PET-Guided Strategy Lets Some HER2-Positive Patients Omit Chemotherapy

Five-year results from the randomized phase 2 PHERGain trial suggest that a positron emission tomography (PET)-guided, pathological complete response (pCR)-adapted strategy can identify patients with HER2-positive early breast cancer who may omit chemotherapy, according to findings published in Nature Medicine.

The open-label, non-comparative trial (NCT03161353) enrolled women with operable stage I-IIIA HER2-positive breast cancer and tumors of at least 1.5cm at 45 hospitals in 7 European countries. Patients were randomized 1:4 to docetaxel, carboplatin, trastuzumab, and pertuzumab (group A) or trastuzumab and pertuzumab with or without endocrine therapy (group B). In group B, patients without a ¹⁸F-fluorodeoxyglucose PET response after 2 cycles, or without pCR at surgery, received chemotherapy.

After a median follow-up of 5.6 years, 5-year invasive disease-free survival (iDFS), a prespecified endpoint, was 89.5% (95% CI, 85.7%-93.4%) among 267 group B patients who underwent protocol-defined surgery. Among 86 PET responders who achieved pCR without chemotherapy, 5-year iDFS was 92.4%, with one distant recurrence. Group A had a 5-year iDFS of 96.7%; the investigators noted that the trial was not designed for between-group comparisons.

In exploratory analyses using a tissue-free, methylation-based circulating tumor DNA (ctDNA) assay (Guardant Reveal, Guardant Health), detectable ctDNA at baseline, after 2 cycles, or before surgery was associated with lower 5-year iDFS. Early ctDNA clearance was associated with higher pCR rates (48.4% vs 22.0%) and higher 5-year iDFS (92.3% vs 75.6%), although the iDFS association was not statistically significant after adjustment for stage and nodal status. None of the 28 patients with detectable ctDNA before surgery achieved pCR.

The authors cautioned that outcomes among PET responders with pCR are descriptive and do not establish that omitting chemotherapy caused the results. Other limitations included attrition from patients who did not reconsent for extended follow-up, the absence of adjuvant trastuzumab emtansine for residual disease, and the exploratory ctDNA analyses, which they said require prospective validation. The trial was funded by F. Hoffmann-La Roche, and Guardant Health funded the ctDNA analyses. 

Source: Pérez-García JM, Cortés J, Ruiz-Borrego M, 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. Nat Med. Published online October 29, 2026. doi:10.1038/s41591-026-04723-w