Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Bone Density Conservation Agents

Antineoplastic Agents

All Drugs and Chemicals

Tamoxifen

Estrogens

Estrogen Receptor Modulators

Selective Estrogen Receptor Modulators

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

patients who received Tamoxifen 20 mg daily for at least 3 years with good response (no relapse) to tamoxifen. Both genotyping assessment and TDM of tamoxifen and its metabolites will be performed and correlated with the records. Follow up for these patients for further assessment of tamoxifen effectiveness will be carried out for 1- 2 years.

patients who received Tamoxifen 20 mg daily for at least 3 years who were good responder to the drug but then the response has been diminished (relapse) and they have been shifted to another therapy. They will be exposed to genotyping study of CYP 2D6 to recognize the phenotyping style of that patient that may explain diminishing of response to tamoxifen therapy.

patients who received Tamoxifen 20 mg daily for not more than 1 year with poor response to tamoxifen (early relapse) and clinically will be shifted to use another medication as they were diagnosed as tamoxifen resistant. Like the second group, they will be exposed to genotyping study of CYP2D6 with the same concept.

Tamoxifen 20 mg is a selective estrogen receptor modulator

Tamoxifen 20 mg

Amira Taha

Ehab Eldesoky

Mohammad Hareedy

Aim of work:

1. To estimate the frequency of Cyp2D6\*1 and \*4 alleles in Egyptian patients maintained on tamoxifen (20 mg/day) for management of ER +ve breast cancer.
2. To measure levels of tamoxifen, 4-hydroxy tamoxifen, N-desmethyl-tamoxifen and 4- hydroxyl-N-desmethyl-tamoxifen (endoxifen) in the serum of these patients.
3. To correlate between the levels of tamoxifen/active metabolite enoxifen ratio and CYP2D6\*1,\*4 genotyping.
4. To investigate which is more valuable investigatory tool for prediction of the clinical outcome (response and/or toxicity) in these patients; either the measurements related to pharmacokinetics: tamoxifen/endoxifen levels or the pharmacogenetic analysis of CYP2D6 \*1,\*4.

Breast cancer is considered to be the most common cancer among women worldwide. The majority of breast cancer cases (almost 80%) are classified as hormone-dependent cancer, since estrogen, acting via estrogen receptor alpha (ER-α) or estrogen receptor beta (ER-β), is the major inducer of the development and growth of the tumor. These are also called ER-positive breast cancers. The remaining cases are not induced by estrogen and are classified as hormone-independent, or ER-negative, cancers. Since the growth of hormone-dependent cancer cells can be down-regulated by the oppositely active hormones, several endocrine therapies that limit the actions of estrogen (through blocking its production or its receptors) have been developed over the past years. These endocrine therapies have played an important part in treating and improving the outcomes of women with all stages of the disease . Selective estrogen receptor modulators (SERMs) have also been studied for their anti-cancer activity.

Selective estrogen receptor modulators (SERMs) are a class of drugs that act on the estrogen receptor (ER); a characteristic that distinguishes these substances from pure ER agonists and antagonists as their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues .

Tamoxifen, which is a SERM, is important for the treatment and prevention of estrogen receptor (ER) positive breast cancer commonly in premenopausal women. It has been shown to decrease disease recurrence and mortality rates by as much as 50% and 30% respectively. It has been also used as a prophylactic treatment for patients who are at high risk of developing breast cancer. Post-menopausal breast cancer patients are commonly treated nowadays with aromatase inhibitors (AIs) for 5 years, alone or combined with tamoxifen for a 3-5 year period. Tamoxifen monotherapy in postmenopausal women with breast cancer may be used for 10 years if the side effects from AIs are too bothersome .

Besides acting as SERMs, it has recently been found that some of tamoxifen's metabolites (as norendoxifen) also act as aromatase inhibitors in vitro. Aromatase converts steroids (e.g., testosterone to estradiol), the inhibition of which severely decreases the amount of available estrogen in the body .

The most common side effects of Tamoxifen:

* Hot flashes, the most common side effect of tamoxifen, affect up to 80% of women.
* Increased risk of endometrial hyperplasia and polyps
* Increased risk for cataract.
* Increased risk for thromboembolic events as well as clinical depression .

Pharmacokinetics of tamoxifen and its clinical implications:

Tamoxifen is a prodrug that is metabolized by several cytochrome P450 enzymes. It is a relatively weak antiestrogen in comparison to its active metabolites, particularly endoxifen. Two parallel pathways bioactivate tamoxifen to endoxifen (4-OH-N-desmethyltamoxifen) through several overlapping cytochrome P450 (CYP) enzymes; primarily CYP3A4/5 and CYP2D6.

