CLINICAL TRIAL / NCT04852887
De-Escalation of Breast Radiation Trial for Hormone Sensitive, HER-2 Negative, Oncotype Recurrence Score Less Than or Equal to 18 Breast Cancer (DEBRA)
- Interventional
- Recruiting
- NCT04852887
Contact Information
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
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.
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.
Gender
All
Age Group
50 Years to 70 Years
Accepting Healthy Volunteers
No
Inclusion Criteria:
- • The patient or a legally authorized representative must provide study-specific
informed consent prior to pre-entry/Step 1 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) or
patients at Canadian provinces or approved international sites where Oncotype
DX Recurrence Score testing would not be covered, who do not already have an
Oncotype DX Recurrence Score at pre-entry/Step 1, a specimen (unstained blocks
or slides) must be sent to the Genomic Health centralized laboratory. Tumor
size sample must be greater than or equal to 0.2 cm for analysis.
*** The Oncotype RS can be run on the biopsy core or surgical specimen. The
patient cannot have initiated endocrine therapy prior to tissue collection.
- An Oncotype RS is required for eligibility, however, for a patient whose tumor
has already had a MammaPrint test completed as part of usual care when being
considered for enrollment and is in the binary "Low" category will meet this
eligibility criteria and an Oncotype RS does not need to be performed.
- 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 pre-entry/Step
1. For study purposes, postmenopausal is defined as:
- Age 56 or older with no spontaneous menses for at least 12 months prior to
pre-entry/Step 1; or a documented hysterectomy; or
- Age 55 or younger with no spontaneous menses for at least 12 months prior to
pre-entry/Step 1 (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 pre-entry/Step 1 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 pre-entry/Step 1.
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.
- pT1 mi and 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, or biotherapy, administered
for the currently diagnosed breast cancer prior to pre-entry/Step 1.
- 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 pre-entry/Step 1.
- 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.
** Patients are eligible for BR007 if they receive a short course of
preoperative endocrine therapy of less than 6 weeks duration (prior to
randomization/Step 2) for this diagnosis after the core biopsy (and can
continue postoperatively if:
- the Oncotype DX Recurrence Score is assessed on the biopsy core and is less
than or equal to 18, AND
- the patient had not initiated endocrine therapy prior to core biopsy tissue
collection.
*** This does not apply to adjuvant endocrine therapy recommended for this
diagnosis which may start any time after surgery including prior to
registration (Pre-entry/Step 1).
- 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 pre-entry/Step 1 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 pre-entry/Step 1.)
- 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 pre-entry/Step 1.