Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Antineoplastic Agents, Hormonal

got surgery for breast cancer in St Olavs Hospital, Trondheim, during 2004-2013

Anne Irene Hagen, md phd

Breast cancer is the most common cancer among women in Norway. In 2016, 3402 new cases were diagnosed (3371 in women). Breast cancer is still the second most common cause of death from cancer among women with 585 breast cancer deaths in Norway in 2015. The majority of the patients (70-75 %) belong to the Luminal subtypes, which comprise the hormone receptor (oestrogen receptor (ER) and/or progesterone receptor (PR)) positive tumours.

The most important systemic adjuvant therapy in luminal breast cancers is a long-lasting administration of per-oral anti-oestrogen medication. A systemic hypo estrogenic state in the body may be created by the selective oestrogen receptor modulator tamoxifen or by inhibitors of the peripheral systemic aromatization of adrenal androgens into estrogens (aromatase inhibitors). Initially, tamoxifen was given adjuvant for 2 years, later prolonged to 5 years and recently an extension to 10 years has been recommended for premenopausal women. Aromatase inhibitors were introduced in Norwegian treatment guidelines in 2002. Currently, they are recommended in postmenopausal patients for 5 years, either as monotherapy or in concert with tamoxifen (aromatase inhibitors for 2 years followed by tamoxifen for 3 years).

In premenopausal breast cancer patients, tamoxifen still is the drug of choice. Two of the major underlying reasons for late recurrences in luminal breast cancer subtypes are development of endocrine resistance to tamoxifen and aromatase inhibitors or failure of taking the medication as prescribed. Higher mortality has been shown for breast cancer patients with reduced tamoxifen adherence. The patients' ability to follow instructions and recommendations are probably overestimated in controlled trials due to patient selection and close follow-up in the study setting. Some patients experience distressing side effects like hot flushes, fatigue, joint pain, mood swings and vaginal dryness. To the investigators' knowledge, there are few studies in Norway regarding discontinuation of endocrine treatment in breast cancer. In this study they will investigate the long-term discontinuation pattern to oral adjuvant systemic endocrine therapy in a large cohort of breast cancer patients treated in St. Olav's hospital in Trondheim, Norway, and the association between adherence to endocrine treatment and long-term survival.

After identifying all patients who were recommended endocrine therapy, data will be linked to the Norwegian Prescription Database (NorPD). Adherence will be estimated based on to which extent the patients actually have effectuated their prescriptions at Norwegian pharmacies. In the 5-year long treatment period, the patients receive a prescription refill of tamoxifen or aromatase inhibitor tablets for a 100 days interval. Medication Possession Ratio (MPR) will be used as proxy for adherence. The estimations will be performed in the following way: For each patient, we will receive the total number of pills and the total length of time from first to latest prescription effectuated. MPR is the number of pills divided by the total number of days in the time from first prescription to discontinuation. Discontinuation will be estimated to date for latest effectuation of the prescription plus 100 days (due to the number of pills prescribed). From these estimations, we will categorize the patients in groups taking MPR and total period of time into consideration. Taking prescript medication equal to or more than 80% is considered as adherent (MPR ≥ 80 %). Likewise, non-adherence is defined as MPR \< 80 %.

Adjuvant Endocrine Therapy in Early Stage Breast Cancer: Adherence and Clinical Outcome

Adjuvant Endocrine Therapy in Early Stage Breast Cancer: Impact of Drug Adherence/Persistence on Clinical Outcome in Various Breast Cancer Subtypes

Breast cancer specific survival according to adherence and non-adherence

Norwegian University of Science and Technology

St. Olavs Hospital

Bone Density Conservation Agents

Tamoxifen

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Estrogen Receptor Modulators

Selective Estrogen Receptor Modulators

Breast cancer patients who underwent surgery with or without chemotherapy, endocrine therapy and/or radiation therapy. The patients are categorized according to the genetic polymorphisms or the activity score of the cytochrome P450 metabolism.

tamoxifen

Byeong-Woo Park, M.D.,ph.D.

Jae-Gook Shin, M.D.,ph.D.

The genetic polymorphisms of the cytochrome P450 may influence on the metabolism of tamoxifen.

The investigators want to

* evaluate the frequency or incidence of the genetic polymorphisms of cytochrome P450 subfamilies(CYP2D6, CYP3A4/5 and CYP2C19) in breast cancer patients, and
* analyze the association between the genetic polymorphisms of cytochrome P450 subfamilies and clinical outcomes in breast cancer patients treated by adjuvant tamoxifen therapy.

Study of Cytochrome P450 Polymorphisms (CYP2D6, CYP3A4/5 and CYP2C19) in Breast Cancer Patients

Association Between Genetic Polymorphisms of CYP2D6 and Outcomes in Breast Cancer Patients With Tamoxifen Treatment

Inje University

Yonsei University

Symptoms and General Pathology

Recurrence

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Adjuvant Endocrine Therapy in Early Stage Breast Cancer: Adherence and Clinical Outcome	NCT03761420	Breast Neoplasm		20 Years - 100 Years	St. Olavs Hospital
Study of Cytochrome P450 Polymorphisms (CYP2D6, CYP3A4/5 and CYP2C19) in Breast Cancer Patients	NCT01169792	Breast Neoplasm... Survival Analys... Antineoplastic ... Therapeutic Use...	tamoxifen	18 Years -	Yonsei University
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.
Adjuvant Endocrine Therapy in Early Stage Breast Cancer: Adherence and Clinical Outcome	NCT03761420	Breast Neoplasm		20 Years - 100 Years	St. Olavs Hospital

Spots Global Cancer Trial Database for antineoplastic agents, hormonal