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`AstraZeneca EX. 2014 p. 1
`Mylan Pharms. Inc. V. AstraZeneca AB IPR2016-01325
`
`

`
`
`
` Estrogens
`
`
`and Antiestrogens
`
`Basic and C1inica1‘Aspects
`
`
`
`
`Editors .
`
`Robert Lindsay, M.B.Ch.B., Ph.D., F.R.C.P.
`Chief Internal Medicine
`Professor of Clinical Medicine, Columbia University
`Clinical Research Center and Regional Bone Center
`College ofPhysicians and Surgeons
`’ Helen Hayes Hospital
`West Haverstraw, New York
`
`David W. Dempster, Ph.D.
`Professor of Clinical Pathology, Columbia University
`Directoz; Clinical Research Center
`and Regional Bone Center
`Helen Hayes Hospital
`West Haverstraw, New York
`
`V. Craig Jordan, Ph.D, D.sc.
`Director, Breast Cancer Research Program
`Robert H. Lurie Cancer Center
`
`Professor of Cancer Pharmacology
`Northwestern University Medical School
`Chicago, Illinois
`
`R Lippincott - Raven
`
`Philadelphia - New York
`
`Astrazeneca Ex. 2014 p. 2
`
`

`
`Acquisitions Editor: Danette Knopp
`Developmental Editor: Juleann Dob
`Manufacturing Manager: Demiis Teston
`Production Manager: Jodi Borgenicht
`Production Editor: Jeff Somers
`
`Cover Designer: Karen Quigley
`Indexer: Lisa Mulleneaux
`
`Compositor: Lippincott—Raven Electronic Production
`Printer: Maple Press
`
`© 1997, by Lippincott—Raven Publishers. All rights reserved. This book is protected by copyright. No part
`of it may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means—
`electronic, mechanical, photocopy, recording, or otherwise—without the prior written consent of the
`publisher, except for brief quotations embodied in critical articles and reviews. For information write
`Lippincott—Raven Publishers, 227 East Washington Square, Philadelphia, PA 19106-3780.
`Materials appearing in this book prepared by individuals as part of their official duties as U.S.
`Government employees are not covered by the above-mentioned copyright.
`
`Printed in the United States of America
`
`987654321
`
`
`Library of Congress Cataloging-in-Publication Data
`
`Estrogens and anti-estrogens : basic and clinical aspects / editors, David W. Dempster, Robert Lindsay,
`V. Craig Jordan.
`p. cm.
`Includes bibliographical references and index.
`ISBN 0-397-517 1 9-X (alk. paper)
`1. Estrogen—Antagonists—Physiological effect. 2. Estrogen—Physiological effect. I. Dempster, David
`W. II. Lindsay, Robert, Ph.D. III. Jordan, V. Craig (Virgil Craig)
`[DNLM: 1. Estrogens-pharmacology. 2. Estrogen Antagonists——pharmacology. WP 522 E808 1997]
`RM295.E883 1997
`’
`615'.366—dc21
`DNLM/DLC
`
`for Library of Congress
`
`
`Care has been taken to confirm the accuracy of the information presented and to describe generally
`accepted practices. However, the authors, editors, and publisher are not responsible for errors or omissions
`or for any consequences from application of the information in this book and make no warranty, express
`or implied, with respect to the contents of the publication.
`The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage
`set forth in this text are in accordance with current recommendations and practice at the time of publica-
`tion. However, in view of ongoing research, changes in government regulations, and the constant flow of
`information relating to drug therapy and drug reactions, the reader is urged to check the package insert
`for each drug for any change in indications and dosage and for added warnings and precautions. This is
`particularly important when the recommended agent is a new or infrequently employed drug.
`Some drugs and medical devices presented in this publication have Food and Drug Administration
`(FDA)'clearance for limited use in restricted research settings. It is the responsibility of the health care
`provider to ascertain the FDA status of each drug or device planned for use in their clinical practice.
`
`Astrazeneca Ex. 2014 p. 3
`
`

`
`Contents
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`Contributing Authors.
`Foreword by Jack Gorski .
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`ix
`xi
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`Preface .
