Clinico-pathological and Genomic Features of HER2-low Early Breast Cancer (eBC). Results of Retrospective Analysis of Seven Adjuvant Trials by the Hellenic Cooperative Oncology Group (HeCOG)

Although breast cancer remains one of the most common and fatal cancer types among women worldwide, earlier diagnosis and improved therapeutic approaches have led to decreased mortality over last years. Indeed, the use of HER2-targeted drugs has improved clinical outcomes for patients with HER2 positive breast cancer, while, on the other hand, until recently, little progress has been made for HER2-negative (IHC score 0 and 1+) patients.

However, it seems that among these HER2-negative breast cancers, substantial heterogeneity exists regarding the expression of hormone receptors (HR) and HER2.

Biomarkers are critical for translating the biological heterogeneity of breast cancer into prognostically and therapeutically useful information. In recent years gene expression profiling and genomic analysis have shown utility in specific clinical scenarios, but immunohistochemistry (IHC) remains the cornerstone of biomarker testing in both early and advanced/metastatic disease.

In breast cancer, achieving efficacy with endocrine therapy or with HER2-blockade requires identifying patients whose tumors show significant survival dependency on the therapeutic target. This is achieved by using appropriate biomarkers cut-offs ensuring a favorable benefit-to-toxicity ratio for specific patients.

This paradigm has recently been challenged by a new class of HER2 drugs that use target expression not as a direct molecular lever but as a vehicle to deliver potent agents to cancer cells, breaking the straightforward link between the molecular target and the corresponding therapy. These drugs exhibit impressive activity at marker expression levels much lower than those required to effectively block HER2 signaling, shifting the diagnostic focus to the lower end of the staining spectrum, specifically distinguishing between HER2-zero and HER2-low expression.

Given the lack of a definitive molecular hallmark for cancers characterized by low HER2 expression, ongoing efforts aim to understand the biology of this heterogeneous group of tumors. This understanding is crucial to triage treatment, investigate resistance mechanisms, and inform potential combination strategies.

To enrich the available data, we perform a retrospective analysis of HER2-low patients in a large cohort of early breast cancer patients from Greece enrolled in 7 randomized and observational clinical studies.

Given the importance of the hormone receptors and the known differential distribution of ER/PgR status between HER2-zero, HER2-low and HER2-positive breast tumors, after analyzing the entire population cohort, ER/PgR status will be treated as a confounding variable in the analysis and the HER2 categories will be compared separately within ER/PR-positive and ER/PR-negative disease.

The study aims to investigate how HER2-zero, HER2-low and HER2-positive tumors are distributed across ER expression categories. Additionally, we will evaluate whether PgR positivity varies across ER expression categories, and if PgR identify heterogeneity within ER-low tumors.

As TP53 mutation is strongly linked to basal-like, high-grade, hormone receptor-negative and HER2-positive biology, we will examine if TP53 mutation frequency differs across ER categories and classic subtypes and if PIK3CA mutation frequency differs across ER categories and PgR-defined groups, as PIK3CA mutations are generally enriched in luminal breast cancer.

TIL biology is also strongly subtype-dependent. TNBC and HER2-positive disease are generally more immune-enriched than luminal disease, so we will examine if stromal TIL levels are associated with ER category, HER2 category and classic subtype in our study.

Summarizing, our aim is to evaluate if HER2-low status retains independent associations with clinicopathologic, immune or genomic features after adjustment for ER category and classic subtype, whether ER/HER2 matrix groups are associated with disease outcome, and associations remain after adjustment for standard prognostic factors and treatment.