A HER2 1+ result on a pathology report means that a small amount of the HER2 protein was detected on the surface of cancer cells, but not enough to classify the tumor as HER2-positive. Until recently, this score was grouped with HER2 0 under the broad umbrella of “HER2-negative,” and it had almost no influence on treatment decisions. That changed with the emergence of newer antibody-drug conjugates, particularly trastuzumab deruxtecan (T-DXd), which showed a meaningful survival benefit in patients whose tumors express HER2 at this low level. A HER2 1+ result now places a tumor in what oncologists call the “HER2-low” category, and it can open the door to a targeted therapy that was previously reserved for patients with much higher HER2 expression.
How HER2 Scoring Works
HER2 (human epidermal growth factor receptor 2) is a protein that sits on the surface of cells and helps regulate their growth. When cancer cells produce too much of it, they can grow and divide more aggressively. HER2 belongs to a family of four related receptors, and it acts as a networking hub: it pairs with other receptors in the family to amplify growth signals. Tumors that massively overproduce HER2 are classified as HER2-positive, and they have long been treated with drugs that specifically target the protein.1PubMed. Biology of HER2 and its importance in breast cancer
To figure out how much HER2 a tumor is making, pathologists use a staining technique called immunohistochemistry (IHC). A tissue sample is treated with antibodies that bind to HER2 on cell surfaces, producing a visible stain under a microscope. The pathologist then assigns a score based on what they see:
- IHC 0: No staining at all, or very faint incomplete staining in a small fraction of cells.
- IHC 1+: Faint, incomplete membrane staining in more than 10% of tumor cells.
- IHC 2+: Weak to moderate complete membrane staining in more than 10% of cells. This score triggers a follow-up test (in situ hybridization) to check whether the HER2 gene itself is amplified.
- IHC 3+: Strong, complete membrane staining in more than 10% of cells. This is HER2-positive.
A score of 1+ means the pathologist saw some HER2 staining, but it was faint and did not fully ring the cell membranes. It confirms the protein is present in low quantities. Traditionally, this result landed in the same treatment bucket as IHC 0, and no HER2-targeted therapy was offered. That binary framework has now been disrupted.
The Rise of “HER2-Low” as a Treatment Category
The term “HER2-low” refers to tumors scored as IHC 1+ or IHC 2+ without gene amplification.2PubMed Central. A review of treatment options in HER2-low breast cancer and proposed treatment sequencing algorithm This category encompasses a large swath of breast cancers. It was not considered clinically meaningful until the results of DESTINY-Breast04, a large randomized trial that tested trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer who had already received prior chemotherapy. The trial showed a substantial survival benefit: T-DXd was associated with improved progression-free and overall survival compared to standard chemotherapy, a result that held for both hormone receptor-positive and hormone receptor-negative patients.3PubMed Central. Targeting HER2-low in metastatic breast cancer: an evolving treatment paradigm
The distinction between HER2-negative and HER2-low had been considered a curiosity in pathology, since earlier HER2-targeting drugs like trastuzumab (Herceptin) showed no benefit at these low expression levels. But trastuzumab deruxtecan works differently. Its success forced oncology guidelines to acknowledge that the old binary positive/negative split was no longer adequate for treatment decisions. The 2023 ASCO-CAP guideline update specifically recognized HER2 1+ and HER2 2+ without amplification as clinically relevant categories because of the drug’s regulatory approval for these patients.4Journal of Clinical Oncology. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-College of American Pathologists Guideline Update
What the Survival Data Actually Show
The numbers from DESTINY-Breast04 are the foundation of everything that has changed for HER2 1+ patients. In the overall study population, patients who received T-DXd had a median overall survival of about 23 months, compared to roughly 17 months for those on standard chemotherapy. Progression-free survival was also substantially longer: around 9 to 10 months versus 4 to 5 months.5PubMed. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer These results held up in a longer follow-up analysis with a median of 32 months: median overall survival in the full cohort was 22.9 months for T-DXd versus 16.8 months for chemotherapy.6PubMed Central. Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial
The benefit was clearest in the hormone receptor-positive group, where median overall survival was about 24 months with T-DXd versus roughly 17.5 months with chemotherapy. In the smaller hormone receptor-negative group, median survival favored T-DXd (about 17 months versus 8 months), though the smaller sample size makes that estimate less precise.7Nature Medicine. Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial For a patient who has just received a HER2 1+ result and has metastatic breast cancer, these numbers represent a real option that simply did not exist a few years ago.
