Summary
In the phase 2 PHERGain trial, a PET- and pathology-guided strategy had an estimated five-year invasive disease-free survival of 89.5% among patients assigned to the adaptive-treatment group who underwent surgery. Exploratory ctDNA analyses linked early clearance with higher pathological complete response rates and better five-year outcomes.
A five-year follow-up of the randomized phase 2 PHERGain trial reports an estimated 89.5% invasive disease-free survival (iDFS) among patients assigned to a PET-guided, response-adapted treatment strategy who underwent surgery. In that strategy, some patients with HER2-positive early breast cancer avoided chemotherapy if they responded to initial treatment and had no invasive cancer detected at surgery. The trial was non-comparative, so its results do not establish that this approach is equivalent to standard chemotherapy.
The researchers also found that circulating tumour DNA (ctDNA) patterns during treatment were associated with pathological response and longer-term outcomes. These biomarker analyses were exploratory; they suggest a possible way to refine risk assessment, rather than a basis for choosing treatment in routine care.
How PHERGain adapted treatment
The trial enrolled women with operable HER2-positive breast cancer, with tumours at least 1.5 cm in size. HER2 is a protein that can be overexpressed, or its gene amplified, in some breast cancers. The study compared two assigned treatment strategies: chemotherapy plus the HER2-targeted medicines trastuzumab and pertuzumab (group A), and an adaptive strategy using those medicines, with endocrine therapy for some patients (group B).
In group B, patients began with two cycles of trastuzumab and pertuzumab. A reduction of at least 40% in a PET measure of tumour activity qualified as a response. Responders continued the HER2-targeted treatment, with or without endocrine therapy, for six more cycles. Patients who did not meet the PET response threshold switched to chemotherapy alongside HER2-targeted treatment. Responders who did not have a pathological complete response (pCR)—no invasive cancer found in the breast and sampled lymph nodes at surgery—were also given chemotherapy after surgery.
Five-year outcomes and the comparison caveat
After a median follow-up of 5.6 years, the estimated five-year iDFS in group B’s 267-patient surgery population was 89.5% (95% confidence interval: 85.7–93.4). iDFS includes remaining alive without specified invasive breast-cancer recurrences, distant recurrence, a second non-breast primary cancer or death. Nearly one-third of patients assigned to group B did not receive chemotherapy.
Among the 86 group B patients who responded on PET, achieved pCR and never received chemotherapy, estimated five-year iDFS was 92.4% (95% CI: 86.7–98.5). Six iDFS events occurred in this subgroup, including one distant recurrence. Because membership in this group depended on responses and pathology assessed after treatment began, this outcome is descriptive, not a causal estimate of chemotherapy omission.
The estimated five-year iDFS in group A was 96.7% (95% CI: 92.2–100) among 63 patients who underwent surgery. PHERGain was not designed for a formal comparison between the groups: the smaller group A served mainly as an internal benchmark. The estimates therefore should not be read as a definitive test of whether the adaptive strategy matches the standard regimen.
ctDNA tracked response and risk
Researchers analysed plasma samples using a tissue-free assay that detects tumour-associated DNA methylation patterns. Among 288 patients with a successfully sequenced baseline sample, ctDNA was detected in 71%. Detection was more common in patients with more advanced disease: it ranged from 33.3% in stage I to 93.2% in stage III.
Among patients with baseline ctDNA, early clearance—no longer detecting ctDNA at the cycle-three assessment—was associated with a higher pCR rate than persistent detection: 48.4% versus 22.0%. Early clearance was also associated with higher estimated five-year iDFS, 92.3% versus 75.6%. In analyses adjusted for disease stage and lymph-node status, however, that survival association did not reach statistical significance. The study’s ctDNA analyses were exploratory, had missing samples at some time points and were not adjusted for multiple comparisons. The authors say prospective validation is needed before ctDNA can guide treatment decisions.