HER2-Low Breast Cancer: Meaning

HER2 stands for human epidermal growth factor receptor 2. It is a protein on the surface of breast cells. When a tumor makes far too much of it, the cancer grows faster, and HER2-targeted drugs work.

For twenty years, HER2 was a yes-or-no question. You were HER2-positive or HER2-negative. HER2-low is not a new biology. It is a slice carved out of the old negative group, because a drug turned out to work there.

The first test is immunohistochemistry, or IHC. It is a stain applied to tumor tissue, scored by eye. The National Cancer Institute gives the scale:

• Negative: 0 or 1+ staining.
• Equivocal: 2+ staining.
• Positive: 3+ staining.

Equivocal means unclear, and it triggers a second test. In situ hybridization, or ISH, counts HER2 gene copies rather than protein. A 2+ result goes to ISH to settle the question.

HER2-low is defined by the FDA label as IHC 1+, or IHC 2+ with a negative ISH result. Read that again alongside the scale above. Every one of those results was called HER2-negative before 2022. Nothing about the tumor changed. The reporting changed.

For the 2022 approval, HER2 status was determined at a central laboratory.

On August 5, 2022, the FDA approved fam-trastuzumab deruxtecan-nxki, sold as Enhertu, for adults with unresectable or metastatic HER2-low breast cancer who had received prior chemotherapy or whose disease had recurred.

The trial was randomized, multicenter, and open-label. It enrolled 557 patients, of whom 494 were hormone receptor-positive and 63 were hormone receptor-negative. Patients were assigned 2 to 1, to the drug or to chemotherapy of the physician's choice.

The results across the whole group:

• Median progression-free survival: 9.9 months, versus 5.1 months with chemotherapy. Hazard ratio 0.50.
• Median overall survival: 23.4 months, versus 16.8 months. Hazard ratio 0.64.

In the hormone receptor-positive group specifically, progression-free survival was 10.1 months versus 5.4 months, with a hazard ratio of 0.51. Overall survival was 23.9 months versus 17.5 months, hazard ratio 0.64.

A hazard ratio of 0.50 means the rate of progression was about half that of the comparison arm. This was a large effect in a group that had no HER2-directed option at all.

On January 27, 2025, the FDA broadened the indication. The drug was approved for unresectable or metastatic hormone receptor-positive breast cancer that is HER2-low, or HER2-ultralow.

HER2-ultralow has its own definition: IHC 0 with membrane staining. That means the pathologist saw faint staining at the cell membrane in a sample that still scores as 0.

The trial was DESTINY-Breast06, which enrolled 866 patients. Of those, 713 had HER2-low disease and 153 fell into the HER2-ultralow subgroup.

In the HER2-low population, median progression-free survival was 13.2 months with the drug and 8.1 months with chemotherapy. The hazard ratio was 0.62, with a 95 percent confidence interval of 0.52 to 0.75, and a p-value below 0.0001.

Fam-trastuzumab deruxtecan-nxki is an antibody-drug conjugate. The antibody part finds HER2 on the cell surface. Attached to it is a chemotherapy payload. The antibody acts as a delivery system, so the chemotherapy is concentrated where HER2 is present, even when there is only a little of it.

The amount given is the same under both approvals: a drip into a vein roughly every three weeks, with the quantity worked out from your body weight by the pharmacy team. Nothing about it is for you to measure or arrange.

The most common adverse reactions listed by the FDA are nausea, fatigue, hair loss, vomiting, anemia, constipation, decreased appetite, diarrhea, and pain in muscles and bones.

The drug carries a boxed warning for interstitial lung disease and for embryo-fetal toxicity. Interstitial lung disease means inflammation and scarring in the tissue between the air sacs of the lung.

This can be serious, and it can appear without a dramatic onset. Report any new or worsening cough, shortness of breath, or fever right away, even if it seems mild and even if you think it is a cold. Treatment is usually held while it is evaluated. Do not wait for the next scheduled visit.

The embryo-fetal warning means effective contraception is required during treatment. Ask for the exact duration to continue it after the last dose.

Being HER2-low does not make a cancer HER2-positive. The classic HER2-targeted antibodies used for 3+ disease are not indicated here.

It also does not replace hormone therapy for hormone receptor-positive disease. Both 2025 and 2022 approvals sit in the metastatic setting, after other treatment. It is not an early-stage or adjuvant therapy on these labels.

And a HER2-low result on one biopsy does not lock in forever. Staining can differ between the original tumor and a later metastasis, and between two blocks from the same specimen.

• What exactly does my report say: IHC 0, 1+, 2+, or 3+? If 2+, what did the ISH show?
• If the report says IHC 0, did the pathologist note any membrane staining, which would make it ultralow?
• Which biopsy was scored, the original tumor or a metastasis, and how old is it?
• Would re-testing a newer biopsy change my options?
• Where does this drug fit in my sequence, and what would come before or after it?
• What is your plan for monitoring my lungs, and who do I call at night for a new cough?

That last one is not a formality. Given the boxed warning, knowing the after-hours number before you need it is part of the treatment plan.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-low-breast-cancer

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-hr-positive-her2-low-or-her2

https://www.cancer.gov/types/breast/hp/breast-treatment-pdq