Testing the Usual Treatment of Radiation Therapy and Hormonal Therapy to Hormonal Therapy alone for Low-Risk, Early Stage Breast Cancer, the DEBRA Trial

This phase III trial compares the effect of radiation therapy combined with hormonal therapy versus hormonal therapy alone in treating patients with low risk, early stage breast cancer with Oncotype Dx Recurrence =< 18. Oncotype DX is a laboratory test which results in a score that is used to help predict whether breast cancer will spread to other parts of the body or come back. Radiation therapy uses high doses of radiation to kill cancer cells and shrink tumors but may result in some side effects. Hormones called estrogen and progesterone may contribute to the growth of breast tumor cells. Hormone therapy, also called endocrine therapy, may stop the growth of tumor cells by blocking or removing these hormones. This clinical trial may help researchers understand if patients with low-risk, early stage breast cancer who have Oncotype recurrence score of =< 18 can safely omit radiation therapy and only be treated with hormonal therapy without losing any radiation treatment benefit.

Inclusion Criteria

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
• The patient must be >= 50 years and < 70 years of age
• The trial is open to female and male patients
• The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• The patient must have undergone a lumpectomy and the margins of the resected specimen or re-excision must be histologically free of invasive tumor and breast ductal carcinoma in situ (DCIS) with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. (Patients with margins positive for breast lobular carcinoma in situ [LCIS] are eligible without additional resection)
• The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination
• Patient must have undergone axillary staging (sentinel node biopsy and/or axillary node dissection)
• The following staging criteria must be met postoperatively according to American Joint Committee on Cancer (AJCC) 8th edition criteria: * By pathologic evaluation, primary tumor must be pT1 (=< 2 cm). * By pathologic evaluation, ipsilateral nodes must be pN0. (Patients with pathologic staging of pN0(i+) or pN0(mol+) are NOT eligible)
• Oncotype DX Recurrence Score of =< 18 on diagnostic core biopsy or resected specimen. * For patients with a T1a tumor (=< 0.5 cm in size) who do not already have an Oncotype DX Recurrence Score at study entry, a specimen (unstained blocks or slides) must be sent to the Genomic Health centralized laboratory
• The tumor must have been determined to be estrogen receptor (ER) and/or progesterone receptor (PgR) positive assessed by current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Guideline Recommendations for hormone receptor testing. Patients with >= 1% ER or PgR staining by immunohistochemistry (IHC) are considered positive
• The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines
• Patients may be premenopausal or postmenopausal at the time of study entry. For study purposes, postmenopausal is defined as: * Age 56 or older with no spontaneous menses for at least 12 months prior to study entry; or a documented hysterectomy; or * Age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard; or * Documented bilateral oophorectomy
• The interval between the last surgery for breast cancer (including re-excision of margins) and study entry must be no more than 70 days
• The patient must have recovered from surgery with the incision completely healed and no signs of infection
• Bilateral mammogram or magnetic resonance imaging (MRI) within 6 months prior to study entry
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients must be intending to take endocrine therapy for a minimum 5 years duration (tamoxifen or aromatase inhibitor). The specific regimen of endocrine therapy is at the treating physician’s discretion

