Five-year data extend the case for a tailored approach
A phase 2 study of people with HER2-positive early breast cancer has reported five-year outcomes for a treatment strategy designed to spare some patients from chemotherapy. The PHERGain trial used early imaging with 18F-fluorodeoxyglucose positron emission tomography, or FDG-PET, to help adapt treatment after it began.
The approach is notable because HER2-positive breast cancer is commonly treated with chemotherapy alongside HER2-targeted medicines. Those treatments can be highly effective, but chemotherapy also carries substantial short- and long-term burdens. PHERGain examined whether some patients whose tumors responded early to HER2-directed treatment could continue on a less intensive path, with chemotherapy added for those whose response did not meet the study’s criteria.
The newly published analysis reports a median follow-up of 5.6 years. In the study’s PET-guided group, five-year invasive disease-free survival was 89.5%, with a 95% confidence interval of 85.7% to 93.4%. Among the subgroup that responded on PET imaging and achieved a pathological complete response without chemotherapy, the reported five-year invasive disease-free survival was 92.4%, with a 95% confidence interval of 86.7% to 98.5%.
Those figures provide longer follow-up for a strategy that had previously reported a three-year invasive disease-free survival rate of 94.3% in the PET-guided group. They do not establish that chemotherapy can be omitted broadly in HER2-positive disease. But they add evidence that response-adapted care may identify a subset of patients for whom a lower-chemotherapy pathway can be explored.
How the PHERGain strategy worked
PHERGain was a randomized, non-comparative phase 2 trial in women with operable, HER2-positive stage I to IIIA breast cancer and tumors at least 1.5 centimeters in size. Participants were assigned either to chemotherapy plus the HER2-targeted drugs trastuzumab and pertuzumab, or to trastuzumab and pertuzumab with or without endocrine therapy.
In the latter group, treatment was not fixed from the outset. Researchers assessed tumor response after two treatment cycles using FDG-PET. Patients whose scans did not show the required response, and patients who did not achieve a pathological complete response, received chemotherapy. The design therefore used imaging and the disease found at surgery to determine who continued without chemotherapy.
Trastuzumab and pertuzumab are directed at HER2, a protein that drives growth in this breast-cancer subtype. The central question was whether intensive systemic treatment could be reserved for patients who appeared to need it, rather than given uniformly before it was known how a tumor would respond to HER2 blockade.
That distinction matters. Treatment de-escalation is not simply a decision to use less therapy. In this trial, it was an adaptive process that relied on specific clinical features, PET results after treatment started, and pathological response. The reported outcomes should be read in the context of that selection process.
What the results show—and what they do not
The 92.4% five-year invasive disease-free survival estimate applies to 86 PET responders who achieved pathological complete response without chemotherapy. The paper reports one distant recurrence in that subgroup. It is an encouraging long-term observation, particularly because the study was designed to investigate whether an imaging-guided strategy could support chemotherapy omission for selected patients.
At the same time, the authors describe that group as a post-randomization subgroup. It was defined after patients had already begun treatment and after their imaging and pathological responses were known. That means its outcome cannot be treated as a direct randomized comparison of chemotherapy versus no chemotherapy for all patients with early HER2-positive breast cancer.
The wider PET-guided group included 267 participants, and its five-year invasive disease-free survival estimate was 89.5%. The confidence intervals around both results also matter: they describe uncertainty around the estimates, especially in the smaller subgroup. The trial was non-comparative, so the new analysis does not provide a head-to-head efficacy conclusion between the two assigned treatment approaches.
Still, the study offers a practical research direction. Rather than framing chemotherapy as an all-or-nothing choice made only from a diagnosis, it tests whether early biological response can inform subsequent treatment intensity. If such a process is validated further, it could help clinicians focus chemotherapy on patients whose cancers show less sensitivity to initial HER2-targeted therapy.
Liquid-biopsy findings add another exploratory layer
The publication also includes exploratory findings involving circulating tumor DNA, or ctDNA. ctDNA refers to fragments of tumor-derived genetic material that can be detected in blood. Researchers are studying it as a potential way to measure residual disease and treatment response without relying only on scans or tissue removed at surgery.
PHERGain’s ctDNA component is exploratory, meaning it should not be interpreted as a ready-to-use decision rule. But its inclusion reflects a wider effort in oncology to combine several sources of information: imaging, pathology, clinical characteristics and blood-based markers. The eventual aim is to make treatment more precise in both directions—intensifying care when risk remains high and reducing toxicity when evidence suggests that more treatment is unlikely to add enough benefit.
Why longer follow-up matters
Early response results are valuable, but they cannot answer whether a reduced-treatment pathway maintains cancer control over time. The five-year analysis therefore supplies an important piece of evidence. It shows that the trial’s selected chemotherapy-free subgroup continued to have a high reported rate of invasive disease-free survival after a median 5.6 years of follow-up.
For now, the findings are best understood as support for continued investigation of PET-guided, response-adapted de-escalation—not as a universal replacement for chemotherapy in HER2-positive early breast cancer. Larger confirmatory studies and careful assessment of which patients fit such strategies will determine whether this approach changes routine practice.
The broader lesson is that treatment intensity may increasingly be shaped by a cancer’s behavior during therapy, not solely by the diagnosis made at the beginning. PHERGain provides one of the clearest long-term tests of that idea in HER2-positive early breast cancer.
This article is based on reporting by Nature Medicine. Read the original article.
Originally published on nature.com
