# DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group

Source: https://onco.cc/key-papers/paper-destiny-breast04-nejm-2022/  
OnCo record `paper-destiny-breast04-nejm-2022` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Breast cancers with only a little HER2 on their surface, long called HER2-negative, responded to trastuzumab deruxtecan and patients lived about six months longer than on chemotherapy. It created the HER2-low category.

## Summary

Open-label phase 3 trial of 557 patients with HER2-low (IHC 1+ or IHC 2+/ISH-negative) metastatic breast cancer after one or two lines of chemotherapy, randomised 2:1 to trastuzumab deruxtecan or physician's choice chemotherapy. About 89% were hormone-receptor positive. Primary endpoint was PFS in the HR-positive cohort.

Median PFS was 10.1 vs 5.4 months (HR 0.51) in the HR-positive cohort and overall survival 23.9 vs 17.5 months (HR 0.64); results in the whole population were similar. Roughly half of all breast cancers are HER2-low, so the trial redefined HER2 testing and opened ADC therapy to a very large population.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2022
- DOI: 10.1056/NEJMoa2203690
- Authors: Modi S, Jacot W, Yamashita T, et al.
- Findings: HR-positive cohort: median PFS 10.1 vs 5.4 months, HR 0.51 (95% CI 0.40-0.64); median OS 23.9 vs 17.5 months, HR 0.64.; All patients: median PFS 9.9 vs 5.1 months (HR 0.50); median OS 23.4 vs 16.8 months (HR 0.64).; Benefit was similar for IHC 1+ and IHC 2+/ISH-negative tumours, questioning whether HER2 level is the true predictor.; The small HR-negative (triple-negative) cohort of about 58 patients showed a consistent trend (PFS HR 0.46).; Drug-related interstitial lung disease in 12.1% of T-DXd patients, including three deaths.
- What it means: Patients whose breast cancer was previously called HER2-negative may now be eligible for an effective HER2-directed drug if their tumour has even low-level HER2 staining, so pathology reports must now distinguish HER2-low (1+ or 2+/ISH-negative) from HER2-zero. This applies to metastatic disease after at least one line of chemotherapy; it does not mean these patients benefit from trastuzumab or other older HER2 drugs.
- Caveats: HER2-low scoring by immunohistochemistry is poorly reproducible between pathologists, and the assay was never designed to distinguish 0 from 1+.; Fatal pneumonitis occurred; patients need CT surveillance and rapid steroid treatment of symptoms.; The triple-negative cohort was exploratory and small.; DESTINY-Breast06 later showed activity in HER2-ultralow (faint staining) tumours, suggesting the biomarker threshold is arbitrary.

## Sources

- NEJM 2022: https://doi.org/10.1056/NEJMoa2203690
- ClinicalTrials.gov NCT03734029: https://clinicaltrials.gov/study/NCT03734029

## Connected records

- ideas: [A randomised trial of antibody-drug conjugate sequence in metastatic triple-negative breast cancer](https://onco.cc/ideas/idea-tnbc-adc-sequencing-trial/), [Payload-class switching as the rule for ADC sequencing](https://onco.cc/ideas/idea-payload-switching/), [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/)
- biomarkers: [HER2-low (IHC 1+ or IHC 2+/ISH-negative)](https://onco.cc/biomarkers/her2-low-ihc/)
- cancers: [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Metastatic triple-negative breast cancer](https://onco.cc/cancers/tnbc-metastatic/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Companion diagnostics](https://onco.cc/technologies/companion-diagnostic/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/)
- 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: [Bystander effect (ADC)](https://onco.cc/terms/bystander-effect/), [HER2-low and HER2-ultralow](https://onco.cc/terms/her2-low/), [Immunohistochemistry (IHC)](https://onco.cc/terms/ihc/), [Interstitial lung disease (ILD) / pneumonitis](https://onco.cc/terms/ild/), [Overall survival (OS)](https://onco.cc/terms/os/), [Progression-free survival (PFS)](https://onco.cc/terms/pfs/)
- trials: [DESTINY-Breast04](https://onco.cc/trials/destiny-breast04/)
- people: [Binghe Xu](https://onco.cc/people/xu-binghe/), [David Cameron](https://onco.cc/people/david-cameron/), [Hope S. Rugo](https://onco.cc/people/hope-rugo/), [Joohyuk Sohn](https://onco.cc/people/sohn-joohyuk/), [Seock-Ah Im](https://onco.cc/people/im-seock-ah/), [Shanu Modi](https://onco.cc/people/shanu-modi/), [Sung-Bae Kim](https://onco.cc/people/kim-sung-bae/), [Yeon Hee Park](https://onco.cc/people/park-yeon-hee/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- 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/)
- 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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