Neoplasms

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Breast Neoplasms

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Breast Diseases

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Tamoxifen

Hormones

Estrogens

Estrogen Receptor Modulators

Selective Estrogen Receptor Modulators

Hormone Antagonists

Antineoplastic Agents, Hormonal

Estrogen Antagonists

Estrogen Receptor Antagonists

The active study group consists of 50 year or older postmenopausal women taking tamoxifen for the prevention of reoccurrence of breast cancer, do not meet exclusion criteria, meet all inclusion criteria, and are enrolled members for Medco clients agreeing to participate.

If the patient's CYP2D6 metabolism status is 'poor' then specialist pharmacist will discuss drug therapy alternatives to tamoxifen.

Poor Metabolism Status Follow Up Therapy Considerations

If the patient after having a CYP2D6 test has any drugs that inhibit tamoxifen metabolism then specialist pharmacist will contact the physician for alternative drug therapies.

CYP2D6 Inhibiting Drugs

Robert Epstein, MD, MS

This study will assess the impact of CYP450 2D6 genotype pharmacogenetic testing and the corresponding prescribing impact for postmenopausal women using tamoxifen in a patient care setting for prevention of recurrent breast cancer.

Tamoxifen is a non-steroidal hormonal drug with weak estrogen agonist and potent estrogen antagonist actions. The liver CYP450 metabolic enzyme systems are responsible for metabolizing tamoxifen (the pro-drug form) into its active metabolites. A secondary tamoxifen metabolite known specifically as 4-hydroxy-N-desmethyl-tamoxifen or endoxifen is recognized as the principal potent metabolite responsible for tamoxifen suppression of estrogen-dependent cell proliferation, the stimulus for breast tumor growth. Biotransformation to endoxifen is through the CYPP450 2D6 pathway; therefore, the ability of tamoxifen to effectively suppress breast cancer is jeopardized in patients with certain CYP450 2D6 genetic variants and/or those receiving drug therapy that are known to alter CYP450 2D6 function (i.e., with CYP450 2D6 inhibitors).

Four phenotype expressions classified as ultrarapid, extensive, intermediate and poor metabolizers can be discerned from genotype testing for CYP450 2D6 activity. Patients with normal metabolic activity are known as extensive metabolizers given that they possess either two (genotype = wt/wt) or one (genotype = wt/vt) functioning CYP450 2D6 gene that converts a sufficient amount of tamoxifen in to its active form. Intermediate metabolizers have at least some or very low CYP450 2D6 activity and there does not appear to be uniform consensus on the impact of this phenotype on tamoxifen drug disposition. Poor metabolizers lack any functional CYP450 2D6 activity, and therefore, they do not metabolize tamoxifen enough to produce sufficient endoxifen activity. Approximately 10% of patients (7% of Caucasians and 1-3% of other ethnic groups) are poor metabolizers with a complete absence of CYP450 2D6 activity.

The genetic variants associated with diminished or absent CYP450 2D6 activity are found on CYP450 2D6 alleles \*3, \*4, \*5, \*6 and \*10. The \*3, \*4, \*5 and \*6 alleles, when present in variant form (genotype = vt/vt), account for approximately 97% of nonfunctional CYP450 2D6 variants in caucasians. Of these mutations, those in CYP450 2D6 \*4 are most significant for endoxifen.

Poor metabolizer phenotype has been associated with worse relapse-free breast cancer survival and increased risk (up to three times that of intermediate metabolizer status who have some CYP450 2D6 activity) for breast cancer recurrence.

Diagnostic technology now exists to aid in determining which tamoxifen patients are potentially receiving suboptimal treatment from existing alterations in one or more of the approximately 80 alleles of the gene coding for the CPYP450 2D6 enzyme. Recognition of this phenomenon provides physicians and their patients the opportunity for considering the use of other anti-estrogen drugs such as aromatase inhibitors in women whose CYP450 2D6 phenotype puts them at risk for poor response to tamoxifen therapy.