For many years, 4-hydroxy-tamoxifen has believed to be primarily responsible for the clinical activity; however, the CYP2D6 metabolites 4-hydroxy-tamoxifen and endoxifen (4-OH-N-desmethyl-tamoxifen) have equal affinity for the estrogen receptor. Because serum concentrations of endoxifen are 6 to 12 times higher than 4-hydroxy-tamoxifen in patients receiving long-term tamoxifen therapy, many think endoxifen is the most significant tamoxifen metabolite.

The rate limiting step in tamoxifen metabolism is catalyzed by the highly polymorphic CYP2D6 enzyme so that CYP2D6 genotype can be translated into predicted metabolic activity phenotypes: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), ultrarapid metabolizer (UM), which are strongly predictive of endoxifen concentration during tamoxifen treatment.

There is substantial variation in CYP2D6 genotypes among different populations. CYP2D6\*1 is the wild-type allele and is associated with normal enzyme activity and the normal "extensive metabolizer" phenotype. The CYP2D6 alleles \*2, \*33, and \*35 are also considered to have near-normal activity. Other alleles include variants that produce a non-functioning enzyme (e.g., \*3, \*4, \*5, and \*6) or an enzyme with reduced activity (e.g., \*10, \*17, and \*41). There are large inter-ethnic differences in the frequency of these alleles, with \*3, \*4, \*5, \*6, and \*41 being more common in the Caucasian population, \*17 more common in Africans, and \*10 more common in Asians. Also it was found that \*1 and \*4 alleles are more common in Egyptians.

Patients with low-activity CYP2D6 phenotypes have substantially lower endoxifen steady-state concentrations . It is unclear whether patients with genotypes that confer low CYP2D6 activity have inferior efficacy from tamoxifen treatment, but if so, preemptive genotyping to guide tamoxifen dose selection could be a viable strategy to improve treatment effectiveness.

Despite the proven efficacy of tamoxifen, some women experience cancer recurrence during or after treatment. Therapeutic failure may be caused by tumor resistance to antiestrogen therapy or inadequate bioactivation of tamoxifen to its active metabolite, endoxifen.

Some studies have reported that patients with low endoxifen concentrations (below 5.9 ng/ml) have increased the risk of inferior tamoxifen efficacy with consequent cancer recurrence compared with its concentration in intermediate and rapid or ultra-rapid metabolizers taking the same dose. This can open the way for application of therapeutic drug monitoring of tamoxifen and its metabolite endoxifen for possible dose escalation especially a fixed dose of the drug is usually used which is 20 mg/day.

The issue of relying on genotyping profile of CYP2D6 and its variants or use of TDM of tamoxifen and its metabolite endoxifen or the combination of both parameters to correlate with clinical response, adverse effect and dose modification of tamoxifen is still under investigation.

Genetic Study of CYP2D6 Enzyme and Therapeutic Drug Monitoring of Tamoxifen

Genetic Study of CYP2D6 Enzyme and Therapeutic Drug Monitoring of Tamoxifen in Premenopausal Women With Breast Cancer

The CYP2D6 genotypes will be determined using the TaqMan Allelic Discrimination Assay.

Plasma concentrations of tamoxifen, 4-hydroxy-tamoxifen (4-OH-tam), N-desmethyl-tamoxifen (N-DM-tam) and 4-hydroxy-N-desmethyl-tamoxifen (endoxifen) will be measured using sensitive HPLC-PDA assay method.

Assiut University

Assistant Lecturer

Carcinoma

Carcinoma in Situ

Carcinoma, Ductal

Carcinoma, Intraductal, Noninfiltrating

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Breast Carcinoma In Situ

Anastrozole

Aromatase Inhibitors

Enzyme Inhibitors

Patients receive 6 months of tamoxifen or anastrozole in a neoadjuvant situation.

Tamoxifen and Anastrozole will be delivered in their original packaging at J0 and M3 :

* Tamoxifen: box of tablets dosed at 20 mg
* Anastrozole: box of tablets 1 mg. Tamoxifen will be initiated in premenopausal patients orally at a standard dose of 20mg/day as a single dose for 6 months.

Anastrozole will be administered orally to postmenopausal patients at the standard dose of 1mg/day in a single dose for 6 months.

Tamoxifen will be initiated in non menopausal patients orally for 6 months in a neoadjuvant situation.

Anastrozole will be initiated in menopausal patients orally for 6 months in a neoadjuvant situation.

Anastrozole 1Mg Tab

Victoire BRILLAUD-MEFLAH, MD

Emilie DEBEAUPUIS

Augustin P REYNARD, MD

Sandrine HIRET, MD

Sophie AURIOL-LEIZAGOYEN, MD

Marian GUTOWSKI, MD

Marie GOSSET, MD

Enora LAAS, MD

Séverine ALRAN, MD

Gabrielle SELMES, MD

Gabrielle SELMES

Ductal carcinoma in situ (DCIS) accounts for approximately 20% of newly diagnosed breast cancer cases. Of these women, 20% require radical management in the form of mastectomy because of the extent of the lesions, which most often manifest as diffuse microcalcifications.

