De-Escalation of Breast Radiation Trial for Hormone Sensitive, HER-2 Negative, Oncotype Recurrence Score Less Than or Equal to 18 Breast Cancer (DEBRA)

Study Overview
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Brief Summary
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This Phase III Trial evaluates 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.

Detailed Description
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Breast conservation therapy for early stage breast cancer has been an important achievement of oncology practice in the last half century and breast radiotherapy (RT) has been essential in its development. Several seminal randomized clinical trials conducted in the 1980's era demonstrated that breast radiotherapy following lumpectomy yielded overall survival outcomes equivalent to mastectomy for treatment of early stage invasive breast cancer leading to the National Institute of Health (NIH) Consensus Conference statement in 1991 supporting breast conservation treatment.This established lumpectomy with RT as an alternative to mastectomy and subsequently the rate of breast conservation for eligible breast cancer patients rose steadily. Shortly thereafter, investigators recognized that the toxicity, patient burden, and geographic barriers associated with the protracted treatment course for breast RT was a potential barrier to breast conservation utilization. Numerous phase III clinical trials were conducted randomizing women post lumpectomy to RT vs. observation aimed at identifying which cases did not derive a significant RT benefit. No such subsets of breast cancer patients were consistently identified, thereby solidifying the standard that breast conservation required both lumpectomy and RT. Two meta-analyses by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) in 2005 and 2011 further reinforced the value of breast RT post lumpectomy by examining the relationship of local recurrence and breast cancer mortality relative to the use of breast RT post lumpectomy. In each analysis, it found for axillary node negative breast cancer patients undergoing breast conservation a small but consistent increase in breast cancer mortality when breast radiotherapy was omitted. As a result, breast RT after lumpectomy has become an established paradigm for breast conservation for early stage breast cancer and is recommended by the NCCN 2018 guidelines (as it has for nearly two decades) that are commonly used today by clinicians and health systems alike. The landscape of early stage breast cancer has changed dramatically over the past three decades since the establishment of breast conservation. Widespread screening with mammography has led to the diagnosis of smaller and earlier stage disease. All breast cancers are now routinely characterized by their hormone sensitivity based on the presence of estrogen and progesterone receptors on tumor cells within the biopsy or surgical specimen and presence of HER2 (human epidermal growth factor receptor 2) which has provided an additional means of stratifying breast cancer into distinct prognostic groups. Small, node negative invasive breast cancer that is hormone sensitive (HS) and HER2-negative has a lower overall recurrence rate (local, regional, and distant) than breast cancers characterized by more adverse clinical pathologic features. However, other than in a smaller subset of women greater than 70 years old, clinical trials in this HS population still demonstrated unacceptable local recurrence risks long term after lumpectomy alone emphasizing that clinical and pathologic features are insufficient for consistently identifying when RT can safely be omitted.

Official Title
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A Phase III Clinical Trial Evaluating De-Escalation of Breast Radiation for Conservative Treatment of Stage I, Hormone Sensitive, HER-2 Negative, Oncotype Recurrence Score Less Than or Equal to 18 Breast Cancer

Conditions
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Stage I Breast Cancer

Intervention / Treatment
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* Other: Radiation and Endocrine Therapy (Tamoxifen, Anastrozol, Letrozole, Exemestane)
* Drug: Endocrine Therapy (Tamoxifen, Anastrozol, Letrozole, Exemestane)


Participation Criteria
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Eligibility Criteria
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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 U.S., authorization permitting release of personal health information. The patient must have an 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 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 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 AJCC 8th edition criteria: By pathologic evaluation, primary tumor must be pT1 (less than or equal to 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 less than or equal to 18 on diagnostic core biopsy or resected specimen. ** For patients with a T1a tumor (less than or equal to 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 ER and/or PgR positive assessed by current ASCO/CAP Guideline Recommendations for hormone receptor testing. Patients with greater than or equal to 1% ER or PgR staining by 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 MRI within 6 months prior to study entry. 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 less than 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 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 less than or equal to 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 RT for any condition. Active collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active skin rash, systemic lupus erythematosis, 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.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1: Breast Radiation Therapy + Endocrine Therapy<br>Radiation therapy to the breast and hormonal drug for at least 5 years. Tamoxifen 20 mg daily Anastrozole 1 mg daily Letrozole 2.5 mg daily Exemestane 25 mg daily | Other: Radiation and Endocrine Therapy (Tamoxifen, Anastrozol, Letrozole, Exemestane)<br>* Post lumpectomy radiation therapy will be external beam radiation to either the whole breast + boost, partial breast irradiation, or Accelerated Partial Breast Irradiation that must begin within 12 weeks of the last breast cancer surgery(including re-excision of margins). Endocrine therapy for a minimum of 5 years. The specific regimen of endocrine therapy is at the treating physician's discretion. The dose and schedule of the drug(s) used for endocrine therapy should be consistent with the instructions in the drug package insert(s). Endocrine therapy may be initiated before, during, or after completion of radiation therapy at the discretion of the investigator.<br>|
| Active Comparator: Arm 2: No Breast Radiation Therapy + Endocrine Therapy<br>No radiation therapy, only hormonal drug for at least 5 years. Tamoxifen 20 mg daily Anastrozole 1 mg daily Letrozole 2.5 mg daily Exemestane 25 mg daily | Drug: Endocrine Therapy (Tamoxifen, Anastrozol, Letrozole, Exemestane)<br>* Endocrine therapy for a minimum of 5 years. The specific regimen of endocrine therapy is at the treating physician's discretion. The dose and schedule of the drug(s) used for endocrine therapy should be consistent with the instructions in the drug package insert(s).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to invasive or noninvasive IBTR. | Time from randomization to any invasive or noninvasive IBTR or last follow-up (expressed as % IBTR-free) | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of women with an intact index breast at report of the primary endpoint inclusive of salvage second breast conservation procedures. | Time from randomization to any breast procedure after the initial surgery or last follow-up (expressed as % with intact index breast) | Through study completion, an average of 15 years. | 
| Time from randomization to the first occurrence of invasive ipsilateral breast tumor recurrence. | Time from randomization to any invasive IBTR or last follow-up (expressed as percentage of invasive IBTR-free | 5 years | 
| Time from randomization to diagnosis of a local, regional or distant recurrence as a first cancer event. | Time from randomization to any breast cancer recurrence at a local, regional or distant site or last follow-up (expressed as percentage of recurrence-free) | 5 years | 
| Time from randomization to the first distant cancer event (either a recurrence or a secondary primary cancer). | Time from randomization to any cancer occurring at a distant site or last follow-up (expressed as percentage of distant disease-free) | 5 years | 
| Time from randomization to any death. | Time from randomization to any death or last follow-up (expressed as percent surviving) | 5 years |