This study will use this diagnostic technology to determine a patient's phenotype provide additional clinical information and alternative drug therapies to the patient's physician.

The Clinical and Economic Impact of Pharmacogenomic Testing for Tamoxifen Metabolism in Postmenopausal Women Receiving Tamoxifen for Prevention of Recurrent Breast Cancer

Tamoxifen Pharmacogenomics and the Prevention of Recurrent Breast Cancer

Laboratory Corporation of America

International Business Machines (IBM)

Indiana University School of Medicine

Mayo Clinic

Medco Health Solutions, Inc.

Carcinoma

Afimoxifene

Blood concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen will be measured.

i) a self-testing capillary kit, the rhelise™ kit for measuring the concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen and ii) a patient interactive digital tool (app) mBraze to collect data about symptoms and guide breast cancer patients on adjuvant tamoxifen.

Tamoxifen 20 mg

Elham Hedayati, MD PhD

Tamoxifen is a potent and effective drug reducing the risk of dying from breast cancer in the adjuvant setting. Although more modern drugs have partly replaced tamoxifen, it is helpful in the neoadjuvant and metastatic settings as a single drug. Despite that, in the adjuvant setting, it is a valuable drug.

This study aims to validate and study the feasibility of serial assessments, including therapeutic drug monitoring of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen by capillary blood sampling, combined with patient-reported symptom scores. This will provide preliminary data to allow us to develop a future multicentre randomised clinical trial of personalised dose monitoring and adjustment of adjuvant tamoxifen therapy to enhance the quality of life and breast cancer outcomes.

This repeated-measures, prospective, open-label, single-centre study is designed for women with stage 0-3 breast cancer receiving adjuvant tamoxifen 20 mg/day.

Inclusion criteria:

1. Female patients aged ≥ 18 years with hormone-positive stage 0-3 breast cancer.
2. Performance status Eastern Cooperative Oncology Group (ECOG) 0-2.
3. Ongoing daily adjuvant tamoxifen minimum of 2 months ± gonadotropin-releasing hormone (GnRH) analogues ± radiation therapy (RT) for stage 3 breast cancer.
4. Locally recurrent disease, previously treated with adjuvant tamoxifen.
5. Able to use software applications developed specifically for small, wireless computing devices, such as smartphones and tablets.
6. Have small, wireless computing devices, such as smartphones and tablets.

Exclusion Criteria:

1. Fulfilling any of the contraindications for tamoxifen.
2. Metastatic (stage IV) breast cancer.
3. Included in other clinical studies receiving not approved investigational medicinal drug.
4. Ongoing pregnancy or lactation.
5. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

No. Of Subjects: 40 female subjects.

Measured components: Tamoxifen, 4-hydroxytamoxifen and Z-endoxifen

Study design: Blood samples for measurement of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen will be drawn capillary in total at 4-time points, at inclusion (baseline), and after 1, 2, and 3 weeks for each participant; and venously in total at 2-time points, at inclusion (baseline), and after 3 weeks for each participant.

At each time, participants will be asked to leave 2 vials of capillary blood (50ul x2) using the rhelise™ kit and 2 samples of conventional venous blood for blood and plasma (5 ml x 2).

Therapeutic Dose Monitoring (TDM) of Tamoxifen

Therapeutic Dose Monitoring (TDM) of Tamoxifen and Its Active Metabolites in Combination With Patient-reported Symptom Scores Among Patients With Breast Cancer Receiving Adjuvant Tamoxifen Treatment

Blood concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen at baseline, two weeks, 1, 2, and 3 weeks by capillary and venous blood sampling (whole blood/plasma).

Correlations of blood concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen between venous blood samples and capillary blood samples (Sensitivity and specificity).

Capillary blood test concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen were taken by the patient and the research nurse.

Correlations between tamoxifen, 4-hydroxytamoxifen and Z-endoxifen concentrations and symptom distress score ((fatigue, insomnia, pain, body image, and systemic therapy side-effect and cognitive-, emotional-, role-, sexual and social functioning).

