What Is the Real Impact of Estrogen Receptor Status on the Prognosis and Treatment of HER2-Positive Early Breast Cancer?

Abstract

HER2⁺ early breast cancer is a heterogeneous disease, comprising all the intrinsic breast cancer subtypes. The only biomarker available nowadays for anti-HER2 treatment selection is HER2 status itself, but estrogen receptor (ER) status is emerging as a robust predictive marker within HER2⁺ disease. In this Perspective, we discuss the biological and clinical differences between patients with HER2⁺/ER-positive (ER⁺) disease versus those with HER2⁺/ER-negative (ER-neg) tumors, namely, short-term and long-term (>5 years after diagnosis) prognosis, response to neoadjuvant treatment and benefit from adjuvant anti-HER2-targeted therapies. We also address other possible biomarkers to be used for patient selection in future clinical trials, such as gene signatures, PAM50 subtypes, tumor-infiltrating lymphocytes, PIK3CA mutations, and changes in Ki67 score during treatment and discuss their limitations. Finally, we suggest new clinical trial designs that can have an impact on clinical practice, aiming to test treatment deescalation separately for patients with HER2⁺/ER⁺ and HER2⁺/ER-neg tumors. We also propose an integrated classification of HER2⁺ disease, comprising DNA, RNA, protein expression, and microenvironment characteristics, in order to identify those tumors that are truly "HER2-addicted" and may benefit the most from anti-HER2 treatment.

Figure 1 –. Current and future classification of HER2+ disease.

Legend: HER2+ tumors can be divided between estrogen receptor (ER)-positive and ER-negative subgroups, according to the immunohistochemical expression of ER. Yet, at the molecular level, these tumors can be divided into the four molecular subtypes (luminal A, luminal B, HER2-enriched and basal-like), showing different molecular alterations, cell pathways activation and immune microenvironment. This leads to different responses to anti-HER2 treatment, as well to chemotherapy and endocrine therapy. ER: estrogen receptor; HER2-E: HER2-enriched molecular subtype; LumA: luminal A molecular subtype; LumB: luminal B molecular subtype; mut: mutation; TILs: tumor-infiltrating lymphocytes; WT: wild-type.

Figure 2 –. Combining biomarkers in HER2+ disease.

Currently, protein expression assessed by immunohistochemistry is the standard method to classify breast cancer into different subtypes, according to tumor’s HER2 and estrogen receptors expression. However, an integrated classification of HER2-positive breast tumors, based on their DNA, RNA, protein expression, and microenvironment is needed to implement more precise and guided treatments and to identify those tumors “addicted” to the HER2 cellular pathway. Here, we propose a definition of “HER2-addicted” tumors that can be further refined in the future, as more data become available. ER: estrogen receptor; HER2-E: HER2-enriched molecular subtype; PR: progesterone receptor; Rbsig: RB loss of function signature; WT: wild-type.