LoTam: A Randomized, Phase III Clinical Trial of Low-Dose Tamoxifen for Selected Patients With Molecular Low-Risk Early-Stage Breast Cancer
试验速览
- 阶段
- 3 期
- 状态
- 暂停
- 入组人数
- 1,556
- 试验地点
- 1,355
- 主要终点
- Recurrence-free interval (RFI)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- 未提供
研究组 & 干预措施
Arm I (anastrozole, letrozole, exemestane, tamoxifen)
Patients receive standard of care endocrine therapy per physician choice with either anastrozole PO, letrozole PO, exemestane PO or standard dose tamoxifen PO QD 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.
干预措施: Anastrozole (Drug)
Arm I (anastrozole, letrozole, exemestane, tamoxifen)
Patients receive standard of care endocrine therapy per physician choice with either anastrozole PO, letrozole PO, exemestane PO or standard dose tamoxifen PO QD 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.
干预措施: Tamoxifen (Drug)
Arm II (low dose tamoxifen)
Patients receive low-dose tamoxifen PO 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.
干预措施: Tamoxifen (Drug)
Arm I (anastrozole, letrozole, exemestane, tamoxifen)
Patients receive standard of care endocrine therapy per physician choice with either anastrozole PO, letrozole PO, exemestane PO or standard dose tamoxifen PO QD 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.
干预措施: Biospecimen Collection (Procedure)
Arm I (anastrozole, letrozole, exemestane, tamoxifen)
Patients receive standard of care endocrine therapy per physician choice with either anastrozole PO, letrozole PO, exemestane PO or standard dose tamoxifen PO QD 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.
干预措施: Questionnaire Administration (Other)
Arm II (low dose tamoxifen)
Patients receive low-dose tamoxifen PO 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.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm II (low dose tamoxifen)
Patients receive low-dose tamoxifen PO 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.
干预措施: Questionnaire Administration (Other)
Arm I (anastrozole, letrozole, exemestane, tamoxifen)
Patients receive standard of care endocrine therapy per physician choice with either anastrozole PO, letrozole PO, exemestane PO or standard dose tamoxifen PO QD 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.
干预措施: Dual X-ray Absorptiometry (Biological)
Arm I (anastrozole, letrozole, exemestane, tamoxifen)
Patients receive standard of care endocrine therapy per physician choice with either anastrozole PO, letrozole PO, exemestane PO or standard dose tamoxifen PO QD 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.
干预措施: Mammogram (Procedure)
Arm I (anastrozole, letrozole, exemestane, tamoxifen)
Patients receive standard of care endocrine therapy per physician choice with either anastrozole PO, letrozole PO, exemestane PO or standard dose tamoxifen PO QD 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.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm II (low dose tamoxifen)
Patients receive low-dose tamoxifen PO 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.
干预措施: Mammogram (Procedure)
Arm II (low dose tamoxifen)
Patients receive low-dose tamoxifen PO 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.
干预措施: Dual X-ray Absorptiometry (Biological)
Arm II (low dose tamoxifen)
Patients receive low-dose tamoxifen PO 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.
干预措施: Biospecimen Collection (Procedure)
Arm I (anastrozole, letrozole, exemestane, tamoxifen)
Patients receive standard of care endocrine therapy per physician choice with either anastrozole PO, letrozole PO, exemestane PO or standard dose tamoxifen PO QD 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.
干预措施: Letrozole (Drug)
Arm I (anastrozole, letrozole, exemestane, tamoxifen)
Patients receive standard of care endocrine therapy per physician choice with either anastrozole PO, letrozole PO, exemestane PO or standard dose tamoxifen PO QD 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.
干预措施: Exemestane (Drug)
结局指标
主要结局
Recurrence-free interval (RFI)
时间窗: From randomization to the first of the following breast cancer events: invasive ipsilateral breast or chest wall recurrence, regional recurrence, distant recurrence, and death from breast cancer up to 5 years
The Kaplan-Meier method will be used to estimate the distribution of RFI times and a stratified log-rank test for non-inferiority will be used to assess whether RFI with low-dose tamoxifen is non-inferior to standard-of-care endocrine therapy in this patient population. Stratified Cox modeling will be used to estimate the hazard ratio and corresponding one-sided 95% confidence interval (CI).
次要结局
- Endocrine therapy extent of nonadherence(Up to 5 years)
- Physician reported incidence of adverse events (AEs)(Up to 10 years)
- Patient reported toxicities(At baseline and up to 10 years)
- Invasive disease-free survival (iDFS)(Up to 10 years)
- Locoregional recurrence free-survival (LRFS)(From randomization until invasive tumor recurs in the ipsilateral breast or chest wall, axillary, supraclavicular, or internal mammary nodes up to 10 years)
- Distant disease-free survival (DDFS)(From randomization until the tumor recurs distantly or death up to 10 years)
- Overall survival (OS)(From randomization until death up to 10 years)
- Cumulative incidence rate of ductal carcinoma in situ (DCIS)(From randomization until the occurrence of an ipsilateral or contralateral DCIS diagnosis up to 10 years)