Correlations between tamoxifen, 4-hydroxytamoxifen and Z-endoxifen concentrations and symptom distress in the same patient.

- The interview on user acceptability and attitudes toward mBraze.

- Self-reported usability and user experience of the mBraze app measured with system usability scale (SUS).

- The interview on user acceptability and attitudes toward self-testing.

Karolinska University Hospital

MD, PhD

Aromatase Inhibitors

The hospital that will be the intervention site will have access to the OPTIMUM e-health tool. The intervention site cancer care team will receive the following OPTIMUM e-health alerts:

1. An electronic alert of increased Adjuvant Endocrine Therapy discontinuation risk.
2. An adherence to Adjuvant Endocrine Therapy monitor.
3. An electronic discontinuation occurrence alert

The hospital that will be the control site will not have access to the OPTIMUM e-health tool. The cancer care team will continue to deliver care according to standard processes.

If you are treated in a hospital that is using the OPTIMUM e-health tool ("intervention" group), once your care team receives any alerts, they may choose to:

* Contact you over the phone or in person to provide medical advice on how to better take your pills,
* Contact your pharmacist(s) and other doctors about your anti-cancer treatment.

OPTIMUM e-health tool

Ari N Meguerditchian, MD

Liane Feldman, MD

Background: In women with hormone receptor positive (HR+) breast cancer, adjuvant endocrine therapy (AET) is associated with a significant survival advantage. Nonadherence is a particular challenge in older women, even though they stand to benefit the most from AET. Therefore, a novel e-health tool (OPTIMUM) that integrates real-time analysis of health administrative claims data was developed to provide point-of-care decision support for clinicians.

Objectives: 1) To determine the effectiveness of a patient-specific, real-time e-health alerts delivered at point-of-care in reducing rates of AET discontinuation and to understand patient-level factors related to AET discontinuation. 2) To assess integration of e-health alerts regarding deviations from best practices in administration of AET by cancer care teams.

Methods: A prospective, two group controlled comparison pilot study will be conducted at two urban, McGill University-affiliated hospitals, the Royal Victoria Hospital and St. Mary's Hospital. A minimum of 43 patients per study arm will be enrolled through site-level allocation. Follow-up is 1.5 years. Healthcare professionals at the intervention site will have access to the e-health tool which will report to them in real-time: medical events with known associations to AET discontinuation, AET adherence monitor, and a discontinuation alert.

A Novel E-Health Approach in Optimizing Treatment for Seniors (OPTIMUM Study)

Adjuvant Endocrine Therapy in Breast Therapy in Breast Cancer: A Novel E-Health Approach in Optimizing Treatment for Seniors (OPTIMUM Study)

In each trial arm, the proportion of patients discontinuing AET treatment will be calculated as the number of patients discontinuing AET treatment divided by the total number of patients in that trial arm.

In each trial arm, the proportion of patients who are prescribed AET treatment but do not fill any prescriptions will be calculated as the number of patients with primary non-adherence divided by the total number of patients in that trial arm.

In each trial arm, the proportion of patients re-initiating after a discontinuation of AET treatment will be calculated as the number of patients who start taking AET after a period of stopping divided by the total number of patients that discontinued in that trial arm.

In each trial arm, mean time to AET treatment re-initiation will be calculated as the average number of days for a patient who has stopped taking AET treatment to start again, among those who start again (re-initiate).

In each trial arm, the proportion of patients that maintain a Medical Possession Ratio ≥80% will be calculated as the proportion patients whose proportion of number of days covered by medication supply in the treatment period is ≥80%.

Upon alert receipt that a patient is at risk of discontinuing adjuvant endocrine therapy treatment or has discontinued AET treatment, for that patient, if a member of the cancer care team called the patient will be assessed qualitatively (yes/no) and quantitatively (if yes, time in number of days before the patient was called).

