Abstract
ER-low and HER2-low breast cancers have emerged as clinically significant subtypes that challenge traditional diagnostic categories and treatment paradigms. These subtypes, representing a spectrum of disease, exhibit distinct biological behaviors, therapeutic responses, and prognostic outcomes. HER2-low breast cancer, defined by low HER2 protein expression (IHC score of 1+ or 2+ without HER2 gene amplification), has achieved clinical significance, particularly following the DESTINY-Breast trials, which demonstrated the efficacy of trastuzumab deruxtecan (T-DXd) in the population of patients with advanced HER2-low disease. Similarly, ER-low breast cancer, characterized by low estrogen receptor expression (in 1%–10 % invasive tumor cells), poses unique challenges due to its intermediate biological behavior and uncertain response to endocrine therapies. The identification of these subtypes is further complicated by inconsistencies in testing methodologies, which can lead to misclassification and impact treatment decisions. As our understanding of these subtypes improves, the need for standardized diagnostic approaches and individualized therapeutic decisions becomes increasingly urgent. Ongoing research and collaboration between pathologists and oncologists are essential for refining diagnostic criteria and improving outcomes for patients with breast cancers characterized by low expression of these theragnostic biomarkers. This review aims to consolidate current knowledge on HER2-low and ER-low breast cancers, focusing on the challenges associated with their identification, the implications for treatment, and future directions in clinical management. By examining recent studies and interlaboratory assessments, this review emphasizes the critical need for accurate and reproducible testing and reporting, and for the development of tailored therapeutic strategies for these “low” expression cancers.
Keywords: Breast cancer, ER-low, HER2-Low, Biomarkers
Highlights
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ER-low (Estrogen Receptor-low) and HER2-low (Human Epidermal Growth Factor Receptor 2-low) breast cancers represent clinically significant subtypes, presenting unique diagnostic and therapeutic challenges.
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Variability in detecting these cancers is a major concern, largely due to inconsistencies in current testing methodologies. Standardized protocols are crucial for improving diagnostic accuracy and reducing misclassification.
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Current treatment strategies include adjuvant endocrine therapy (AET) for ER-low cancers, though the effectiveness remains controversial. HER2-low cancers have seen advancements through antibody-drug conjugates like trastuzumab deruxtecan (T-DXd).
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The lack of inclusion of HER2-zero patients in clinical trials raises important questions about the future relevance of the HER2-low category.
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Collaboration between pathologists and oncologists is essential to refine diagnostic criteria, explore personalized treatment options for ER-low cancers, and ensure improved outcomes through targeted therapies.
1. Introduction
The emergence of ER-low and HER2-low breast cancer concept has raised new complexities into the diagnostic and therapeutic landscapes of breast cancer [1,2]. ER-low breast cancer, defined by low estrogen receptor (ER) expression (in 1%–10 % invasive tumor cells), presents its own set of challenges [3,4]. ER-low tumors occupy an intermediate space between ER-positive and ER-negative breast cancers, often displaying heterogeneous biological behavior and variable responses to adjuvant endocrine therapy (AET) [[5], [6], [7]]. This necessitates the exploration of alternative therapeutic strategies, e.g. those for triple-negative breast cancers (TNBC) and a deeper understanding of the molecular underpinnings of ER-low disease.
Similarly, HER2-low breast cancer, characterized by low HER2 protein expression (IHC score 1+ or 2+ without HER2 gene amplification), has gained momentum following the results of clinical trials such as DESTINY-Breast04 (DB-04) and DAISY [8,9]. More recently, the DESTINY-Breast06 (DB-06) study has highlighted how even an HER2 ultra-low expression (IHC score 0 with faint positivity in <10 % of the tumor cells) may be clinically relevant [10,11]. These studies have drawn attention to the importance of accurately and reproducibly identifying HER2-low tumors, as patients with advanced/metastatic HER2-low disease have shown excellent responses to novel therapies like trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) [12,13]. The recognition of HER2-low status has challenged the historical binary classification of HER2, and emphasized the need for more precise diagnostic approaches [14,15].
Both ER-low and HER2-low breast cancers illustrate the limitations of traditional diagnostic criteria and highlight the need for more refined and integrated approaches for breast cancer characterization. As the understanding of HER2-low and ER-low breast cancers continues to evolve, it is crucial for pathologists and oncologists to collaborate in refining diagnostic standards and developing tailored treatment protocols. This collaborative effort will be essential in addressing the unique challenges posed by these subtypes, and ultimately improving outcomes of patients with breast cancers with low expression of theragnostic biomarkers.
