DOCSLIB.ORG

Oral Low Dose and Topical Tamoxifen for Breast Cancer Prevention: Modern Approaches for an Old Drug

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Oral Low Dose and Topical Tamoxifen for Breast Cancer Prevention: Modern Approaches for an Old Drug Lazzeroni et al. Breast Cancer Research 2012, 14:214 http://breast-cancer-research.com/content/14/5/214 REVIEW Oral low dose and topical tamoxifen for breast cancer prevention: modern approaches for an old drug Matteo Lazzeroni1,*, Davide Serrano1, Barbara K Dunn2, Brandy M Heckman-Stoddard2, Oukseub Lee3, Seema Khan3 and Andrea Decensi1,4 Abstract Tamoxifen is a drug that has been in worldwide use for the treatment of estrogen receptor (ER)-positive breast cancer for over 30 years; it has been used in both the metastatic and adjuvant settings. Tamoxifen’s approval for breast cancer risk reduction dates back to 1998, after results from the Breast Cancer Prevention Trial, co-sponsored by the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project, showed a 49% reduction in the incidence of invasive, ER-positive breast cancer in high-risk women. Despite these positive fi ndings, however, the public’s attitude toward breast cancer chemoprevention remains ambivalent, and the toxicities associated with tamoxifen, particularly endometrial cancer and thromboembolic events, have hampered the drug’s uptake by high-risk women who should benefi t from its preventive eff ects. Among the strategies to overcome such obstacles to preventive tamoxifen, two novel and potentially safer modes of delivery of this agent are discussed in this paper. Low-dose tamoxifen, expected to confer fewer adverse events, is being investigated in both clinical biomarker- based trials and observational studies. A series of systemic biomarkers (including lipid and insulin-like growth factor levels) and tissue biomarkers (including Ki-67) are known to be favorably aff ected by conventional tamoxifen dosing and have been shown to be modulated in a direction consistent with a putative anti-cancer eff ect. These fi ndings suggest possible benefi cial clinical preventive eff ects by low-dose tamoxifen regimens and they are supported by observational studies. An alternative approach is topical administration of active tamoxifen metabolites directly onto the breast, the site where the cancer is to be prevented. Avoidance of systemic administration is expected to reduce the distribution of drug to tissues susceptible to tamoxifen-induced toxicity. Clinical trials of topical tamoxifen with biological endpoints are still ongoing whereas pharmacokinetic studies have already shown that appropriate formulations of drug successfully penetrate the skin to reach breast tissue, where a preventive eff ect is sought. Introduction of tamoxifen, while still retaining its benefi cial anti- At present, tamoxifen is the only proven oral agent for cancer properties, are currently being explored. One such the adjuvant hormonal treatment of hormone receptor- strategy for improving the risk/benefi t profi le of this positive breast cancer in premenopausal women [1], and agent has been to examine the effi cacy of lower doses, it can be used in both pre- and postmenopausal women which are anticipated to be associated with lower toxicity. who are at increased risk of breast cancer [2]. However, Another novel preventive strategy that is currently under the toxicities of tamoxifen, such as thromboembolic investigation is the topical application of either tamoxifen events and endometrial cancer, still pose a clinically or its active metabolites. Th ese two promising alter na- signifi cant problem overall, especially in the prevention tives, oral low dose and topical administration of tamoxi- setting. Novel strategies to reduce the adverse side eff ects fen or its active metabolites, are discussed in the present review (Figure 1). Here we present the results of several phase II trials (listed in Table 1), a description of ongoing *Correspondence: [email protected] 1Divisions of Cancer Prevention and Genetics, European