HER2 in Cancer: Testing, HER2-Low, and Targeted Treatment Explained

HER2, also written ERBB2, is a receptor protein normally found in small amounts on the surface of many healthy cells, where it helps regulate normal cell growth and repair. The HER2 gene provides the instructions for building this receptor. In some cancers, the gene is copied too many times, a change called gene amplification, which leads the cell to produce far more HER2 receptor than usual. This is HER2 overexpression. The excess receptors cluster together and send continuous signals telling the cell to grow and divide, even without the usual outside triggers, which drives tumour growth.

HER2 status is not simply present or absent; it is reported along a spectrum. Pathologists use immunohistochemistry (IHC) to stain a tissue sample and estimate how much HER2 protein is on the cell surface, giving a score of 0, 1+, 2+ or 3+. A score of 3+ is considered HER2-positive. A score of 2+ is equivocal and is usually confirmed with FISH, which directly counts copies of the HER2 gene inside the cell nucleus. Scores of 0 and 1+ have traditionally been called HER2-negative, but recent research has shown that many of these tumours still express a small, detectable amount of HER2 protein — a category now called HER2-low — and an even smaller subset, HER2-ultralow, shows the faintest trace of staining. This more detailed spectrum matters because newer HER2-directed drugs can help even at these lower expression levels, something that was not true of earlier HER2 therapies.

If your pathology report shows HER2-positive results (IHC 3+, or IHC 2+ confirmed positive by FISH), it generally means your cancer is a candidate for HER2-targeted therapy, most often an antibody, an antibody-drug conjugate, or a combination of both alongside chemotherapy. This is discussed as part of your overall treatment implications and is usually a central part of the plan rather than an optional addition.

If your report shows HER2-low (IHC 1+, or IHC 2+ with a negative FISH result) or HER2-ultralow (IHC 0 with faint, incomplete staining), this does not by itself qualify you for the antibody-only drugs used in classic HER2-positive disease, but it may make you eligible for certain modern antibody-drug conjugates, particularly in breast cancer. It is worth asking your oncologist explicitly whether your tumour falls into one of these categories, since HER2-low and HER2-ultralow reporting is relatively new and testing practices are still becoming standardised worldwide.

If your cancer is HER2-negative across the whole spectrum, HER2-directed treatment is not expected to help, and your care team will focus on other therapies suited to your cancer type and other biomarkers, such as hormone receptor status or PD-L1 expression. Because HER2 status can change as a cancer evolves or after previous treatment, retesting at the time of recurrence or disease progression is often recommended and can meaningfully affect the choice of your next treatment.

HER2 testing is not used to diagnose cancer itself; a cancer diagnosis is made first through imaging, biopsy and standard pathology review that determines the tumour type and stage. Once a diagnosis of an eligible cancer type is confirmed, HER2 testing is then performed on that same tissue sample as a routine, and in many guidelines mandatory, part of the diagnostic work-up. This means most patients do not need an additional biopsy solely for HER2 testing, since it uses tissue already collected. Results are reported alongside stage, grade and other biomarkers in the full pathology report, and together these findings guide the multidisciplinary discussion of treatment options.

HER2 testing begins with tumour tissue obtained through a biopsy or during surgery, prepared as slides for the pathology laboratory. Immunohistochemistry (IHC) is usually performed first: a stain that binds specifically to the HER2 protein is applied to the slide, and a pathologist scores the intensity and completeness of staining around the cell membrane on a scale from 0 to 3+. A score of 0 or 1+ is HER2-negative in the traditional sense (though it may still be HER2-low or HER2-ultralow, as discussed above); a score of 3+ is HER2-positive; a score of 2+ is equivocal and requires a second test.

That second test is fluorescence in situ hybridisation (FISH), which uses fluorescent probes to directly count copies of the HER2 gene, and often a reference chromosome, in the tumour cell nucleus under a microscope. FISH gives a more direct readout of gene amplification and resolves cases where IHC alone is ambiguous. Some laboratories use alternative in situ hybridisation techniques with similar principles.

HER2 testing is typically done alongside testing for hormone receptors (oestrogen and progesterone receptor) in breast cancer, since these results together shape the overall treatment strategy. In gastric, oesophageal and other cancers, HER2 testing follows a broadly similar IHC-then-FISH pathway, though scoring criteria differ slightly by tumour type because HER2 expression patterns vary between organs. Newer approaches to detecting HER2 status, including next-generation sequencing and blood-based tests, are being studied and used in some settings, particularly to look for HER2 mutations or amplification rather than protein expression, but tissue-based IHC and FISH remain the standard of care.

HER2 alterations are best known in breast cancer, where roughly 15 to 20 percent of tumours are classically HER2-positive, and a much larger proportion — often 50 to 60 percent of the remaining tumours — turn out to be HER2-low when tested with the newer, more sensitive scoring approach. HER2-positive breast cancer can occur at any stage, from early, potentially curable disease to metastatic disease, and treatment approaches differ accordingly.

In gastric and gastroesophageal junction (oesophageal) cancer, HER2 overexpression or amplification is found in roughly 10 to 20 percent of tumours, most often in adenocarcinomas, and testing is recommended for all patients with advanced disease because it directly changes first-line treatment selection.

HER2 alterations also occur, though less frequently, in non-small cell lung cancer, where specific HER2 mutations (rather than amplification) can drive tumour growth and are increasingly targetable with dedicated therapies; in biliary tract cancer (cancer of the bile ducts and gallbladder), where HER2 amplification is found in a meaningful minority of cases and is now an established target; and in colorectal cancer, where HER2 amplification is uncommon overall but is particularly relevant in tumours without RAS or BRAF mutations, offering a targeted option for a group that would otherwise rely solely on chemotherapy. Because HER2 testing is increasingly built into comprehensive genomic profiling panels alongside markers such as KRAS, BRAF and MSI, more patients across these cancer types are now identified as candidates for HER2-directed treatment than in the past.

HER2-targeted therapy falls into two broad drug classes. Monoclonal antibodies attach to the outside of the HER2 receptor, blocking its growth signal and also flagging the cancer cell for attack by the immune system; these are usually combined with chemotherapy and, in some regimens, with a second antibody that blocks a different part of the receptor for a stronger combined effect. Antibody-drug conjugates (ADCs) are a more recent innovation: they link a HER2-targeting antibody to a potent chemotherapy payload, so the antibody acts as a delivery vehicle that carries the chemotherapy specifically into HER2-expressing cancer cells, sparing much of the surrounding healthy tissue. This design is part of why ADCs can work even against tumours with only low levels of HER2, since even modest binding is enough to deliver the drug's payload.

Small-molecule HER2 inhibitors taken as tablets, which work inside the cell to block HER2 signalling, are used in some settings, including for cancer that has spread to the brain, since some can cross the blood-brain barrier more readily than antibodies. Chemotherapy, hormone therapy in hormone-receptor-positive breast cancer, and, in some tumours, immunotherapy, are often used together with or after HER2-targeted treatment, and the exact sequence depends on cancer type, stage, prior treatment and overall health. Discussions about targeted therapy sequencing, and whether a clinical trial of a newer HER2-directed agent is appropriate, are a normal part of ongoing HER2-positive or HER2-low cancer care.