HER2 Explorer

Redefining HERness: HER2-low and ultralow breast cancers

Last updated: 26 August 2024 | In: HER2 Explorer

Introduction: The evolving spectrum of HER2-positivity in breast cancer

The 2018 guidelines from the American Society of Clinical Oncology (ASCO) and the College of American Pathology (CAP) classify human epidermal growth factor receptor-2 (HER2) status in breast cancer (BC) according to immunohistochemistry (IHC) staining results of biopsy specimens, ranging from IHC 0 to IHC 3+, plus in situ hybridization (ISH) test results.¹ Tumors classified as IHC 3+ or IHC 2+ with gene amplification by reflex ISH, are described as “HER2-positive”, and there are clinical recommendations for traditional anti-HER2 drugs in such patients.¹ Tumors not meeting these criteria are classified as “HER2-negative” and do not respond to earlier generations of anti-HER2 drugs.² These concepts have been reiterated in the 2023 update of the ASCO/CAP guideline (Figure 1).³

However, more recent trials of HER2-directed therapies in BC have shown promising results in patients who do not meet the ASCO/CAP criteria for HER2-positive status.² This has led to some authors proposing the terms “HER2-low” and “HER2-ultralow” to expand the spectrum of HER2 status^2,4, and these concepts have been incorporated into the 2023 European Society for Medical Oncology (ESMO) expert consensus statements on the definition, diagnosis and management of HER2-low BC (Figure 1).⁵

Figure 1. A summary of HER2 positivity as defined by the ESMO 2023 Expert Consensus Statements and 2023 ASCO/CAP Guideline Update

Clinical significance and implication of HER2-low and ultralow expression in BC

Definitions of HER2-low and ultralow

The 2023 update of the ASCO/CAP guidelines did not adopt the HER2-low or ultralow terminology in reporting, but the definition of HER2-low is clearly specified (IHC 1+ or 2+/ ISH not amplified).³ This update reaffirmed the 2018 guidance that defined IHC 0–3+ and interpreted it as HER2-negative/positive accordingly. The update recommended that pathology labs report the semiquantitative IHC score and include a footnote to ensure that oncologists are aware that patients with IHC 1+ or IHC 2+/ISH- disease may be eligible for treatments that target lower levels of HER2 expression (Box 1).³

Box 1. ASCO/CAP-recommended footnote when reporting HER2 IHC scores³

An expert consensus publication from ESMO has proposed definitions of HER2-low and ultralow⁵; other authors have proposed similar definitions.^6,7

HER2-positive: Defined as per ASCO/CAP 2018 (IHC 3+ or IHC 2+ with ISH+)
HER2-low: IHC 1+ or IHC 2+ with ISH-
HER2-0: Includes “HER2-ultralow” and “HER2-null”
- HER2-ultralow: IHC 0 with incomplete/faint staining in ≤10% of invasive tumor cells
- HER2-null: IHC 0 with no staining

Prevalence of HER2-low and ultralow BC

HER2-low BC covers a heterogeneous group of tumors with diverse molecular profiles.⁷ The estimated prevalence of HER2-low is at 45–55% of primary BC (Figure 2).⁸ Other prevalence estimates include an analysis of 1,363 HER2-negative patients that found that 29.0% could be classified as HER2-ultralow and 64.7% as HER2-low.⁹ Another study of 300 patients with advanced BC classified as IHC 0 found that 43–45% could be reclassified as HER2-ultralow.¹⁰ These data suggest that the HER2-low concept has the potential to expand the population of patients who may benefit from HER2-directed therapies.⁸ Additionally, HER2 status evolves during BC progression and may be enriched in an advanced disease state for both estrogen receptor (ER)-positive tumors and triple negative breast cancer (TNBC) (Figure 3).^11,12 The prognostic implication of this shift is not clear.

Figure 2. Prevalence of HER2-0, HER2-low and HER2-positive breast cancers

Figure 3. Evolution of HER2 status between early and advanced-stage breast cancer

Implications of HER2-low and HER2-0 status for prognosis and treatment

Studies comparing outcomes in HER2-low and HER2-0 BC patients suggest that HER2-low may have a slightly better overall survival (OS); however this could be driven by hormone receptor status.^14,15 Overall, studies suggest that HER2-low is not a new biological entity (compared to HER2-0), and prognostic differences relative to HER2-0 appear limited.¹⁴ The 2023 ASCO/CAP guidelines note that there is no evidence to attribute prognostic value to HER2-low status (vs. HER2-null/IHC 0).⁵ However, studies demonstrating the benefits of HER2-directed therapies are unequivocal, and the benefits seen in them are likely due to some levels of HER2 present in the tumor cell membranes.¹⁴ Studies of HER2-directed therapies in HER2-low and HER2-ultralow BC patients with unresectable tumors have shown positive results, including longer OS and progression-free survival^16,17, and numerous clinical studies of other HER2-directed agents in HER2-low or HER2-ultralow BC patients are ongoing.^2,7

Challenges and limitations for the detection of HER2-low and HER2-ultralow

Techniques for HER2 evaluation and classification have several limitations. There is a need for a formal definition of HER2-low and HER2-ultralow status, standardized protocols for IHC, and validation of these categories.^2,7 IHC staining is prone to artifacts and variability due to the pre-analysis treatment of tissue.² IHC may not be the ideal method to detect HER2 low expression, and the use of different IHC assays may impact the identification of patients.⁷ Furthermore, manual interpretation of IHC staining is prone to inter-observer variability; automation with artificial intelligence-based tools may reduce this problem.⁷ Heterogeneity of HER2 expression levels between samples may also pose challenges to classification and treatment selection.^7,18

Summary

There is a growing effort to re-evaluate the concept of HER2 status, shifting from the simple dichotomy of HER2-positive/negative to a paradigm that classifies patients along a spectrum of HER2 positivity.^2,7 HER2-low and HER2-ultralow are currently emerging concepts, but as analytical techniques improve and new clinical evidence evolves, they are likely to become more established in the diagnostic approach to BC.

The HER2-low and HER2-ultralow categories can potentially increase the proportion of BC patients who may benefit from HER2-directed therapies⁸; therefore, it is critical to identify these patients to ensure they can receive these treatments.¹⁴ HER2-directed therapies are already indicated in some regions for HER2-low and numerous trials are ongoing.^2,7 HER2-low status is also an emerging concept in the treatment of gastric cancer; preliminary data suggest HER2-directed therapies have efficacy for HER2-low gastric cancer but larger studies are needed to confirm these results.¹⁹

References

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Bardia A, et al. N Engl J Med. 2024. DOI:10.1056/NEJMoa2407086.

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The article is sponsored by Daiichi Sankyo and AstraZeneca.

MED-HK-TRAS-00038 HK-11206 11/2024

Disclaimer

This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).