Institute of Oncology, phase III trials, and future prospects using this approach. Milan, Italy Full list of author information is available at the end of the article Oral low-dose tamoxifen for breast cancer prevention An overview of the adjuvant tamoxifen clinical trials © 2010 BioMed Central Ltd © 2012 BioMed Central Ltd revealed that the effi cacy of 20 mg/day of tamoxifen was Lazzeroni et al. Breast Cancer Research 2012, 14:214 Page 2 of 11 http://breast-cancer-research.com/content/14/5/214 Figure 1. The eff ects of tamoxifen on human tissues. (a,b) Systemic administration of low tamoxifen (a) and topical administration of tamoxifen metabolites (b). Topical tamoxifen avoids high systemic exposure to 4-hydroxytamoxifen compared with standard oral tamoxifen, a 16- to 18-fold diff erence, thus reducing the risk of systemic side eff ects. Breast tissue concentrations seem to be suffi cient to achieve inhibition of tumor cell proliferation to the same degree as that seen with the standard dose of oral tamoxifen (20 mg/day) but with much lower plasma levels. Tamoxifen has both good and bad eff ects on specifi c human tissues. Development of new approaches should maximize the good eff ects and minimize the bad eff ects. equivalent to that of higher doses of the drug (that is, 30 reducing the tamoxifen dose to the human-equivalent to 40 mg/day) [3]. Clinical studies addressing the minimal dose of 1 mg/day does not diminish the drug’s inhibitory active dose of tamoxifen have not been conducted so far. activity on mammary tumor formation [4]. Additional On the other hand, data from animal studies indicate that preclinical evidence has shown that the antitumor eff ect Lazzeroni et al. Breast Cancer Research 2012, 14:214 Page 3 of 11 http://breast-cancer-research.com/content/14/5/214 Table 1. Summary of the main published trials on low dose tamoxifen Number of Study Treatment patients Population Primary endpoint Comment Breuer et al. TAM 20 mg/day (91%) 1,385 Women 65 years and older Bone fracture Although standard treatment 1998 [80] TAM 10 mg/day (9%) matched of 20 mg TAM daily off ers no with 5,196 apparent protection against bone controls fracture in older nursing home residents, a daily 10 mg dose seems to be protective Decensi et al. Placebo 127 Healthy women Total cholesterol (primary) Up to a 75% reduction in the 1998 [11] TAM 20 mg/day Hysterectomized Surrogate markers of conventional dose of TAM (that cardiovascular disease, IGF-I is, 20 mg/day) does not aff ect TAM 10 mg/day 35 to 70 years the activity of the drug on a large TAM 10 mg alternate number of biomarkers, most of days which are surrogate markers of cardiovascular disease de Lima et al. Placebo 56 Premenopausal women ER alpha PgR Ki-67 apoptotic Excisional biopsy was performed 2003 [25] TAM 5 mg/day with a diagnosis of bodies and mitotic index on the 50th day of therapy. fi broadenoma of the breast Normal breast tissue samples TAM 10 mg/day were collected during surgery. TAM 20 mg/day Diff erences in the expression of ERa, PgR, Ki-67, apoptotic bodies and mitotic index between the diff erent groups after treatment can be seen on the normal breast tissue Decensi et al. TAM 1 mg/day 120 ER+, BC patients Ki-67 modulation Ki-67 expression decreased to 2003 [26] TAM 5 mg/day 4 weeks before surgery a similar degree among the three TAM dose groups. Ki-67 Decensi et al. TAM 20 mg/day 2010 (f-up) [30] expression after short-term TAM is a good predictor of recurrence- free survival and overall survival Decensi et al. TAM 1 mg/day 210 Current or de novo HRT IGF-I IGF-I declined in all TAM arms 2007 [44] TAM 5 mg/day users (P = 0.005), with a greater change on 5 mg/day. Tamoxifen did TAM 10 mg/week not increase endometrial Ki-67 Placebo expression Decensi et al. TAM 5 mg/day 235 Premenopausal women Plasma IGF-I Despite favorable eff ects 2009 [35] FEN 200 mg/day pT1mic/pT1a BC; Mammographic density; on plasma IGF-I levels and mammographic density, the TAM + FEN OR Intraepithelial neoplasia; uterine eff ects; breast neoplastic events after combination of low-dose