Interconnected HER receptors on a breast cancer cell surface.

Decoding Breast Cancer: Can Analyzing All HER Receptors Improve Treatment?

Samir D’Costa in Health & Wellness December 2025 • 5 min read.

"A new study investigates the prognostic value of all four HER family receptors in metastatic breast cancer patients treated with trastuzumab, potentially paving the way for more personalized treatment strategies."

Metastatic breast cancer (MBC) remains a formidable challenge, demanding innovative approaches to treatment. While therapies have advanced, allowing patients to live longer, understanding the nuances of how cancers develop resistance to treatment is critical. The HER2 receptor, when overexpressed, is a known driver of aggressive breast cancer, making drugs like trastuzumab essential. However, not all patients respond, and resistance often develops, highlighting the need for more refined predictive tools.

The HER family, encompassing EGFR, HER2, HER3, and HER4, plays a crucial role in cell signaling and cancer development. Interactions between these receptors can influence treatment response, making a comprehensive analysis of all four receptors potentially more informative than assessing HER2 alone. Current methods for HER2 assessment, primarily immunohistochemistry (IHC), have limitations, necessitating more accurate and comprehensive approaches.

This article explores a recent study by the Hellenic Cooperative Oncology Group (HeCOG), which delves into the prognostic value of all four HER family receptors in patients with metastatic breast cancer treated with trastuzumab. By examining gene amplification, mRNA expression, and protein levels, this research offers new insights into predicting treatment response and tailoring therapies for better outcomes.

Comprehensive HER Analysis: Unlocking Treatment Insights

Interconnected HER receptors on a breast cancer cell surface.

The HeCOG study collected tumor tissue samples from 227 patients initially considered HER2-positive based on local lab assessments. The researchers employed multiple methods—gene amplification analysis, copy number variation (CNV) assessment, mRNA expression profiling, and protein expression analysis—to evaluate all four HER family receptors. They also examined other relevant factors like pHER2 and PTEN expression through immunohistochemistry (IHC).

Central review of HER2 status using IHC and FISH revealed that only 61.2% (139 patients) were truly HER2-positive. This discrepancy underscores the variability in HER2 assessment and the need for stringent central testing. Outcome-related analyses focused on 191 patients who received trastuzumab as a first-line therapy.

Key Findings:

In HER2-positive patients, high HER3 mRNA expression correlated with better time to progression (TTP) and overall survival.
In HER2-negative patients, EGFR copy gain and EGFR protein expression were associated with a higher risk of disease progression.
Positive HER3 protein expression was a favorable prognostic factor for TTP in HER2-negative patients.

Multivariate analysis confirmed that EGFR copy gain was a significant negative prognostic factor for TTP in HER2-negative patients, while high HER3 mRNA expression remained a favorable prognostic factor for TTP in HER2-positive patients. These results suggest that beyond HER2 status, the expression patterns of other HER family members can significantly impact treatment outcomes.

Future Directions: Towards Personalized HER-Targeted Therapies

This study highlights the importance of a comprehensive approach to understanding HER receptor dynamics in breast cancer. While HER2 remains a crucial target, the interplay between all four HER family members can significantly influence treatment outcomes. The identification of EGFR copy gain as a negative prognostic factor in HER2-negative patients and high HER3 mRNA expression as a favorable factor in HER2-positive patients opens new avenues for personalized treatment strategies.

Further research is needed to validate these findings in larger cohorts and explore the mechanisms underlying the observed associations. Integrating HER receptor analysis into routine clinical practice could refine patient stratification and guide treatment decisions, potentially improving outcomes for individuals with metastatic breast cancer.

Ultimately, a deeper understanding of HER receptor signaling networks will pave the way for developing more effective and targeted therapies, moving towards a future where breast cancer treatment is tailored to the unique molecular profile of each patient’s tumor.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1371/journal.pone.0207707, Alternate LINK

Title: Evaluation Of The Prognostic Value Of All Four Her Family Receptors In Patients With Metastatic Breast Cancer Treated With Trastuzumab: A Hellenic Cooperative Oncology Group (Hecog) Study

Subject: Multidisciplinary

Journal: PLOS ONE

Publisher: Public Library of Science (PLoS)

Authors: Angelos Koutras, Georgios Lazaridis, Georgia-Angeliki Koliou, George Kouvatseas, Christos Christodoulou, Dimitrios Pectasides, Vassiliki Kotoula, Anna Batistatou, Mattheos Bobos, Eleftheria Tsolaki, Kyriaki Papadopoulou, George Pentheroudakis, Pavlos Papakostas, Stavroula Pervana, Kalliopi Petraki, Sofia Chrisafi, Evangelia Razis, Amanda Psyrri, Dimitrios Bafaloukos, Konstantine T. Kalogeras, Haralambos P. Kalofonos, George Fountzilas

Published: 2018-12-06

Everything You Need To Know

What exactly is the HER family of receptors, and why is understanding all four important in breast cancer?

The HER family consists of four receptors: EGFR, HER2, HER3, and HER4. These receptors play a critical role in cell signaling pathways that influence cell growth and differentiation. In cancer, particularly breast cancer, aberrant expression or activation of these receptors can drive tumor growth and resistance to therapies. Understanding the interactions and expression levels of all four HER receptors is vital for developing more effective treatment strategies.

What were the key findings of the HeCOG study regarding the different HER receptors in metastatic breast cancer?

The HeCOG study revealed that in HER2-positive patients, high HER3 mRNA expression was associated with improved time to progression (TTP) and overall survival. Conversely, in HER2-negative patients, EGFR copy gain and EGFR protein expression were linked to a higher risk of disease progression. Additionally, positive HER3 protein expression was identified as a favorable prognostic factor for TTP in HER2-negative patients.

How might analyzing all HER receptors beyond HER2 impact the effectiveness of trastuzumab treatment?

Trastuzumab targets the HER2 receptor, which is often overexpressed in aggressive breast cancers. However, not all patients respond to trastuzumab, and resistance can develop over time. The HeCOG study suggests that the expression levels of other HER family members, such as EGFR and HER3, can influence the effectiveness of trastuzumab. Therefore, a comprehensive analysis of all HER receptors can help predict which patients are most likely to benefit from trastuzumab and identify alternative treatment strategies for those who may not respond.

What are the limitations of current methods for assessing HER2 status, and how can a comprehensive HER analysis overcome these limitations?

Current methods for assessing HER2 status, such as immunohistochemistry (IHC), have limitations and can lead to variability in results. The HeCOG study found that a significant proportion of patients initially classified as HER2-positive based on local lab assessments were later found to be HER2-negative upon central review using IHC and FISH. This discrepancy highlights the need for more accurate and comprehensive approaches, such as gene amplification analysis, mRNA expression profiling, and protein expression analysis, to evaluate all HER receptors and improve treatment decisions.

What are personalized HER-targeted therapies, and how could they improve outcomes for breast cancer patients based on the understanding of all HER receptors?

Personalized HER-targeted therapies involve tailoring treatment strategies based on the unique expression patterns of all four HER receptors in a patient's tumor. For example, the identification of EGFR copy gain as a negative prognostic factor in HER2-negative patients suggests that these patients may benefit from therapies that target EGFR. Similarly, high HER3 mRNA expression as a favorable factor in HER2-positive patients could inform decisions about the duration or intensity of trastuzumab treatment. A comprehensive understanding of HER receptor dynamics can help clinicians select the most effective therapies for each patient, improving outcomes and reducing the risk of treatment resistance.