HER2-low breast cancer is a relatively new classification describing tumors that have small amounts of the HER2 protein on their surface, but not enough to qualify as HER2-positive. It accounts for roughly 55 to 64% of all breast cancers, making it the most common HER2 category. Until recently, these tumors were grouped together with cancers that had no HER2 at all and labeled simply “HER2-negative.” That changed in 2022, when a targeted drug was approved that could treat these low-level tumors specifically, giving the distinction real clinical significance.
How HER2-Low Differs From Other Categories
Every breast cancer tumor is tested for a protein called HER2, which sits on the surface of cells and promotes their growth. Pathologists score HER2 levels on a scale from 0 to 3+ using a staining test called immunohistochemistry (IHC). A score of 3+ means the tumor is HER2-positive, with high levels of the protein. A score of 0 means essentially no detectable HER2. Everything in between is now considered HER2-low.
Specifically, HER2-low includes two scoring results: IHC 1+ (faint, incomplete staining on more than 10% of tumor cells) and IHC 2+ with a negative follow-up gene amplification test. Before 2022, both of these results were treated the same as a zero score. Patients were told they were HER2-negative, and that was the end of the HER2 conversation. Now, the difference between a 0 and a 1+ can determine whether you’re eligible for a targeted therapy.
Why This Category Matters Now
The reason HER2-low became its own category is a drug called trastuzumab deruxtecan, sold as Enhertu. The FDA approved it in August 2022 for adults with metastatic or inoperable HER2-low breast cancer who had already received at least one prior chemotherapy. This was the first time a targeted HER2 therapy worked in tumors with such low protein levels, and it reshaped how oncologists think about the HER2 spectrum.
The approval was based on a large clinical trial called DESTINY-Breast04, which compared the drug against standard chemotherapy in patients with HER2-low metastatic breast cancer. After about 32 months of follow-up, patients receiving the targeted drug lived a median of 22.9 months, compared to 16.8 months for those on standard chemotherapy. That’s roughly six extra months of overall survival. Among patients whose tumors were also hormone receptor-positive, the benefit was similar: 23.9 months versus 17.6 months.
How the Drug Works With Low HER2 Levels
You might wonder how a drug targeting HER2 can work when there’s barely any HER2 on the tumor. The answer lies in how this particular type of drug is built. It’s an antibody-drug conjugate, essentially a guided missile: an antibody that latches onto HER2, attached to a potent chemotherapy payload. Once the antibody binds to even a small amount of HER2 on a cancer cell, the whole package gets pulled inside the cell, where the chemotherapy is released and kills it.
But there’s a second trick. After the drug payload is released inside one cancer cell, it can leak out and kill neighboring cells that may have little or no HER2 on their surface. This is called the bystander effect. Enzymes naturally present in the tumor environment can also clip the drug free before it even enters a cell, allowing it to diffuse into surrounding tissue. This means even tumors with patchy, low-level HER2 expression can be vulnerable.
Who Has HER2-Low Breast Cancer
HER2-low is not rare. In a study of over 14,500 early-stage breast cancer patients treated at MD Anderson Cancer Center, 60.4% were classified as HER2-low. Among those, about 80% also have hormone receptor-positive disease (meaning the cancer is fueled by estrogen or progesterone), while 15 to 20% are triple-negative, meaning they lack hormone receptors as well.
If you were diagnosed with breast cancer before 2022 and told you were HER2-negative, your tumor may actually fall into the HER2-low category. This is worth discussing with your oncologist, particularly if your cancer has spread or returned, because it could open up a treatment option that didn’t exist when you were first diagnosed.
Prognosis Compared to HER2-Zero
One question patients naturally ask is whether having some HER2 makes the cancer more or less aggressive than having none. Current evidence suggests there’s no meaningful difference in prognosis between HER2-low and HER2-zero tumors on their own. A study comparing 351 HER2-zero patients to 184 HER2-low patients found no significant difference in overall survival over more than 11 years of follow-up. The differences researchers did find in tumor characteristics, like size and grade, appeared to be driven by estrogen receptor status rather than the HER2 level itself.
In other words, HER2-low is not a more dangerous type of breast cancer. Its importance is almost entirely about treatment eligibility. Having even a small amount of HER2 gives the targeted drug something to grab onto, which is what makes the distinction clinically useful.
The Challenge of Accurate Testing
The line between HER2-zero (score 0) and HER2-low (score 1+) is genuinely difficult for pathologists to draw. Both involve faint or absent staining under a microscope, and the distinction can come down to whether barely visible staining appears in more or fewer than 10% of cells. Research has confirmed that in laboratories with rigorous quality standards, scores of 0 and 1+ do correspond to measurably different amounts of HER2 gene copies. But in routine practice, the scoring can vary between pathologists and between labs.
Updated guidelines from ASCO and the College of American Pathologists in 2023 now emphasize the importance of accurately distinguishing these low-level scores and recommend standardized reporting. If your pathology report shows a HER2 score of 0, and especially if it’s close to the borderline, requesting a second opinion or retesting at a specialized center is reasonable.
HER2-Ultralow: An Even Newer Category
Researchers are now exploring a category below HER2-low called HER2-ultralow. These are tumors that currently score as 0 under standard guidelines, but under closer inspection show trace amounts of staining, typically in 1 to 9% of cells. Early data suggest some of these patients may also benefit from antibody-drug conjugates, though this hasn’t yet changed treatment guidelines. The median staining in ultralow cases is only about 3% of cells, and distinguishing genuine low-level staining from laboratory artifacts like background noise or nonspecific patterns remains a significant challenge for pathologists.
This evolving landscape means the way breast cancers are classified by HER2 status is becoming more granular. What was once a simple positive-or-negative question is now a spectrum, and where you fall on that spectrum increasingly shapes which treatments are available to you.