Amending protocol to increase sample size

This phase III trial compares the effect of low dose tamoxifen to usual hormonal therapy, including aromatase inhibitors, in treating post-menopausal women with hormone positive, HER2 negative early stage breast cancer. Tamoxifen is in a class of medications known as antiestrogens. It blocks the activity of estrogen (a female hormone) in the breast. This may stop the growth of some breast tumors that need estrogen to grow. Aromatase inhibitors, such as anastrozole, letrozole, and exemestane, prevent the formation of estradiol, a female hormone, by interfering with an aromatase enzyme. Aromatase inhibitors are used as a type of hormone therapy to treat postmenopausal women with hormone-dependent breast cancer. Giving low dose tamoxifen may be more effective compared to usual hormone therapy in treating post-menopausal women with hormone-positive, HER2 negative early stage breast cancer.

The primary and secondary objectives of the study:

PRIMARY OBJECTIVE:

I. To evaluate whether the recurrence-free interval (RFI) with low-dose tamoxifen is non-inferior to standard-of-care endocrine therapy among post-menopausal women with early-stage, low molecular risk breast cancer.

SECONDARY OBJECTIVES:

I. To compare endocrine therapy nonadherence rates between treatment arms. II. To compare the incidence of adverse events between treatment arms, including osteoporosis, fracture, endometrial carcinoma, stroke, and deep vein thrombosis.

III. To compare endocrine therapy-related patient reported symptoms between treatment arms.

IV. To compare the invasive disease-free survival between treatment arms. V. To compare the locoregional breast cancer recurrence between treatment arms. VI. To compare distant recurrence free survival between treatment arms. VII. To compare overall survival between treatment arms. VIII. To compare ductal carcinoma in situ (DCIS) incidence (ipsilateral and contralateral) between treatment arms.

IX. To evaluate the association between radiotherapy modality (no radiation, partial breast radiation, and whole breast radiation) and RFI in each arm.

X. To explore important measures of quality of life that would reasonably be expected to vary by study arm, including global quality of life and reasons for nonadherence.

XI. To compare change in mammographic density at two years between treatment arms.

XII. To conduct a within patient comparison of automated versus (vs) semi-automated mammographic density determination.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive standard of care endocrine therapy per physician choice with either anastrozole orally (PO), letrozole PO, exemestane PO or standard dose tamoxifen PO once daily (QD) for up to 5 years in the absence of disease progression or unacceptable toxicity. Patients may also undergo mammogram or magnetic resonance imaging (MRI), dual X-ray absorptiometry (DEXA), and blood sample collection on study.

ARM II: Patients receive low-dose tamoxifen PO every other day (QOD) for up to 5 years in the absence of disease progression or unacceptable toxicity. Patients may also undergo mammogram or MRI, DEXA, and blood sample collection on study.

After completion of study treatment, patients are followed up for 10 years after registration.

Inclusion Criteria:

• Unilateral invasive adenocarcinoma of the breast that is histologically confirmed

  • Invasive breast cancer is estrogen receptor positive in ≥ 10% of cells
  • HER2 negative by current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines

• The patient must have a multigene assay with a low-risk score, including any of the following (if more than one genomic assay was obtained, both are required to be low-risk):

  • Oncotype DX recurrence score ≤ 25
  • Mamma Print low risk
  • Prosigna risk of recurrence ≤ 40 Patients with pathologic tumor size ≤ 0.5cm who meet all other eligibility criteria are eligible for enrollment without multigene assay testing. The total number of enrolled patients with tumor size ≤ 0.5cm without genomic testing will be limited

• Tumor size must be ≤ 3 cm by pathologic evaluation. Multifocal tumors are permitted if the largest focus of disease is ≤ 3 cm

• Adequate surgical removal of all clinically evident disease in the breast with either breast conserving surgery or mastectomy. Negative margins on final pathology are required. Additional excisions may be performed to obtain clear margins before registration

• No clinical (cN1, cN2, cN3) or pathologic (pN1mi, pN1, pN2, or pN3) evidence of lymph node involvement on either needle biopsy or surgical lymph node assessment. Patients with pN0(i+) or pN0 (mol+) are eligible

  • Surgical axillary staging (sentinel lymph node biopsy ± axillary lymph node dissection) is completed according to physician discretion
  • For patients age <70, clinicians may selectively choose to forego surgical axillary staging if an Ipsilateral axillary ultrasound or preop MRI shows no lymph node involvement with no evidence of lymphadenopathy or suspicious thickening is required in this scenario
  • For patients age ≥ 70 without surgical axillary staging, axillary ultrasound is not required in this scenario but may be obtained at the discretion of the treating investigator

• No tumors that are considered pT4

• No definitive clinical or radiologic evidence of metastatic disease

• No palpable or radiographically suspicious axillary, supraclavicular, infraclavicular, or internal mammary lymph nodes, unless there is histologic confirmation that these lymph nodes are negative for tumor

• No suspicious microcalcifications, densities, or palpable abnormalities in the ipsilateral or contralateral breast, unless biopsied and found to be benign

• An interval of no more than 20 weeks between the date of surgery and the date of registration

• Must have had a bilateral mammogram or MRI within 9 months prior to registration

• Must be intending to take endocrine therapy for 5 years duration

• No prior treatment with endocrine therapy or chemotherapy for the currently diagnosed breast cancer prior to registration. (Short course endocrine therapy of ≤ 6 weeks duration is acceptable after core biopsy and before surgery, if genomic testing is assessed on the biopsy core and meets eligibility requirements for a low-risk score.)

• No use of oral hormone replacement therapy or transdermal estrogen replacement therapy (patch) within 7 days prior to registration

• Age ≥ 18 years and female

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Postmenopausal status confirmed as one of the following:

  • No spontaneous menses ≥ 1 year or
  • No menses for < 1 year with follicle stimulating hormone (FSH) and estradiol levels within a postmenopausal range according to institutional standards or
  • Previous bilateral surgical oophorectomy

• None of the following conditions:

  • Abnormal or dysfunctional uterine bleeding within 1 year prior to study enrollment or
  • Any patient with known atypia or endometrial pathology that the opinion of the treating investigator would place the patient at undue risk of endometrial cancer with tamoxifen or
  • Any patient with a known hypercoagulable state that in the opinion of the treating investigator would put the patient at undue risk of venous thromboembolism with tamoxifen

• No history of breast or thoracic radiotherapy for any previous condition. Patients may complete radiotherapy for the currently diagnosed breast cancer prior to registering for the study. In this scenario, registration must be completed within 12 weeks of completing breast radiotherapy

• No previous history of ipsilateral invasive breast cancer or ipsilateral ductal carcinoma in situ (DCIS), regardless of the disease-free interval

• No synchronous or previous history of contralateral invasive breast cancer or DCIS

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• No current treatment with any endocrine therapy for breast cancer prevention or osteoporosis, including raloxifene, tamoxifen, or other selective estrogen receptor modulator. Patients intending to continue oral hormone replacement are not eligible

• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial