5-year outcomes of chemotherapy de-escalation in HER2-positive early breast cancer and exploratory circulating tumor DNA analyses from the randomized phase 2 PHERGain trial
In brief
86 PET responders with pCR had 92% five-year invasive disease-free survival
After a median 5.6 years, 92.4% of 86 patients who responded on PET and achieved a complete pathologic response without chemotherapy remained free of invasive disease; one had a distant recurrence. This was a selected subgroup, so the result does not prove chemotherapy can safely be omitted; detectable circulating tumor DNA also tracked with worse outcomes and needs further study.
- Journal
- Nature medicine (Q1)
- Published
- 29 October 2026
- Study design
- Phase 2 randomized trial (exploratory)
- Evidence level
- Level 2, Moderate (CEBM 2b)
- Authors
- Pérez-García JM, Cortés J, Ruiz-Borrego M, Stradella A, Bermejo B, Escrivá-de-Romaní S, et al.
- PMID
- 42957778
- DOI
- 10.1038/s41591-026-04723-w
Why clinicians should know about it
- Picked for Oncology and Radiation Oncology (paper of the day, 1 November 2026): Randomized phase 2 trial reports long-term chemotherapy de-escalation outcomes
Abstract
PHERGain was a randomized, non-comparative phase 2 trial evaluating a positron 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET)-guided, pathological complete response (pCR)-adapted strategy to omit chemotherapy in HER2-positive early breast cancer. Female patients with HER2-positive stages I-IIIA operable breast cancer (tumor size ≥ 1.5 cm) were randomized to receive chemotherapy plus trastuzumab and pertuzumab (HP; group A) or HP ± endocrine therapy (group B). In group B, treatment was adapted according to 18F-FDG-PET response after two cycles and pCR, with chemotherapy administered to nonresponders or patients without pCR. We previously reported that this de-escalation approach revealed a 3-year invasive disease-free survival (iDFS) of 94.3% (95% confidence interval (CI): 90.9 to 96.8) in group B. Here we report the prespecified secondary endpoint, 5-year iDFS and exploratory circulating tumor DNA (ctDNA) findings. After a median follow-up of 5.6 years, the 5-year iDFS was 89.5% (95% CI: 85.7 to 93.4) in group B (n = 267) and 92.4% (95% CI: 86.7 to 98.5) among 18F-FDG-PET responders achieving pCR without chemotherapy (n = 86), with one distant recurrence. The latter estimate describes a long-term outcome in a post-randomization subgroup defined by 18F-FDG-PET response and pCR and should be interpreted as descriptive rather than as causal effects of omitting chemotherapy. Detectable ctDNA at baseline or during treatment was associated with inferior iDFS, whereas ctDNA clearance correlated with higher pCR rates and improved long-term outcomes. These findings continue to support the clinical validity of an 18F-FDG-PET-guided, pCR-adapted approach and suggest a potential role for ctDNA in refining treatment individualization. ClinicalTrials.gov identifier: NCT03161353 .
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.