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Kaimen Rigor review

Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial.

Modi S, Jacot W, Iwata H, Park YH, Vidal Losada M, Li W, Tsurutani J, Ueno NT, Zaman K, Prat A, Papazisis K, Rugo HS, Yamashita T, Harbeck N, Im SA, De Laurentiis M, Pierga JY, Wang X, Gombos A, Tokunaga E, Orbegoso Aguilar C, Yung L, Xiao F, Cheng Y, Cameron D

DOI: 10.1038/s41591-025-03981-4
Record issued: 2026-08-15
Engine: 7.39.0
Exported: 2026-09-22

Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/eec92997-4664-4022-ae6d-cdd82d582cb1 is authoritative.

Kaimen Rigor review

Kaimen Rigor reviewed

4.5 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.

Biggest issues

01Other integrity concern
mediumAuthenticityreviewer-assessedFull detail
Trial NCT02564900 was first submitted to ClinicalTrials.gov on 2015-09-21, after the registered study start date of 2015-09-01. Retrospective registration means the protocol and outcomes were not on the public record before the study ran, which is what prospective registration exists to establish.
NCT02564900
reviewer’s wording

Findings by category

01ArithmeticNone found 102OverreachOverstated conclusions 103AuthenticityData authenticity concerns 04DisclosureNone found 05AvailabilityNone found 06Copyedit5 minor suggestions

This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

This is a well-conducted, transparently reported phase 3 randomized trial update. All eight rigor dimensions are adequately addressed, with minor reporting gaps (e.g., no explicit CONSORT statement, no exact p-values, no power analysis for the update) that do not undermine the core findings. The main caveats are the open-label design and the small number of male patients, both acknowledged in the paper.

Both reviewers classified the study as interventional, and I adopt that. The evaluation covered the full text, with all eight dimensions applicable. The statistics verification component checked 0 tests (none recomputable), so statistical correctness is not independently confirmed beyond the reported methods. The integrity check flagged retrospective registration of the phase 1b trial (NCT02564900), which is a transparency concern but does not affect the current trial's reporting.

Numerical inconsistencies

None found

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

Checked — nothing surfaced.

Overstated conclusions

1 finding · worst low

Conclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.

Conclusions only partially backed by the presented evidenceAssessed

6 major claims checked against the paper's own evidence: 2 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

partialReviewer 1
T-DXd is effective in HR− and ER-low-positive subgroups.
Exploratory analyses show benefit, but sample sizes are small and confidence intervals wide, so the claim is partially supported.
Evidence: HR− cohort HR 0.58 (95% CI 0.31–1.08); ER-low-positive HR 0.40 (95% CI 0.20–0.79).
In the HR− cohort, median OS was 17.1 months (95% CI 13.6–23.0) in the T-DXd arm and 8.3 months (95% CI 5.6–20.4) in the TPC arm (hazard ratio 0.58; 95% CI 0.31–1.08).
Resultsreviewer’s wording
partialReviewer 2
T-DXd is effective in hormone receptor-negative and ER-low subgroups.
Exploratory analyses show benefit, but sample sizes are small and analyses are not powered, so the claim is partially supported.
Evidence: HR− cohort: median OS 17.1 vs 8.3 months, HR 0.58 (95% CI 0.31-1.08); ER-low: HR 0.40 (95% CI 0.20-0.79).
“Median OS also favored T-DXd in exploratory analyses of hormone receptor-negative, estrogen receptor IHC 1%–10% and estrogen receptor IHC >10% cohorts.”
ResultsFind in source
supportedReviewer 1
T-DXd significantly improved OS compared with TPC in HER2-low metastatic breast cancer.
The updated analysis shows a hazard ratio of 0.69 with 95% CI excluding 1, supporting the claim.
Evidence: Median OS 22.9 vs 16.8 months, HR 0.69 (95% CI 0.55–0.86).
“median OS in the overall cohort was 22.9 months for T-DXd and 16.8 months for TPC (hazard ratio 0.69; 95% confidence interval 0.55–0.86).”
AbstractFind in source
supportedReviewers 1, 2
The safety profile of T-DXd is acceptable and generally manageable.
Safety data show manageable toxicity with no new ILD cases, supporting the claim.
Evidence: Grade ≥3 TEAEs 54.4% vs 67.4%; ILD rate 12.1% with no new cases.
“The overall safety profile of T-DXd was acceptable and generally manageable.”
AbstractFind in source
supportedReviewer 2
Trastuzumab deruxtecan significantly improved overall survival compared with chemotherapy in HER2-low metastatic breast cancer.
The updated analysis shows a hazard ratio of 0.69 with 95% CI excluding 1, supporting the claim.
Evidence: Median OS 22.9 vs 16.8 months, HR 0.69 (95% CI 0.55-0.86).
trastuzumab deruxtecan (T-DXd) significantly improved overall survival (OS) and progression-free survival compared with treatment of physician’s choice of chemotherapy (TPC) for patients with human epidermal growth factor receptor 2-low (HER2-low) metastatic breast cancer.
Abstractreviewer’s wording
supportedReviewer 2
T-DXd is the standard of care after prior chemotherapy in HER2-low metastatic breast cancer.
The updated results confirm the primary analysis and support this conclusion, though 'standard of care' is a clinical judgment.
Evidence: Consistent OS benefit and manageable safety across cohorts.
“Results confirm T-DXd as standard of care after prior chemotherapy in patients with HER2-low metastatic breast cancer.”
AbstractFind in source

