (allowing for the use of different drugs within the same therapeutic class, so long as they are considered ‘equivalent and interchangeable’ for the purpose of MRD testing, as determined by national or society guidelines);

7. Clinical validity (CV) of any analytes (or expression profiles) measured must be established through a study published in the peer-reviewed literature for the intended use of the test in the intended population;

8. The test is being used (a) in a patient who is part of the population in which the test was analytically validated and (b) according to the intended use of the test;

9. The MRD test    [unless it is a Food and Drug Administration (FDA) approved and established standard-of-care single-gene polymerase chain reaction (PCR)]     satisfactorily completes a technical assessment (TA) that will evaluate and confirm that the analytical validity, clinical validity, and clinical utility criteria set in this policy are met to establish the test as Reasonable and Necessary;

10. Tests utilizing      a similar methodology or evaluating a similar molecular analyte to a test for which there is a generally accepted testing standard or for which existing coverage exists        must demonstrate equivalent or superior test performance (i.e., sensitivity and/or specificity) when used for the same indication in the same intended-use population.

MRD testing often requires 2 types of assays to be performed as part of the service. First, a sample is taken from tumor diagnostic material to establish a baseline (solid and/or liquid) tumor signature as defined by the test methodology. This is followed by a series of assays run on a minimally invasive specimen (i.e., liquid biopsy or bone marrow aspirate) to detect the presence or recurrence of tumor, based on the measured biomarkers, expression, or other analytes over various timepoints. 

Other approaches are also acceptable, based on the validity established for the individual test comprising the service. This series of assays comprises a single test when the patient is known to have cancer.

When the patient is NOT known to have cancer (specifically when there is no clinical, radiographical, or other biological evidence that tumor cells remain post treatment and subsequently the patient is no longer being subjected to therapeutic interventions for cancer), a second kind of test may exist wherein a single timepoint may constitute a single test. In such patients, the frequency of MRD testing is in accordance with national or society guidelines or recommendations.

[BQ - the above section navigates repeat testing for a patient "with cancer" which is otherwise affected by NCD 90.2; if a patient had a full resection (e.g. mastectomy, colectomy, nephrectomy) they may become a patient without current evidence of cancer at present.]

For patients with or without cancer (as defined above), established standard-of-care MRD tests using single-gene PCR (i.e., BCR-ABL1) are covered under this policy according to testing schedules outlined in national (i.e., NCCN) or society guidelines.

MRD testing in accordance with this policy can be performed using PCR and/or sequencing-based technologies and is not restricted to a single type of biological material or defined number of genes.


New articles on MRD appear constantly; here's one from Nov. 19 on use of MRD in postsurgical lung cancer.