Medicare's ctDNA MRD Testing Coverage in 2026: What Molecular Labs Need to Know
Short answer: Medicare covers ctDNA minimal residual disease (MRD) testing, but coverage runs through a patchwork of MolDX local coverage determinations that differ by test and cancer type. Signatera, Guardant Reveal, Oncodetect, and clonoSEQ each cleared coverage separately and on different dates. New 2026 hematologic malignancy LCDs explicitly exclude MRD monitoring, so labs must still route those claims through the original MRD-specific policy.
Why MRD Coverage Looks Fragmented in 2026
Minimal residual disease testing uses circulating tumor DNA (ctDNA) to detect molecular signs of cancer recurrence months before imaging can. Medicare's foundational coverage for this category, MolDX's LCD L38835, "Minimal Residual Disease Testing for Cancer" (administered by Wisconsin Physicians Service across MolDX jurisdictions), went effective December 26, 2021 and was last revised October 26, 2023. It does not name specific tests. Instead it sets seven conditions a test must meet: appropriate use of next-generation sequencing under NCD 90.2 where applicable, a documented personal cancer history matching the test's intended population, alignment with NCCN or other established guidelines showing that earlier detection of recurrence changes management, demonstrated ability to identify molecular recurrence before clinical or radiographic evidence with comparable sensitivity and specificity, avoidance of duplicative surveillance, published clinical validity for the intended use, and clinical validity for therapy-response monitoring specifically.
Because the LCD is criteria-based rather than a named-test list, every MRD assay has had to clear that bar independently — and on its own timeline. That is why coverage looks fragmented: a lab offering one MRD test in one cancer type can be fully covered while an adjacent use case for the same test, or a competitor's test in a different cancer, is not.
The Coverage Map, Test by Test
Four tests account for most of the MRD coverage activity molecular labs and RCM teams are tracking in 2026:
Natera's Signatera was among the first MRD tests covered under L38835, initially for colorectal cancer, muscle-invasive bladder cancer, adjuvant and recurrence-monitoring breast cancer, and pan-cancer immunotherapy response monitoring, billed under PLA code 0340U. On February 26, 2024, Natera announced Medicare extended that coverage to ovarian cancer and neoadjuvant breast cancer. The ovarian expansion cited a validation study of 163 plasma samples from 69 stage I–IV patients showing 100% sensitivity and 100% specificity, with ctDNA detection preceding imaging by an average of 10 months. The neoadjuvant breast cancer expansion cited 283 patients and 1,024 plasma samples followed for a median of more than three years, in which early ctDNA clearance predicted therapy response (p=0.0002) and Signatera-negative status was associated with improved distant recurrence-free survival (p<0.0001).
Guardant Health's Guardant Reveal, a tissue-free, methylation-based ctDNA assay, received Medicare coverage on January 21, 2025 for surveillance and recurrence monitoring in colorectal cancer patients following curative-intent surgery or chemotherapy, expanding beyond an earlier post-surgical-only window. Guardant's announcement cited CMS/MolDX data that of roughly 18 million U.S. cancer patients who could benefit from MRD testing, fewer than 3% currently receive it; more than 12 million patients are five or more years past surgery, and over 3 million lack an accessible tumor tissue sample for tissue-informed tests — the gap Guardant Reveal's tissue-free design is meant to close.
Exact Sciences' Oncodetect received Medicare coverage on July 9, 2025 for stage II, III, and resectable stage IV colorectal cancer in adjuvant and recurrence-monitoring settings, approved for serial use over a five-year surveillance period. Exact Sciences cited its Beta-CORRECT and Alpha-CORRECT studies — the latter described as one of the longest-followed MRD cohorts for colorectal cancer recurrence — and said the tumor-informed assay, which tracks up to 200 ctDNA variants, can flag recurrence up to two years before imaging. The company put the addressable population at roughly 3 million Americans eligible for MRD testing across solid tumors.
Adaptive Biotechnologies' clonoSEQ covers a different lane entirely: it was named alongside Signatera in MolDX's original MRD coverage announcement for B-cell acute lymphoblastic leukemia, multiple myeloma, and chronic lymphocytic leukemia, using immune repertoire sequencing rather than tumor-informed ctDNA.
The 2026 Wrinkle: New Heme LCDs Explicitly Carve Out MRD
On August 21, 2026, MolDX posted proposed LCD DL40425, covering multigene NGS panels for hematologic malignancies at initial diagnosis, disease progression or transformation, and confirmed relapse, spanning 356 ICD-10-CM diagnosis codes. As ScreenMyGene covered when the proposal dropped, DL40425 requires that results drive WHO/ICC classification or an immediate management decision — and it explicitly excludes circulating tumor DNA assays, germline testing, and MRD monitoring from its scope. The companion proposal, DL40407, covering genome-wide detection of copy number alterations and structural variants as a replacement for traditional cytogenetic panels, carries the same exclusion: "MRD/therapy-response testing is excluded."
