Testing Low Dose Tamoxifen for Invasive Breast Cancer, LoTam Trial

Phase 3SuspendedNCT06671912

Alliance for Clinical Trials in Oncology1,556 enrolled

Overview

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Recurrence-free interval (RFI)

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).

Time frame: 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

Secondary Outcomes

Endocrine therapy extent of nonadherence

The proportion of patients who stopped treatment early will be compared between the two treatment arms with a chi-square test. Additional analyses will be performed with respect to nonadherence. The proportion of patients who report any nonadherence will be compared between the two treatment arms using generalized estimating equations for logistic regression

Time frame: Up to 5 years

Physician reported incidence of adverse events (AEs)

AEs will be evaluated and graded using the Common Terminology Criteria for Adverse Events version 5.0 with special focus on the incidence of fracture, osteoporosis, stroke and thromboembolic events.

Time frame: Up to 10 years

Patient reported toxicities

Patient reported symptoms assessed using Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE). The proportion of patients with a maximum post-baseline score greater than 0 will be compared between arms using Fisher's exact test. The proportion of patients with a maximum post-baseline score greater than or equal to 3 will be compared between arms using Fisher's exact test. The same procedure will be applied to patients' maximum baseline-adjusted scores. Patients' maximum baseline-adjusted scores will be calculated using the method described by Dueck et al. The proportion of patients who report a grade 3 or higher AEs using PRO-CTCAE will be compared between the two treatment arms with a chi-square test. The proportion of patients with reported grade 3 or higher endocrine-related adverse event (any one of fracture, stroke, or deep vein thrombosis) will be compared with a chi-square test or Fisher's exact test, whichever is more appropriate.

Time frame: At baseline and up to 10 years

Invasive disease-free survival (iDFS)

IDFS will be defined as local, regional or distant recurrences, or contralateral invasive breast cancer, second non-breast primary cancer, and death from any cause. IDFS will be compared between the treatment arms with a stratified log rank test and a stratified Cox model will be used to generate the hazard ratio estimates (both a point estimate and a 95% CI).

Time frame: Up to 10 years

Locoregional recurrence free-survival (LRFS)

LRFS will be defined as the time from randomization until invasive tumor recurs in the ipsilateral breast or chest wall, axillary, supraclavicular, or internal mammary nodes (if before or synchronous with a systemic recurrence), whichever comes first. LRFS will be compared between the treatment arms with a stratified log rank test and a stratified Cox model will be used to generate the hazard ratio estimates (both a point estimate and a 95% CI).

Time frame: 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)

DDFS will be defined as the time from randomization until the tumor recurs distantly, or the patient dies, whichever comes first. DDFS will be compared between the treatment arms with a stratified log rank test and a stratified Cox model will be used to generate the hazard ratio estimates (both a point estimate and a 95% CI).

Time frame: From randomization until the tumor recurs distantly or death up to 10 years

Overall survival (OS)

OS will be defined as the time from randomization until death due to any cause. OS will be compared between the treatment arms with a stratified log rank test and a stratified Cox model will be used to generate the hazard ratio estimates (both a point estimate and a 95% CI).

Time frame: From randomization until death up to 10 years

Cumulative incidence rate of ductal carcinoma in situ (DCIS)

Cumulative incidence rate of DCIS will be measured as the time from randomization until the occurrence of an ipsilateral or contralateral DCIS diagnosis. The cumulative incidence of DCIS will be analyzed with Kaplan-Meier estimates (curve starting at 0 rather than 1) and compared with a log rank test.

Time frame: From randomization until the occurrence of an ipsilateral or contralateral DCIS diagnosis up to 10 years

RFI in patients who did not receive radiation therapy

A key analysis will be to report on the updated estimate of the primary endpoint (RFI) after all patients have been followed for 10 years, if the primary analysis took place prior to this time. There are two key subgroup analyses. These analyses will occur once the requisite number of events have been observed within the subgroup or after all patients have been followed for 10 years, whichever occurs first. All endpoints will be evaluated and reported for patients who did not receive radiation therapy. Will also determine whether there is evidence for differential treatment effects in these subgroups by including the subgroup, the treatment arm, and the interaction term. Will compare outcomes by arm and subgroup using Kaplan-Meier curves and Cox models where the control arm and better prognosis group within the grouping variable will be the reference.

Time frame: At the time requisite number of events have been observed within the subgroup or after all patients have been followed for 10 years, whichever occurs first

RFI in patients who had an intermediate Oncotype DX score

A key analysis will be to report on the updated estimate of the primary endpoint (RFI) after all patients have been followed for 10 years, if the primary analysis took place prior to this time. There are two key subgroup analyses. These analyses will occur once the requisite number of events have been observed within the subgroup or after all patients have been followed for 10 years, whichever occurs first. All endpoints will be evaluated and reported for patients who had an intermediate Oncotype DX score. Will also determine whether there is evidence for differential treatment effects in these subgroups by including the subgroup, the treatment arm, and the interaction term. Will compare outcomes by arm and subgroup using Kaplan-Meier curves and Cox models where the control arm and better prognosis group within the grouping variable will be the reference.