Efficacy claim is anchored to an adequate endpoint and a meaningful effect.

ADEQUATESurrogate endpoint
The primary efficacy claim is based on overall survival (OS), a hard clinical outcome, and progression-free survival (PFS), which is a validated surrogate for metastatic breast cancer. The paper reports a median OS of 22.9 months for T-DXd vs 16.8 months for TPC (HR 0.69), and median PFS of 8.8 vs 4.2 months (HR 0.36). OS is a direct clinical benefit, so the surrogate is adequate.
“median OS in the overall cohort was 22.9 months for T-DXd and 16.8 months for TPC (hazard ratio 0.69; 95% confidence interval 0.55–0.86)”
Find in source
ADEQUATEEffect size
The effect size is clinically meaningful: a 31% reduction in risk of death (HR 0.69) and a 6.1-month improvement in median OS (22.9 vs 16.8 months) in the overall cohort. The 24-month OS rate was 32.6% vs 11.8%, more than double. These are anchored to survival benefit, which is clinically material.
“The OS rate at 24 months was more than two times greater in the T-DXd arm compared with the TPC arm (32.6% versus 11.8%, respectively)”
Find in source

Data authenticity concerns

1 finding · worst medium

An adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.

Other integrity concernAssessed

1 integrity concern flagged (0 high).

mediumother
Trial NCT02564900 was first submitted to ClinicalTrials.gov on 2015-09-21, after the registered study start date of 2015-09-01. Retrospective registration means the protocol and outcomes were not on the public record before the study ran, which is what prospective registration exists to establish.
NCT02564900
reviewer’s wording

Reporting gaps

None found

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Checked — nothing surfaced.

Eight Dimensions8 pass

The introduction cites prior studies (phase 1b, primary DESTINY-Breast04 results, ASCO/CAP guidelines) and explains the biological rationale for HER2-low as a targetable category. It acknowledges limitations such as challenges in HER2-low identification and the exploratory nature of subgroup analyses. The hypothesis follows logically from the cited evidence.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior research on HER2-low breast cancer and the rationale for T-DXd, and it addresses limitations of prior work.

Evidence

paraphrase[Introduction, paragraph 3]

“The DESTINY-Breast04 primary analysis (data cutoff 11 January 2022) showed that T-DXd significantly improved progression-free survival (PFS) by blinded independent central review (BICR), the primary endpoint (in the HR+ cohort), and OS compared with TPC.”

