Research report
A research report is the sourced material a domain
dossier is synthesized from — generated on a plan and a cadence, one topic per file.
A report carries no confidence tags. Its bracketed markers say who might have
an incentive to shade a line; none of them says anyone checked it. To reach a score, a line has
to be drafted onto a candidate as unverified and pass the Verifier or the
Corroborator, like everything else.
Section clinical-evidence · Version 2026-09-01 · Cadence quarterly · Evidence class mixed · Sources 9 · Supersedes none
Domain: ctdna-mrd-assay-validation · Scope: Peer-reviewed and trial-registry sources only, reachable by this repo's `literature`, `literature-detail`, `trials` and `trial-detail` connectors and WebSearch/WebFetch to their primary documents. A registered outcome with no results posted is a sponsor's intention, not a finding. Excludes society guideline websites (nccn.org, asco.org) fetched directly, CAP/CLIA checklist text, and any non-US trial registry (e.g., UMIN, ANZCTR) beyond the identifier a peer-reviewed paper itself carries.
Sourcing: Rests on one ASCO practice guideline, two MRD-assay-validation/consensus statements, four peer-reviewed randomized or large observational ctDNA-MRD trials, and one ClinicalTrials.gov registry record; the guideline and consensus lines are each single-source and the two colorectal-cancer RCTs are the only pair here that independently corroborate one another.
ASCO issued its first ctDNA-testing practice guideline in 2026, covering solid tumors and lymphoma broadly, and it explicitly declines to issue MRD-specific recommendations yet, naming molecular residual disease as future work [1]. The strongest clinical-utility signal for acting on a positive ctDNA MRD result is tumor-type-specific: a phase 3 trial in muscle-invasive bladder cancer met both its primary and secondary survival endpoints for ctDNA-guided treatment escalation [4], while the two largest randomized trials of the same escalation strategy in colorectal cancer did not [8][9]. Separately, a standards consortium has published FDA-facing generic analytical-validation protocols for tumor-informed ctDNA MRD assays [2], and an independent multidisciplinary consensus panel has stated plainly that variable assay sensitivity currently precludes routine clinical use of MRD-guided de-escalation outside a trial [3]. ctDNA positivity itself remains one of the strongest published prognostic markers in resectable colorectal cancer, with hazard ratios for recurrence and death in the range of 6–12 in a cohort exceeding 2,000 patients [6][7].
_Baseline (v1). No prior version; this establishes the starting point for future diffs._
ASCO's 2026 ctDNA-testing guideline (Journal of Clinical Oncology Practice, PMID 42314080) is built on a systematic review of the literature from January 2017 to February 2025 that "identified 54 meta-analyses and 22 study reports, including reports of seven randomized trials." Its substantive recommendations are about mutation-detection use cases, not MRD: ctDNA testing for tumor genetic alterations "may be used" when tissue testing is infeasible, too slow, or required by a drug's label, and — directly relevant to any product marketing a quantitative ctDNA burden metric — "fractional, percentage, or concentration-based measures of ctDNA or total cell-free DNA concentration are not recommended as a surrogate measure of disease." On MRD specifically, the panel states its own limit: "The panel recognizes this is a rapidly evolving field and guidelines are anticipated to change, bringing in tumor-type specific recommendations and incorporating more data on molecular residual disease settings" [1]. This is the single formal-society guideline document located this pass, so the finding that ASCO has not yet committed to an MRD-specific position rests on it alone [single-source] [1].
A separate, non-ASCO/NCCN body reached a more cautionary position for one tumor type. The Asian Thoracic Oncology Research Group's 27-expert Delphi consensus on early-stage non-small-cell lung cancer (Journal of Thoracic Oncology, PMID 41903701) produced 23 position statements, "all except one" reaching strong consensus, and states: "Although current MRD assays demonstrate high specificity and positive predictive value, variable sensitivity precludes routine use for adjuvant therapy de-escalation outside clinical trials." The same statement calls for the field to "define minimum analytical performance thresholds for MRD assays" and "improve standardization of reporting metrics" [single-source] [3]. This is a different tumor type (NSCLC, not the colorectal-cancer evidence base this domain otherwise concentrates on) and a research-group consensus rather than a formal society guideline; it is recorded here as the closest guideline-adjacent statement located that speaks directly to assay analytical performance as a barrier to clinical use.
