NRG-BR007 (“DEBRA”): A Phase III Clinical Trial Evaluating the De-escalation of Breast Radiation for a More Conservative Treatment of Patients With Low-Risk, Hormone-Sensitive, Node-Negative Breast Cancer

October 12 2022

Over the last three decades, radiotherapy has become an established part of the paradigm for breast conservation in early-stage breast cancer. Recognizing that the toxicity and patient burden associated with a protracted course of radiotherapy are potential barriers to the use of breast conservation, investigators have made multiple attempts to identify subsets of patients who do not derive a significant benefit from radiotherapy and could therefore be spared from receiving it.

Initially, these attempts failed to successfully identify successfully any such subsets of patients, but the landscape of early-stage breast cancer has changed dramatically over the same three decades. Widespread screening with mammography has led to the diagnosis of smaller and earlier stage disease, and all breast cancers are now routinely characterized by their hormone sensitivity, which has provided an additional means of stratifying breast cancer into distinct prognostic groups.

A small, node-negative, invasive breast cancer that is hormone-sensitive and HER2-negative has a lower overall risk of recurrence (local, regional, and distant) than breast cancers characterized by more adverse clinical pathologic features. However, clinical trials in this hormone-sensitive population still demonstrated unacceptable long-term local recurrence risks after lumpectomy alone, which emphasized that clinical and pathologic features are insufficient for consistently identifying when radiotherapy can safely be omitted.

Fortunately, over the past decade, numerous biomarkers have emerged for guiding adjuvant systemic therapy decision-making for early-stage breast cancer, adding yet another means of stratification, which unlike previous means, have shown great promise in definitively identifying groups of patients for whom radiotherapy can be omitted. There has therefore been increasing clinical enthusiasm for evaluating the role of biomarkers in reducing overtreatment with radiotherapy by selecting low-risk, hormone-sensitive, node-negative breast cancer patients for whom breast conservation is safely achievable with lumpectomy alone.

The Oncotype DX™ Recurrence Score in particular is a commercially available multigene assay using RNA expression profiling which has been used in the USA for over 10 years for systemic therapy decision-making and has been included in the NCCN guidelines since 2008. Recently, confidence in and enthusiasm for the Oncotype DX™ Recurrence Score in guiding clinical decision-making was greatly enhanced by the TAILORx trial, which now allows tens of thousands of women annually to omit chemotherapy and its associated toxicities from their breast cancer treatment.

The NRG BR007 (“DEBRA”) trial will include patients with stage I (T1N0), hormone-sensitive, HER-2 negative, oncotype recurrence score (RS) £ 18 breast cancer who have undergone a lumpectomy with histologically clear margins. These patients will be entered into the trial and randomized into one of two arms—Arm 1: radiation therapy and endocrine therapy versus Arm 2: endocrine therapy alone—in order to evaluate whether treatment with endocrine therapy alone results in a non-inferior rate of invasive or non-invasive ipsilateral breast recurrence (IBR) in comparison to a treatment including radiotherapy. Secondary objectives will compare relapse-free interval (RFI), distant disease-free survival (DDFS), and overall survival (OS), as well as patient-reported breast pain, worry about recurrence, and patient adherence to treatment between the two arms. Post lumpectomy breast radiation using standard methods (Hypo- or conventionally fractionated whole breast irradiation with or without boost or Accelerated Partial Breast Irradiation are permitted. The type of endocrine therapy (tamoxifen or aromatase inhibitor) is at the physician’s discretion and for at least 5 years. The trial will accrue 1670 patients.

The NRG BR007 (“DEBRA”) trial may not only pave the way for future studies utilizing biomarkers such as the Oncotype DX™ Recurrence Score to guide clinical practice, but also could allow as many as 25,000 or more breast cancer patients annually to omit breast radiotherapy safely after lumpectomy.

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