“Here we report a preplanned updated OS analysis, long-term safety and exploratory analyses of HR−, ER-low-positive and ER IHC >10% subgroups from DESTINY-Breast04 after longer follow-up (data cutoff 1 March 2023).”

IntroductionFind in source

paraphrase[Discussion, paragraph 8]

“Although high concordance (78%) was observed between historical (local) and centrally assessed patient samples for DESTINY-Breast04 we acknowledge the difficulties in accurately identifying low levels of HER2 expression and differentiating them from samples that lack HER2 expression (IHC 0 with no staining observed).”

PASSReviewer 2· 90% conf

The paper establishes a strong scientific premise by citing prior research on HER2-low breast cancer and the rationale for T-DXd, and it addresses limitations of prior work.

Evidence

paraphrase[Introduction, paragraph 1-3]

“The HER2-low category, defined as an IHC score of 1+ or IHC 2+/ISH−, was introduced after results from a phase 1b study (NCT02564900) of T-DXd and primary results of the DESTINY-Breast04 trial were released.”

paraphrase[Discussion, paragraph 8]

paraphrase[Introduction, last paragraph]

“Here we report a preplanned updated OS analysis, long-term safety and exploratory analyses of HR−, ER-low-positive and ER IHC >10% subgroups from DESTINY-Breast04 after longer follow-up.”

Randomization method (2:1 ratio) and stratification factors are described. The unit of randomization is the patient. Blinding is not performed (open-label), which is stated. Power analysis is not explicitly reported in this update, but the primary analysis was event-driven (318 PFS events). Inclusion/exclusion criteria are detailed. Outlier handling is addressed via censoring and no imputation. Controls are the TPC arm. Independent replication is not applicable for a single pivotal trial.

Sub-criteria

controlsADEQUATE

power analysisINADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial design is rigorous: randomized, open-label, with pre-specified endpoints, stratification, and a clear analysis plan. Blinding is not applicable due to open-label design, but this is stated.

Evidence

paraphrase[Methods, Study design]

“Patients were randomly assigned in a 2:1 ratio to receive T-DXd or TPC, which included capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel. Randomization stratification factors were HER2 IHC/ISH status (IHC 1+ versus IHC 2+/ISH−), number of previous lines of chemotherapy for metastatic disease (1 versus 2), and HR status (positive versus negative).”

paraphrase[Methods, Study design]

“DESTINY-Breast04 (NCT03734029) is a multicenter, open-label, randomized, phase 3 study”

“Eligible patients had centrally confirmed HER2-low breast cancer and had received chemotherapy for metastatic disease or had disease recurrence during or within 6 months after completing adjuvant chemotherapy.”

MethodsFind in source

PASSReviewer 2· 90% conf

The study design is rigorous with clear randomization, stratification, and pre-specified endpoints, though blinding is not applicable due to open-label design.

Evidence

paraphrase[Methods, Study design]

“Patients were randomly assigned in a 2:1 ratio to receive T-DXd or TPC... Randomization stratification factors were HER2 IHC/ISH status (IHC 1+ versus IHC 2+/ISH−), number of previous lines of chemotherapy for metastatic disease (1 versus 2), and HR status (positive versus negative).”

paraphrase[Methods, Study design]

“DESTINY-Breast04 is a multicenter, open-label, randomized, phase 3 study.”

MethodsFind in source

Sex is reported (99.5% female in T-DXd arm). Age, race, ethnicity, ECOG performance status, and metastatic sites are reported in Table 1. Since both sexes are included, sex_justified is not applicable. Demographics are comprehensive.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographics and baseline characteristics are thoroughly reported, including sex, age, race, and disease characteristics. Sex is reported, and the study includes both sexes, so sex justification is not applicable.

Evidence

“Female, n (%) | 371 (99.5) | 184 (100) | 329 (99.4) | 163 (100.0) | 40 (100) | 18 (100)”

Table 1Find in source

“Age, median (range), years | 57.5 (31.5–80.2) | 55.9 (28.4–80.5) | 56.8 (31.5–80.2) | 55.7 (28.4–80.0) | 58.9 (36.6–78.9) | 55.9 (32.6–80.5)”

Table 1Find in source

PASSReviewer 2· 90% conf

Demographics including sex, age, and race are reported; sex is not justified as single-sex because both sexes are included, though only three males were enrolled.

