# HER2-low and HER2-ultralow metastatic breast cancer

Source: https://onco.cc/cancers/her2-low-metastatic-breast-cancer/  
OnCo record `her2-low-metastatic-breast-cancer` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

HER2-low is not a new kind of breast cancer but a new way of reading an old test: tumours once called HER2-negative that carry a little HER2 protein. That trace is enough for the antibody-drug conjugate trastuzumab deruxtecan to deliver its chemotherapy payload, and since 2022 it has been the standard for these patients after endocrine therapy or a first chemotherapy.

## Summary

HER2 status was binary for two decades: 3+ by immunohistochemistry or amplified by in situ hybridisation meant trastuzumab, anything less meant nothing. Trastuzumab deruxtecan changed that because its payload, a topoisomerase I inhibitor carried eight to an antibody with a cleavable linker, is released inside the cell and diffuses into neighbours, so tumours with only a few receptors per cell still respond. HER2-low is defined as 1+ or 2+ without amplification, and HER2-ultralow as a score of 0 with membrane staining in 10 percent of cells or fewer; the 2023 ASCO and CAP testing update recognised the categories, and because expression varies between the primary and metastases and between blocks, retesting a metastatic biopsy is recommended before ruling a patient out.

DESTINY-Breast04 randomised 557 patients with HER2-low metastatic breast cancer after one or two chemotherapy lines to trastuzumab deruxtecan or the physician's choice of chemotherapy. In the hormone receptor-positive cohort progression-free survival rose from 5.4 to 10.1 months (hazard ratio 0.51) and overall survival from 17.5 to 23.9 months (hazard ratio 0.64), with the small hormone receptor-negative cohort pointing the same way. Adjudicated interstitial lung disease occurred in about 12 percent and was fatal in under one percent, and the FDA approved the indication in August 2022, the first time a HER2-directed drug had been licensed for HER2-negative disease.

DESTINY-Breast06 moved the drug earlier and wider: 866 patients with hormone receptor-positive HER2-low or ultralow disease who had progressed on endocrine therapy but never had chemotherapy for metastases were randomised to trastuzumab deruxtecan or chemotherapy, and progression-free survival rose from 8.1 to 13.2 months in HER2-low disease (hazard ratio 0.62) with a similar effect in the ultralow group; approval followed in 2025. The triple-negative share of HER2-low disease sits behind the TROP2 antibody-drug conjugates in sequence, and whether any threshold of HER2 expression matters at all, how to sequence one topoisomerase payload after another and how to prevent lung toxicity are the open questions.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: HER2 IHC 1+ or 2+ ISH-negative breast cancer; Metastatic breast cancer with low HER2 expression
- Tags: subtype-page
- Group: breast
- Burden: About half of all breast cancers, and around six in ten hormone receptor-positive tumours, show low HER2 expression (immunohistochemistry 1+, or 2+ without gene amplification) that was long classed as HER2-negative; ultralow adds tumours scored 0 with faint staining in a tenth of cells or fewer.
- Subtypes: Hormone receptor-positive HER2-low disease (about six in ten luminal tumours); Hormone receptor-positive HER2-ultralow disease (IHC 0 with faint staining); Triple-negative HER2-low disease (about a third of triple-negative tumours); HER2-low disease after chemotherapy (DESTINY-Breast04 population); HER2-low disease after endocrine therapy, chemotherapy-naive (DESTINY-Breast06 population)
- Biomarkers: HER2 immunohistochemistry score 0, ultralow, 1+ or 2+ with in situ hybridisation for 2+; Retesting on a metastatic biopsy because HER2-low status changes over time; Hormone receptor status; Baseline chest imaging and lung function for interstitial lung disease surveillance; PIK3CA, ESR1 and germline BRCA status to sequence against targeted options