The BLOODPAC Consortium's Molecular Residual Disease Analytical Validation Working Group published generic analytical-validation (AV) protocols for tumor-informed ctDNA MRD assays (JCO Precision Oncology, PMID 41533993), explicitly built "such that methods described can be adapted and applied for any tumor-informed MRD assay irrespective of technology, panel design algorithm, or workflow component." Each protocol follows "the US Food and Drug Administration (FDA) Center for Devices and Radiological Health standard format," and "the protocols were submitted to the FDA via the presubmission process for formal written feedback followed by a meeting" [single-source] [2]. This is the single closest primary document located, in this pass or the dossier's own, to what a regulator expects from a tumor-informed MRD assay's own analytical validation — it names FDA's CDRH presubmission process specifically. It does not state whether FDA accepted, required, or even discussed a third-party commutable reference-material panel as opposed to an assay developer's in-house dilution series; that specific question is not addressed by this source and remains open.
IMvigor011 (New England Journal of Medicine, PMID 41124204; ClinicalTrials.gov NCT04660344) is a phase 3, double-blind RCT in muscle-invasive bladder cancer that is the first ctDNA-guided-escalation trial in this evidence base to meet both its primary and a hierarchically-tested secondary endpoint. Of 761 patients enrolled and monitored by serial ctDNA testing after cystectomy, 250 who tested ctDNA-positive were randomized 2:1 to atezolizumab or placebo. Median disease-free survival was 9.9 months with atezolizumab versus 4.8 months with placebo (hazard ratio 0.64, 95% CI 0.47–0.87, P=0.005); median overall survival was 32.8 versus 21.1 months (hazard ratio 0.59, 95% CI 0.39–0.90, P=0.01). Among the 357 patients who remained persistently ctDNA-negative and received no study drug, disease-free survival was 95% at one year and 88% at two years [4]. The ClinicalTrials.gov record for this trial confirms enrollment of 761 (an ACTUAL, not an estimated, figure) and lists disease-free survival, overall survival and four further outcomes among the sponsor's registered measures, but the registry entry itself carries hasResults=false — the effect sizes above come only from the published NEJM report, not from the registry, whose own outcome list remains a sponsor's registered intention until results are posted there [sponsor-reported] [5].
This positive result sits against two negative colorectal-cancer trials that this domain's own dossier already carries and this pass independently re-retrieved. DYNAMIC-III (Nature Medicine, PMID 41115959) randomized 968 evaluable stage III colon cancer patients; escalated therapy in ctDNA-positive patients "did not improve outcomes over standard management (2-year RFS 51% versus 61%)." ALTAIR (Nature Medicine, PMID 42260101), 243 patients, found FTD/TPI initiated on molecular recurrence produced a median disease-free survival of 9.30 months versus 5.55 months with placebo, but the hazard ratio of 0.79 (95% CI 0.60–1.05, P=0.107) did not meet the primary endpoint. These are two independent, non-affiliated randomized trials (one Australian/New Zealand-led, one CIRCULATE-Japan) that agree: acting on a positive ctDNA MRD signal with the specific escalation strategies each trial tested did not reliably improve outcomes in resected colorectal cancer [8][9]. Read against IMvigor011, the evidence for ctDNA-guided escalation is intervention- and tumor-type-specific, not a generalizable "ctDNA-positive → treat and it works" effect.
