HER2-low and HER2-ultralow metastatic breast cancer
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.
Overview
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.
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.
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- Interstitial lung disease monitoring protocols have cut fatal cases as experience has grown.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowSkin reaction
Blisters, peeling, or sores in the mouth or eyes with a rash. Enfortumab vedotin carries a boxed warning for Stevens-Johnson syndrome and toxic epidermal necrolysis, mostly in the first cycle.
- Call the 24-hour line nowInterstitial lung disease or pneumonitis
Any new or worsening cough, breathlessness or fever. The label says to interrupt treatment for any suspected ILD and to permanently discontinue for grade 2 or higher.
- Check before combiningTrastuzumab deruxtecan with Sacituzumab govitecan: major interaction
Sequential TOP1 ADCs share the payload class and cross-resistance; efficacy of the second is lower and toxicity additive (see the ADC-after-ADC caution pairing).. Do not give concurrently; consider an intervening non-TOP1 line.
- Check before combiningFood and drink: Sacituzumab govitecan
UGT1A1*28 homozygotes: higher neutropenia risk; G-CSF prophylaxis is often used.
- Check before combiningFood and drink: Trastuzumab deruxtecan
Interstitial lung disease in 10-15%: hold for any respiratory symptom and image; permanently discontinue for grade 2 or above. Moderately emetogenic: three-drug prophylaxis.
- Good to knowInterstitial lung disease (ILD) / pneumonitis
Interstitial lung disease (ILD) is lung inflammation, a serious side effect of some ADCs (especially Enhertu) and immunotherapy.
See all on the product pages:Datopotamab deruxtecanSacituzumab govitecanTrastuzumab deruxtecan·Printable cards in the navigator
Anatomy and lymph node drainage
- Ducts (most cancers start here)
- Lobules (lobular carcinoma; phyllodes tumours arise from the surrounding stroma)
- Upper outer quadrant (commonest site)
- Nipple-areola
- Nodes: axillary level I
- Nodes: axillary level II-III
- Nodes: internal mammary
- Nodes: supraclavicular
Most cancers start in the ducts and drain first to the axillary nodes, which is why the armpit is checked and a sentinel node is sampled.
- Ducts (most cancers start here)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)
- Lobules (lobular carcinoma; phyllodes tumours arise from the surrounding stroma)
- Upper outer quadrant (commonest site)
- Nipple-areola
- axillary level I
- axillary level II-III
- internal mammary
- supraclavicular
Same organ: Triple-negative breast cancer (TNBC), Breast cancer (all types), HR-positive / HER2-negative breast cancer, HER2-positive breast cancer, Male breast cancer, Ductal carcinoma in situ (DCIS), High-risk early HR-positive breast cancer, HR-positive metastatic breast cancer after CDK4/6 inhibitors, Early HER2-positive breast cancer, HER2-positive breast cancer with brain metastases, Early triple-negative breast cancer, Metastatic triple-negative breast cancer, Inflammatory breast cancer, Paget disease of the nipple, Phyllodes tumour of the breast
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.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Trastuzumab deruxtecan ahead of chemotherapy for HER2-low or ultralow disease (DESTINY-Breast06).
Trastuzumab deruxtecan for HER2-low disease of either hormone receptor status (DESTINY-Breast04).
TROP2 antibody-drug conjugates first (ASCENT, TROPION-Breast02), trastuzumab deruxtecan as a later option.
Baseline and interval CT, prompt corticosteroids and permanent discontinuation for grade 2 or higher interstitial lung disease.
Subtypes & biomarkers
top- 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)
- 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
How often this target appears
- 1998Trastuzumab approved for HER2-overexpressing disease
- 2019Phase 1b: trastuzumab deruxtecan responses in HER2-low tumours
- 2020HER2-low proposed as a clinical category
- 2022DESTINY-Breast04 and FDA approval
- 2023ASCO and CAP HER2 testing update recognises HER2-low
- 2024DESTINY-Breast06: earlier line and HER2-ultralow
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 11 changes by month →- 2026-09-17This recordHER2-low and HER2-ultralow metastatic breast cancerFacts on this page last checked
When this page itself was last checked or edited.
- 2025Trial resultTROPION-Breast02TROPION-Breast02 reported
OS 23.
- 2024Trial resultDESTINY-Breast06DESTINY-Breast06 reported
PFS HR 0.
- 2024MilestoneDESTINY-Breast06DESTINY-Breast06: earlier line and HER2-ultralow
A milestone in how this cancer is treated.
- 2023MilestoneHER2-low and HER2-ultralow metastatic breast cancerASCO and CAP HER2 testing update recognises HER2-low
A milestone in how this cancer is treated.
- 2022Trial resultDESTINY-Breast04DESTINY-Breast04 reported
OS HR 0.