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`Acknowledgments .
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`xv
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`Section I: Structure and Function
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`1. History of the Estrogen Receptor Concept and Its Relation to
`Antiestrogens .
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`Elwood VJensen
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`3
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`9
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`2. The Origin of Antiestrogens .
`V Craig Jordan
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`3. Chemistry: Structure and Function Relationships .
`Timothy M. I/Wllson
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`4. Metabolism of Antiestrogens .
`V Craig Jordan, Michael Piette, and Angela Cisneros
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`5. Mode of Action at the Cellular Level with Specific Reference to
`Bone Cells .
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`John A. Robinson and Thomas C. Spelsberg
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`21
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`29
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`43
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`6. The Postmenopausal State and Estrogen Deficiency .
`Rogerio A. Lobo
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`Section II: Target Tissues
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`7. Estrogenic Effects on the Central Nervous System: Clinical Aspects .
`Barbara B. Sherwin
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`8. Effects on the Cardiovascular System: Basic Aspects .
`Thomas B. Clarlcson and Mary S. Anthony
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`9. Effects on the Cardiovascular System: Clinical Aspects .
`Alison J Cooper and John C. Stevenson
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`10. Effects on Bone and Mineral Metabolism: Basic Aspects .
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`75
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`Russell T Turner
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`11. Clinical Effects of Estrogens and Antiestrogens on the Skeleton
`and Skeletal Metabolism .
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`Felicia Cosman, David W. Dempster, and Robert Lindsay
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`151
`
`AstraZeneca Ex. 2014 p. 4
`
`

`
`viii
`
`CONTENTS
`
`12. Clinical Implications of Target Organ—Specific Actions of Selective
`Antiestrogens .
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`Alan E. Wakeling
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`13. Effects on Breast Cancer: Clinical Aspects .
`Kathleen I. Pritchara’
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`14. Estrogenic and Antiestrogenic Actions of Tamoxifen in the
`Female Reproductive Tract .
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`PG. Salyaswaroop
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`15. Effects on the Reproductive Tract: Clinical Aspects .
`T 3'Sc0tz‘ Jennings and William fl? Creasman
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`223
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`16. Estrogens, Antiestrogens, and the Urogenital Tract .
`Con .1 Kelleher and Linda Cardozo
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`Section III: Treatment
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`17. The Complexity of Selective Estrogen Receptor Modulation: The
`Design of a Postmenopausal Prevention Maintenance Therapy .
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`Jennifer MacGreg0I: Debra A. Tonetti, and V Craig Jordan
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`Subject Index .
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`261
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`279
`
`AstraZeneca Ex. 2014 p. 5
`
`

`
`Estrogens and Antiestrogens, edited by
`Robert Lindsay,
`David W. Dempster, and
`V. Craig Jordan,
`Lippincott—Raven Publishers, Philadelphia © 1997.
`
`13
`
`Effects on Breast Cancer: Clinical Aspects
`
`Kathleen Pritchard
`
`Division ofMedical Oncology/Haematology,
`Toronto-Sunnybrook Regional Cancer Center, Toronto, Ontario, Canada
`
`
`
`ANTIESTROGENS
`
`The ovarian dependence of breast cancer
`has been recognized since at least the turn of
`the century (1), when ovarian ablation and
`subsequently adrenalectomy and hypothesec-
`tomy were used with some success for the
`control of metastatic breast cancer. Later,
`drugs such as diethylstilbestrol (DES), prog-
`estationals, and androgens were also used in
`the treatment of metastatic disease. Thus,
`when the first antiestrogens were discovered
`in the late 1950s,
`there was considerable
`interest in them in relation to the treatment of
`
`breast cancer. The first nonsteroidal antiestro-
`gen, MER—25, was discovered in 1958 by
`Lerner and colleagues (2), but was too toxic
`for clinical use. Subsequently, clomiphene
`was briefly tested in breast cancer, but also
`proved too toxic for chronic use and was
`developed clinically only as a fertility drug
`(3).
`.
`Tamoxifen was first identified in 1962 as
`
`aneffective postcoital contraceptive in rats
`(4,5) and was initially of most interest as a
`“morning after” pill.
