Breast cancer is one of the most commonly diagnosed cancers and the fifth leading cause of cancer-related death, with an estimated 2.3 million new cases worldwide in 2020, according to the Global Cancer Observatory: Cancer Today (GLOBOCAN) data.1 The American Cancer Society predicted that an estimated 268,600 new cases of invasive breast cancer and 48,100 cases of ductal carcinoma in situ would be diagnosed in 2019 and over 41,760 women would die of this disease in the United States.2 In 2020, breast cancer was the leading cause of cancer death in women worldwide.3

Treatment decisions for breast cancer are predicated on conventional histologic factors and 4 primary subtypes with prognostic and predictive relevance in clinical practice: luminal A-like, luminal B-like (human epidermal growth factor receptor 2 [HER2]-negative), HER2-positive, and triple-negative breast cancer (TNBC). In patients with HER2-positive breast cancer, genetic amplification of ERBB2 leads to HER2 overexpression, more aggressive behavior, and poor prognosis if untreated. The recent development of multiple agents targeting HER2 has provided significant clinical benefit in patients with early- and advanced-stage disease.4

Moving Away From the Binary Paradigm: Emergence of HER2-Low Breast Cancer

According to the 2018 American Society of Clinical Oncology (ASCO®)/College of American Pathologists guidelines,5 breast cancer is considered HER2-positive when there is evidence of HER2 overexpression as shown by an immunohistochemistry (IHC) assay score of 3+ or gene amplification on an in situ hybridization (ISH) assay in at least 1 tumor sample. In the case of an IHC score of 2+, reflex ISH testing is required to define HER2 status.4,5

For patients with IHC scores of 0 and 1+, or those with an IHC score of 2+ and a negative ISH result, breast cancer is characterized as HER2-negative. In clinical practice, HER2-negative tumors are classified as TNBC or, if a hormone receptors (HRs) are expressed, as luminal breast cancer. Patients with HER2-negative tumors do not benefit from anti-HER2 therapies.4,6

These guideline-directed binary distinctions — HER2-positive vs HER2-negative — have until now guided physicians’ treatment decisions.5

New research suggests that patients with HER2-2+, ISH-negative breast cancer present a clinical picture closer to that of patients with HER2-positive breast cancer (Figure 2).7,8 In a larger prospective study, HER2-2+ and HER2-negative status was associated with worse disease-free survival.9

In light of these observations, a new nomenclature has been proposed in which tumors with an IHC assay score of 1+ or 2+ and negative ISH assay results are characterized as HER2-low.

The distinguishing clinical and molecular characteristics of HER2-low breast cancer and its response to neoadjuvant therapy were delineated in a 2021 pooled analysis of data from 4 clinical trials ( Identifiers: NCT01583426, NCT02125344, NCT02682693, and NCT01690702).10 The data were from 1098 women with HER2-low-positive breast cancer, defined as IHC 1+ or 2+ and ISH-negative, and 1212 women with HER2-negative breast cancer. Denkert and colleagues reported that pathological complete response to neoadjuvant therapy was significantly lower in women with HER2-low-positive tumors (29.2%) compared with women with HER2-negative tumors (39.0%; P =.0002). Women in the HR-positive subgroup saw that pathological complete response was significantly lower in those with HER2-low-positive tumors (17.5%) compared with women with HER2-negative tumors (23.6%; P =.024). However, this association was not seen in women in the HR-negative subgroup (50.1% vs 48.0%, respectively; P =.21).

By contrast, survival was significantly longer in patients with HER2-low-positive tumors than in patients with HER2-negative tumors. The 3-year disease-free survival was 83.4% compared with 76.1%, respectively (P =.0084) and the 3-year overall survival was 91.6% compared with 85.8%, respectively (P =.0016).

In patients with HR-negative tumors, the 3-year disease-free survival was 84.5% for patients with HER2-low-positive tumors and 74.4% for patients with HER2-negative tumors (P =.0076) and the 3-year overall survival was 90.2% compared with 84.3%, respectively (P =.016). The survival difference was not seen in patients with HR-positive tumors, where the 3-year disease-free survival was 82.8% for patients with HER2-low-positive tumors and 79.3% for patients with HER2-negative tumors (P =.39) and the 3-year overall survival was 92.3% and 88.4%, respectively (P =.13).

What percentage of breast cancer is characterized as HER2-low?
HER2-low breast cancer accounts for about 45% to 55% of all breast cancer.

