What Do HER2 2+ or Discordant Results Mean in Breast Cancer?

A HER2 2+ or “equivocal” result means your initial breast cancer biopsy showed a borderline amount of the HER2 protein—not enough to be clearly positive, but too much to be considered completely negative. By itself, a 2+ score does not mean you have HER2-positive breast cancer ^[1]. Instead, it requires a “reflex confirmatory test” to look deeper into the cells ^[1][2]. A discordant result means your HER2 test results conflict across different tests or tissue samples, or they do not match the physical appearance (morphology) of the tumor cells under the microscope. Waiting for these extra tests or reviews can be stressful, but these are common situations in pathology that have clear steps for resolution.

Step 1: The Initial Protein Test (IHC)

When a biopsy is taken, pathologists first use a test called Immunohistochemistry (IHC) to measure how much HER2 protein is on the surface of the cancer cells.

Note: A 2+ result means weak-to-moderate staining was found ^[1]. Because it is borderline, it automatically triggers a second type of test ^[2].

Step 2: The Reflex Confirmatory Test (ISH or FISH)

If you score a 2+, the lab will perform a test called In Situ Hybridization (ISH) or Fluorescence In Situ Hybridization (FISH). While the initial IHC test looks at the protein on the outside of the cell, ISH looks inside the cell at the genes to see if there is gene amplification (extra copies of the HER2 gene) ^[2].

This is not a simple yes/no test. Pathologists interpret the results by calculating the HER2/CEP17 ratio and the average HER2 copy number.

• If these numbers meet the guideline thresholds for a positive result, your cancer is classified as HER2-positive, making you eligible for standard HER2-targeted therapies ^[3].
• If the result is negative, your cancer is classified as HER2-negative under standard definitions ^[3].

What If the Results Conflict? (Discordance)

Sometimes, a HER2 result feels out of place. True discordance usually refers to a mismatch between tests (e.g., your initial core needle biopsy result differs from the larger tumor tissue removed during surgery) or a result that doesn’t match the physical characteristics of the tumor ^[4]. (Note: HER2 is biologically independent of estrogen and progesterone receptors, so having different HER2 and hormone statuses is not technically a mismatch.)

Differences can happen for several reasons:

• Tumor Heterogeneity: A breast cancer tumor is not always uniform. If the biopsy needle only grabs a section with lower HER2 levels, it might not represent the whole tumor ^[4].
• Tissue Processing (Fixation): How the tissue is chemically preserved in the laboratory before testing can sometimes alter the HER2 score ^[5].
• Borderline Cutoffs: If your genetic numbers hover right on the boundary line, the results can fall on either side depending on the exact sample.

How it is resolved: Routine re-testing of every negative biopsy is not necessary if the sample was adequate ^[6]. However, if the tissue was poorly preserved, the tumor looks highly unusual, or there is a genuine conflict between biopsy and surgical samples, your care team may request an expert breast pathologist to review the slides, or they may order a new test on a different tissue block ^[6][4].

HER2-Low and HER2-Ultralow: Treatment Descriptors

Historically, tumors graded IHC 1+ or IHC 2+ with a negative ISH test were strictly labeled HER2-negative. Today, they are still considered HER2-negative for standard treatments, but they are additionally described as HER2-low ^[7]. There is also a newer descriptive term called HER2-ultralow, which refers to an IHC 0 score that has very faint, incomplete staining in more than 0% and up to 10% of the cells ^[8]. Distinguishing these tiny amounts of protein can be difficult and varies between laboratories ^[8].

It is important to understand that HER2-low and HER2-ultralow are not new biological subtypes of breast cancer. If you have early-stage breast cancer, these labels do not change your treatment plan—you are treated as HER2-negative ^[3].

However, if you have unresectable or metastatic breast cancer, these descriptors become highly relevant. Depending on your hormone receptor status, prior treatments, and local regulatory approvals, you may be eligible for targeted antibody-drug conjugates, such as trastuzumab deruxtecan ^[9][10]. These drugs carry powerful medication to cells with even tiny amounts of HER2 protein, destroying them and neighboring cancer cells (the “bystander effect”).

While effective, these advanced therapies are not for everyone and are not harmless. Trastuzumab deruxtecan carries serious risks, including a potentially severe lung inflammation called interstitial lung disease (ILD) or pneumonitis, as well as nausea and fatigue ^[11]. Patients on these treatments must be carefully monitored, and any new cough or shortness of breath should be reported immediately.