`It was subsequently
`found to induce ovulationyin women (6,7) and
`is currently marketed in some countries for
`that. indication. Early trials by Cole and col-
`leagues (8) and Ward (9), however, showed
`that tamoxifen was effective in treating
`metastatic breast cancer in postmenopausal
`women. From that time,
`there was intense
`
`interest in its development. Its role evolved
`rapidly from palliative therapy for metastatic
`disease in postmenopausal and subsequently
`premenopausal women,
`to widespread use
`alone and in combination in the adjuvant set-
`ting. Currently, tamoxifen is being explored
`as a preventive agent in healthy women at
`high risk for breast cancer development.
`Subsequent to the discovery of tamoxifen,
`a number of other antiestrogens were devel-
`oped. Like tamoxifen, they have varying pro-
`portions of antiestrogenic and estrogenic
`effects, depending on the animal and on the
`organ in which they are acting. Two drugs cur-
`rently under intensive development for use in
`breast cancer are toremifene and droloxifene.
`
`Toremifene is a chlorinated derivative of
`
`tamoxifen, which, like tamoxifen, has shown
`an encouraging profile of anticancer proper-
`ties with low toxicity (10). Unlike tamoxifen,
`‘ however, toremifene has not been shown to
`produce liver tumors in the rat (1 1). Drolox-
`ifene or 3-hydroxytamoxifen, an antiestrogen
`with higher binding affinity for the estrogen
`receptor (ER) than tamoxifen and reduced
`estrogenic activity compared with tamoxifen,
`appears to cause no increase in the incidence
`of rat liver tumors (l2,l3) and does not pro-
`duce DNA adducts in laboratory assays of
`carcinogenesis (14).
`A number of pure antiestrogens have been
`synthesized. ICI 164,384 and ICI 182,780 are
`analogues of l7[3-estradiol with a long alky-
`
`AstraZeneca Ex. 2014 p. 6
`
`

`
`I76
`
`BREAST CANCER: CLINICAL ASPECTS
`
`the 70c position that
`lamine side chain at
`appears essential for the pure antiestrogenic
`properties. Because these drugs produce a
`complete blockade by combining with ERS to
`form a paralyzed complex, which is rapidly
`destroyed, they are of considerable interest.
`Early stage clinical studies are being com-
`pleted.
`
`TAMOXIFEN
`
`As discussed, tamoxifen was first synthe-
`sized in the late 1960s by Dora Richardson at
`ICI Limited Pharmaceuticals Division and
`was subsequently shown to be an antifertility
`agent in rodents (4,5). Harper and Walpole
`discovered that the trans and cis isomers of
`tamoxifen had opposing biological properties,
`the cis isomer acting as an estrogen and the
`trans isomer as an antiestrogen (4,5). It was
`also learned early that tamoxifen exhibited
`species specificity, acting as an estrogen in
`the mouse and an antiestrogen in the rat (4,5).
`Subsequent
`investigation in humans has
`shown a varying proportion of estrogenicity
`and antiestrogenicity in women, depending on
`the organ involved and on the length of ther-
`apy given. As tamoxifen has evolved through
`a spectrum of use, its effects on various organ
`systems have become somewhat more clear
`and there is great interest in its variable hor-
`monal properties. Tamoxifen remains one of
`the most useful drugs for the treatment of
`breast cancer and is continuing to be studied
`for use in a broader range of indications.
`
`ROLE OF TAMOXIFEN IN
`
`METASTATIC DISEASE
`
`Use in Postmenopausal Women
`
`postmenopausal women receiving 20 to 40
`mg of tamoxifen daily, with disease stabiliza-
`tion in a further 19% and a median or mean
`duration of response of 2 to more than 24
`months (15-17). In 60 publications in which
`response was related to age, a 43% response
`rate was reported in women older than 60
`years (18). Several large randomized (19-21)
`or dose-finding (22) studies have shown no
`major dose-response effect
`for doses of
`tamoxifen ranging from 2 to 100 mg/m2 body
`surface area given twice daily. Thus, a some-
`what arbitrarily chosen dose of 20 to 40 mg
`daily was initially most widely tested, and 20
`mg daily has been the dose most commonly
`used in recent years. As with other endocrine
`therapies,
`response rates
`are higher
`in
`patients with positive ER or progesterone
`receptor (PgR) measurements. A response
`rate of approximately 30% in unselected
`patients increases to 40% to 60% in women
`with
`ER-positive
`tumors
`(l7,23-27).