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/her2-low-metastatic-breast-cancer/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/her2-low-metastatic-breast-cancer/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/her2-low-metastatic-breast-cancer/#what-it-is [5 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/her2-low-metastatic-breast-cancer/#finding-it [5 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/her2-low-metastatic-breast-cancer/#treating-it [4 settings, 1 decision with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/her2-low-metastatic-breast-cancer/#evidence [10 trials, 3 key papers, 6 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/her2-low-metastatic-breast-cancer/#science [2 targets]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/her2-low-metastatic-breast-cancer/where-you-are/ [16 UK centres]
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/her2-low-metastatic-breast-cancer/#living-with-it [19 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/her2-low-metastatic-breast-cancer/coming/ [7 medicines, 8 trials, 2 ideas, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/her2-low-metastatic-breast-cancer/data/ [51 connected records]

## Standard of care

- Hormone receptor-positive, after endocrine therapy, chemotherapy-naive: Trastuzumab deruxtecan ahead of chemotherapy for HER2-low or ultralow disease (DESTINY-Breast06). ([Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [DESTINY-Breast06](https://onco.cc/trials/destiny-breast06/), [HER2-low and HER2-ultralow](https://onco.cc/terms/her2-low/))
- After one or two lines of chemotherapy: Trastuzumab deruxtecan for HER2-low disease of either hormone receptor status (DESTINY-Breast04). ([Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [DESTINY-Breast04](https://onco.cc/trials/destiny-breast04/), [HER2-low and HER2-ultralow](https://onco.cc/terms/her2-low/))
- Triple-negative HER2-low disease: TROP2 antibody-drug conjugates first (ASCENT, TROPION-Breast02), trastuzumab deruxtecan as a later option. ([Sacituzumab govitecan](https://onco.cc/drugs/sacituzumab-govitecan/), [Datopotamab deruxtecan](https://onco.cc/drugs/datopotamab-deruxtecan/), [ASCENT](https://onco.cc/trials/ascent/), [TROPION-Breast02](https://onco.cc/trials/tropion-breast02/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/))
- Lung toxicity: Baseline and interval CT, prompt corticosteroids and permanent discontinuation for grade 2 or higher interstitial lung disease. ([CT (computed tomography)](https://onco.cc/technologies/ct/), [Interstitial lung disease (ILD) / pneumonitis](https://onco.cc/terms/ild/))

## State of the art

- Roughly half of all metastatic breast cancers became eligible for a HER2-directed drug in 2022.
- The ultralow category, defined by DESTINY-Breast06, pushes the boundary to tumours pathologists once called negative.
- Interstitial lung disease monitoring protocols have cut fatal cases as experience has grown.

## Open problems

- Immunohistochemistry was never designed to score low expression and pathologists disagree at the 0 to 1+ boundary.
- Whether a second topoisomerase I payload works after the first.
- Interstitial lung disease remains unpredictable.
- The triple-negative HER2-low group has only exploratory randomised data.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Trastuzumab_deruxtecan
- DESTINY-Breast04 (NEJM 2022): https://doi.org/10.1056/NEJMoa2203690
- DESTINY-Breast06 on ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT04494425
- Wikipedia: https://en.wikipedia.org/wiki/Trastuzumab_deruxtecan

