In Sweden, approximately 7000 women are diagnosed with hormone-sensitive breast cancer annually. According to international and national guidelines, most of these women are recommended anti-hormonal therapy for five to ten years to improve prognosis. Tamoxifen, one of the most widely used anti-hormonal agents globally, reduces the risk of recurrence by 40% and breast cancer mortality by 30%. Tamoxifen is a pro-drug that undergoes hepatic metabolism to form endoxifen and other active metabolites. Variability in metabolic capacity affects therapeutic efficacy: poor metabolisers produce insufficient endoxifen and other active metabolites, risking therapeutic failure, while ultrarapid metabolisers generate excessive amounts, leading to intolerable adverse effects. Today, 30-50% of patients discontinue treatment prematurely due to severe side effects, resulting in suboptimal outcomes. Currently, tamoxifen is uniformly prescribed at a daily dose of 20 mg, and so far, no clinical trials have tested whether individualised dosing could enhance adherence and improve survival outcomes. The primary objective is to evaluate whether individualised tamoxifen dosing reduces discontinuation rates and enhances patient outcomes in breast cancer treatment.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,100
Each subject starts their treatment with the standard dose 20 mg tamoxifen daily by oral intake. During visits 2 (3 months), 3 (six months) and 4 (twelve months), the investigator will either let the patient remain on 20 mg tamoxifen or individualise the dose. The investigator may change the daily tamoxifen from 20 mg per day to: a halved dose to 10 mg, or a doubled dose to 40 mg. The recommendation for oral intake of tablet(s) tamoxifen for a daily dose of 10, 20 or 40 mg is accordingly: for 10 mg: one tablet (20 mg) every two days for 20 mg: one tablet (20 mg) every day for 40 mg: two tablets (20 mg) every day.
The global standard dose for everyone is 20 mg orally once per day. Each subject undergoes treatment with the standard dose 20 mg daily by oral intake of one tablet, with no possibility of dose adjustment during the trial.
S:a Älvsborgs Sjukhus
Borås, Sweden
NOT_YET_RECRUITINGSkaraborgs Sjukhus
Skövde, Sweden
RECRUITINGCapio S:t Görans Sjukhus
Stockholm, Sweden
NOT_YET_RECRUITINGSödersjukhuset, Onkologiska kliniken
Stockholm, Sweden
RECRUITINGDiscontinuation of tamoxifen.
The primary outcome is discontinuation of tamoxifen. This will be declared when any of the following four criteria are satisfied: * Agreement between patient and doctor that the patient will discontinue tamoxifen. * Patient notifies doctor that she has discontinued tamoxifen. * Patient-reported tamoxifen tablet intake of zero tablets for 13 consecutive weeks. * Patient refuses dose of tamoxifen as recommended per protocol by their clinician.
Time frame: From enrollment to end of treatment at 60 months.
Patient reported outcomes.
At baseline and two weeks before the doctor's appointment at 3, 6 and 12 months after start of tamoxifen therapy all patients will answer the POWER symptom burden questionnaire. Patients will be answering questionnaires yearly year 2-5 from start of tamoxifen. The purpose is evaluate treatment-related side effects (e.g., tamoxifen). The symptom burden questionnaire includes the BCPT Eight Symptom Scale (BESS) (derived from the 42-item Breast Cancer Prevention Trial checklist), which is a 30-item, 5-point Likert-type, self-report tool measuring symptom distress in breast cancer patients over the past four weeks. It covers eight specific domains (hot flashes, nausea, bladder/vaginal problems, pain, cognitive, weight, arm problems). Higher scores indicate higher symptom distress, where patients rate how "bothered" they were on a scale of 0 (Not at all) to 4 (Extremely).
Time frame: From enrollment to end of treatment at 60 months.