Upon alert receipt that a patient is at risk of discontinuing adjuvant endocrine therapy treatment or has discontinued AET treatment, for that patient, if a member of the cancer care team called the patient's pharmacist will be assessed qualitatively (yes/no) and quantitatively (if yes, time in number of days before the patient's pharmacist was called).

Upon alert receipt that a patient is at risk of discontinuing adjuvant endocrine therapy treatment or has discontinued AET treatment, for that patient, if a member of the cancer care team arranged for the patient to return to the clinic to see the doctor will be assessed qualitatively (yes/no) and quantitatively (if yes, time in number of days before the cancer care team arranged a return to clinic with doctor).

Upon alert receipt that a patient is at risk of discontinuing adjuvant endocrine therapy treatment or has discontinued AET treatment, for that patient, if a member of the cancer care team arranged for the patient to return to the clinic to see the nurse will be assessed qualitatively (yes/no) and quantitatively (if yes, time in number of days before the cancer care team arranged a return to clinic with nurse).

Upon alert receipt that a patient is at risk of discontinuing adjuvant endocrine therapy treatment or has discontinued AET treatment, for that patient, if a member of the cancer care team referred the patient to a doctor will be assessed qualitatively (yes/no) and quantitatively (if yes, time in number of days before the cancer care team referred the patient to a doctor). Note that this action is different than the outcome "arrange for return to clinic with doctor" because this outcome occurs when a nurse directly schedules a patient to see a specific doctor without discussing with a doctor first.

Upon alert receipt that a patient is at risk of discontinuing adjuvant endocrine therapy treatment or has discontinued AET treatment, for that patient, if a member of the cancer care team referred the patient to a cancer nurse will be assessed qualitatively (yes/no) and quantitatively (if yes, time in number of days before the cancer care team referred the patient to a cancer nurse).

Upon alert receipt that a patient is at risk of discontinuing adjuvant endocrine therapy treatment, for that patient, if no action by the cancer care team was taken will be assessed qualitatively (yes/no) and quantitatively (how many alerts per patient were ignored). Note that "ignore the alert" is an explicit option that care teams can specify. They will be trained to understand that the "ignore the alert" option represents that the patient has not discontinued AET treatment and that they are of the opinion that the patient is not at risk of discontinuing AET treatment despite reading the alert.

Upon alert receipt that a patient is at risk of discontinuing adjuvant endocrine therapy treatment or has discontinued AET treatment, for that patient, if no changes by the cancer care team were taken will be assessed qualitatively (yes/no) and quantitatively (how many alerts per patient were ignored). Note that this "no changes" is an explicit option that care teams can specify. They will be trained to understand that the "no changes" option represents that the patient requires other considerations beyond adhering to AET such as is stopping AET for upcoming surgery or no longer is indicated for AET based on disease progression (for e.g., brain metastases).

Any care team action that cannot be described by the predefined actions will be described by the care team in a free-text field for subsequent qualitative analysis. An overall theme or logical grouping of these qualitative outcomes will be explored and reported upon.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Clinical and Economic Impact of Pharmacogenomic Testing for Tamoxifen Metabolism in Postmenopausal Women Receiving Tamoxifen for Prevention of Recurrent Breast Cancer	NCT00830973	Breast Neoplasm... Tamoxifen	Poor Metabolism... CYP2D6 Inhibiti...	50 Years -	Medco Health Solutions, Inc.
Therapeutic Dose Monitoring (TDM) of Tamoxifen	NCT05133674	Breast Cancer Breast Carcinom... Breast Tumors Cancer of Breas... Malignant Neopl...	Tamoxifen 20 mg	18 Years -	Karolinska University Hospital
A Novel E-Health Approach in Optimizing Treatment for Seniors (OPTIMUM Study)	NCT02876848	Breast Neoplasm... Medication Adhe...	OPTIMUM e-healt...	65 Years -	McGill University Health Centre/Research Institute of the McGill University Health Centre

Spots Global Cancer Trial Database for selective estrogen receptor modulators