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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.
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.
Averages across everyone diagnosed, often years ago. A median is the middle of a group: half the people counted lived longer than the figure shown, and some lived far longer. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
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.
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.
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, Basal-like 1 triple-negative breast cancer (BL1), Basal-like 2 triple-negative breast cancer (BL2), Mesenchymal triple-negative breast cancer (M), Mesenchymal stem-like triple-negative breast cancer (MSL), Luminal androgen receptor triple-negative breast cancer (LAR), Immunomodulatory triple-negative breast cancer (IM), Metaplastic breast carcinoma, Carcinoma with medullary pattern (medullary breast cancer), Adenoid cystic carcinoma of the breast, Apocrine carcinoma of the breast, Secretory carcinoma of the breast, BRCA-associated triple-negative breast cancer, Inflammatory breast cancer, Paget disease of the nipple, Phyllodes tumour of the breast, Invasive lobular carcinoma of the breast, Invasive breast carcinoma of no special type (invasive ductal carcinoma), Tubular carcinoma of the breast, Mucinous carcinoma of the breast, Papillary carcinomas of the breast (encapsulated, solid and invasive papillary), Invasive cribriform carcinoma of the breast, Invasive micropapillary carcinoma of the breast, Neuroendocrine neoplasms of the breast, Lobular carcinoma in situ (LCIS)
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.
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Patients with hormone-receptor-positive metastatic breast cancer that has stopped responding to endocrine therapy can be offered trastuzumab deruxtecan as their first chemotherapy-type treatment if the tumour shows any HER2 staining, rather than waiting until after conventional chemotherapy. Whether to use it before or after chemotherapy is now a choice, since overall survival was not shown to differ and the drug carries a risk of lung inflammation.
The trial-grade HER2-low share for TNBC is about a third, and the survival difference hints that HER2-zero triple-negative disease is the more aggressive group.
HER2-low is a drug eligibility label, not a biological subtype, in triple-negative disease; because a third of patients qualify for trastuzumab deruxtecan on a score pathologists disagree about, re-scoring and digital assistance for HER2 0 versus 1+ is a practical gap.
Query 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.
The targets of this cancer's medicines and the ones linked to it directly.
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.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Temperature of 38 C or higher, or feeling shivery and unwell even without a fever. Antibody-drug conjugates suppress the bone marrow, and several carry a boxed warning for severe neutropenia.
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.
Temperature of 38 C or higher. Sacituzumab govitecan carries a boxed warning for severe or life-threatening neutropenia.
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.
UGT1A1*28 homozygotes: higher neutropenia risk; G-CSF prophylaxis is often used.
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.
See all on the product pages:Datopotamab deruxtecanSacituzumab govitecanTrastuzumab deruxtecan·Printable cards in the navigator
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.
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