Exclusion Criteria

• Definitive clinical or radiologic evidence of metastatic disease
• pT2 - pT4 tumors including inflammatory breast cancer
• Pathologic staging of pN0(i+) or pN0(mol+), pN1, pN2, or pN3 disease
• Patient had a mastectomy
• Palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes, unless there is histologic confirmation that these nodes are negative for tumor
• Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign
• Non-epithelial breast malignancies such as sarcoma or lymphoma
• Proven multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by 4 or more centimeters. (Patients with multifocal carcinoma are eligible)
• Paget's disease of the nipple
• Any history, not including the index cancer, of ipsilateral invasive breast cancer or ipsilateral DCIS treated or not treated. (Patients with synchronous or previous ipsilateral LCIS are eligible)
• Synchronous or previous contralateral invasive breast cancer or DCIS. (Patients with synchronous and/or previous contralateral LCIS are eligible.)
• Surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re-excision, the patient is eligible.)
• Treatment plan that includes regional nodal irradiation
• Any treatment with radiation therapy, chemotherapy, biotherapy, and/or endocrine therapy administered for the currently diagnosed breast cancer prior to study entry. (Short course endocrine therapy of < 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is =< 18)
• History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to study entry
• Current therapy with any endocrine therapy such as raloxifene (Evista), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or breast cancer prevention. (Short course endocrine therapy of < 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is =< 18)
• Patients intending to continue on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible. Patients that discontinue oral, transdermal, or subdermal estrogen replacement prior to registration are eligible
• Prior breast or thoracic radiation therapy (RT) for any condition
• Active collagen vascular disease, specifically dermatomyositis with a creatine phosphokinase (CPK) level above normal or with an active skin rash, systemic lupus erythematosus, or scleroderma
• Pregnancy or lactation at the time of study entry or intention to become pregnant during treatment. (Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to study entry)
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of study therapy or that may affect the interpretation of the results or render the patient at high risk from treatment complications
• Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results
• Use of any investigational product within 30 days prior to study entry

PRIMARY OBJECTIVE:

I. To evaluate whether breast conservation surgery and endocrine therapy results in a non-inferior rate of invasive or non-invasive ipsilateral breast tumor recurrence (IBTR) compared to breast conservation with breast radiation and endocrine therapy.

SECONDARY OBJECTIVES:

I. To evaluate whether breast conservation surgery and endocrine therapy inclusive of any second breast conservation surgery for salvage of IBTR results in a non-inferior rate of overall breast conservation compared to breast conserving surgery, endocrine therapy, and radiation for IBTR.

II. To evaluate whether breast conservation surgery and endocrine therapy results in a non-inferior rate of invasive ipsilateral breast tumor recurrence (IIBTR) compared to breast conservation, breast radiation, and endocrine therapy.

III. To evaluate whether breast conservation surgery and endocrine therapy results in a non-inferior relapse free interval (RFI) compared to breast conservation, breast radiation, and endocrine therapy.

IV. To evaluate whether breast conservation surgery and endocrine therapy results in a non-inferior distant disease-free survival (DDFS) compared to breast conservation, breast radiation, and endocrine therapy.

V. To evaluate whether breast conservation surgery and endocrine therapy results in a non-inferior overall survival (OS) compared to breast conservation, breast radiation, and endocrine therapy.

VI. To evaluate whether there is a difference in patient-reported breast pain in women who do and do not receive breast radiation.

VII. To evaluate whether there is a difference in patient-reported worry about recurrence in women who do and do not receive breast radiation.

VIII. To evaluate whether adherence to endocrine therapy following breast conservation surgery alone is non inferior compared to endocrine therapy with breast conservation surgery and breast radiation.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Within 12 weeks of the last breast cancer surgery, patients undergo external beam radiation therapy. Patients also receive endocrine therapy for a minimum of 5 years initiated before, during, or after completion of radiation therapy at the discretion of the investigator. Endocrine therapy may include tamoxifen, anastrozole, letrozole, exemestane, or luteinizing hormone-releasing hormone (LHRH) agonist/antagonist. Treatment continues in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive endocrine therapy for a minimum of 5 years at the discretion of the investigator. Endocrine therapy may include tamoxifen, anastrozole, letrozole, exemestane, or LHRH agonist/antagonist. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 24 months, and then every 12 months from year 3 through year 10 after randomization.

Trial Phase Phase III

Trial Type Treatment

Lead Organization
NRG Oncology

Principal Investigator
Julia R. White

• Primary ID NRG-BR007
• Secondary IDs NCI-2021-00222
• Clinicaltrials.gov ID NCT04852887