This mutilating surgical management contrasts with the excellent prognosis of this pathology and considerably alters the quality of life of patients.

Neoadjuvant hormone therapy has shown its efficacy in hormone-dependent infiltrating ductal carcinomas and offers the possibility of conservative surgery after hormone therapy.

Adjuvant hormone therapy with Tamoxifen or anti-aromatase drugs has shown its efficacy in the prevention of homo or contralateral recurrence.

The HORNEO 01 trial fits perfectly in the current context of surgical de-escalation of ductal carcinomas in situ. The objective of the study is to evaluate the impact of neoadjuvant hormone therapy on the surgical management of extensive DCIS.

Description of the modalities for recruiting :

Following screening and discovery of a DCIS, patients are referred to the center for surgical management.

During a standard consultation, the surgeon presents the study to the patient who has been diagnosed with extensive DCIS with an indication for mastectomy. The surgeon provides the patient with the information note and the consent form to participate in the study. Once the consent form is signed by the patient and the investigator, the investigator prescribes a screening test to be performed within 30 days prior to the start of hormone therapy.

Screening assessment includes :

A clinical exam and a breast imaging exam (mammography and breast and axillary ultrasound). In case of a suspicious breast ultrasound image, microbiopsy will be performed to eliminate an infiltrating component.

One or more macrobiopsy. Each biopsied site will be located using an X-ray clip inserted at the time of sample.

A MRI post-macrobiopsy. Research of estrogen receptor expression

Once the investigator has verified and validated all the eligibility criteria, the patient will be included.

Prescriptions for Tamoxifen (non-menopausal patients) or Anastrozole (menopausal patients) are given to patients and dispensed by the center's pharmacy.

Monitoring during treatment :

Patients will benefit from imaging monitoring (Mammography, +/- breast ultrasound, +/- axillary ultrasound, MRI) at 3 months and 6 months during hormonotherapy.

In case of progression observed during treatment, hormone therapy will be stopped and you will then benefit from a mastectomy.

Surgery :

Mastectomy or tumorectomy will be performed according to the tumor response to hormone therapy observed on MRI.

All patients will benefit sentinel node detection. An additional axillary dissection will be performed based on the results of the sentinel node analysis.

Analysis of biomarkers and tumor microenvironment before and after treatment on diagnostic macrobiopsies and on tumorectomy or mastectomy will be performed at Institut de Cancérologie de l'Ouest.

Patients will be seen in postoperative consultation. Adjuvant treatments or re-surgical interventions will be prescribed, carried out, and the patients will be followed up and examined at 6 months after surgery or at the end of adjuvant treatments and then annually for 10 years (with control mammography).

Patients who have had conservative surgery will have an MRI at 6 months from the end of radiotherapy.

All patients will be asked to complete quality of life questionnaires at baseline, 6 and 12 months post-surgery, and annually for 9 years:

EORTC QLQ-C30 (up to 5 years only), Short Form (36) Health Survey questionnaire.

Patients with extensive ductal carcinoma in situ with an indication for mastectomy receiving neoadjuvant hormone therapy with Tamoxifen (non-menopausal patients) or Anastrozole (postmenopausal patients)

Impact of Neoadjuvant Hormonal Therapy on the Surgical Management of Extensive Ductal Carcinomas in Situ

% of conservative surgeries performed after hormonotherapy

Survival rates at 5 and 10 years post-surgery

Pathologic complete response is defined as no residual invasive cancer in the surgical specimen

Response is defined by the variation in the diameter of the longest dimension of the target lesion measured by MRI

Institut Cancerologie de l'Ouest

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Genetic Study of CYP2D6 Enzyme and Therapeutic Drug Monitoring of Tamoxifen	NCT03582865	Breast Cancer	Tamoxifen 20 mg	20 Years - 50 Years	Assiut University
Impact of Neoadjuvant Hormonal Therapy on the Surgical Management of Extensive Ductal Carcinomas in Situ	NCT04666961	Ductal Carcinom... Extensive Disea... Mastectomy	Tamoxifen 20 mg Anastrozole 1Mg...	40 Years -	Institut Cancerologie de l'Ouest
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
Impact of Neoadjuvant Hormonal Therapy on the Surgical Management of Extensive Ductal Carcinomas in Situ	NCT04666961	Ductal Carcinom... Extensive Disea... Mastectomy	Tamoxifen 20 mg Anastrozole 1Mg...	40 Years -	Institut Cancerologie de l'Ouest

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