2. ER-low breast cancer: controversies and treatment approaches
2.1. Diagnostic challenges
ER-low breast cancer, characterized by tumors with estrogen receptor (ER) immunoreactivity in 1%–10 % invasive tumor cells, occupies a challenging and somewhat ambiguous space in the landscape of breast cancer subtypes [16]. Traditionally, breast cancers have been categorized based on their ER status, with ER-positive tumors generally showing better prognosis and responsiveness to AET, while ER-negative tumors are often more aggressive and not responsive to such treatments [17]. In the majority of breast cancers, ER expression is bimodal, either with no staining of any tumor cells, or with staining of most of them [18,19]. ER-low breast cancers, representing approximately 2%–5% of all breast carcinomas in large-scale cohorts [1,6,[20], [21], [22], [23], [24], [25], [26], [27]], do not fit neatly into either category. Their biological characteristics are intermediate, presenting a complex therapeutic dilemma for oncologists and researchers [18,28]. The focus on ER-low breast cancer is relatively recent, driven by advances in our understanding of breast cancer biology and by the availability of more sensitive immunohistochemical assays [28,29]. Variability in diagnostic techniques and pathologist interpretation poses a significant challenge in the accurate detection of ER-low tumors. Differences in pre-analytical conditions, antibody sensitivity, and pathologist expertise can lead to inconsistencies in identifying these cases. Studies have suggested that this variability may impact clinical decision-making and outcomes in ER-low breast cancer patients. These tumors are not sufficiently hormone receptor-positive to behave like classic ER-positive cancers, yet they are not completely devoid of ER expression either, which makes their behavior unpredictable [30]. Current guidelines recommend treating ER-low breast cancers similarly to ER-positive cancers, which includes the use of AET in addition to chemotherapy. However, the effectiveness and appropriateness of this approach are subjects of ongoing debate within the medical community due to the heterogeneity of ER-low breast cancers and their varying responses to treatment.
2.2. Clinical implications
One of the central controversies in the treatment of ER-low breast cancer revolves around the use of AET, a cornerstone of treatment for ER-positive breast cancer to reduce the risk of recurrence and improve survival [3]. Despite their eligibility to this type of treatment, however, the benefit of AET in patients with ER-low breast cancer is not indisputable [31]. Several studies have shown mixed outcomes, leading to uncertainty about whether AET should be routinely recommended for all of these patients [1,7,17,32]. Very recent data from the Mayo Clinic, presented at ASCO 2024, have provided intriguing insights into this issue [7]. According to the investigators, patients with ER-low breast cancer who were treated with chemotherapy and did not receive AET had significantly worse overall survival (OS) compared to those who received AET. This finding suggests that AET may offer a survival benefit even for patients with ER-low disease. The magnitude of this benefit, however, appears to be smaller than that in patients with higher levels of ER expression, raising questions about the cost-effectiveness and impact of AET in this population. Taken together, there is a need for more nuanced treatment guidelines that consider the specific risks and benefits of AET in patients with estrogen receptor ER-low breast cancer. While some of these patients may derive significant benefit from AET, others may not, and in certain cases, AET could lead to unnecessary side effects without a corresponding improvement in survival outcomes [33]. This underscores the importance of personalized medicine in the treatment of ER-low breast cancer, where a one-size-fits-all approach is unlikely to be effective [31,34,35]. The management of ER-low breast cancer remains a significant challenge due to the inherent heterogeneity of this subgroup [36]. Unlike classic ER-positive or ER-negative breast cancers, ER-low tumors do not respond uniformly to standard treatments, making it difficult to predict which patients will benefit from therapies like AET. Likely, therapeutic decisions should be based not only on ER status but also on other factors such as tumor biology, patient characteristics, and potential biomarkers. Recent studies, including those presented at ESMO 2024, have explored the treatment of ER-low tumors as TNBC, with pembrolizumab showing efficacy in this group (reference). Furthermore, data from large population-based studies, including (reference), demonstrate no significant differences in outcomes between TNBC and ER-low patients treated similarly. These findings suggest that certain ER-low tumors may benefit from treatment strategies more commonly employed in TNBC, though further research is needed to refine these therapeutic approaches. Current treatment guidelines, which recommend treating ER-low breast cancer similarly to ER-positive cancer, may need to be re-evaluated in light of emerging evidence [37]. There is a growing consensus that ER-low breast cancers are clinically and biologically more alike TNBC [38,39]. Ongoing research is focused on identifying complementary and/or surrogate biomarkers that can better predict the response of patients with ER-low disease to AET [24,40,41]. Such biomarkers could help clinicians distinguish between patients who are likely to benefit from endocrine therapy and those who may require alternative treatments [42,43]. Furthermore, there is interest in developing targeted therapies that address the unique biology of ER-low tumors [[44], [45], [46]]. These therapies could potentially offer more effective treatment options for patients with ER-low breast cancer, reducing the reliance on AET and minimizing the risk of adverse side effects. The development of such therapies would represent a significant advancement in the management of this challenging subtype of breast cancer.