Evidence

“Female, n (%) | 371 (99.5) | 184 (100) | 329 (99.4) | 163 (100.0) | 40 (100) | 18 (100)”

Table 1Find in source

“Age, median (range), years | 57.5 (31.5–80.2) | 55.9 (28.4–80.5) | 56.8 (31.5–80.2) | 55.7 (28.4–80.0) | 58.9 (36.6–78.9) | 55.9 (32.6–80.5)”

Table 1Find in source

paraphrase[Table 1]

“Race, n (%) | White | 176 (47.2) | 91 (49.5) | 156 (47.1) | 78 (47.9) | 19 (47.5) | 11 (61.1)”

The trial was approved by the institutional review board at each study site. Written informed consent was provided by all patients. The trial was conducted in adherence with ICH-GCP, Declaration of Helsinki, and local regulations. These are reported adequately.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals are adequately reported: IRB approval, informed consent, and regulatory compliance are all stated.

Evidence

“The trial was designed and sponsored by Daiichi Sankyo in collaboration with AstraZeneca and was approved by the institutional review board at each study site.”

MethodsFind in source

“Written informed consent was provided by all patients before trial participation.”

MethodsFind in source

“The trial was conducted in adherence with the International Council for Harmonisation Good Clinical Practice guidelines, the Declaration of Helsinki, and local regulations on the conduct of clinical research.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethics approval by institutional review boards, informed consent, and regulatory compliance are clearly stated.

Evidence

“The trial was designed and sponsored by Daiichi Sankyo in collaboration with AstraZeneca and was approved by the institutional review board at each study site.”

MethodsFind in source

“Written informed consent was provided by all patients before trial participation.”

MethodsFind in source

T-DXd is identified as an ADC with dose and regimen. TPC options are listed. The VENTANA HER2/neu (4B5) assay is identified with catalog numbers. Statistical software (SAS v9.3 or later) is identified. No cell lines or antibodies are used in this clinical trial, so those criteria are not applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (T-DXd) and comparator chemotherapies are identified, and the HER2 IHC assay is specified. Software used for analysis is identified.

Evidence

paraphrase[Methods, Study design]

“T-DXd was administered intravenously at a dose of 5.4 mg kg−1 of body weight every 3 weeks.”

“The Roche 4B5 assay is marketed as PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody in the USA (cat. no. 05999570001)”

MethodsFind in source

“Statistical analyses were conducted using Statistical Analysis System Software v.9.3 or later.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The investigational product T-DXd and the comparator chemotherapies are identified with dose and regimen; the HER2 IHC assay is specified with vendor and catalog number.

Evidence

paraphrase[Methods, Study design]

“T-DXd was administered intravenously at a dose of 5.4 mg kg−1 of body weight every 3 weeks.”

paraphrase[Methods, IHC scoring]

“Adequately archived or recent tumor biopsy specimens were assessed using the VENTANA HER2/neu (4B5) assay (Roche Diagnostics)... The Roche 4B5 assay is marketed as PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody in the USA (cat. no. 05999570001).”

“Statistical analyses were conducted using Statistical Analysis System Software v.9.3 or later.”

Statistical analysisFind in source

The paper reports hazard ratios with 95% CIs, which is the standard for clinical trials. Tests are named (stratified Cox model, Kaplan-Meier). Assumptions are checked via visual inspection of log-negative-log plots. Exact p-values are not reported, but the analysis is estimation-based, so this is not a deficiency. Software is identified. Data presentation includes Kaplan-Meier curves and forest plots. Mathematical plausibility checks are not applicable due to large N and continuous outcomes.