TAM Placebo OR Gail risk at fi ve years 5.5 years plus FEN did not reduce breast ≥1.3% neoplastic events Bonanni et al. ANA 1 mg/day 75 Postmenopausal women Plasma drug concentrations The addition of weekly TAM 2009 [41] TAM 10 mg/week with previous breast Biomarker modulation administration did not impair intraepithelial neoplasia anastrozole bioavailability and ANA + TAM modulated favorably its safety profi le Guerrieri Gonzaga TAM 20 mg/week 680 Women with previous DIN Second primary breast High ER and especially high PgR et al. 2010 [49] TAM 5 mg/day cancer (in situ or invasive) expression is a signifi cant adverse prognostic indicator of DIN, and low-dose TAM appears to be an active treatment. Women with low-expression ER or PgR DIN do not seem to benefi t from TAM ANA, anastrozole; BC, breast cancer; DIN, ductal intraepithelial neoplasia; ER, estrogen receptor; ER+, estrogen-receptor positive; FEN, fenretinide; HRT, hormone replacement therapy; IGF, insulin-like grow factor; PgR, progesterone receptor; TAM, tamoxifen. of the drug reaches a plateau above the concentration cancer during tamoxifen treatment [7-9] and taking into that saturates estrogen receptors [5,6]. account the long plasma half life (4 to 11 days after the Given the consistent data from adjuvant therapy trials steady state is reached [10]), dose reduction and inter- of a dose- and duration-dependent risk of endometrial mittent administration off er plausible ways to improve Lazzeroni et al. Breast Cancer Research 2012, 14:214 Page 4 of 11 http://breast-cancer-research.com/content/14/5/214 the safety profi le of tamoxifen. Together, all these obser- setting involved a study of the eff ect on levels of vations suggest that the use of lower doses of the drug ultrasensitive C-reactive protein (CRP), an index of low- off ers a reasonable approach to minimizing toxicity while grade vascular infl ammation and an important risk retaining activity.
Load more

Recommended publications
  • Phase II Study of Hormone Therapy with Tamoxifen in Patients with Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression (HORMONET)
    Phase II study of hormone therapy with tamoxifen in patients with well differentiated neuroendocrine tumors and hormone receptor positive expression (HORMONET) Time of researchers and respective Departments: Rachel Riechelmann (Main Investigador)1, Milton Barros 1, Marcos Camandaroba1,2, Virgilio Souza1,2, Celso Abdon Mello1, Paula Nicole3, Eduardo Nóbrega4, Ludmilla Chinen5, Marina De Brot6, Héber Salvador7. Departaments: 1- Clinical Oncology; 2- postgraduate student; 3- Radiology; 4- Nuclear Medicine; 5-International Research Center (CIPE); 6-Pathologic anatomy; 7- Abdomen Surgery AC Camargo Cancer Center - Brazil Registration Number on Institutional Research Ethics Committee: 2626/18 March,06,2019 Introduction Neuroendocrine tumors (NET) are rare neoplasms, but with increasing incidence and prevalence in the last decades. Although they may manifest in the most diverse tissues, the vast majority of cases will affect organs of the digestive tract and lung. At diagnosis, more than half of the cases present metastatic disease, and among patients with localized disease, up to one-third will have recurrence of the disease. Unfortunately, the minority of patients with metastatic disease are eligible for curative intent.1 Although there are many types of NET, they are often studied together as a group because their cells share common histological findings, have special secretory granules, and the ability to secrete bioactive amines and polypeptide hormones. Approximately 25 percent of the tumors present functional hormonal syndromes (situation of great morbidity for these patients), being the carcinoid syndrome, the most common one. From the molecular point of view, these neoplasias are largely dependent on the activation of the mTOR pathway and neoangiogenesis.2 Another striking feature of neuroendocrine cells is the expression of cell surface hormone receptors whose activation or blockade may exert an important regulatory function.
