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ESMO E-Learning: HER2 Low Breast Cancers

Learning objectives

  1. To provide an update on the latest HER2 testing guidelines
  2. To understand the evolution of HER2 status definition and how to distinguish truly HER2 negative from HER2 low breast cancer
  3. To understand the clinical relevance of defining HER2 low breast cancer in terms of opportunities from targeted therapies under development


This E-Learning module underlines the fact that the dichotomous view of HER2 status, being either positive or negative, has come to an end. The author emphasizes that it becomes clinically important to distinguish truly HER2 negative from HER2 low breast cancer as treatment options are becoming available. Therefore, it is relevant to accurately distinguish tumours with an immunohistochemistry score 1+ from those scored 0.

The author starts the module by stating that treatment decisions in clinical practice are based on conventional histopathological factors that divide breast cancer into four surrogate subgroups: luminal A-like, luminal B-like (HER2-negative), HER2-positive and triple negative breast cancer. This classification has both, prognostic and predictive value.

HER2 gene amplification is a strong oncogenic driver. HER2 receptor shows overexpression in approximately 15% of breast cancers. HER2 amplification is an actionable pathway that has been targetable since more than 20 years ago. In this module, the author provides an overview of the history of HER2 testing, especially in terms of the cut-off controversy.

The module features HER2 recommendations from the guidelines in terms of questions, such as when to test, acceptable methods, which specimen, immunohistochemistry rules, HER2 scoring and magnification, and provides an algorithm for the evaluation of HER2 amplification assay. Clear messages for the practice are summarised. HER2 testing is optimised to guide treatment decisions for the use of classical anti-HER2 therapies.

The author also tackles unresolved issues of heterogeneity. The aspects such as heterogeneity and long-term outcomes, heterogeneity and anti-HER2 therapies are also elaborated in the module.

About 55% of breast cancers express low levels of HER2 in the absence of gene amplification. A part of the module is dedicated to HER2 low disease and the benefit from trastuzumab. The author elaborates the results from the trial which demonstrated that adjuvant trastuzumab is not effective in these tumours, likely due to their low or absent addiction to HER2 signalling. Similarly, other agents disrupting HER2 pathway have shown modest activity in HER2 low tumours.

The author provides new definitions of HER2 status from the aspect of HER2 low patients, who may benefit from emerging therapies. Recent data suggest that a subset of HER2-expressing breast cancer not addicted to HER2 could also derive benefit from targeting this receptor with drugs under development.

This E-Learning module was published in 2020 and expired in 2022.

Last update: 29 May 2020

The author has reported: honoraria for speaker, advisory board role from AstraZeneca, Roche, BMS, MSD, Lilly, Novartis, Sanofi, Pfizer, Janssen, Bayer. Honoraria for advisory board role from cor2ed and Abbvie; honoraria for speaker role from Daiichy, Nanostring, Medscape and Myriad.

Financial support for contracted research from AstraZeneca, Roche/Ventana, Nanostring, Bayer, Abbvie, MSD, BMS and Myriad.

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