Sub-criteria

tests namedADEQUATE

exact p valuesN/A

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Statistical methods are appropriate and well-described, with effect sizes and confidence intervals reported. P-values are not reported for the main analyses, but this is acceptable as the trial reports by estimation.

Evidence

“For OS and PFS, the median event times were estimated using the Kaplan–Meier method; the Brookmeyer and Crowley method was used to calculate the two-sided 95% CIs for the medians of each treatment arm. A stratified Cox proportional hazards regression model was used to estimate hazard ratios and 95% CIs.”

Statistical analysisFind in source

“The proportional hazard assumption was examined through visual inspection of the graphs of the log of negative log of estimated survival functions.”

Statistical analysisFind in source

“median OS in the overall cohort of 22.9 months (95% CI 21.2–24.5) for T-DXd and 16.8 months (95% CI 14.1–19.5) for TPC (hazard ratio 0.69; 95% CI 0.55–0.86)”

ResultsFind in source

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with effect sizes and confidence intervals reported; p-values are not the primary reporting style.

Evidence

“A stratified Cox proportional hazards regression model was used to estimate hazard ratios and 95% CIs.”

Statistical analysisFind in source

“median OS in the overall cohort of 22.9 months (95% CI 21.2–24.5) for T-DXd and 16.8 months (95% CI 14.1–19.5) for TPC (hazard ratio 0.69; 95% CI 0.55–0.86)”

ResultsFind in source

“The proportional hazard assumption was examined through visual inspection of the graphs of the log of negative log of estimated survival functions.”

Statistical analysisFind in source

The data availability statement names Vivli as the platform and provides a URL for the request procedure. This is a managed-access route, which is adequate for individual patient data. Repository deposit and accession numbers are not applicable for IPD. Code sharing is not applicable as no bespoke code is mentioned.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability is adequately reported with a concrete access route via Vivli, and the data-sharing procedure is described.

Evidence

paraphrase[Data availability]

“Anonymized individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org.”

PASSReviewer 2· 90% conf

Data availability statement provides a concrete route via Vivli, and the trial is registered; code sharing is not applicable.

Evidence

paraphrase[Data availability]

“Anonymized individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org.”

“ClinicalTrials.gov identifier: NCT03734029”

AbstractFind in source

Trial registration number (NCT03734029) is given. Methods are comprehensive. A reporting guideline is not explicitly mentioned, but the paper follows CONSORT-like reporting. All outcomes are reported, including exploratory analyses. Limitations are discussed (e.g., open-label, small HR− subgroup). Conclusions are proportional. Funding and competing interests are disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The manuscript is transparent: trial registration is provided, methods are detailed, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov identifier: NCT03734029”

AbstractFind in source

“However, recognition of HER2-low and, more recently, HER2-ultralow breast cancer remains challenging and is an ongoing area of research.”

Discussion ¶8Find in source

“The authors declare the following competing interests:”

Competing interestsFind in source

PASSReviewer 2· 90% conf

The manuscript is transparent with detailed methods, trial registration, discussion of limitations, proportional conclusions, and funding/COI statements.

Evidence

“ClinicalTrials.gov identifier: NCT03734029”

AbstractFind in source

“However, recognition of HER2-low and, more recently, HER2-ultralow breast cancer remains challenging and is an ongoing area of research.”

Discussion ¶8Find in source

“The authors declare the following competing interests: S.M. has received grants from Genentech, AstraZeneca, Seattle Genetics, Pfizer, Daiichi Sankyo, Duality Bio, D3 Bio, Nuvation Bio and BioNTech;”

Competing interestsFind in source

Registered (5 IDs: ClinicalTrials.gov). No reporting guideline cited.

ClinicalTrials.gov

ClinicalTrials.gov

ClinicalTrials.gov

ClinicalTrials.gov

ClinicalTrials.gov

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 34 references by DOI: 2 verified — 32 no DOI (shown, not verified).