    [Show full text]
  • A Simple Method to Measure Sulfonation in Man Using Paracetamol As Probe Drug Natália Marto 1,2*, Judit Morello1,3, Alexandra M
    www.nature.com/scientificreports OPEN A simple method to measure sulfonation in man using paracetamol as probe drug Natália Marto 1,2*, Judit Morello1,3, Alexandra M. M. Antunes3, Sofa Azeredo4, Emília C. Monteiro1,5 & Sofa A. Pereira1,5 Sulfotransferase enzymes (SULT) catalyse sulfoconjugation of drugs, as well as endogenous mediators, gut microbiota metabolites and environmental xenobiotics. To address the limited evidence on sulfonation activity from clinical research, we developed a clinical metabolic phenotyping method using paracetamol as a probe substrate. Our aim was to estimate sulfonation capability of phenolic compounds and study its intraindividual variability in man. A total of 36 healthy adult volunteers (12 men, 12 women and 12 women on oral contraceptives) received paracetamol in a 1 g-tablet formulation on three separate occasions. Paracetamol and its metabolites were measured in plasma and spot urine samples using liquid chromatography-high resolution mass spectrometry. A metabolic ratio (Paracetamol Sulfonation Index—PSI) was used to estimate phenol SULT activity. PSI showed low intraindividual variability, with a good correlation between values in plasma and spot urine samples. Urinary PSI was independent of factors not related to SULT activity, such as urine pH or eGFR. Gender and oral contraceptive intake had no impact on PSI. Our SULT phenotyping method is a simple non-invasive procedure requiring urine spot samples, using the safe and convenient drug paracetamol as a probe substrate, and with low intraindividual coefcient of variation. Although it will not give us mechanistic information, it will provide us an empirical measure of an individual’s sulfonator status. To the best of our knowledge, our method provides the frst standardised in vivo empirical measure of an individual’s phenol sulfonation capability and of its intraindividual variability.
    [Show full text]
  • Tanibirumab (CUI C3490677) Add to Cart
    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
    [Show full text]
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • TE INI (19 ) United States (12 ) Patent Application Publication ( 10) Pub
    US 20200187851A1TE INI (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No .: US 2020/0187851 A1 Offenbacher et al. (43 ) Pub . Date : Jun . 18 , 2020 ( 54 ) PERIODONTAL DISEASE STRATIFICATION (52 ) U.S. CI. AND USES THEREOF CPC A61B 5/4552 (2013.01 ) ; G16H 20/10 ( 71) Applicant: The University of North Carolina at ( 2018.01) ; A61B 5/7275 ( 2013.01) ; A61B Chapel Hill , Chapel Hill , NC (US ) 5/7264 ( 2013.01 ) ( 72 ) Inventors: Steven Offenbacher, Chapel Hill , NC (US ) ; Thiago Morelli , Durham , NC ( 57 ) ABSTRACT (US ) ; Kevin Lee Moss, Graham , NC ( US ) ; James Douglas Beck , Chapel Described herein are methods of classifying periodontal Hill , NC (US ) patients and individual teeth . For example , disclosed is a method of diagnosing periodontal disease and / or risk of ( 21) Appl. No .: 16 /713,874 tooth loss in a subject that involves classifying teeth into one of 7 classes of periodontal disease. The method can include ( 22 ) Filed : Dec. 13 , 2019 the step of performing a dental examination on a patient and Related U.S. Application Data determining a periodontal profile class ( PPC ) . The method can further include the step of determining for each tooth a ( 60 ) Provisional application No.62 / 780,675 , filed on Dec. Tooth Profile Class ( TPC ) . The PPC and TPC can be used 17 , 2018 together to generate a composite risk score for an individual, which is referred to herein as the Index of Periodontal Risk Publication Classification ( IPR ) . In some embodiments , each stage of the disclosed (51 ) Int. Cl. PPC system is characterized by unique single nucleotide A61B 5/00 ( 2006.01 ) polymorphisms (SNPs ) associated with unique pathways , G16H 20/10 ( 2006.01 ) identifying unique druggable targets for each stage .
    [Show full text]
  • Differences Between the Non-Steroidal Aromatase Inhibitors Anastrozole and Letrozole – of Clinical Importance?
    British Journal of Cancer (2011) 104, 1059 – 1066 & 2011 Cancer Research UK All rights reserved 0007 – 0920/11 www.bjcancer.com Minireview Differences between the non-steroidal aromatase inhibitors anastrozole and letrozole – of clinical importance? ,1 J Geisler* 1 Institute of Clinical Medicine, University of Oslo, Faculty Division at Akershus University Hospital, Sykehusveien 27, Lørenskog N-1478, Norway Aromatase inhibition is the gold standard for treatment of early and advanced breast cancer in postmenopausal women suffering from an estrogen receptor-positive disease. The currently established group of anti-aromatase compounds comprises two reversible aromatase inhibitors (anastrozole and letrozole) and on the other hand, the irreversible aromatase inactivator exemestane. Although exemestane is the only widely used aromatase inactivator at this stage, physicians very often have to choose between either anastrozole or letrozole in general practice. These third-generation aromatase inhibitors (letrozole/Femara (Novartis Pharmaceuticals, Basel, Switzerland) and anastrozole/Arimidex (AstraZeneca, Pharmaceuticals, Macclesfield, Cheshire, UK)), have recently demonstrated superior efficacy compared with tamoxifen as initial therapy for early breast cancer improving disease-free survival. However, although anastrozole and letrozole belong to the same pharmacological class of agents (triazoles), an increasing body of evidence suggests that these aromatase inhibitors are not equipotent when given in the clinically established doses. Preclinical and clinical evidence indicates distinct pharmacological profiles. Thus, this review focuses on the differences between the non-steroidal aromatase inhibitors allowing physicians to choose between these compounds based on scientific evidence. Although we are waiting for the important results of a still ongoing head-to-head comparison in patients with early breast cancer at high risk for relapse (Femara Anastrozole Clinical Evaluation trial; ‘FACE-trial’), clinicians have to make their choices today.