The GALAXY observational study (CIRCULATE-Japan) is the primary source underlying this domain's already-cited pooled network-meta-analysis hazard ratios. Its original 1,039-patient report (Nature Medicine, PMID 36646802) found postsurgical ctDNA positivity at four weeks associated with a recurrence hazard ratio of 10.0 (P<0.0001), rising to 10.82 (P<0.001) within stage II/III patients, and ctDNA positivity also identified which stage II/III patients benefited from adjuvant chemotherapy (hazard ratio 6.59, P<0.0001). Its updated analysis (Nature Medicine, PMID 39284954), n=2,240, 23-month median follow-up, reported disease-free survival hazard ratio 11.99 and overall survival hazard ratio 9.68 (both P<0.0001) for postsurgical ctDNA positivity, and found "sustained ctDNA clearance in response to [adjuvant chemotherapy] was an indicator of favorable DFS and OS compared to transient clearance (24-month DFS: 89.0% versus 3.3%; 24-month OS: 100.0% versus 82.3%)," with a "true spontaneous clearance rate with no clinical recurrence" of only 1.9% (2/105) [6][7]. Both reports describe the same continuing CIRCULATE-Japan cohort at different follow-up points rather than two independent studies, so this magnitude of prognostic effect is recorded as single-source [single-source] [6][single-source] [7], even though the cohort size (>2,000 patients) is large.
[1] Circulating Tumor DNA Testing in Solid Tumors and Lymphoma: ASCO Guideline — JCO Oncology Practice (published 2026-06-18; accessed 2026-09-01). PMID 42314080 — https://pubmed.ncbi.nlm.nih.gov/42314080/ [guideline] [2] Generic Protocols for Analytical Validation of Tumor-Informed Circulating Tumor DNA Assays for Molecular Residual Disease: The Blood Profiling Atlas in Cancer's Molecular Residual Disease Analytical Validation Working Group Consensus Recommendation — JCO Precision Oncology (published 2026-01, day not given in the PubMed record; accessed 2026-09-01). PMID 41533993 — https://pubmed.ncbi.nlm.nih.gov/41533993/ [peer-reviewed] [3] Consensus Statement on ctDNA Minimal Residual Disease Testing in Early Stage NSCLC: A Delphi Study by the Asian Thoracic Oncology Research Group — Journal of Thoracic Oncology (published 2026-08, day not given in the PubMed record; accessed 2026-09-01). PMID 41903701 — https://pubmed.ncbi.nlm.nih.gov/41903701/ [peer-reviewed] [4] ctDNA-Guided Adjuvant Atezolizumab in Muscle-Invasive Bladder Cancer — The New England Journal of Medicine (published 2025-12-18; accessed 2026-09-01). PMID 41124204 — https://pubmed.ncbi.nlm.nih.gov/41124204/ [peer-reviewed] [5] A Study of Atezolizumab Versus Placebo as Adjuvant Therapy in Participants With High-risk Muscle-invasive Bladder Cancer (MIBC) Who Are ctDNA Positive Following Cystectomy (IMvigor011) — ClinicalTrials.gov (record last updated 2026-03-27; accessed 2026-09-01). NCT04660344 — https://clinicaltrials.gov/study/NCT04660344 [trial-registry] [6] ctDNA-based molecular residual disease and survival in resectable colorectal cancer — Nature Medicine (published 2024-11, day not given in the PubMed record; accessed 2026-09-01). PMID 39284954 — https://pubmed.ncbi.nlm.nih.gov/39284954/ [peer-reviewed] [7] Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer — Nature Medicine (published 2023-01, day not given in the PubMed record; accessed 2026-09-01). PMID 36646802 — https://pubmed.ncbi.nlm.nih.gov/36646802/ [peer-reviewed] [8] Circulating tumor DNA-guided adjuvant therapy in locally advanced colon cancer: the randomized phase 2/3 DYNAMIC-III trial — Nature Medicine (published 2025-12, day not given in the PubMed record; accessed 2026-09-01). PMID 41115959 — https://pubmed.ncbi.nlm.nih.gov/41115959/ [peer-reviewed] [9] Post-adjuvant chemotherapy in ctDNA-positive patients with resected colorectal cancer: a randomized phase 3 trial (ALTAIR, CIRCULATE-Japan) — Nature Medicine (published 2026-07, day not given in the PubMed record; accessed 2026-09-01). PMID 42260101 — https://pubmed.ncbi.nlm.nih.gov/42260101/ [peer-reviewed]
Well established: DYNAMIC-III [8] and ALTAIR [9] are two independent, non-affiliated randomized phase 3 trials (different trial groups, different regions) that agree: the specific escalation strategies each tested did not reliably improve outcomes in ctDNA-positive resected colorectal cancer patients. That negative-escalation finding is stated plainly, with no marker, on that basis.