What is in development for HER2-low and HER2-ultralow metastatic breast cancer, drawn from the whole corpus: 3 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Technologies being tested · 1
Trials reported · 2
- DESTINY-Breast04 · phase 3 · 2022 · positive
- DESTINY-Breast06 · phase 3 · 2024 · positive
Open problems and what is being done
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.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
| France | none recorded | 0 | 1,855 | 31,182 | #6 | ||
Tokyo · government | Japan | none recorded | 0 | 1,599 | 21,937 | none recorded | #13 |
Beijing · cancer center | China | none recorded | 0 | 371 | 4,070 | none recorded | #50 |
Los Angeles · cancer center | United States | 0 | 2,019 | 32,934 | - | ||
Beijing · cancer center | China | none recorded | 0 | 1,344 | 18,195 | - | |
| Italy | none recorded | 0 | 962 | 12,326 | - | ||
Rotterdam · cancer center | Netherlands | none recorded | 0 | 852 | 12,180 | - | |
Goyang · cancer center | South Korea | none recorded | 0 | 573 | 9,401 | - | |
Brussels · cancer center Programme: Breast International Group, Breast cancer genomics and ctDNA | Belgium | none recorded | 0 | 489 | 8,689 | - | |
Shanghai · hospital | China | none recorded | 0 | 464 | 6,795 | - | |
Barcelona · hospital Programme: Breast cancer trials (SOLTI) | Spain | none recorded | 0 | 431 | 4,125 | - | |
| Italy | none recorded | 0 | 399 | 5,644 | - | ||
Candiolo · cancer center | Italy | none recorded | 0 | 324 | 4,466 | - | |
Washington, DC · cancer center Programme: Breast cancer (CLEOPATRA) | United States | 0 | 100 | 2,434 | - | ||
| Argentina | none recorded | 0 | 95 | 547 | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with HER2-low and HER2-ultralow metastatic breast cancer but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about HER2-low and HER2-ultralow metastatic breast cancer
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example 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), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Hormone receptor-positive HER2-low disease, Hormone receptor-positive HER2-ultralow disease, Triple-negative HER2-low disease.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Hormone receptor-positive, after endocrine therapy, chemotherapy-naive
- For my situation (hormone receptor-positive, after endocrine therapy, chemotherapy-naive), which of the standard options do you recommend and why?Why: Guideline options include: Trastuzumab deruxtecan ahead of chemotherapy for HER2-low or ultralow disease (DESTINY-Breast06).
- Am I a candidate for Trastuzumab deruxtecan, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of DESTINY-Breast06 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
After one or two lines of chemotherapy
- For my situation (after one or two lines of chemotherapy), which of the standard options do you recommend and why?Why: Guideline options include: Trastuzumab deruxtecan for HER2-low disease of either hormone receptor status (DESTINY-Breast04).
- Am I a candidate for Trastuzumab deruxtecan, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of DESTINY-Breast04 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Triple-negative HER2-low disease
- For my situation (triple-negative her2-low disease), which of the standard options do you recommend and why?Why: Guideline options include: TROP2 antibody-drug conjugates first (ASCENT, TROPION-Breast02), trastuzumab deruxtecan as a later option.
- Am I a candidate for Sacituzumab govitecan, Datopotamab deruxtecan, Trastuzumab deruxtecan, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of ASCENT and TROPION-Breast02 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Lung toxicity
- For my situation (lung toxicity), which of the standard options do you recommend and why?Why: Guideline options include: Baseline and interval CT, prompt corticosteroids and permanent discontinuation for grade 2 or higher interstitial lung disease.
Any stage
- Are there clinical trials I could join, for example of Trastuzumab deruxtecan, Sacituzumab tirumotecan, Trastuzumab rezetecan, Disitamab vedotin?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Immunohistochemistry was never designed to score low expression and pathologists disagree at the 0 to 1+ boundary”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Whether a second topoisomerase I payload works after the first”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with HER2-low and HER2-ultralow metastatic breast cancer, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
5targets
2drugs
7companies
11terms
2trials
4key papers
1Latest papers
topQuery for this cancer: (TITLE:"HER2-low and HER2-ultralow metastatic breast cancer" OR ABSTRACT:"HER2-low and HER2-ultralow metastatic breast cancer" OR TITLE:"HER2 IHC 1+ or 2+ ISH-negative breast cancer" OR ABSTRACT:"HER2 IHC 1+ or 2+ ISH-negative breast cancer" OR TITLE:"Metastatic breast cancer with low HER2 expression" OR ABSTRACT:"Metastatic breast cancer with low HER2 expression") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about HER2-low and HER2-ultralow metastatic breast cancer, not a curated reading list.
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