NO DOI
Breast cancer
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP Guideline update
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Human epidermal growth factor receptor 2 testing in breast cancer
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
HER2-low breast cancer: pathological and clinical landscape
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
ESMO Expert Consensus Statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Standardized pathology report for HER2 testing in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Retrospective study to estimate the prevalence and describe the clinicopathological characteristics, treatments received, and outcomes of HER2-low breast cancer
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Impact of breast cancer subtypes on prognosis of women with operable invasive breast cancer: a population-based study using SEER database
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Estrogen-receptor-low-positive breast cancer: pathological and clinical perspectives
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Impact of low versus negative estrogen/progesterone receptor status on clinico-pathologic characteristics and survival outcomes in HER2-negative breast cancer
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Borderline ER-positive primary breast cancer gains no significant survival benefit from endocrine therapy: a systematic review and meta-analysis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The significance of highlighting the oestrogen receptor low category in breast cancer
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Outcome of breast cancer patients with low hormone receptor positivity: analysis of a 15-year population-based cohort
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The latest research and development into the antibody–drug conjugate, [fam-] trastuzumab deruxtecan (DS-8201a), for HER2 cancer therapy
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Assessment of predictive biomarkers in breast cancer: challenges and updates
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Pooled analysis by best confirmed response to trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ metastatic breast cancer (mBC) from DESTINY-Breast-01, -02, and -03
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2025
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)-related interstitial lung disease/pneumonitis—focus on proactive monitoring, diagnosis, and management
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Determination of HER2-low status in tumors of patients with unresectable and/or metastatic breast cancer in DESTINY-Breast04
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Human epidermal growth factor receptor 2 (HER2)-low and HER2-ultralow status determination in tumors of patients (pts) with hormone receptor-positive (HR+) metastatic breast cancer (mBC) in DESTINY-Breast06 (DB-06)
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Concordance between the DESTINY-Breast04 clinical trial assay (4B5[CDx]) and other HER2 IHC assays for HER2-low breast cancer in real-world practice: first phase of a large-scale, multicenter global ring study
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Examination of low ERBB2 protein expression in breast cancer tissue
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).

2 data/code links checked; 2 live.

datahttps://vivli.orgLIVEHTTP 200
Resolves, but the content could not be matched to the paper.
datahttps://vivli.org/ourmember/daiichi-sankyo/LIVEHTTP 200
Resolves, but the content could not be matched to the paper.

Copyediting

5 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 5 minor suggestions below.

5 copyedit issues flagged: mostly typo, consistency, clarity.

MINORtypoAbstract
“trastuzumab deruxtecan (T-DXd) significantly improved overall survival (OS) and progression-free survival compared with treatment of physician’s choice of chemotherapy (TPC)”
→ Consider adding 'progression-free survival (PFS)' for clarity.
Abbreviation not defined at first use.
MINORconsistencyTable 1
“Female, n (%) | 371 (99.5) | 184 (100) | 329 (99.4) | 163 (100.0) | 40 (100) | 18 (100)”
→ Use consistent decimal formatting (e.g., 100.0 instead of 100).
Minor formatting inconsistency.
MINORconsistencyAbstract
“hormone receptor-positive cohort”
→ Use consistent abbreviation 'HR+' after first use.
Abbreviation introduced later in text.
MINORclarityResults, Safety
“The most common TEAEs associated with drug discontinuation were investigator-assessed interstitial lung disease (ILD) and/or pneumonitis at 10.2% in the T-DXd arm and peripheral sensory neuropathy at 2.3% in the TPC arm.”
→ Clarify that the percentages refer to the proportion of patients in each arm.
Ambiguous phrasing.
MINORtypoDiscussion, paragraph 8
“Although high concordance (78%) was observed between historical (local) and centrally assessed patient samples for DESTINY-Breast04 we acknowledge”
→ Add a comma after 'DESTINY-Breast04'.
Missing comma.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported; an informed reader should weigh the open-label design, the small male subgroup, and the retrospective registration of the earlier phase 1b trial as minor caveats. No erratum or correction appears warranted based on this audit; the minor copyedit issues (e.g., missing comma, inconsistent decimal formatting) are cosmetic and do not affect scientific integrity.

