# Reflex re-scoring of HER2 0 versus 1+ with digital assistance so every eligible triple-negative patient reaches trastuzumab deruxtecan

Source: https://onco.cc/ideas/idea-tnbc-her2-ultralow-testing-uptake/  
OnCo record `idea-tnbc-her2-ultralow-testing-uptake` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

About a third of triple-negative tumours are HER2-low and so eligible for trastuzumab deruxtecan, but the difference between a HER2 score of 0 and 1+ is the one pathologists agree on least, and most triple-negative tumours were scored before the label mattered. Re-scoring archived slides with digital help when a patient relapses would find the eligible third.

## Summary

Schettini's 3,689-patient study found HER2-low in 36.6 percent of triple-negative tumours, no biological difference between HER2-low and HER2 0 triple-negative disease, and suboptimal reproducibility of the HER2-low call among pathologists; DESTINY-Breast04 showed trastuzumab deruxtecan lengthens survival in HER2-low metastatic disease including the triple-negative cohort. The HER2 score was designed to find amplification, so the 0 versus 1+ distinction was never quality-assured, and the HER2-ultralow category (0 with faint staining in 10 percent or fewer cells) that DESTINY-Breast06 validated in hormone receptor-positive disease has no triple-negative evidence yet. Digital scoring algorithms for HER2 low expression are in validation.

## Fields

- Kind: Idea
- Last checked: 2026-09-24
- Tags: tnbc-evidence
- Hypothesis: Pathology-initiated re-scoring of HER2 on the diagnostic or metastatic specimen at relapse, using a standardised low-expression protocol with digital assistance, will raise the proportion of metastatic triple-negative patients recorded as HER2-low from under 25 percent to the 35 percent prevalence measured in cohorts and double the number receiving trastuzumab deruxtecan within two years.
- Rationale: The drug and the approval exist; the limiting step is a score that was not designed for the decision it now makes, and the fix is a protocol and a re-read rather than a new test.
- Proposed test: Before-and-after audit across a pathology network: proportion of metastatic triple-negative cases with a documented HER2-low or HER2 0 status, concordance of re-scored versus original calls, proportion treated with trastuzumab deruxtecan; a nested validation of digital HER2 low-expression scoring against a reference panel; a prospective HER2-ultralow triple-negative cohort within the next trastuzumab deruxtecan trial.
- Maturity: early-clinical
- Actor: clinic

## Sources

- Schettini et al.: clinical, pathological and PAM50 features of HER2-low breast cancer (NPJ Breast Cancer 2021): https://europepmc.org/article/MED/33397968

## Connected records

- cancers: [HER2-low and HER2-ultralow metastatic breast cancer](https://onco.cc/cancers/her2-low-metastatic-breast-cancer/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Digital pathology & AI](https://onco.cc/technologies/digital-pathology-ai/)
- targets: [HER2](https://onco.cc/targets/her2/)
- drugs: [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/)
- companies: [AstraZeneca](https://onco.cc/companies/astrazeneca/), [Daiichi Sankyo](https://onco.cc/companies/daiichi-sankyo/)
- terms: [HER2-low and HER2-ultralow](https://onco.cc/terms/her2-low/), [Immunohistochemistry (IHC)](https://onco.cc/terms/ihc/)
- biomarkers: [HER2-ultralow (IHC 0 with membrane staining)](https://onco.cc/biomarkers/her2-ultralow/)
- trials: [DESTINY-Breast04](https://onco.cc/trials/destiny-breast04/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Knowledge reaches practice too slowly](https://onco.cc/bottlenecks/b-knowledge-diffusion/)
- key papers: [Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer](https://onco.cc/key-papers/paper-schettini-her2-low-features-npj-breast-cancer-2021/), [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/), [Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial](https://onco.cc/key-papers/paper-destiny-breast04-nat-med-2025-update/)
- 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/)

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