For labs and RCM teams, the practical takeaway is that these two new LCDs do not change how hematologic MRD testing is covered. A clonoSEQ or Signatera claim for a blood cancer patient still lives under the original MRD-specific policy family (L38835 and its jurisdictional counterparts, including L38779, L38816, and L38822), not under the new diagnostic NGS LCDs. Billing a hematologic MRD claim as though it falls under DL40425's diagnostic-testing coverage — rather than the MRD-specific LCD — is a documentation mismatch that MolDX's medical review is positioned to catch.
Billing Reality: Why an Unlisted Code Still Dominates
Despite the volume of MRD coverage activity, much of it is still billed under CPT 81479, the unlisted molecular pathology procedure code, because it lacks a specific fee on the Clinical Laboratory Fee Schedule. Labs that have secured a Proprietary Laboratory Analyses (PLA) code — Signatera's 0340U is the clearest example — get test-specific, more predictable reimbursement; others negotiate percentage-of-charge carve-outs with individual payors in the absence of one. Coverage policy also varies meaningfully across regional MACs, and prior authorization turnaround is uneven: some national payors clear MRD prior auth requests within a few business days, while smaller regional payors can take up to 90 days, according to reimbursement consultancy XiFin. Because MRD testing is inherently serial — patients are tested repeatedly over months or years of surveillance — every recurring claim reopens the same documentation questions: is the testing frequency justified, does the ordering diagnosis match the covered population, and is medical necessity re-established each time. These are the same root causes behind most genetic test denials generally, which ScreenMyGene has broken down in detail.
What This Means for Molecular Labs and RCM Teams
Three practical steps follow from the current landscape. First, confirm which LCD governs a given MRD claim before submission — hematologic MRD testing still routes through the MRD-specific LCD family, not the new diagnostic NGS LCDs, even though both cover blood cancers. Second, where a PLA code exists for the specific assay being billed, use it rather than defaulting to CPT 81479; a generic unlisted code invites manual review and inconsistent payment. Third, build documentation templates for serial MRD testing that re-establish medical necessity at each surveillance interval, since payors are explicitly scrutinizing testing frequency as a denial reason. Labs building out MRD panels or expanding into new cancer types covered by these policies should expect that Medicare's criteria-based LCD structure means every new indication requires its own evidence package — coverage does not automatically follow from an adjacent approval. Ordering clinicians and lab partners can review current Medicare and commercial coverage policies for specific tests through ScreenMyGene's coverage lookup tools.
Frequently Asked Questions
What is MRD testing and why does Medicare treat it differently from other genetic tests?
MRD testing uses circulating tumor DNA or immune repertoire sequencing to detect molecular signs of cancer recurrence before imaging can. Medicare covers it under a criteria-based LCD (L38835) rather than a fixed list, so each test and cancer-type combination must independently demonstrate clinical validity and a management impact.
Which MRD tests currently have Medicare coverage in 2026?
Signatera (colorectal, bladder, breast, ovarian, pan-cancer immunotherapy monitoring), Guardant Reveal (colorectal cancer surveillance), Exact Sciences' Oncodetect (colorectal cancer, stages II–IV), and Adaptive Biotechnologies' clonoSEQ (B-ALL, multiple myeloma, CLL) all hold Medicare coverage, each cleared on its own timeline.
Why don't the new 2026 hematologic malignancy LCDs cover MRD monitoring?
DL40425 and DL40407 were scoped to diagnostic and classification testing at initial diagnosis, progression, or relapse. MolDX explicitly excluded ctDNA assays and MRD/therapy-response monitoring from both, leaving hematologic MRD claims under the original MRD-specific LCD family instead.
What CPT or PLA code should labs bill for MRD testing?
Use a test-specific PLA code where one exists, such as 0340U for Signatera. Absent a PLA code, most labs still bill CPT 81479, the unlisted molecular pathology procedure code, which lacks a set CLFS rate and often requires payor-specific negotiation.
How can labs reduce MRD claim denials?
Match documentation to the governing LCD's specific criteria, confirm the ordering diagnosis matches the test's covered population, and re-establish medical necessity at each serial testing interval rather than relying on the initial authorization to cover ongoing surveillance.
This article is provided for general educational and informational purposes only. It summarizes publicly available coverage policies, company announcements, and industry commentary as of the publication date and does not constitute legal, coding, billing, reimbursement, or medical advice. Coverage policies change frequently and vary by Medicare Administrative Contractor and commercial payor; laboratories and ordering clinicians should verify current LCD language and payor-specific requirements directly with CMS, MolDX, and individual payors before making billing or coverage decisions.
Sources: CMS Medicare Coverage Database, LCD L38835; AJMC, "Palmetto GBA's MolDX Announces Coverage of MRD Testing"; Natera, Feb. 26, 2024 press release; Guardant Health, Jan. 21, 2025 investor press release; Exact Sciences, Jul. 9, 2025 press release; XiFin, "Demystifying MRD Testing" (Dec. 10, 2024); Discoveries in Health Policy, Sept. 2026; ScreenMyGene, "MolDX's New NGS Coverage Rules for Blood Cancers (2026)".