NRG-BR008 (“HERO”): A Phase III Randomized Trial Seeking to Optimize Use of Radiotherapy in Patients with Early-Stage, Low Risk, HER2-Positive Breast Cancer

October 12 2022

There has long been a movement in radiation oncology to identify patient populations least likely to benefit from adjuvant radiotherapy in order to scale back the use of radiotherapy in those patient populations. In recent years, this effort has begun to be met with success—two examples being “good risk” DCIS patients and favorable-risk older patients with small, node-negative, biologically less aggressive (hormone receptor-positive and HER2-negative) invasive cancers.

Scaling back radiation among patients who may not stand to benefit significantly spares these patients potentially unnecessary costs and inconveniences and toxicity associated with radiation, in addition to reducing the cost of treatment to our healthcare system. It behooves us to empower our patients to make informed decisions by ascertaining the true benefit of radiotherapy, particularly in settings of putatively low oncologic risk.

One such setting is patients with early-stage, low risk, HER2-positive breast cancer. While the original trials that cemented radiotherapy as a necessary component after lumpectomy were conducted in an era when HER2-positive breast cancer patients had among the highest recurrence rates, the advent of HER2-directed therapies has now made the prognosis for this subtype of breast cancer among the most favorable.

To that end, two chemotherapy trials—APT and ATEMPT—have demonstrated exceedingly favorable outcomes among early-stage, HER2-positive patients who undergo breast conservation therapy and receive systemic treatment that is relatively brief and has limited long-term toxicities while being highly effective at minimizing distant recurrence.

In the wake of those two studies, the NRG-BR008 (“HERO”) trial will be comparing the recurrence-free interval (RFI) among patients with early-stage, low risk HER2+ breast cancer who undergo breast conserving surgery and receive HER2-directed therapy and are randomized not to receive adjuvant breast radiotherapy versus those who are randomized to receive adjuvant radiotherapy per the current standard of care.

Given that radiotherapy is known approximately to halve local recurrence rates following lumpectomy, it is hypothesized that local recurrences may increase modestly with the omission of radiotherapy in the proposed populations (pT1N0 for those receiving adjuvant chemotherapy and, clinically T ≤3 cm N0 at baseline and ypT0N0 after neoadjuvant therapy for those receiving neoadjuvant chemotherapy + HER2-targeted therapy).

Moreover, it is anticipated that this small rise in local recurrences will not be associated with regional or distant recurrences and that breast-cancer-specific survival events will not increase significantly. As a result, it is hypothesized that the RFI without radiotherapy will not decrease to a clinically significant extent (a 3.6% increase in composite RFI events is the maximum that will be tolerated in the study; in other words, a reduction in 7-year RFI from 97.5% with RT to 93.9% without RT will be the maximum acceptable decrement).

Secondary objectives include estimating the 7-year cumulative incidence of ipsilateral breast recurrence (IBR) for the radiation-omitting arm and testing the hypothesis that the 7-year IBR rate is <7% for patients not receiving radiation therapy; estimating the time to ipsilateral breast recurrence (IBR) by treatment arm; determining the time to local regional recurrence (LRR), disease-free survival (DFS), and overall survival (OS) by treatment arm; and evaluating whether there is a difference in patient-reported breast pain and worry about recurrence in patients who do and do not receive radiation.

Studying the omission of radiotherapy among this population of HER2+ breast cancer patients who are now appreciated to have favorable risk will enable them to weigh the attendant inconveniences, cost, and morbidity of radiotherapy in light of an established absolute benefit, which may prove to be modest.

Key Eligibility Criteria:

  • Patients age ≥40 years
  • HER2+ invasive breast cancer
  • pT1N0 (≤2cm) following lumpectomy (if receiving adjuvant chemotherapy)
  • OR clinically ≤3cm and node negative at diagnosis with pCR following lumpectomy (ypT0N0 if receiving neoadjuvant chemotherapy and HER2 targeted therapy)
  • ECOG 0, 1, or 2

This study will open in the first quarter of 2023.

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