    [Show full text]
  • Tamoxifen Metabolite Testing
    Tamoxifen Metabolite Testing Tamoxifen (Tam) , the anti-estrogen used to treat seen in active metabolites. The Anti-estrogenic activity estrogen receptor (ER)-positive breast cancer, is a score (ASS) was developed, based on the plasma pro-drug that is converted to its therapeutically active active isomer concentrations and their respective metabolites, Z- and Z’-endoxifen isomers and Z- and antiestrogenic activities, to arrive at a more accurate Z’-4-hydroxy-tamoxifen (Z-4-OH-Tam) isomers by several estimate of the biologic eectiveness of Tam metabolic enzymes. Both Z-endoxifen and Z-4-OH-Tam treatment 2. Both Tam metabolite testing and CYP2D6 have an ~100-fold greater anity towards the ER and a genotyping are oerred together at Mount Sinai Genetic 30- to 100-fold greater potency in suppressing estrogen- Testing Laboratory for personalized Tam treatment. dependent cell proliferation than Tam, whereas the Z’ isomers of endoxifen and 4-OH-Tam have ~10% of their respective Z isomer activity levels 1. Eective treatment depends on adequate Tam conversion to its active metabolite isomers. The plasma active metabolite concen- trations vary due to several factors: common genetic variants in genes encoding the biotransformation enzymes (e.g., CYP2D6), environmental factors that inhibit these enzymes (e.g., concomitant drugs), and compliance to the medication. The polymorphic CYP2D6 enzyme is critical in the Tam conversion to Z-endoxifen; however, CYP2D6 Figure: Schema of tamoxifen biotransformation in (a) CYP2D6 extensive genotype can only account for 30% – 40% of the variability and ultra-rapid metabolizers and (b) CYP2D6 poor metabolizers. Testing Methods, Sensitivity and Turnaround Time: tion is available at Mount Sinai Genetic Testing Labora- Biochemical analysis: Mount Sinai Genetic Testing tory and should be ordered the first time blood is drawn Laboratory is the only clinical lab that oers Tam for metabolite testing.