1.
MEDIUMreporting
Add an explicit statement in the Methods or a footnote that the trial follows CONSORT reporting guidelines, and include a CONSORT flow diagram in the main text (currently referenced as Fig. 1).
Explicitly naming the reporting guideline enhances transparency and reader confidence in the completeness of reporting.
2.
MEDIUMstatistics
Report exact p-values for the primary and secondary endpoints in addition to hazard ratios and confidence intervals, or state that the trial reports by estimation and p-values are available in the supplementary appendix.
Exact p-values facilitate meta-analyses and reader comprehension, and address a common reviewer request.
3.
MEDIUMreporting
Add a brief statement on the power analysis or event-driven design for the updated OS analysis, clarifying the sample size rationale.
Clarifying the power/event-driven design helps readers assess the adequacy of the sample size for the updated analysis.
4.
MEDIUMreporting
Clarify the statistical analysis plan for the exploratory subgroups, including pre-specification and multiplicity control, and state how missing data were handled in these analyses.
Exploratory subgroup analyses are prone to overinterpretation; explicit pre-specification and missing-data handling strengthen their interpretation.
5.
MEDIUMreporting
Add a note on the generalizability of the results given the small number of male patients and the open-label design, to temper overinterpretation.
Acknowledging these limitations helps readers weigh the applicability of the findings to broader populations.
6.
LOWdata code
Consider depositing the statistical analysis code (e.g., SAS programs) in a public repository to enhance reproducibility, even though the data are managed-access.
Sharing analysis code improves transparency and allows independent verification of the statistical methods.
7.
LOWcopyedit
Define 'PFS' at first use in the Abstract (e.g., 'progression-free survival (PFS)').
Abbreviations should be defined at first use for clarity.
8.
LOWcopyedit
Use consistent decimal formatting in Table 1 (e.g., '100.0' instead of '100').
Consistent formatting improves readability and professionalism.
9.
LOWcopyedit
Use consistent abbreviation 'HR+' after first use in the Abstract.
Consistent abbreviation usage avoids confusion.
10.
LOWcopyedit
Clarify in the Safety results that the percentages (e.g., 10.2% and 2.3%) refer to the proportion of patients in each arm.
Ambiguous phrasing can mislead readers about the denominator.
11.
LOWcopyedit
Add a comma after 'DESTINY-Breast04' in the Discussion paragraph 8 sentence.
Missing comma is a minor grammatical error.

Full text (59,559 chars)Analyzed: Aug 15, 2026

RigorReviewer 1

RigorReviewer 2

RigorPre-Submission Reviewer

CopyeditAgent Scribe

CitationsCitation Integrity

StatisticsStatistics Consistency

ReproducibilityLink verification (liveness + content)· no model (rule-based)

PreregistrationDeterministic check· no model (rule-based)

The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”

How stars are deducted

Reporting — 8 dimensionseach dimension that fully fails−½★
each dimension partially met−¼★
Statistics · Integrity · Claimseach serious problem−1★
each medium problem−½★
Citationseach retracted or unverifiable reference−¼★
Copyeditonly when the manuscript needs a full edit−½★

The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.

The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.

The eight reporting dimensions

Scientific PremisePrior work, rationale, and how it addresses gaps.

Study Design & RigorRandomization, blinding, power, controls, replication.

Biological VariablesSex, age, species/strain, housing, demographics.

Ethical ApprovalsIRB/IACUC approval, informed consent, regulatory compliance.

Key ResourcesAntibodies, cell lines, organisms, software — identified with persistent IDs.

Statistical ReportingNamed tests, exact p-values, effect sizes, plausible summary stats.

Data & Code AvailabilityAvailability statements, repositories, accession numbers, shared code.

Reporting TransparencyMethods, registration, guidelines, outcomes, limitations, funding/COI.

Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.

This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.

Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial.

DOI

10.1038/s41591-025-03981-4

Record issued

2026-08-15

Engine

7.39.0

Exported

2026-09-22