3. HER2-low breast cancer: diagnostic and clinical implications
3.1. Diagnostic challenges
Breast cancers with low expression of HER2 represent nearly 2/3 of all breast malignancies, with a higher prevalence in ER-positive tumors [47]. Historically, HER2-low breast carcinomas have been overlooked, because the diagnostic focus has always been on identifying HER2-positive cancers characterized by high HER2 expression levels (IHC 3+ or IHC 2+ with gene amplification), and candidate to treatment with established HER2-targeted therapies [48]. The introduction of T-DXd for treatment of patients in the advanced/metastatic setting, however, has brought renewed focus to HER2-low and -ultralow tumors, highlighting the need for revisiting current diagnostic practices [49]. This shift is essential to ensure that patients with HER2-low tumors are accurately identified and receive appropriate treatment [50,51]. One of the major challenges in detecting HER2-low breast cancer lies in the variability and sensitivity of current testing methodologies [52]. HER2 immunohistochemical testing has traditionally been optimized for detecting high levels of HER2 protein expression, due to the significant clinical impact of distinguishing HER2-positive from HER2-negative cancers [53]. However, the same assays may not be as reliable when it comes to identifying low levels of HER2 expression [54]. The variability in detection across different laboratories is influenced by several factors, including the type of assay used and the pre-analytical conditions such as tissue fixation and antigen retrieval methods [52]. Even slight differences in these variables can significantly affect the intensity of HER2 staining, leading to inconsistent results in the identification of HER2-low tumors [55]. The distinction between IHC scores of 0 and 1+ is particularly challenging, as it often relies on the pathologist's interpretation of faint and incomplete membrane staining [56]. This challenge is exacerbated by the intratumoral heterogeneity often seen in HER2-low breast cancers, where different areas of the same tumor may show varying levels of HER2 expression [57,58]. Such heterogeneity not only complicates the accurate classification of HER2 status but also raises questions about the potential impact on treatment efficacy, particularly with ADCs like T-DXd, which rely on the presence of even low levels of HER2 for effective targeting [59].
The implications of misclassification are significant. Incorrectly identifying a tumor as HER2-zero rather than HER2-low can exclude patients from receiving effective therapies [60]. Conversely, overestimating HER2 expression could expose patients to unnecessary side effects from treatments that may not be effective for them [61]. This highlights the urgent need for more accurate and reproducible testing methods.
To address these challenges, there has been growing interest in the development and implementation of more precise diagnostic approaches. Digital pathology and artificial intelligence (AI) are emerging as promising tools to enhance the accuracy and reproducibility of HER2 testing but they have not yet been validated clinically and/or analytically for the lower spectrum of HER2 expression [62]. Standardization of HER2 testing protocols is another critical step toward improving the detection of HER2-low breast cancer [63]. This includes the development of clear guidelines for the use of specific antibody clones and detection systems, as well as standardized procedures for tissue handling and processing. Ensuring that all laboratories follow these guidelines can help to minimize variability and improve the reliability of HER2-low classification across different clinical settings. All pathology laboratories are now mandated to adhere to the 2023 ASCO/CAP updates and the 2023 ESMO consensus statements, ensuring high-quality testing and accurate reporting [64].