    [Show full text]
  • Nci 2017-09-01 Phase I Trial of Endoxifen Gel Versus
    NWU2017-09-01 Protocol Version 6.5, May 11, 2020 COVER PAGE DCP Protocol #: NWU2017-09-01 Local Protocol #: NCI 2017-09-01 PHASE I TRIAL OF ENDOXIFEN GEL VERSUS PLACEBO GEL IN WOMEN UNDERGOING BREAST SURGERY Consortium Name: Northwestern Cancer Prevention Consortium Organization Name: Northwestern University Name of Consortium Principal Seema A. Khan, M.D. Investigator: 303 E. Superior, Suite 4-111 Chicago, IL 60611 Tel: (312) 503-4236 Fax: (312) 503-2555 E-mail: [email protected] Organization Name: Northwestern University Protocol Principal Seema A. Khan, M.D. Investigator and Protocol Chair: Professor of Surgery 303 E. Superior, Suite 4-111 Chicago, IL 60611 Tel: (312) 503-4236 Fax: (312) 503-2555 E-mail: [email protected] Organization: Memorial Sloan-Kettering Cancer Center Investigator: Melissa Pilewskie, M.D. Evelyn H. Lauder Breast Center 300 East 66th Street New York, NY 10065 Tel: 646-888-4590 Fax: 646-888-4921 E-mail: [email protected] Organization: Cedars-Sinai Medical Center Investigator: Scott Karlan, M.D. Saul and Joyce Brandman Breast Center in the Samuel Oschin Cancer Center 310 N. San Vicente Blvd., Room 314 West Hollywood, CA 90048-1810 Tel: (310) 423-9331 Fax: (310) 423-9339 E-mail: [email protected] Organization: Northwestern University Statistician: Masha Kocherginsky, Ph.D. 680 N. Lake Shore Dr., Suite 1400 –1– NWU2017-09-01 Protocol Version 6.5, May 11, 2020 Chicago, IL 60611 Telephone: (312) 503- 4224 Fax: (312) 908- 9588 Email: [email protected] IND Sponsor: NCI/Division of Cancer Prevention IND# Agent(s)/Supplier: National Cancer Institute NCI Contract # HHSN2612201200035I Protocol Template: Version 8.5 08/31/2016 Protocol Version Date: May 11, 2020 Protocol Revision or Amendment # Version 6.5 –2– NWU2017-09-01 Protocol Version 6.5, May 11, 2020 SCHEMA NWU2017-09-01: Phase I trial of endoxifen gel versus placebo gel in women undergoing breast surgery Women scheduled for mastectomy1 Screening Visit 1 – consent, baseline tests, BESS Q, skin photos 2:1 Randomization in Cohorts 1 and 2.
    [Show full text]
  • Randomized Biomarker Trial of Anastrozole Or Low-Dose
    Published OnlineFirst November 3, 2009; DOI: 10.1158/1078-0432.CCR-09-1354 Randomized Biomarker Trial of Anastrozole or Low-Dose Tamoxifen or Their Combination in Subjects with Breast Intraepithelial Neoplasia Bernardo Bonanni,1 Davide Serrano,1 Sara Gandini,2 Aliana Guerrieri-Gonzaga,1 Harriet Johansson,1 Debora Macis,1 Massimiliano Cazzaniga,1 Alberto Luini,3 Enrico Cassano,4 Sabina Oldani,5 Ernst A. Lien,7 Giuseppe Pelosi,6 and Andrea Decensi1,8 Abstract Purpose: In the Anastrozole, Tamoxifen Alone or in Combination trial, the combination arm was inferior to anastrozole alone in terms of disease-free survival possibly due to an adverse pharmacokinetic interaction or a predominant estrogenic effect of tamoxi- fen under estrogen deprivation. We assessed whether the addition of a lower dose of tamoxifen influenced anastrozole bioavailability and favorably modulated biomarkers of bone fracture, breast cancer, cardiovascular disease, and endometrial cancer risk. The influence of CYP2D6 genotype on tamoxifen effects was also determined. Experimental Design: Seventy-five postmenopausal women with breast intraepithelial neoplasia were randomly allocated to either 1 mg/d anastrozole or 10 mg/wk tamoxifen or their combination for 12 months. Study endpoints were plasma drug concentrations and changes of C-telopeptide, osteocalcin, estradiol/sex hormone binding globulin (SHBG) ratio, estrone sulfate, insulin-like growth factor-I (IGF-I)/insulin-like growth fac- tor binding protein-3 (IGFBP-3), C-reactive protein, antithrombin-III, endometrial Ki-67 expression, and thickness. Results: Anastrozole concentrations were not affected by the combination with low- dose tamoxifen, whereas endoxifen levels were lower in poor CYP2D6 metabolizers. C-telopeptide increased by 20% with anastrozole and decreased by 16% with tamoxifen and by 7% with their combination (P < 0.001); osteocalcin showed similar changes.
