The POWER Trial: Personalised Dose Optimisation With Adjuvant Tamoxifen Therapy in Breast cancER

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Measure genetic polymorphism in germline DNA and relate it to the primary endpoint and other secondary and exploratory endpoits, e.g. discontinuation, (z)-endoxifen concentrations, and side effects. It will be explored if, and to what extent, genetic polymorphism in germline DNA is contributing information that could be used in the interpretation of the primary and secondary findings.

Exploratory analysis will be done after the primary analysis, in plasma collected at baseline and follow-up blood drawls, and stored at the Karolinska Institutet Biobank.

Exploratory analysis will be used to identify biomarkers of potential use for therapy effect, dose-response, side effects and tolerability, and heterogeneity of drug response. Exploratory analyses will also be used for deconvolute dominant phenotypes and markers and predictors of heterogeneity. Exploratory analyses will, among others, include endogenous hormones, proteomics, metabolomics, lipidomics, extracellular vesicles, ctDNA, cfDNA, miRNA and siRNA.