LoTam: A Randomized, Phase III Clinical Trial of Low-Dose Tamoxifen for Selected Patients With Molecular Low-Risk Early-Stage Breast Cancer
LoTam: A Randomized, Phase III Clinical Trial of Low-Dose Tamoxifen for Selected Patients With Molecular Low-Risk Early-Stage Breast Cancer
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
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):
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
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:
None of the following conditions:
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
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