`Response rates appear
`to increase with
`increasing levels of ER protein (28). The
`presence of both ER and PgR is associated
`with response rates as high as 70% to 80%
`(27-30). Those relatively rare patients with
`ER-negative and PgR-positive tumors may
`still have response rates of 40% to 50%
`(27-30). » Response rates
`in ER-negative
`tumors or in ER-negative and PgR-negative
`tumors are usually less than 10% and may be
`that high in part because of recognized varia-
`tions in receptor level within a tumor, speci-
`men handling problems, or receptor measure-
`ment errors that may lead to false‘-negative
`receptor values (27-30). There may also be
`some degree of action of tamoxifen by mech-
`anisms unrelated to estrogen blockade, such
`as intracellular calcium antagonism or inhibi-
`tion of calmodulan activity (31,32).
`
`General Role
`
`Comparison with Other Endocrine Agents
`
`The first clinical evaluation of tamoxifen
`was in postmenopausal women with metasta-
`tic breast cancer (8). A review of 85 major
`clinical studies involving 5353 patients has
`shown an overall response rate of 34% in
`
`Tamoxifen "has been compared in random-
`ized trials with almost every other major
`form of
`endocrine
`therapy
`for
`post-
`menopausal women. There are at least six
`randomized studies of tamoxifen versus DES
`
`AstraZeneca Ex. 2014 p. 7
`
`

`
`BREAST CANCER: CLINICAL ASPECTS
`
`177
`
`(33-38) and two comparing tamoxifen with
`ethinyl estradiol (39,40) in postmenopausal
`women with metastatic disease.
`In all of
`
`these studies, response rates, response dura-
`tion, and survival rate are similar in women
`given tamoxifen, DES, or ethinyl estradiol.
`Tamoxifen is consistently less toxic, however.
`Although h_ot flushes and leukopenia may be
`seen more frequently in patients receiving
`tamoxifen, patients receiving DES or ethinyl
`estradiol have significantly more nausea,
`edema, heart failure, and phlebitis. More
`patients receiving DES require withdrawal of
`therapy (34).
`Tamoxifen has also been compared with
`various progestational agents in standard
`doses
`including
`medroxyprogesterone
`acetate (MPA) (41-45) and megestrol acetate
`(MA)
`(25,26,46-48). These
`randomized
`studies have shown no major difference in
`response rate, response duration, or survival
`rate between tamoxifen and the progestins in
`virtually every instance. One recent random-
`ized Swiss trial (49) has shown a signifi-
`cantly higherlremission rate (50% Vs 30%,
`P=O.23) and a marginally significant longer
`median time to progression (8.8 vs 5.4
`months, P=0.5l) in women given high-dose
`parenteral MPA compared with women
`given tamoxifen. A second randomized trial _
`from the Piedmont Oncology Association
`also
`showed
`a
`significantly
`increased
`response rate (34% vs 17%, P=0.01) for
`high-dose MPA given orally in comparison
`to tamoxifen, but time to treatment failure
`was not significantly increased (6.3 vs 5.5
`months, P=4.8) (50). The overall survival
`rate was not significantly different between
`the two treatments in either study and,
`in
`both trials, there was significantly greater
`toxicity, in particular, high blood pressure,
`tremor, and weight gain in the women given
`high-dose MPA.
