Understanding HER2-Low Breast Cancer

HER2-low breast cancer has moved from a pathology footnote to a clinically consequential finding in a remarkably short time. For years, breast cancer care treated HER2 status as a binary problem: Tumors were either HER2-positive and eligible for HER2-directed therapy or HER2-negative and managed according to hormone receptor status and line of therapy. That framework no longer captures the whole story. In contemporary metastatic breast cancer care, low-level HER2 expression can influence treatment selection, particularly because antibody-drug conjugates have shown benefit in tumors that do not meet classic HER2-positive thresholds. 

At the same time, HER2-low breast cancer should not be misunderstood as a cleanly separate molecular subtype. The 2023 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline update did not create a formal HER2-low interpretive category, and large genomic analyses have not shown major biologic differences between HER2-low and HER2-0 tumors after adjustment for hormone receptor status. In other words, HER2-low breast cancer is clinically actionable, but it is not yet a stand-alone disease taxonomy on the same footing as HER2-positive breast cancer. 

That distinction is the key to understanding the field. HER2-low breast cancer matters because drug development changed, not because the underlying pathology framework was entirely rewritten. For clinicians, the practical questions are now straightforward but important: what exactly counts as HER2-low, how should it be reported, when should a metastatic lesion be retested, and where does trastuzumab deruxtecan fit into breast cancer management today. 

How HER2-low breast cancer is defined

In current clinical use, HER2-low breast cancer refers to tumors with an immunohistochemistry (IHC) score of 1+ or 2+ with negative in situ hybridization (ISH). Those tumors are not HER2-positive by standard ASCO/CAP criteria, but they may still be relevant for metastatic treatment selection. The Food and Drug Administration’s (FDA’s) Jan. 27, 2025, approval further expanded the conversation by recognizing HER2-ultralow hormone receptor-positive metastatic breast cancer, defined operationally as IHC 0 with incomplete, faint or barely perceptible membrane staining. 

The important nuance is that the scoring system itself did not suddenly become a new low-end quantification assay. The 2023 ASCO/CAP update reaffirmed the existing 2018 scoring framework and explicitly stated that there was not enough evidence to support HER2-low as a new interpretive result category. CAP explained that DESTINY-Breast04 used trial eligibility criteria based on IHC 1+ or 2+/ISH-negative disease, but that this did not validate a new predictive threshold separating those tumors from IHC 0 tumors. Laboratories are still expected to report the underlying IHC score and ISH result, rather than replacing standard interpretation with a separate disease label. 

What has changed is reporting detail. CAP’s 2025 breast biomarker template now distinguishes score 0 without membrane staining from score 0 with faint incomplete membrane staining in 10% or fewer tumor cells, labeled in the template as 0+ with membrane staining. The same template includes an optional comment explaining that DESTINY-Breast04 defined HER2-low as IHC 1+ or 2+/ISH-negative, and DESTINY-Breast06 defined HER2-ultralow as that 0+ staining pattern. That is a reporting evolution, not a wholesale abandonment of the current HER2 testing framework. 

Why this matters in breast cancer now, not ten years ago

The reason HER2-low breast cancer became clinically important is not that conventional HER2-directed therapy suddenly started working in these tumors. In fact, the opposite history is worth remembering. In the NSABP B-47 trial, adding trastuzumab to adjuvant chemotherapy for HER2-low breast cancer did not improve invasive disease-free survival, overall survival, or other major endpoints. That negative result is one reason HER2-low remained largely a research concept for so long. 

The inflection point came with antibody-drug conjugates, particularly trastuzumab deruxtecan. Unlike conventional trastuzumab, trastuzumab deruxtecan couples a HER2-directed antibody to a potent topoisomerase I inhibitor payload. The drug was designed with a high drug-to-antibody ratio, and its membrane-permeable payload supports a bystander antitumor effect that may allow activity even when HER2 expression is heterogeneous or low. That pharmacology helps explain why a tumor that is not HER2-positive in the classic sense can still be clinically targetable. 

That shift has practical consequences across breast cancer care. Retrospective analyses cited in the long-term DESTINY-Breast04 report suggest that roughly 65% of tumors once classified broadly as HER2-negative may meet HER2-low criteria. Even if that proportion varies across cohorts and depends on assay performance, the core point is stable: this is not an edge case in breast cancer. It is a common therapeutic question embedded within what used to be called HER2-negative disease. 