Quality of life questionnaire
At baseline and two weeks before the doctor's appointment at 3, 6 and 12 months after start of tamoxifen therapy all patients will answer the quality-of-life questionnaire designed for this study. A prespecified set of answers from the questionnaire will be available for the doctor and patient to discuss at the appointment. Patient will be answering the same questionnaire yearly year 2-5 in the study. The results from the questionnaires will not be discussed with the patient but analysed at the end of the study.
Time frame: From enrollment to end of treatment at 60 months.
Concentration of circulation plasma metabolites
Tamoxifen and the metabolites 4-OH-tamoxifen, N-DM-tamoxifen, and endoxifen will be analysed in plasma at each blood collection time point. For patients in the intervention arm, the endoxifen concentration will be accessible in the patient eCRF and discussed at the doctor's visit for decision on the appropriate dose. For patients in the control arm, neither the patient nor the doctor will have access to the endoxifen concentrations during the trial. Endoxifen concentrations in the control arm will remain pseudonymised and stored on servers without access for investigators or relevant study personnel until end-of-trial.
Time frame: From 3 months after treatment start to end of treatment at 60 months
Invasive disease-free survival (iDSF)
iDSF measures the time from randomized treatment or surgery until the first occurrence of an invasive cancer recurrence, a new primary invasive cancer, or death from any cause. Study site will report first recurrence, local or distant during the patients 5 years in the study. For long-term follow-up the information about first recurrence or death will be collected from the National Cancer Registry.
Time frame: From enrollment to end of treatment at 60 months.
Distant relapse-free survival (DRFS)
DRFS measures the time from primary cancer treatment until the first recurrence at a distant site (metastasis) or death from the cancer, excluding local-regional recurrences. Site will report first recurrence during the patients 5 years in the study. For long-term follow-up the information about first recurrence or death will be collected from the National Cancer Registry.
Time frame: From enrollment to end of treatment at 60 months.
Breast cancer specific survival (BCSS)
BCSS is the percentage of people with a specific type and stage of breast cancer who are alive at a certain time (often 5 or 10 years) following diagnosis, accounting only for deaths caused by that cancer. Unlike overall survival, BCSS excludes deaths from other causes. The site will report during the patients 5 years in the study. For long-term follow-up, the information about death will be collected from the National Cancer Registry.
Time frame: From enrollment to end of treatment at 60 months.
Overall survival (OS)
The study site will report death during the first 5 years in the study. For long-term follow-up the information about death will be collected from the National Cause-of-Death registry.
Time frame: From enrollment to end of treatment at 60 months.
Mammographic breast density
Assess change in mammographic density including time-and dose-dependent trends in density change. The mammograms will be collected for a centralised assessment of density and density change. An automated, digital software, e.g. the Stratus software, will be used to measure mammographic features such as density, macrocalcifications and masses.
Time frame: From enrollment to end of treatment at 60 months.
Cost effectiveness Analysis (CEA)
CEA will be used to compare relative costs and effects of the intervention, expressed as Quality-Adjusted Life Years (QUALYs) gained. Cost effectiveness and values of the intervention i.e. individualised adjuvant tamoxifen will be evaluated using the POWER trial questionnaires, medical records, National Register information, number and extents of health care contacts, and concomitant medications, collected through the trial.
Time frame: From enrollment to end of treatment at 60 months.
Cost-Benefit Analysis (CBA)
CBA will be used to investigate any monetary value of individualised tamoxifen, measured by impacts on all direct and indirect costs. Values of the intervention i.e. individualised adjuvant tamoxifen will be evaluated using the POWER trial questionnaires, medical records, National Register information, number and extent of health care contacts. and concomitant medications, collected through the trial.
Time frame: From enrollment to end of treatment at 60 months.
Incremental cost-effectiveness ratio (ICER)
ICER will be calculated by dividing the incremental cost of the intervention i.e. individualised adjuvant tamoxifen by its incremental health benefit. Cost effectiveness and values of the intervention will be evaluated using the POWER trial questionnaires, medical records, National Register information, number and extents of health care contacts, and concomitant medications, collected through the trial.
Time frame: From enrollment to end of treatment at 60 months.
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