`At least two studies compare tamoxifen
`and androgens (51,52). Tamoxifen has been
`shown to produce a significantly longer time
`to treatment failure—(P=0.003) and a signifi-
`cantly longer survival
`time (P=0.05) than
`fluoxymesterone in a randomized study of
`
`79 patients (52). Response rates were 40%
`for tamoxifen and 19% for fluoxymesterone,
`consistent with the older literature, which
`suggests that androgens are somewhat less
`effective than estrogens. A more recent study
`in which 164 postmenopausal women were
`randomized to receive 50 to 100mg of nan-
`drolone decanoate every 2 to .3 weeks by
`intramuscular injection or 20 to 40 mg of
`tamoxifen daily by mouth showed compara-
`ble response rates and comparable median
`remission durations. Side effects of both
`drugs were rare and mild (51).,Tamoxifen,
`however, held the advantage of being given
`orally.
`Several small randomized trials compar-
`ing tamoxifen with hypophysectomy (53)
`and adrenalectomy (54) suggest no advan-
`tage to the more difficult and toxic ablative
`procedures. The aromatase inhibitors, how-
`ever, have emerged as the potential medical '
`equivalent of these older surgical proce-
`dures. A number of studies have suggested
`that aminoglutethimide-hydrocortisone and
`tamoxifen have equivalent response rates,
`except, perhaps, in the treatment of osseous
`metastases for which it has been suggested,
`at
`least
`in subset analyses,
`that aminog-
`lutethimide may be somewhat more effective
`(55-58).
`In addition, subjective relief of
`bone pain is sometimes seen even without
`objective: remission in patients receiving
`aminoglutethimide (59). In part because it
`must be used with hydrocortisone, however,
`aminoglutethimide has more side effects
`than other major additive treatments, partic-
`ularly than tamoxifen, when used in the
`treatment of breast cancer. Currently, a new
`generation of aromatase inhibitors are under
`investigation. These drugs, such as Arimidex
`(60),
`fadrozole (46),
`letrozole (CGS-16-
`949),
`(6l,62), and vorozole (63,64), are
`being compared with tamoxifen in random-
`ized trials for the treatment of metastatic dis-
`
`ease. Based on already published compar-
`isons with the progestational agents, these
`newer aromatase inhibitors may be equally
`effective with a similarly benign toxicity
`profile to tamoxifen (65-68).
`
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`
`178
`
`BREAST CANCER: CLINICAL ASPECTS
`
`Comparison with Endocrine Combinations
`
`of
`administration
`sequential
`Because
`endocrine therapies is such an effective form
`of management in breast cancer, often pro-
`ducing repeated tumor regressions, there have
`been a number of efforts made to improve
`antitumor effect by giving various endocrine
`agents simultaneously. Because tamoxifen is
`so nontoxic, it has often been the core element
`or standard treatment arm in randomized
`studies of this type. Tamoxifen has been com-
`pared with tamoxifen plus estrogen in one
`study (69) and with tamoxifen plus estrogen
`and MPA in another (70). In neither study was
`the combination advantageous, either in terms
`of objective response rate or in duration of
`response or overall survival. Tamoxifen has
`been compared with a
`combination of
`aminoglutethimide—hydrocortisone
`and
`tamoxifen in at least six randomized trials
`(71~76). In none of these was improvement in
`response rate, response duration, or overall
`survival rate reported, but
`the addition of
`aminoglutethimide—hydrocortisone did result
`in additional toxicity.
`evaluated
`One
`randomized study has
`tamoxifen in varying doses compared with
`tamoxifen in the same doses plus 7 mg/m2 of
`fluoxymesterone given orally twice daily. The
`investigators found a higher response rate
`(38% vs 15%, P=0.0l6) in patients receiving
`both drugs. The response durations were sim-
`ilar, but overall time to treatment failure was
`longer (180 vs 64 days, P=0.01) for those
`receiving tamoxifen and fluoxymesterone.
