Evidence map›Paper›PMID 42340017›Full record

ArticleThe breast journal2026

HER2-Ultralow: Prevalence, Characteristics, and Treatment Choices Among Advanced Breast Cancer Patients With Tumors Initially Scored as IHC 0.

Anushree R Iyengar, Erinn P Downs, Sandhya Mehta, Nivedita Rangarajan, Michele Sue-Ann Woo, Simone T Sredni, Rosemarie Di Donato, Safak Simsek, Darren M Wilson, Katherine Krieser and 7 more

Registry-linked trialAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The breast journal, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03734029 (A Phase 3, Multicenter, Randomized, Open-label, Active Controlled Trial of DS-8201a, an Anti-HER2-antibody Drug Conjugate), which is not on this map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT03734029 phase3active not recruitingnot on this map

A Phase 3, Multicenter, Randomized, Open-label, Active Controlled Trial of DS-8201a, an Anti-HER2-antibody Drug Conjugate (ADC), Versus Treatment of Physician's Choice for HER2-low, Unresectable and/or Metastatic Breast Cancer Subjects

TypeinterventionalSponsorDaiichi SankyoRan2018 to 2026Enrolled557ConditionsBreast CancerArmsTrastuzumab deruxtecan (DS-8201a), Capecitabine, Eribulin, Gemcitabine, Paclitaxel
3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Anushree R IyengarDepartment of Biomedical Research, Nference, Inc., Cambridge, Massachusetts, USA.ORCID https://orcid.org/0009-0000-3561-7818
Erinn P DownsDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona, USA, mayo.edu.
Sandhya MehtaUS Medical Affairs, Daiichi Sankyo, Inc., Basking Ridge, New Jersey, USA.
Nivedita RangarajanDepartment of Biomedical Research, Nference, Inc., Cambridge, Massachusetts, USA.ORCID https://orcid.org/0009-0006-6774-3927
Michele Sue-Ann WooUS Medical Affairs, Daiichi Sankyo, Inc., Basking Ridge, New Jersey, USA.
Simone T SredniBiomarker Science and Technology, AstraZeneca, LLC, Gaithersburg, Maryland, USA.
Rosemarie Di DonatoBiomarker Science and Technology, AstraZeneca, LLC, Gaithersburg, Maryland, USA.
Safak SimsekDepartment of Biomedical Research, Nference, Inc., Cambridge, Massachusetts, USA.
Darren M WilsonDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA, mayo.edu.
Katherine KrieserBioPharma Diagnostics, Mayo Clinic, Rochester, Minnesota, USA, mayo.edu.
Elise Bieri PatzkeBioPharma Diagnostics, Mayo Clinic, Rochester, Minnesota, USA, mayo.edu.
Natalie KyekClinical Research Operations, Mayo Clinic, Rochester, Minnesota, USA, mayo.edu.
Christian AndersonDepartment of Biomedical Research, Nference, Inc., Cambridge, Massachusetts, USA.
Tyler WagnerDepartment of Biomedical Research, Nference, Inc., Cambridge, Massachusetts, USA.ORCID https://orcid.org/0000-0001-7347-8708
Jason HippBioPharma Diagnostics, Mayo Clinic, Rochester, Minnesota, USA, mayo.edu.
Aziza NassarMayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida, USA, mayo.edu.ORCID https://orcid.org/0000-0002-6678-9329
Hannah BarmanDepartment of Biomedical Research, Nference, Inc., Cambridge, Massachusetts, USA.ORCID https://orcid.org/0009-0008-4685-0680

Funding

AstraZeneca T-DXd; DS-8201Daiichi Sankyo Company
6 · The paper itself

Abstract

Historically, HER2 status in invasive breast cancer has been categorized as HER2-positive (IHC 3+, IHC 2+/ISH+) or HER2-negative (IHC 0, IHC 1+, IHC 2+/ISH-). Patients meeting IHC 0 with membrane staining (HER2-ultralow) criteria may benefit from HER2-targeted therapies such as trastuzumab deruxtecan. This cohort study assessed the prevalence of HER2-ultralow expression by re-scoring HER2 IHC slides using Mayo Clinic electronic health record data. Three hundred patients with advanced breast cancer (Stages III-IV) and documented HER2 IHC 0 status (January 2017-March 2023) were identified. One slide per patient was digitized and independently re-scored by two Mayo Clinic pathologists following the 2023 ASCO-CAP guidelines, including tumor staining percentage to denote HER2-ultralow status. A sensitivity analysis was performed by a third independent pathologist. The re-scored patients had a mean age of 57.7 years (SD = 13.6). Most samples (95%, n = 285) remained scored IHC 0 by at least one pathologist; 60% of these met HER2-ultralow criteria per at least one pathologist. HER2-ultralow prevalence ranged from 43% to 45% per pathologist, with 57% overall interpathologist concordance. Samples with no observable staining comprised most of the concordant cases. Treatment patterns were similar between HER2-ultralow and no-staining groups; however, time to treatment failure (TTF) varied between groups across lines of therapy (LOT). In HR- positive cohorts, median TTF for LOT1 was 7.73 months in patients with HER2-ultralow versus 9.43 months with no observable IHC staining. In HR- negative cohorts, median TTF was 5.00 months for HER2-ultralow versus 3.17 months with no observable IHC staining. Similar TTF trends were observed in LOT2-LOT3. Approximately three in five samples originally classified as IHC 0 met HER2-ultralow criteria, suggesting many patients may benefit from HER2-directed therapy if reclassified. These findings highlight potential challenges of identifying HER2-ultralow expression and suggest the need for enhanced pathologist training, adherence to best practices, and integration of digital pathology and artificial intelligence solutions. Trial Registration: ClinicalTrials.gov_identifier: NCT03734029.

Indexed as

Breast NeoplasmsErb-b2 Receptor Tyrosine KinasesAdultAgedBiomarkers, TumorFemaleHumansImmunohistochemistryMiddle AgedPrevalenceBiomarkers, TumorERBB2 protein, humanErb-b2 Receptor Tyrosine Kinasesbreast cancerHER2immunohistochemistry

Identifiers

PMID42340017
PMCPMC13291886

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.