A study published by Won and colleagues reported that HER2-low, HR-positive breast cancer develops more frequently in patients who are premenopausal and it is associated with fewer T4 tumors, higher histologic grade, and negative lymphatic invasion compared with HER2-negative breast cancer.11 They also found that HER2-low breast cancer was more frequent in patients who are overweight, defined as a BMI of at least 25.11

These trials reaffirm that HER2-low-positive tumors have a specific biology and show differences in response to therapy and prognosis, particularly for therapy-resistant, HR-negative tumors. Overall, these findings provide a basis for a better understanding of the biology of breast cancer subtypes and the importance of using more sensitive IHC assessments in daily practice.

Ongoing Clinical Trials for HER2-Low Breast Cancer Treatment Options

Targeted treatment options for patients with HER2-low breast cancer remain a significant challenge. Sequenced endocrine therapies such as tamoxifen, aromatase inhibitors, or fulvestrant used with or without cyclin-dependent kinase 4 and 6 inhibitors, everolimus, or alpelisib often seem to fail for patients who are HR-positive. However, patients with positive programmed death-ligand 1 (PD-L1) receptor expression may respond to immunotherapy.12 Furthermore, reliance on traditional cytotoxic chemotherapies has its own constraints, such as cumulative toxicities.13

While several therapies undergoing clinical trials have failed to show significant benefit for patients with HER2-low breast cancer, novel and more potent anti-HER2 agents have emerged with demonstrated efficacy for this population.

Trastuzumab plus chemotherapy: A phase 3 study assessed whether trastuzumab, a first-generation antibody-drug conjugate (ADC), plus chemotherapy would improve invasive disease-free survival in patients with HER2-negative breast cancer compared with chemotherapy alone ( Identifier: NCT01275677). Of the 3270 patients with HER2-low breast cancer treated, study results indicated that the addition of trastuzumab to adjuvant chemotherapy did not improve invasive disease-free survival, distant recurrence-free interval, or overall survival in women with non-HER2-expressing invasive breast cancer.14

Pertuzumab: In a phase 2 clinical trial, pertuzumab, a recombinant humanized monoclonal antibody targeting the dimerization domain of HER2, was found to have limited efficacy in patients with HER2-negative breast cancer.15  

Nelipepimut-S: Primary analysis of a phase 2b trial indicated that nelipepimut-S did not benefit patients with high-risk HER2-low expressing breast cancer. However, a subset analysis revealed that patients with TNBC experienced significant improvement in 36-month disease-free survival when treated with nelipepimut-S compared with placebo.16

Trastuzumab-deruxtecan (T-DXd): T-DXd is a novel HER2-targeted ADC in clinical development. In a preliminary phase 1b study ( Identifier: NCT02564900) of patients with advanced HER2-expressing or mutated solid tumors, including HER2-low breast cancer, who were highly pretreated, T-DXd showed promise as an antitumor agent. HER2-low breast cancer was defined as IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested. Baseline characteristics of the 54 patients included in the study noted that over 83.3% of patients have previously tried at least 5 cancer regimens (Table).17 The median duration of response was 10.4 months, median progression-free survival was 11.1 months, and median overall survival was 29.4 months (95% CI, 12.9-29.4). The objective response rate confirmed by independent central review was 37%.17

Preliminary results of the DESTINY-Breast04 trial ( Identifier: NCT03734029) showed that T-DXd achieved clinically meaningful improvement in both progression-free survival and overall survival regardless of HR status in patients with HER2-low, unresectable and/or metastatic breast cancer who were treated with either T-DXd or chemotherapy.18

Trastuzumab-duocarmazine (T-Duo): T-Duo, an ADC in early phases of clinical development, demonstrated efficacy in patients with varying levels of HER2 expression who were heavily pretreated ( Identifier: NCT02277717).19

Anti-HER2 ADCs have class-related adverse events, such as myelotoxicity, hepatotoxicity, cardiotoxicity, gastrointestinal toxicity, ocular toxicity, and other life-threatening adverse events. A better understanding of the pathophysiology of such adverse events, together with delineation of risk factors, prevention, and treatment measures, will further improve the safety profile of these ADCs.20


Research has shown that most patients with HER2-negative breast cancer are IHC 1+ or IHC 2+/ISH-negative and have low levels of HER2 expression.4 HER2-low tumors should be distinguished by IHC assessment in daily clinical practice. The ability of ADCs such as T-DXd and T-Duo to target and kill HER2-expressing breast cancer cells even with low-level HER2 expression is much-needed progress, as the targeting of HER2-expressing cells were once a limiting step in clinical development. While therapies such as T-DXs and T-Duo are still in early stages of development, the growing drug class has given rise to a dramatic shift in the management of advanced or metastatic HER2-low breast cancer.


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                                                                                                            Reviewed May 2022