3.2. Clinical implications
The clinical relevance of accurately identifying HER2-low breast cancer has been highlighted by recent therapeutic advancements [65]. The efficacy of T-DXd in HER2-low and -ultralow breast cancer is rooted in the unique mechanism of action of this ADC, which selectively targets HER2-expressing cancer cells and delivers a cytotoxic payload, inducing tumor cell death [66]. The drug's design also enables a bystander effect, killing neighboring tumor cells regardless of their HER2 expression levels [67,68]. These findings emphasize the importance of accurately identifying HER2-low patients to ensure they receive therapies that significantly improve survival outcomes. HER2-low, while not a novel or distinct breast cancer subtype, has been increasingly recognized as a biomarker that identifies a specific therapeutic regimen linked to favorable prognoses [69]. One limitation of current trials investigating T-DXd is the exclusion of HER2-zero patients, leaving a critical question unanswered regarding the potential benefits of T-DXd in this group. Including HER2-zero patients in future studies could clarify whether the distinction between HER2-low and HER2-zero will remain clinically relevant or if HER2-low may eventually become obsolete as a diagnostic category. While the advent of therapies targeting HER2-low tumors has shifted the treatment landscape, the variability in HER2 testing methods remains a challenge. Discrepancies in assay sensitivity can affect patient selection and treatment outcomes, highlighting the need for more precise diagnostic tools. Through continued efforts in research, standardization, and education, we can ensure that all patients with HER2-low breast cancer are accurately identified and receive the treatments that offer them the best possible outcomes. Efficacy of education and training of pathologists to ensure a correct and reproducible diagnosis of HER2-low disease has been recently documented by a global study involving 77 pathologists from 14 Countries. After a virtual 4-h training study pathologists achieved a negative percentage agreement of 91.1 % and a positive percentage agreement of 89.2 % [63].
4. Conclusion
The classification of breast cancer traditionally relies on the expression levels of specific biomarkers, specifically estrogen and progesterone receptors, as well as HER2. While HER2-positive and ER-positive breast cancers have established treatment protocols, recent attention has shifted towards subtypes characterized by low expression of these markers—namely, HER2-low and ER-low breast cancers. These subtypes present diagnostic challenges and exhibit distinct clinical behaviors, prompting a reevaluation of existing diagnostic and therapeutic strategies. HER2-low and ER-low breast cancers challenge traditional paradigms, underscoring the need for standardized testing protocols to ensure accurate diagnosis and appropriate treatment selection. As the therapeutic landscape evolves, particularly with the advent of novel targeted therapies, it is imperative to refine our understanding of the “low” expression spectrum to optimize patient outcomes. Future research should focus on elucidating the biological mechanisms underlying HER2-low and ER-low breast cancers, as well as developing tailored treatment strategies that address their unique characteristics. The complexities associated with ER-low breast cancer, in particular, highlight the necessity for continued investigation to optimize treatment strategies. One promising area of focus is the identification of novel biomarkers that can stratify patients based on their likelihood of responding to AET. Such biomarkers, which may be genetic, molecular, or immunological in nature, could provide a more precise indication of which patients are most likely to benefit from endocrine therapy. Additionally, there is a critical need for clinical trials specifically designed to address the unique challenges of treating ER-low breast cancer. These trials should explore the efficacy of various treatment regimens, including combinations of AET with other therapies, to determine the most effective approaches for these patients. Certainly, they were not eligible for the majority of randomized clinical trials either for TNBC or for ER-positive disease, and it may be very difficult to design and conduct a prospective clinical study for this population of patients, given the low prevalence of the disease. Furthermore, long-term studies examining the outcomes of patients with ER-low breast cancer could provide valuable insights into the optimal duration and intensity of treatment. In conclusion, HER2-low and ER-low breast cancers represent challenging diagnostic categories that require a more nuanced and personalized clinical approach. By refining our understanding of these subtypes and tailoring diagnostic strategies accordingly, we can eventually improve patient outcomes and advance the standard of care in breast cancer.
CRediT authorship contribution statement
Nicola Fusco: Writing – review & editing, Writing – original draft. Giuseppe Viale: Writing – review & editing, Writing – original draft.
Ethical approval
Not applicable.
Declaration of competing interest
N.F. has received honoraria for consulting, advisory role, speaker bureau, travel, and/or research grants from Merck Sharp & Dohme (MSD), Merck, Novartis, AstraZeneca, Roche, Menarini, Daiichi Sankyo, GlaxoSmithKline (GSK), Gilead, Sysmex, Veracyte Inc., Sakura, Leica Biosystems, Lilly, Pfizer. G.V. reported personal fees from Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Agilent, Eli Lilly, and Gilead. These companies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and/or in the decision to publish the results. All other authors declare no potential conflicts of interest.
Acknowledgements
None.
Contributor Information
Nicola Fusco, Email: nicola.fusco@ieo.it.
Giuseppe Viale, Email: giuseppe.viale@ieo.it.
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