## Connected records

- cancers: [Breast cancer (all types)](https://onco.cc/cancers/breast-cancer/), [HER2-positive breast cancer](https://onco.cc/cancers/breast-her2-positive/), [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- key papers: [Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials](https://onco.cc/key-papers/paper-denkert-her2-low-pooled-neoadjuvant-lancet-oncol-2021/), [Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer](https://onco.cc/key-papers/paper-schettini-her2-low-features-npj-breast-cancer-2021/), [DESTINY-Breast06: trastuzumab deruxtecan before any chemotherapy in hormone-receptor-positive, HER2-low or ultralow breast cancer](https://onco.cc/key-papers/paper-destiny-breast06-nejm-2024/)
- drugs: [Datopotamab deruxtecan](https://onco.cc/drugs/datopotamab-deruxtecan/), [Disitamab vedotin](https://onco.cc/drugs/disitamab-vedotin/), [Sacituzumab govitecan](https://onco.cc/drugs/sacituzumab-govitecan/), [Sacituzumab tirumotecan](https://onco.cc/drugs/sacituzumab-tirumotecan/), [Trastuzumab](https://onco.cc/drugs/trastuzumab/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Trastuzumab rezetecan](https://onco.cc/drugs/trastuzumab-rezetecan/)
- trials: [A Clinical Trial of TQB2102 for Injection in the Treatment of HER2 Low-Expressing Recurrent/Metastatic Breast Cancer](https://onco.cc/trials/nct06561607/), [A Study Comparing BL-M07D1 With DS-8201 in Patients With HR-Positive, HER2-Low Expressing Recurrent/Metastatic Breast Cancer](https://onco.cc/trials/nct07678957/), [A Study of DB-1303/BNT323 vs Investigator's Choice Chemotherapy in HER2-Low, Hormone Receptor Positive Metastatic Breast Cancer (DYNASTY-Bre](https://onco.cc/trials/nct06018337/), [ASCENT](https://onco.cc/trials/ascent/), [DESTINY-Breast04](https://onco.cc/trials/destiny-breast04/), [DESTINY-Breast06](https://onco.cc/trials/destiny-breast06/), [JSKN003 Versus Treatment Of Physician'S Choice For HER2-low, Unresectable and/or Metastatic Breast Cancer Subjects](https://onco.cc/trials/nct06079983/), [Study of Sacituzumab Govitecan Versus Treatment of Physician's Choice in Patients With Hormone Receptor-positive/Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) Metastatic Breast Cancer Who Have Received Endocrine Therapy](https://onco.cc/trials/nct05840211/), [Trastuzumab Deruxtecan (T-DXd) in Patients Who Have Hormone Receptor-negative and Hormone Receptor-positive HER2-low or HER2 IHC 0 Metastatic Breast Cancer](https://onco.cc/trials/nct05950945/), [TROPION-Breast02](https://onco.cc/trials/tropion-breast02/)
- technologies: [CT (computed tomography)](https://onco.cc/technologies/ct/), [HER2 PET](https://onco.cc/technologies/her2-pet/)
- terms: [HER2 testing in the UK: reflex ISH, the ratio against the copy number, and where the UK differs from ASCO/CAP](https://onco.cc/terms/her2-testing-uk-breast/), [HER2-low and HER2-ultralow](https://onco.cc/terms/her2-low/), [HER2-low eligibility for trastuzumab deruxtecan, and TROP2 ADCs without a test (triple-negative disease)](https://onco.cc/terms/her2-low-and-trop2-adc-eligibility-tnbc/), [Interstitial lung disease (ILD) / pneumonitis](https://onco.cc/terms/ild/), [Receptor conversion: when the receptors change between the primary and a recurrence](https://onco.cc/terms/receptor-conversion-breast/)
- roadmaps: [Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem](https://onco.cc/roadmaps/tnbc-roadmap/)
- ideas: [A randomised trial of antibody-drug conjugate sequence in metastatic triple-negative breast cancer](https://onco.cc/ideas/idea-tnbc-adc-sequencing-trial/), [Reflex re-scoring of HER2 0 versus 1+ with digital assistance so every eligible triple-negative patient reaches trastuzumab deruxtecan](https://onco.cc/ideas/idea-tnbc-her2-ultralow-testing-uptake/)
- biomarkers: [HER2 IHC 0 (HER2-negative, including ultralow)](https://onco.cc/biomarkers/her2-ihc-0/), [HER2 IHC 1+](https://onco.cc/biomarkers/her2-ihc-1-plus/), [HER2 IHC 2+ (equivocal, reflex to ISH)](https://onco.cc/biomarkers/her2-ihc-2-plus/), [HER2-low (IHC 1+ or IHC 2+/ISH-negative)](https://onco.cc/biomarkers/her2-low-ihc/), [HER2-ultralow (IHC 0 with membrane staining)](https://onco.cc/biomarkers/her2-ultralow/)

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JSON: https://onco.cc/api/v1/entities/her2-low-metastatic-breast-cancer.json