Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

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

Name: Kaimen Rigor review — Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial.
Item: Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial.
Rating: 100
Author: Alpha1

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

Paper source

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Kaimen Rigor review — 4.5★ (Strong), 0 critical, 0 high issues for “Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial.”

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Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

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

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DOI

10.1038/s41591-025-03981-4

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742e21bb6ba8240b5e5afaebbc19ff87ee050cb6f7a28aaef1424d6c32ae9112

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

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

Paper source

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

Read full text (PMC)

Embed this Rigor badge

Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

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.

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

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).

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.

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).

2 data/code links checked; 2 live.

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.

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

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Read alongside

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

Read full text (PMC)

DOI

10.1038/s41591-025-03981-4

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Record fingerprint

742e21bb6ba8240b5e5afaebbc19ff87ee050cb6f7a28aaef1424d6c32ae9112

Verify via API

Issued Aug 15, 2026Engine 7.39.0

Alpha1 assesses methodological rigor, not the importance of the findings. See how we calibrate →

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

Numerical inconsistencies

None found

Checked — nothing surfaced.

Overstated conclusions

1 finding · worst low

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.

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

Data authenticity concerns

1 finding · worst medium

Other integrity concernAssessed

1 integrity concern flagged (0 high).

Reporting gaps

None found

Checked — nothing surfaced.

Eight Dimensions8 pass

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]

IntroductionFind in source

paraphrase[Discussion, paragraph 8]

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]

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.”

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]

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

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]

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

MethodsFind in source

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

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)”

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

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

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]

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

Statistical analysisFind in source

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

Evidence

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

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

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

Competing interestsFind in source

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

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).

2 data/code links checked; 2 live.

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.

Kaimen Rigor Action ItemsFinal pass before journal submission

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