`Despite these benefits in favor of the drug
`combination, overall survival rate was no dif-
`ferent in the two treatment groups. There was
`no evaluation of subsequent response to flu-
`oxymesterone in women receiving tamoxifen
`alone initially. Thus, the value of sequential
`versus concomitant use of these" two agents
`was not fullyvassessed. The addition of flu-
`oxymesterone did, however, increase toxicity,
`particularly masculinization, which occurred
`in 39% of patients receiving the two drugs,
`but
`‘in none of those receiving tamoxifen
`alone (22). Two more recent trials of tamox-
`
`ifen versus tamoxifen plus fluoxymesterone
`demonstrated a marginally higher response
`rate for the combination (77,78), and one of
`those studies showed an increased time to
`progression (77)
`for
`tamoxifen and flu-
`oxymesterone. In both studies, however, toxi-
`city was higher when fluoxymesterone was
`added and in neither was response duration or
`overall survival rate improved. In one of these
`studies, 52 patients who were initially given
`tamoxifen received fluoxymesterone as sec-
`ond line therapy with »a 40% objective
`response
`rate
`(77). Thus,
`the
`additive
`response rate for the two agents used sequen-
`tially was at least equivalent (50 + 21 in 119 =
`60%) to the two used concurrently (63 in 119
`= 53%). However, a subset analysis -as part of
`an updated report of one of these trials (77)
`found that both time to progression and over-
`all survival rate were significantly prolonged
`when tamoxifen and fluoxymesterone were
`used concurrently in women older than age 65
`years with ER > 10 fmoles/mg (79). Thus,
`there may be real benefit to the use of the two
`drugs simultaneously in this particular subset
`of highly
`endocrine-responsive women,
`although this remains to be confirmed in a
`prospective randomized trial. Tamoxifen plus
`nandrolone decanoate has also been com-
`pared with tamoxifen alone, but without ben-
`efit (so).
`Tamoxifen and MPA compared with '
`tamoxifen alone in 101 patients resulted in
`lower response rates for the combination (81)
`as did a randomized comparison of MPA plus
`tamoxifen used concurrently with the two
`drugs used sequentially in 46 patients (82).
`Tamoxifen versus MA versus tamoxifen plus
`MA in one small randomized trial resulted in
`similar response rates, time to treatment fail-
`ure, and survival rate‘ in all three treatment
`arms. Because of increased toxicity, particu-
`larly Weight gain in the combined arm, the
`authors concluded that tamoxifen alone as
`first line therapy was most appropriate (83).
`Alternating tamoxifen and MPA has been
`more effective than either drug alone in the
`dimethylberizanthracene-induced rat mam-
`mary model (84). The alternating use of these
`
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`

`
`BREAST CANCER: CLINICAL ASPECTS
`
`179
`
`agents has been tested in women in a random-
`ized trial by comparing tamoxifen alone with
`an alternating regimen of tamoxifen for 15
`days followed by MPA for 15 days. The
`response rate was 60% for alternating therapy
`Versus 48% for tamoxifen alone. Response
`duration was prolonged to 25 months with the
`alternating combination, in comparison with
`10 months for tamoxifen alone (84). A second
`small randomized study of a similar schedule
`of alternating tamoxifen and MPA versus
`tamoxifen alone in ‘women with metastatic
`
`disease showed comparable response rates
`(60% vs 48%, p=not significant) and com-
`plete response rates (17% vs 7%; p=not sig-
`nificant), but a significantly prolonged mean
`response duration (>25 months vs 9.5 months,
`P <0.0l) for the alternating therapy (85). A
`third study of continuous tamoxifen, 30 mg
`daily, versus tamoxifen, 30 mg daily for 8
`weeks alternating with MPA 500 mg twice
`daily for 8 weeks, demonstrated a signifi-
`cantly higher response rate (62% vs 41%,
`-P=0.02) for the alternating regimen, but no
`difference in remission duration or survival
`
`rate (86).
`The three-drug combination of tamoxifen,
`aminoglutethimide—hydrocortisone, and dana-
`zol
`(TAD) was compared with tamoxifen
`alone in a large randomized study. The initial
`response rate was significantly higher for the
`combination (43.2% vs 30.6%, P=0.05). The
`additive response rate to sequential TAD was
`more similar (34 + 8 + 1= 43 in 111 = 38.7%)
`to that for TAD (48 in 111 = 43.2%), however.
`Time to remission was slightly shorter and,
`therefore,
`time in remission was slightly
`longer for TAD patients. Remission duration
`and overall survival rates were equivalent.
`Toxicity was
`tolerable in both treatment
`groups (87,88).