Thin: the ASCO guideline's stated non-position on MRD [1], the BLOODPAC AV protocol consensus [2], the ATORG NSCLC Delphi consensus [3], the IMvigor011 positive-escalation result [4], and the GALAXY prognostic magnitude findings [6][7] are each supported by exactly one document — no second, independent guideline body, consortium, trial, or cohort was located that corroborates any of these five lines. Each carries [single-source] above. The ClinicalTrials.gov entry for IMvigor011 [5] itself carries hasResults=false; its own outcome list is the sponsor's registered intention, not a finding, and is marked [sponsor-reported] accordingly — the effect sizes cited come from the peer-reviewed NEJM report, never from the registry.
Rescoped from class 3: none. This report's questions — what a guideline body has stated, what a pivotal trial measured, what a registry record contains — are class 1 (the registry fact of what NCT04660344 lists) and class 2 (published findings) as posed; no "would a clinician/lab adopt this" question was asked or required rescoping.
Out of scope: the NCCN Guidelines (any edition) fetched directly from nccn.org, the ASCO guideline's own web landing page at asco.org, and the CAP Molecular Pathology checklist were all excluded by this report's declared scope (peer-reviewed and trial-registry sources only) and were not fetched even where a search result pointed toward them.
Not searched vs. not found: Not found — a dedicated PubMed search for "NCCN guidelines circulating tumor DNA minimal residual disease" returned four records, none of them an NCCN guideline document itself (see search log); a dedicated search for a concordance/discordance study comparing tumor-informed ctDNA MRD assays head-to-head returned zero PubMed records. Not searched — CAP/CLIA proficiency-testing program specifics (member-paywalled, consistent with this domain's dossier, not reattempted here); any non-US guideline body (e.g., ESMO); a formal NCCN MRD-specific position statement search using NCCN's own indexed terminology beyond the query run.
[inference] The reading that "the evidence for ctDNA-guided escalation is intervention-and-tumor-type-specific, not a generalizable effect" is this report's own synthesis of the IMvigor011/DYNAMIC-III/ALTAIR contrast in section 3 — none of the three source papers makes that comparative claim itself.
| Proposition | Evidence class | Resolvable identifier | Dossier section |
|---|---|---|---|
| ASCO's 2026 ctDNA-testing guideline states that fractional, percentage, or concentration-based measures of ctDNA are not recommended as a surrogate measure of disease | 2 published | PMID 42314080 | 4. Standard of care & clinical evidence |
| IMvigor011 found ctDNA-guided adjuvant atezolizumab significantly improved disease-free survival (HR 0.64, 95% CI 0.47–0.87, P=0.005) and overall survival (HR 0.59, 95% CI 0.39–0.90, P=0.01) versus placebo in ctDNA-positive muscle-invasive bladder cancer patients after cystectomy | 2 published | PMID 41124204 / NCT04660344 | 4. Standard of care & clinical evidence |
| The BLOODPAC Consortium's MRD Analytical Validation Working Group published generic, FDA CDRH-format analytical-validation protocols for tumor-informed ctDNA MRD assays and submitted them to FDA via the presubmission process | 2 published | PMID 41533993 | 4. Standard of care & clinical evidence / 5. Reference products |
| The GALAXY (CIRCULATE-Japan) 2,240-patient cohort found postsurgical ctDNA positivity associated with a disease-free survival hazard ratio of 11.99 and an overall survival hazard ratio of 9.68 (both P<0.0001) | 2 published | PMID 39284954 | 4. Standard of care & clinical evidence |
| The Asian Thoracic Oncology Research Group's Delphi consensus states that variable MRD assay sensitivity precludes routine use for adjuvant therapy de-escalation outside clinical trials in early-stage NSCLC | 2 published | PMID 41903701 | 4. Standard of care & clinical evidence |