A randomised phase 2 trial shows that tailoring treatment to 18F-fluorodeoxyglucose PET response and pathological complete response allows a group of patients with HER2-positive breast cancer to undergo surgery and stay off chemotherapy, with five-year invasive disease-free survival of 89.5% in the experimental arm.
What was known
Standard treatment for early HER2-positive breast cancer combines chemotherapy with trastuzumab and pertuzumab. It adds benefit but also toxicity: low blood counts, neuropathy, cardiac risk and an impact on working and family life. Hence the question of whether excellent responders to targeted therapy can be spared it. PHERGain tested that idea with two tools: functional PET imaging and pathological complete response in the surgical specimen.
What this work adds
This randomised, non-comparative phase 2 trial enrolled women with HER2-positive, operable stage I to IIIA breast cancer and a tumour of at least 1.5 cm. One group received chemotherapy plus trastuzumab and pertuzumab; the other received targeted therapy alone, with or without endocrine therapy, adapted to PET after two cycles and pathological complete response: non-responders received chemotherapy. The paper reports the secondary endpoint of five-year invasive disease-free survival, with median follow-up of 5.6 years, plus circulating tumour DNA analyses.
Main results
Five-year invasive disease-free survival was 89.5% (95% CI: 85.7 to 93.4) in the de-escalation arm of 267 participants. Among the 86 patients who responded on PET and achieved pathological complete response without chemotherapy it was 92.4% (86.7 to 98.5), with a single distant recurrence; the authors note this is descriptive, not causal, and comes from a subgroup defined after randomisation. Detectable circulating tumour DNA at baseline or during treatment was associated with worse invasive disease-free survival, and its clearance with higher complete response rates and better outcomes.
What it means
The study supports a PET-guided, response-adapted approach and suggests circulating tumour DNA could refine individualisation. It deserves caution: this is a non-comparative phase 2 trial and the most striking figure comes from a subgroup defined retrospectively. It does not justify omitting chemotherapy across the board, but it reinforces that treatment intensity can follow tumour biology and early response, not stage alone.
A view from the breast unit
For a breast unit the message is twofold: de-escalation requires PET and expert reading before the second cycle, plus fast surgery and pathology to confirm complete response; and sparing chemotherapy frees day-hospital capacity and reduces the toxicities that consume outpatient visits and emergency care.
Reference: Pérez-García JM, Cortés J, Ruiz-Borrego M, Stradella A, Bermejo B, Escrivá-de-Romaní S, et al. 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. Nature Medicine, 2026. https://doi.org/10.1038/s41591-026-04723-w