Why This Drug Works When Others Did Not
Earlier HER2-targeted therapies like trastuzumab and T-DM1 need a large number of HER2 targets on cell surfaces to work well. They bind, get pulled inside the cell, and release their toxic payload there. When HER2 levels are low, there are not enough binding events to deliver a meaningful dose of cell-killing drug. Trastuzumab deruxtecan gets around this limitation in two key ways.
First, it carries a higher ratio of drug molecules per antibody than older designs, so each binding event delivers more payload. Second, the chemical payload it releases (called DXd) is highly membrane-permeable. Once the drug is cleaved from the antibody inside or near a tumor cell, DXd can leak across cell membranes and kill neighboring cancer cells that may not express HER2 at all. This is called the “bystander effect.” In laboratory experiments, T-DXd killed both HER2-positive and HER2-negative cells growing near each other, while older drugs like T-DM1 only killed the HER2-positive ones.8PubMed Central. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity The bystander killing stayed local, affecting only cells in the immediate neighborhood rather than spreading throughout the body, which limits collateral damage to healthy tissue.
There is also evidence that the drug can release its payload outside cells entirely. Tumor environments are rich in enzymes called cathepsins, and research has shown that cathepsin L can cleave T-DXd’s linker and free the payload in the space around tumor cells, enabling cell killing even without direct HER2 binding and internalization.9Nature Communications. Effective extracellular payload release and immunomodulatory interactions govern the therapeutic effect of trastuzumab deruxtecan (T-DXd) Together, the high drug-to-antibody ratio, the membrane-permeable payload, and the cleavable linker design explain why T-DXd can benefit patients with HER2-low tumors where earlier HER2-targeting drugs could not.10PubMed Central. Advances in Targeted Therapy for Human Epidermal Growth Factor Receptor 2-Low Tumors: From Trastuzumab to Antibody-Drug Conjugates
The Scoring Problem
One of the uncomfortable realities behind HER2 1+ is that the score itself is not especially reliable. Pathologists are trained professionals, but distinguishing IHC 0 from IHC 1+ under a microscope involves judgment calls about very faint staining patterns. This was never a high-stakes distinction before, since both scores led to the same treatment. Now that HER2 1+ can qualify a patient for a targeted therapy while HER2 0 traditionally cannot, the accuracy of that borderline call matters a great deal.
A multi-institutional study found substantial disagreement among pathologists when scoring the lower categories. Agreement on IHC 1+ specifically was less than 1%, meaning that when multiple pathologists scored the same slides, they almost never all called a sample 1+. Even for IHC 0, the overall agreement rate was only about 25%.11PubMed Central. Multi-institutional Assessment of Pathologist Scoring HER2 Immunohistochemistry Pathologists trained specifically in distinguishing HER2-low showed better performance, with agreement around 91 to 94% for the HER2-low cutoff and kappa values indicating substantial consistency, but this level of training is not yet universal.12PubMed Central. Accuracy of human epidermal growth factor receptor 2 (HER2) immunohistochemistry scoring by pathologists in breast cancer, including the HER2-low cutoff
Adding another layer of variability, the antibody reagents used in IHC testing differ in sensitivity. One commonly used antibody (HercepTest) tends to detect more low-level staining than another widely used option (PATHWAY 4B5). In one comparison, of 41 tumors scored as completely negative by PATHWAY 4B5, only about 46% also scored as IHC 0 with HercepTest; the rest showed some staining, including cases that would qualify as HER2-low.13PubMed Central. HER2-low breast cancer: insights on pathological testing A nationwide study has confirmed that different HER2 antibodies vary in sensitivity, and this can directly affect whether a patient is classified as HER2 0 or HER2-low.14PubMed Central. HER2-low breast cancer in routine practice: a nationwide study of diagnostic variability across pathology laboratories
There is also a difference between biopsy samples and surgical specimens. A study of over 5,600 patients found meaningful discordance: among patients whose core needle biopsy was scored HER2 0, about half were reclassified as HER2-low when the full surgical specimen was examined. And among those scored HER2-low on biopsy, roughly 12% came back as HER2 0 on the surgical sample.15PubMed Central. HER2-Low Status Is Not Accurate in Breast Cancer Core Needle Biopsy Samples: An Analysis of 5610 Consecutive Patients If you have a HER2 0 score from a small biopsy, the full picture from a larger tissue sample might tell a different story.