Is HER2-low breast cancer a true biologic subtype

Clinically, HER2-low breast cancer is now meaningful. Biologically, the answer is more restrained. CAP’s 2023 update stated that the guideline panel did not find evidence that HER2-low was a prognostic or predictively distinct result category. That position reflects a recurring theme in the literature: the current HER2-low label captures a heterogeneous collection of tumors whose behavior is still driven largely by hormone receptor biology, intrinsic subtype, and treatment history. 

A large Nature Communications analysis of 1,039 patients with HER2-negative metastatic breast cancer compared HER2-low and HER2-0 tumors and found no significant differences in mutational landscape, copy number variation, or tumor mutational burden after accounting for hormone receptor status, apart from somewhat higher ERBB2 copy count in HER2-low tumors and more ERBB2 hemideletions in HER2-0 tumors. The authors concluded that HER2-low tumors, as currently defined, should not be considered a distinct molecular subtype of breast cancer. 

That does not make the category unhelpful. It means HER2-low is best understood as a therapeutic descriptor layered on top of established breast cancer biology. A hormone receptor-positive HER2-low tumor still behaves more like hormone receptor-positive breast cancer than like triple-negative breast cancer. A triple-negative HER2-low tumor still inherits the broader clinical behavior of triple-negative disease. The HER2-low label matters, but it does not erase the rest of the tumor’s identity. 

How HER2-low breast cancer is tested and reported

The main testing challenge in HER2-low breast cancer is not identifying obvious 3+ overexpression. It is consistently distinguishing IHC 0 from IHC 1+. CAP notes that HER2 IHC assays were originally designed to separate high-level overexpression from non-overexpression, not to finely discriminate low-end membrane staining. That is why low-range scoring can be fragile, especially in small biopsies, marginally stained samples, or cases with interpretive artifacts. 

CAP’s current guidance for improving low-end scoring is practical. Laboratories should report the semi-quantitative IHC result, including 0, 1+, 2+, and 3+, use standard ASCO/CAP scoring criteria, review at high power when searching for faint focal staining, consider second review for borderline cases, and maintain appropriate controls with a range of HER2 expression. CAP also emphasizes common interpretive pitfalls such as edge artifact, cytoplasmic staining that obscures membrane evaluation, overstaining, and accidental scoring of ductal carcinoma in situ instead of invasive carcinoma. 

The difficulty is not theoretical. Interobserver studies continue to show variability in the HER2-low range, especially near the 0 versus 1+ threshold. That variability is one reason the field remains cautious about treating HER2-low as a rigid biologic class rather than a clinically useful reporting construct. 

The 2025 CAP biomarker template is therefore valuable because it makes low-end reporting more explicit without pretending the underlying biology is fully settled. It separates score 0 without staining from score 0 with faint incomplete membrane staining in 10% or fewer cells, and it provides optional standardized language connecting those patterns to DESTINY-Breast04 and DESTINY-Breast06 eligibility concepts. For oncologists reading pathology reports, that added granularity is likely to matter most in metastatic breast cancer, where access to trastuzumab deruxtecan may depend on whether a tumor is truly absent for staining, low, or ultralow. 

Why retesting can matter in recurrent or metastatic breast cancer

One of the most clinically useful lessons in the HER2-low era is that HER2 status is not perfectly stable across the natural history of breast cancer. A 2023 open-access study in the British Journal of Cancer comparing 512 primary tumors and matched recurrences found HER2 status changed in 37.3% of recurrences, with HER2-low tumors becoming more prevalent at relapse than at diagnosis. The authors concluded that retesting recurrent disease is important, especially in hormone receptor-positive tumors, to identify candidates for new anti-HER2 therapies. 

That message aligns with routine metastatic breast cancer practice. A primary tumor that was reported as HER2-0 years earlier may not fully represent the biology of a current metastasis, and a lesion that was once broadly classified as HER2-negative may become actionable once the exact low-end score is revisited. CAP also notes that metastatic breast cancer patients with HER2 IHC 1+ or 2+/ISH-negative results on either the primary or metastatic sample can be considered for trastuzumab deruxtecan if they meet other clinical criteria. 

This is also where pathology quality and clinical timing intersect. If a current metastatic biopsy is feasible and safe, retesting can help avoid both false exclusion and false confidence. The benefit is greatest when the historical sample was limited, predated the HER2-low era, or came from a biologically different phase of disease. 