    [Show full text]
  • Phase 1 Study of Z-Endoxifen in Patients with Advanced Gynecologic, Desmoid, and Hormone Receptor-Positive Solid Tumors
    www.oncotarget.com Oncotarget, 2021, Vol. 12, (No. 4), pp: 268-277 Research Paper Phase 1 study of Z-endoxifen in patients with advanced gynecologic, desmoid, and hormone receptor-positive solid tumors Naoko Takebe1, Geraldine O'Sullivan Coyne1, Shivaani Kummar1,8, Jerry Collins1, Joel M. Reid2, Richard Piekarz1, Nancy Moore1, Lamin Juwara3, Barry C. Johnson3, Rachel Bishop4, Frank I. Lin5, Esther Mena5, Peter L. Choyke5, M. Liza Lindenberg5, Larry V. Rubinstein6, Cecilia Monge Bonilla7, Matthew P. Goetz2, Matthew M. Ames2, Renee M. McGovern2, Howard Streicher1, Joseph M. Covey1, James H. Doroshow1,7 and Alice P. Chen1 1Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA 2Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA 3Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA 4Consult Services Section, National Eye Institute, Bethesda, MD 20892, USA 5Molecular Imaging Program, National Cancer Institute, Bethesda, MD 20892, USA 6Biometric Research Program, National Cancer Institute, Bethesda, MD 20892, USA 7Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA 8Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA Correspondence to: Alice P. Chen, email: [email protected] Keywords: Z-endoxifen; phase 1; tamoxifen; pharmacokinetics Received: September 30, 2020 Accepted: January 19, 2021 Published: February 16, 2021 Copyright: © 2021 Takebe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    [Show full text]
  • Hormonal and Non-Hormonal Management of Vasomotor Symptoms: a Narrated Review
    Central Journal of Endocrinology, Diabetes & Obesity Review Article Corresponding authors Orkun Tan, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology Hormonal and Non-Hormonal and Infertility, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas, TX 75390 and ReproMed Fertility Center, 3800 San Management of Vasomotor Jacinto Dallas, TX 75204, USA, Tel: 214-648-4747; Fax: 214-648-8066; E-mail: [email protected] Submitted: 07 September 2013 Symptoms: A Narrated Review Accepted: 05 October 2013 Orkun Tan1,2*, Anil Pinto2 and Bruce R. Carr1 Published: 07 October 2013 1Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology Copyright and Infertility, University of Texas Southwestern Medical Center, USA © 2013 Tan et al. 2Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, ReproMed Fertility Center, USA OPEN ACCESS Abstract Background: Vasomotor symptoms (VMS; hot flashes, hot flushes) are the most common complaints of peri- and postmenopausal women. Therapies include various estrogens and estrogen-progestogen combinations. However, both physicians and patients became concerned about hormone-related therapies following publication of data by the Women’s Health Initiative (WHI) study and have turned to non-hormonal approaches of varying effectiveness and risks. Objective: Comparison of the efficacy of non-hormonal VMS therapies with estrogen replacement therapy (ERT) or ERT combined with progestogen (Menopausal Hormone Treatment; MHT) and the development of literature-based guidelines for the use of hormonal and non-hormonal VMS therapies. Methods: Pubmed, Cochrane Controlled Clinical Trials Register Database and Scopus were searched for relevant clinical trials that provided data on the treatment of VMS up to June 2013.
    [Show full text]
  • Association of CYP2D6 Genotype and Tamoxifen Metabolites with Breast Cancer Recurrence in a Low-Dose Trial
    www.nature.com/npjbcancer BRIEF COMMUNICATION OPEN Association of CYP2D6 genotype and tamoxifen metabolites with breast cancer recurrence in a low-dose trial ✉ Andrea DeCensi 1 , Harriet Johansson 2, Thomas Helland 3, Matteo Puntoni4, Debora Macis 2, Valentina Aristarco2, Silvia Caviglia1, Tania Buttiron Webber1, Irene Maria Briata1, Mauro D’Amico1, Davide Serrano2, Aliana Guerrieri-Gonzaga2, Ersilia Bifulco5, Steinar Hustad5, Håvard Søiland 5,6, Luca Boni 7, Bernardo Bonanni 2 and Gunnar Mellgren5 Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9–16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3–11.4) in patients who recurred vs 7.5 (5.1–10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p < 0.05), and a CRP increase after 3 years was associated with higher risk of recurrence (HR = 4.37, 95% CI, 1.14–16.73, P = 0.03). In conclusion, endoxifen is below 9 nM in most subjects treated with 5 mg/day despite strong efficacy and there is no association with recurrence, suggesting that the reason for tamoxifen failure is not poor drug metabolism. Trial registration: ClinicalTrials.gov, Identifier: NCT01357772.
    [Show full text]