HER2 Status Can Change Over Time
HER2 expression is not fixed. A tumor’s biology can shift between the initial diagnosis and later stages, especially when cancer spreads to new sites. A study comparing primary breast tumors to their matched metastatic sites found that HER2 expression category changed in about 12% of patients.16PubMed. Changes in expression of breast cancer tumor biomarkers between primary tumors and corresponding metastatic sites: common patterns and relationships with survival Another study found an overall HER2 conversion rate of about 34% between primary and metastatic breast cancer. Among those conversions, most involved shifts into or out of the HER2-low range. About 15% of patients who started with HER2 0 in their primary tumor were found to have HER2-low expression in their metastatic disease, while about 6% of originally HER2-low tumors lost HER2 expression entirely.17Journal of Cancer Research and Clinical Oncology. Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases
This instability has practical implications. A patient initially told they are HER2 0 might benefit from retesting if their cancer recurs or metastasizes. Conversely, a HER2-low result from the original diagnosis does not guarantee the metastatic site still expresses HER2 at that level. Many oncologists now recommend retesting metastatic lesions, particularly when considering T-DXd as a treatment option.
What About HER2-Ultralow
Research is already pushing past HER2-low. The DESTINY-Breast06 trial tested T-DXd in patients with even less HER2 expression than the 1+ threshold, a category being called “HER2-ultralow.” These are tumors scored as IHC 0 but that show some faint membrane staining, just not enough to qualify as 1+ under traditional scoring criteria. The trial demonstrated superior efficacy for T-DXd over standard chemotherapy in patients with HER2-low and HER2-ultralow metastatic breast cancer.18ESMO Open. Patient-reported outcomes from the DESTINY-Breast06 trial: trastuzumab deruxtecan versus physician’s choice of chemotherapy in patients with HER2-low and HER2-ultralow metastatic breast cancer
This is an evolving area, and the ASCO-CAP guidelines have noted that it is premature to formally create new scoring categories like “HER2-ultralow.” But the clinical evidence is gradually eroding the idea that any sharp cutoff between 0 and 1+ meaningfully predicts who will benefit from T-DXd.4Journal of Clinical Oncology. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-College of American Pathologists Guideline Update If the bystander effect and extracellular payload release really are major contributors to the drug’s efficacy, then even tumors with minimal HER2 could theoretically benefit, which would make the entire low-end scoring question less about precision and more about whether there is any HER2 target present at all.
Side Effects Worth Knowing About
Trastuzumab deruxtecan is effective, but it carries a specific risk that patients and their care teams need to monitor closely: lung toxicity in the form of interstitial lung disease (ILD) or pneumonitis. This side effect has potentially fatal consequences if it goes unrecognized and progresses. When caught early at the asymptomatic stage, it can often be managed, and treatment may even continue. But once symptoms appear and the condition advances to higher grades, T-DXd must be permanently discontinued.19PubMed Central. Managing the Risk of Lung Toxicity with Trastuzumab Deruxtecan (T-DXd): A Canadian Perspective Monitoring typically involves regular imaging and prompt attention to any new cough or shortness of breath. The underlying cause of T-DXd-related lung damage is not fully understood, and research is ongoing to identify who is at greatest risk.20PubMed Central. Trastuzumab Deruxtecan-Induced Interstitial Lung Disease/Pneumonitis in ERBB2-Positive Advanced Solid Malignancies: A Systematic Review
Other common side effects include nausea, fatigue, and drops in blood cell counts, which are familiar with many chemotherapy-like regimens. The lung risk is the one that sets T-DXd apart from typical chemotherapy options and demands specific vigilance.
