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

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 .