# Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer

Source: https://onco.cc/key-papers/paper-schettini-her2-low-features-npj-breast-cancer-2021/  
OnCo record `paper-schettini-her2-low-features-npj-breast-cancer-2021` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A 3,689-patient study showing that 36.6 percent of triple-negative tumours are HER2-low, that in triple-negative disease HER2-low tumours are biologically no different from HER2-zero ones, and that pathologists agree poorly on the score; the label matters only because a drug now depends on it.

## Summary

Schettini, Chic, Brasó-Maristany, Paré and colleagues collected retrospective clinicopathological and PAM50 data from 3,689 patients with HER2-negative breast cancer. HER2-low (immunohistochemistry 1+ or 2+ without ERBB2 amplification) was more common in hormone receptor-positive disease (65.4 percent) than triple-negative disease (36.6 percent). Within hormone receptor-positive disease ERBB2 and luminal genes were more expressed in HER2-low than HER2 0 tumours, whereas in triple-negative disease no gene was differentially expressed by HER2 level; within HER2-low, ERBB2 levels were higher in hormone receptor-positive than triple-negative tumours; HER2-low was not associated with overall survival in either group; and reproducibility of the HER2-low call among pathologists was suboptimal.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: tnbc-evidence
- Journal: NPJ Breast Cancer
- Year: 2021
- DOI: 10.1038/s41523-020-00208-2
- Authors: Schettini F, Chic N, Brasó-Maristany F, et al.
- Findings: HER2-low in 36.6 percent of triple-negative vs 65.4 percent of hormone receptor-positive HER2-negative tumours.; No gene differentially expressed between HER2-low and HER2 0 triple-negative tumours; HER2-low not associated with overall survival.; Suboptimal inter-pathologist reproducibility of the HER2-low score.
- What it means: HER2-low is a drug eligibility label, not a biological subtype, in triple-negative disease; because a third of patients qualify for trastuzumab deruxtecan on a score pathologists disagree about, re-scoring and digital assistance for HER2 0 versus 1+ is a practical gap.
- Caveats: Retrospective, multiple cohorts and scoring eras.; Predates the HER2-ultralow category and the DESTINY-Breast06 result in hormone receptor-positive disease.

## Sources

- NPJ Breast Cancer 2021: https://doi.org/10.1038/s41523-020-00208-2
- PubMed: https://pubmed.ncbi.nlm.nih.gov/33397968/

## Connected records

- key papers: [DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group](https://onco.cc/key-papers/paper-destiny-breast04-nejm-2022/)
- biomarkers: [HER2-low (IHC 1+ or IHC 2+/ISH-negative)](https://onco.cc/biomarkers/her2-low-ihc/), [HER2-ultralow (IHC 0 with membrane staining)](https://onco.cc/biomarkers/her2-ultralow/)
- cancers: [HER2-low and HER2-ultralow metastatic breast cancer](https://onco.cc/cancers/her2-low-metastatic-breast-cancer/), [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [Digital pathology & AI](https://onco.cc/technologies/digital-pathology-ai/)
- targets: [HER2](https://onco.cc/targets/her2/)
- drugs: [HER2 IHC and ISH companion assays (HercepTest, PATHWAY 4B5, HER2 Dual ISH)](https://onco.cc/drugs/her2-testing-assays/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/)
- terms: [HER2-low and HER2-ultralow](https://onco.cc/terms/her2-low/), [Immunohistochemistry (IHC)](https://onco.cc/terms/ihc/), [PAM50 / intrinsic subtypes](https://onco.cc/terms/pam50/)
- trials: [DESTINY-Breast04](https://onco.cc/trials/destiny-breast04/)
- people: [Aleix Prat](https://onco.cc/people/aleix-prat/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/)
- roadmaps: [Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem](https://onco.cc/roadmaps/tnbc-roadmap/)
- ideas: [Reflex re-scoring of HER2 0 versus 1+ with digital assistance so every eligible triple-negative patient reaches trastuzumab deruxtecan](https://onco.cc/ideas/idea-tnbc-her2-ultralow-testing-uptake/)

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