HER2 1+ Beyond Breast Cancer
Although most of the attention around HER2-low has focused on breast cancer, HER2 expression at low levels is found across many cancer types. A large study found that about half of all cancers tested showed some HER2 expression (IHC 1 through 3+), with HER2-low expression appearing in nearly half of breast, lung, endometrial, urothelial, and gallbladder cancers, and about a third of gastric cancers.21PubMed Central. HER2-low expression in patients with advanced or metastatic solid tumors
Whether a HER2 1+ result matters therapeutically in cancers other than breast is still being worked out. Early results in colorectal cancer were not encouraging: in the DESTINY-CRC01 trial, patients with HER2 IHC 1+ colorectal tumors showed no confirmed treatment responses to T-DXd, unlike the clear activity seen in HER2-positive colorectal patients.22Targeted Oncology. Anti-HER2 Agents Explored Further in Gastric, Colorectal, and NSCLC Settings The biology of HER2-low expression may interact differently with T-DXd depending on tumor type, and results from breast cancer cannot simply be extrapolated to other cancers without dedicated trials.
Making Sense of Your Report
Research suggests many patients do not clearly understand their own tumor characteristics. One study found that only about 35% of breast cancer patients reported knowing their HER2 status, and of those, only about a third were correct about what it was.23PubMed Central. Patients’ awareness about their own breast cancer characteristics This is not surprising: before HER2-low became actionable, there was less reason for patients to learn the nuances of their HER2 score. Now there is.
If your pathology report says HER2 IHC 1+, ask your oncologist whether this qualifies your cancer as HER2-low and whether T-DXd is an option at your stage of treatment. The drug was studied in patients who had already received at least one prior line of chemotherapy for metastatic disease, so it is not typically a first-line treatment. For early-stage breast cancer, HER2-low targeted therapy is not yet standard of care, though clinical trials are exploring it. If your report says IHC 0, it may be worth asking whether there was any faint staining noted, as the scoring landscape is shifting, and retesting on a larger sample or with a different antibody might yield a different result.
Resistance and Next-Generation Approaches
Like most targeted cancer therapies, T-DXd does not work forever. Tumors eventually find ways around it. Early research into resistance mechanisms has identified several paths tumors may use to escape the drug’s effects. Some tumors appear to alter their HER2 levels further. Others activate drug-efflux pumps, molecular transporters that actively expel the payload from cells before it can do its damage. Mutations in genes that regulate these pumps have been found more frequently in tumor samples taken after T-DXd treatment compared to samples from patients who had never received the drug.24PubMed Central. Mechanisms of resistance to trastuzumab deruxtecan in breast cancer elucidated by multi-omic molecular profiling
Meanwhile, researchers are developing next-generation antibody-drug conjugates designed to overcome some of these limitations. One approach involves bispecific antibody-drug conjugates that target HER2 alongside a second receptor. By engaging a rapidly internalizing receptor in addition to HER2, these drugs can potentially get pulled into cells more efficiently, even when HER2 levels are very low.25PubMed Central. Recent advances in bispecific antibody-drug conjugates for breast cancer therapy New diagnostic technologies are also in development, including quantitative IHC methods paired with artificial intelligence that aim to measure HER2 expression more precisely than a pathologist’s eye can, particularly in the 0 and 1+ range where the treatment-relevant distinctions are hardest to make.26Journal of Pathology Informatics. Quantification of HER2-low and ultra-low expression in breast cancer specimens by quantitative IHC and artificial intelligence