DESTINY-Breast04 made HER2-low breast cancer actionable

The trial that established HER2-low breast cancer as a therapeutic category was DESTINY-Breast04. Based on that study, the FDA approved trastuzumab deruxtecan on Aug. 5, 2022, for adults with unresectable or metastatic HER2-low breast cancer who had received prior chemotherapy in the metastatic setting or recurred during or within six months of completing adjuvant chemotherapy. The study enrolled 557 patients, including 494 with hormone receptor-positive disease and 63 with hormone receptor-negative disease. 

The efficacy results were practice changing. In the hormone receptor-positive cohort, median progression-free survival was 10.1 months with trastuzumab deruxtecan versus 5.4 months with physician’s-choice chemotherapy. Median overall survival was 23.9 months vs. 17.5 months. In the overall population, median progression-free survival was 9.9 months vs. 5.1 months, and overall survival was 23.4 months vs. 16.8 months. Those are not marginal gains. They are the kind of results that justify a new treatment-selection category in metastatic breast cancer. 

The long-term follow-up published in 2025 reinforced that conclusion rather than softening it. After a median follow-up of 32 months, median overall survival in the overall cohort remained better with trastuzumab deruxtecan, 22.9 months vs. 16.8 months, respectively, and in the hormone receptor-positive cohort, 23.9 months vs. 17.6 months, respectively. The authors concluded that the results confirmed trastuzumab deruxtecan as standard of care after prior chemotherapy in HER2-low metastatic breast cancer. 

For breast cancer clinicians, the conceptual consequence was just as important as the efficacy data. DESTINY-Breast04 showed that classic HER2 positivity was no longer the only HER2-relevant state in metastatic disease. Once that happened, the old shorthand of “HER2-negative means not HER2-targetable” stopped being reliable. 

DESTINY-Breast06 pushed HER2-low and HER2-ultralow earlier in metastatic care

The next major shift came from DESTINY-Breast06 and the FDA’s Jan. 27, 2025, approval. This indication applies to unresectable or metastatic hormone receptor-positive HER2-low or HER2-ultralow breast cancer that has progressed on one or more endocrine therapies in the metastatic setting. In other words, trastuzumab deruxtecan moved upstream for a defined subset of hormone receptor-positive breast cancer, before metastatic chemotherapy was required. 

In the FDA review of DESTINY-Breast06, median progression-free survival in the HER2-low population was 13.2 months with trastuzumab deruxtecan versus 8.1 months with physician’s-choice chemotherapy. The overall study population, which included HER2-ultralow disease, showed the same median progression-free survival values, 13.2 vs. 8.1 months, with overall survival still immature at the time of the final progression-free survival analysis. The companion diagnostic landscape evolved in parallel, with the FDA also approving Ventana’s PATHWAY anti-HER-2 (4B5) assay to identify HER2-ultralow disease for this indication. 

This approval created an important practical distinction in metastatic breast cancer. Trastuzumab deruxtecan now has one label path for HER2-low disease after prior chemotherapy, and a separate label path for hormone receptor-positive HER2-low or HER2-ultralow disease after progression on endocrine therapy in the metastatic setting. That is more than a regulatory nuance. It changes when clinicians need the pathology details and when a prior “HER2-negative” label is no longer specific enough for treatment planning. 

What HER2-ultralow means, and what it does not mean

HER2-ultralow is best thought of as an operational extension of the HER2-low conversation, not proof that every HER2-0 breast cancer is equally targetable. CAP’s 2025 reporting template defines the relevant pattern as score 0 with incomplete, faint (or barely perceptible) membrane staining in 10% or fewer cells, and notes that tumors with no membrane staining remain excluded from trastuzumab deruxtecan eligibility in the metastatic setting. 

That distinction matters because the phrase HER2-zero has become less clinically comfortable than it used to be. The DAISY phase 2 trial found confirmed objective response rates of 37.5% in HER2-low metastatic breast cancer and 29.7% even in a HER2 non-expressing cohort, helping to support the idea that HER2 biology may behave more like a continuum than a clean dichotomy. But DAISY was not a registrational trial, and current clinical use should still follow the approved label rather than extrapolate broadly to all no-staining tumors. 

