A Phase III Randomized, Placebo-Controlled Clinical Trial Evaluating the Use of Adjuvant Endocrine Therapy +/- One Year of Everolimus in patients with High-Risk, Hormone Receptor-Positive and HER2/neu Negative Breast Cancer


Breast - Female | Breast - Male | Cancer

Trial Phase

Phase III

Trial Purpose and Description

Trial Purpose

The primary objective of this study is to compare whether the addition of one year of everolimus (10 mg daily) to standard adjuvant endocrine therapy improves invasive disease-free survival (IDFS) in patients with high-risk, hormone-receptor (HR) positive and HER2-negative breast cancer.

Participation Guidelines


Eligibility Criteria


Patients must have a histologically confirmed diagnosis of invasive breast carcinoma with positive estrogen (ER)- and/or progesterone-receptor (PR) status, and negative human epidermal growth factor receptor (HER)2, for whom standard adjuvant endocrine therapy is planned
ER and PR positivity must be assessed according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines as either ER or PR &ge 1% positive nuclear staining
HER2 will be determined by immunohistochemistry (IHC) or non-amplified fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH)
If HER2 IHC is 2+, FISH/CISH must be performed and must not be positive (must be a ratio of &le 2), but otherwise FISH/CISH is not required if IHC is 0 or 1+ by institutional standards
Patients must not have inflammatory breast cancer and must not have metastatic breast cancer (stage IV disease) patients with multifocal, multicentric, and synchronous bilateral breast cancers are allowed
Multifocal disease is defined as more than one invasive cancer < 2 cm from the largest lesion within the same breast quadrant
Multicentric disease is defined as more than one invasive cancer &ge 2 cm from the largest lesion within the same breast quadrant or more than one lesion in different quadrants
Synchronous bilateral disease is defined as invasive breast cancer in both breasts, diagnosed within 30 days of each other
Patients must be high risk by belonging to one of the following risk groups:
Completion of adjuvant chemotherapy and pathologically negative axillary nodes, and a tumor measuring &ge 2 cm in greatest diameter, and an Oncotype DX® recurrence score (RS) > 25 (completed as standard of care)
Completion of adjuvant chemotherapy, and pathologically 1-3 positive axillary lymph nodes, and an Oncotype DX® RS > 25 (screened via S1007 or otherwise)
Completion of adjuvant chemotherapy and pathologically 4 or more positive axillary lymph nodes independent of the Oncotype DX® RS in the primary tumor
Completion of neoadjuvant chemotherapy and 4 or more positive nodes pathologically determined prior to or after chemotherapy
Patients must have completed either breast-conserving surgery or total mastectomy, with negative margins and appropriate axillary staging a negative margin is defined as no evidence of tumor or ductal carcinoma in situ (DCIS) at the line of resection additional operative procedures may be performed to obtain clear margins
Patients who had breast-conserving surgery must have completed whole-breast radiation use of regional nodal-basin radiation will be at the discretion of the investigator according to institutional guidelines
Patients with &ge 4 positive lymph nodes must have completed breast/chest wall and nodal-basin radiation therapy according to standard-of-care guidelines before randomization omission of radiation therapy is not allowed in this high-risk population of patients
Patients must be registered no sooner than 21 days after completion of radiation therapy and must have recovered (&le grade 1) from any of the effects of radiation
Patients must have undergone axillary staging by sentinel-node biopsy or axillary lymph node dissection (ALND)
For patients with 1-3 positive lymph nodes, sentinel-node biopsy alone is allowed provided that the patient completed either whole-breast or chest-wall radiation and the primary tumor is < 2 cm
All patients with &ge 4 positive lymph nodes must have completed ALND (with or without prior sentinel-node biopsy)

Peripheral granulocyte count &ge 1,500/mL
Hemoglobin &ge 9 g/dL
Platelet count &ge 100,000/mL
Bilirubin &le 1.5 mg/dL (&le 3.0 mg/dL if due to Gilbert syndrome)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) &le 1.5 times institutional upper limit of normal (IULN)
Alkaline phosphatase &le 1.5 times IULN
Serum creatinine level &le IULN
Fasting cholesterol &le 300 mg/dL and triglycerides &le 2.5 times IULN patients may be on lipid-lowering agents to reach these values
Patients must have a performance status of 0-2 by Zubrod criteria
Patients must not have any grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia
Patients must not have uncontrolled diabetes (defined as a hemoglobin [Hg] A1C > 7% within 28 days prior to registration)
Patients known to be human immunodeficiency virus (HIV) positive may be enrolled if baseline CD4 count is > 500 cells/mm³ and they are not taking anti-retroviral therapy
Patients with known hepatitis are not eligible
Patients must not have any known uncontrolled, underlying pulmonary disease
Patients must be able to take oral medications
Patients may not have any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of blinded drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
Patients must not be pregnant or nursing
Women/men of reproductive potential must have agreed to use an effective non-hormonal contraceptive method during and for 8 weeks after completion of study therapy
In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation corresponding procedures for men include castration, vasectomy, and barrier-contractive devices
If at any point a previously celibate patient chooses to become heterosexually active during the protocol therapy, he/she is responsible for beginning contraceptive measures
No other prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for 5 years

See Disease Characteristics
Patients must have completed standard neoadjuvant or adjuvant chemotherapy prior to randomization completion of chemotherapy will be determined by the treating oncologist, but should include a minimum of 4 courses (a course of weekly paclitaxel is considered 3 doses) patients must be registered within 21 weeks after completion of chemotherapy patients may have started endocrine therapy at any time after the diagnosis of the current breast cancer
Patients must not be receiving or planning to receive trastuzumab
Concurrent bisphosphonate therapy is allowed
Patients must not have prior exposure to mTOR inhibitors (rapamycin, everolimus, temsirolimus, deforolimus)
Patients must not have prior treatment with any investigational drug within the preceding 28 days and must not be planning to receive any other investigational drug for the duration of the study
Patients must not be planning to receive any other anticancer drug for the duration of the study
Patients must not have an organ allograft or other history of immune compromise patients must not be receiving chronic, systemic treatment with corticosteroids or other immunosuppressive agent topical or inhaled corticosteroids are allowed
Patients must not have received immunization with an attenuated live vaccine (e.g., intranasal influenza, measles, mumps, and rubella [MMR], oral polio, varicella, zoster, yellow fever, and Bacillus Calmette-Guérin [BCG] vaccines) within seven days prior to registration nor have plans to receive such vaccination while on protocol treatment
Patients must not have taken within 14 days prior to registration, be taking, nor plan to take while on protocol treatment, strong cytochrome P450 3A4 (CYP3A4) inhibitors and/or CYP3A4 inducers

Southwest Oncology Group (SWOG)
Last Updated:
Study HIC#: