The short answer
HER2 testing was once simply positive or negative. HER2-low and HER2-ultralow are newer categories created because trastuzumab deruxtecan works in tumors previously called HER2-negative.
HER2 testing starts with an IHC score of 0 to 3+; ambiguous 2+ results go on to FISH.
HER2-low is defined by the FDA as IHC 1+ or IHC 2+ with negative ISH, and roughly half of breast cancers fall into it.
The category exists because trastuzumab deruxtecan worked in these tumors, not because a new biological subtype was discovered.
In DESTINY-Breast04, median progression-free survival in the hormone receptor-positive group was 10.1 months versus 5.4 months with chemotherapy, and overall survival 23.9 versus 17.5 months.
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The full explanation.
What HER2 is and how it is measured
HER2 is a protein on the surface of breast cells. It signals them to grow. Some breast cancers make far too much of it. Testing usually starts with immunohistochemistry (IHC), a stain that shows which proteins a cell is making. IHC scores staining from 0 to 3+. Unclear results, scored 2+, go on to an in situ hybridization test such as FISH. That test counts copies of the HER2 gene.
For two decades the result was yes or no. IHC 3+, or IHC 2+ with a positive FISH, meant HER2-positive. That gave access to HER2-targeted drugs. Everything else was HER2-negative and got none of them.
What changed
That split no longer holds. Trastuzumab deruxtecan is an antibody-drug conjugate. It carries chemotherapy to cells with even modest HER2 on their surface. It turned out to work in tumors that were never considered HER2-positive.
On August 5, 2022, the FDA approved trastuzumab deruxtecan for unresectable or metastatic HER2-low breast cancer. It defined HER2-low as "IHC 1+ or IHC 2+/ISH-." The DESTINY-Breast04 trial gave the figures. In the hormone receptor-positive group, median progression-free survival was 10.1 months with trastuzumab deruxtecan. It was 5.4 months with the physician's choice of chemotherapy. Median overall survival was 23.9 versus 17.5 months.
In January 2025 the FDA extended this further, to HER2-ultralow disease. That means IHC 0 with faint, incomplete membrane staining. The approval covers hormone receptor-positive metastatic breast cancer after endocrine therapy.
Why an old pathology report may need re-reading
Here is the practical consequence. Before 2022, the difference between IHC 0 and IHC 1+ carried no treatment implications. So pathology reports often said only "HER2-negative" without recording which. Some laboratories did not separate faint staining from no staining at all, because nothing depended on it.
Now it does. Your report may predate these approvals, or say only "negative." If so, it is reasonable to ask whether the original slides can be reviewed. You can also ask whether a newer biopsy should be tested. HER2 expression can differ between the original tumor and a metastatic site. It can also shift over time. That is one reason biopsies of new lesions are sometimes done.
HER2-low is not a new biological subtype that someone discovered. It is a category created because a drug turned out to work there. That is an unusual origin story for a diagnosis. It explains why the definition has kept moving.
What HER2-positive treatment looks like
HER2-positive disease has a deep toolbox. Trastuzumab and pertuzumab are antibodies given with chemotherapy. In early-stage disease they are often given before surgery. Ado-trastuzumab emtansine and trastuzumab deruxtecan are antibody-drug conjugates. Tucatinib, neratinib, and lapatinib are oral drugs that block HER2 signaling inside the cell. Tucatinib in particular is used when there is brain involvement. Margetuximab is another antibody option.
HER2-positive breast cancer was once among the most feared diagnoses. Anti-HER2 therapy changed that substantially. It remains one of the clearest examples of targeted treatment altering the course of a cancer.
What HER2-low does and does not mean
HER2-low is currently a treatment-eligibility category for the metastatic setting. It is not a prognosis. Roughly half of breast cancers fall into it. Your hormone receptor status still governs most of your treatment order. If you are hormone receptor-positive, endocrine therapy typically comes first, with trastuzumab deruxtecan considered later. HER2-low does not qualify you for trastuzumab and pertuzumab. Those need true HER2 overexpression.
Trastuzumab deruxtecan carries a boxed warning for interstitial lung disease and embryo-fetal toxicity. New or worsening cough, shortness of breath, or fever is something to report the same day rather than at the next visit.
Worth asking
Ask for the exact IHC score and any FISH ratio, not just positive or negative. Ask whether your most recent biopsy was tested, rather than your original one. And ask how HER2-low affects the order of your options, rather than whether it changes them at all.
When to get help sooner
- Call 911 or go to an emergency department if you are suddenly fighting for breath at rest, or your lips or fingertips turn blue or grey.
- Get seen the same evening, not the next morning, if your temperature reaches 100.4°F (38°C) or higher while you are on treatment. CDC calls a fever during chemotherapy a medical emergency. Ring the oncology line first if you can, and if nobody answers within minutes, go to an emergency department and say you are on cancer treatment.
- Call your care team the same day if you are receiving trastuzumab deruxtecan and a cough appears, or breathing gets harder doing things you managed last week. The drug's boxed warning asks for cough, breathlessness and fever to be reported immediately, because they can be the opening sign of lung inflammation.
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Common questions
My report says HER2-negative. Could I actually be HER2-low?
Possibly. Before 2022 the difference between IHC 0 and IHC 1+ had no treatment implications, so many reports recorded only negative and some laboratories did not distinguish faint staining from none. Asking whether the original slides can be reviewed, or whether a newer biopsy should be tested, is reasonable.
Is HER2-low a worse or better prognosis?
HER2-low is currently a treatment-eligibility category for metastatic disease, not a prognostic group. Your hormone receptor status still governs most of the treatment sequence.
Does HER2-low mean I can have trastuzumab and pertuzumab?
No. Those antibodies require true HER2 overexpression, meaning IHC 3+ or IHC 2+ with positive FISH. HER2-low opens the door to antibody-drug conjugates such as trastuzumab deruxtecan, which deliver chemotherapy to cells carrying even modest amounts of HER2.
What is HER2-ultralow?
IHC 0 with faint, incomplete membrane staining. In January 2025 the FDA extended trastuzumab deruxtecan to this group in hormone receptor-positive metastatic breast cancer after endocrine therapy.
Can my HER2 status change over time?
It can differ between the original tumor and a site of spread, and can shift over the course of the disease. This is one reason a biopsy of a new lesion is sometimes recommended rather than relying on the original pathology.
Questions to ask your doctor
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Written by: Cancer ExplainedSources last checked: 2026-08-13 what this meansLast updated: 2026-08-13Next planned review: 2027-07-30
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How this page was created
Cancer Explained does not originate medical claims. Every page restates guidance already published by the National Cancer Institute, the CDC, the USPSTF and the FDA, in plain language, with the source cited so you can check the original yourself. AI does the translating and organizing; automated checks test claims, citations, clarity and safety before anything publishes. We do not employ clinicians and do not intend to — our work is translation and navigation, not clinical judgment. Nothing here is personal medical advice, and no page can account for your particular situation.
Editorial status: Source checked — This page was written with AI assistance and checked line by line against the sources listed on it. That confirms the sources support what the page says. It is not a medical review, and it does not confirm the page is complete or right for your situation.
Human medical review: not completed. Pages here are not signed off by a clinician before they publish. That is not an oversight we are quietly working around: we restate published guidance and cite it, so the authority belongs to the source rather than to us, and every page names where its claims come from — you can verify us instead of trusting us. Where a volunteer clinician has reviewed a page, their name and credentials appear on it; where no name appears, no clinician has checked it. We are glad to have reviewers and are recruiting them, and we do not hold pages back waiting for one. Use this site to understand your situation and to ask better questions of the people treating you.
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