The safest way to apply this in practice is to stop using HER2-negative as a sufficient standalone phrase in metastatic breast cancer documentation. The exact IHC score and ISH result now matter. For some patients, the meaningful distinction is not between positive and negative, but between absent membrane staining, ultralow staining, and low staining. 

What HER2-low means in early-stage breast cancer

In current U.S. practice, HER2-low breast cancer has its clearest treatment implications in unresectable or metastatic disease, not in early-stage breast cancer. That conclusion is based on three facts taken together: Conventional trastuzumab did not improve outcomes in HER2-low disease in NSABP B-47, ASCO/CAP did not redefine HER2-low as a formal new interpretive category, and the current FDA indications for trastuzumab deruxtecan in HER2-low and HER2-ultralow breast cancer are metastatic indications. 

So, while HER2-low status may eventually shape earlier-line strategies through ongoing research, it does not currently replace the standard treatment logic for early breast cancer. Hormone receptor-positive, HER2-low early breast cancer is still approached as hormone receptor-positive, HER2-negative disease for most adjuvant decision-making. Triple-negative, HER2-low early breast cancer is still managed within the triple-negative framework. The HER2-low descriptor adds information, but it does not yet redefine early-stage care the way classic HER2-positive status does. That is an inference from current trial results and current labeling, not a separate formal guideline statement. 

Safety remains central to trastuzumab deruxtecan use

The enthusiasm around HER2-low breast cancer should never obscure the toxicity profile of trastuzumab deruxtecan. The current prescribing information carries boxed warnings for interstitial lung disease or pneumonitis and embryo-fetal toxicity. The label also highlights neutropenia and left ventricular dysfunction as important risks requiring monitoring. 

In DESTINY-Breast04, common adverse reactions included nausea, fatigue, alopecia, vomiting, anemia, constipation, decreased appetite, diarrhea, and musculoskeletal pain. The original trial publication also reported drug-related interstitial lung disease or pneumonitis in 12.1% of patients, including fatal events in 0.8%. Those are manageable risks in experienced hands, but they are not trivial. Any discussion of sequencing trastuzumab deruxtecan in breast cancer has to weigh efficacy alongside pulmonary history, symptom monitoring, and the logistics of rapid evaluation if cough, dyspnea, or fever emerge during treatment. 

For that reason, HER2-low breast cancer should not be reduced to a simple “new target found” narrative. The therapy is meaningful, but its use depends on careful pathology, appropriate patient selection, and a low threshold for toxicity intervention. 

A practical way to think about HER2-low breast cancer in clinic

The most useful clinical mindset is to treat HER2-low breast cancer as a therapeutic overlay on standard breast cancer classification. First, continue to interpret hormone receptor status, stage, and clinical tempo the same way you always would. Second, insist on exact HER2 reporting rather than a generic HER2-negative shorthand. Third, in metastatic disease, revisit HER2 on a current specimen whenever it is feasible and likely to alter treatment access. Fourth, read low-end IHC scores in the context of the patient’s actual treatment window, because the relevance of HER2-low and HER2-ultralow is now different before versus after metastatic chemotherapy. 

This is especially important in hormone receptor-positive metastatic breast cancer, where the 2025 FDA approval means the HER2-low or HER2-ultralow designation can matter after progression on endocrine therapy, before a patient has received chemotherapy for metastatic disease. In hormone receptor-negative disease, trastuzumab deruxtecan remains relevant in HER2-low tumors after prior chemotherapy based on the earlier metastatic indication, but the newer HER2-ultralow approval does not create the same broad earlier-line path outside the hormone receptor-positive setting. 

Where the field is headed

The next phase of the HER2-low story is less about inventing another label and more about improving precision at the low end of HER2 expression. CAP’s updated reporting template, the expanding role of HER2-ultralow, and the persistent evidence of interobserver variability all point in the same direction: pathology workflows will need more reproducibility, more training, and likely better quantitative support than routine visual scoring alone has historically provided. 

The broader lesson for breast cancer care is that biomarker categories can become clinically important before they become biologically tidy. HER2-low breast cancer is the clearest current example. It is not a replacement for established breast cancer taxonomy, but it is now too important to ignore. When the pathology is reported carefully and revisited when disease evolves, it can open access to a therapy with meaningful survival benefit in metastatic disease. That is why understanding HER2-low breast cancer now belongs in routine oncology practice rather than in a purely academic discussion. 

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