`‘
`Two randomized trials comparing primary
`endocrine therapy (PET), consisting of ovarian
`irradiation in premenopausal
`-women and
`tamoxifen, 20 mg daily,
`in postmenopausal
`women, with PET plus prednisolone, 5 mg
`twice daily, have been carried out in Guy’s
`Hospital, London, each with a similar result
`(89,90). In the more recent trial, the response
`
`rate was significantly increased by the addi-
`tion of prednisolone
`in
`premenopausal
`women, and,
`in postmenopausal women, a
`similar but not significant
`trend occurred
`(31% vs 46%; 0.05 < P < 0.1). Median dura-
`tion of response was prolonged from 9 to 20
`months in postmenopausal women (P=0.02),
`whereas median time to disease progression
`was prolonged in postmenopausal women by 4
`months (P=0.02). Overall survival rate was
`significantly improved for the entire group
`receiving prednisolone in comparison with the
`A group receiving PET alone (17 vs 21 months,
`P<0.»05), but this effect was not significant in
`postmenopausal patients (17.5 vs 21 months,
`P=0.3). Toxicity with PET or-PET plus pred-
`nisolone was mild. Weight gain occurred only
`in patients receiving prednisolone and afiected
`15% of such patients. Hot flushes were exac-
`erbated in premenopausal and postmeno-
`pausal patients receiving prednisolone (89).
`Incidences of tumor flare and hypercalcemia
`were not affected by the addition of pred-
`nisolone in the second trial (89) but were
`reduced by prednisolone in the first study
`(90). Secondary responses to prednisolone in
`patients receiving PET alone as initial therapy
`were rare (2 in 62 = 3%) (89). Thus, the addi-
`tion of prednisolone to PET, although worth-
`while in premenopausal patients, is of mar-
`ginal benefit and does add some toxicity in
`postmenopausal women.
`In summary,
`the combination of one or
`more endocrine therapies added to tamoxifen
`may improve the initial but not the overall or
`additive response rate and seldom seems to
`improve overall response duration or overall
`survival rate. Toxicity is- generally increased
`by the addition of other hormonal agents to
`tamoxifen, however. The exception may be
`the addition of prednisolone to tamoxifen for
`which a significant increase in response dura-
`tion and time to progression and a trend
`toward improved overall survival rate with
`minimal increase in toxicity has been clearly
`demonstrated in two studies, albeit from the
`same institution. It is also possible that the use
`of fluoxymestrone and tamoxifen concur-
`rently may be advantageous for an older, ER-
`
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`
`

`
`180
`
`BREAST CANCER: CLINICAL ASPECTS
`
`this
`positive population of women, but
`remains to be confirmed in a prospective ran-
`domized trial of this particular subset of
`patients with metastatic disease.
`
`Tamoxifen in Combination
`with Chemotherapy
`
`When used concurrently, cytotoxic drugs
`and hormones,
`including tamoxifen, may
`have effects that are additive, synergistic, or
`antagonistic.
`In some in vitro systems,
`tamoxifen acts
`synergistically with the
`antimetabolites methotrexate and 5-fluo-
`rouracil (91,92) and with cyclophosphamide
`(93) but antagonistically with melphalan
`(94).
`In other in vitro systems, however,
`tamoxifen may act antagonistically with
`cyclophosphamide (95).
`In assessing the
`combination of tamoxifen and chemotherapy,
`as in assessing tamoxifen in combination
`with other hormones, it is helpful to recog-
`nize that an increased response rate is not
`necessarily the important endpoint. To be
`truly advantageous, any combination should
`provide an increased response rate and
`response duration compared with the additive
`or overall response rate and response dura-
`tion of the same agents used sequentially.
`Better yet, an overall survival advantage
`favoring the combination over the sequential
`use of the same agent would establish real
`benefit. In addition, the combination of two
`therapies,
`in particular,
`the addition of
`chemotherapy to tamoxifen, will almost cer-
`tainly increase toxicity. Thus, careful assess-
`ments of quality of life should be carried out
`before recommending a combination, partic-
`ularly in situations in which no overall sur-
`vival benefit has been shown.
`Attempts to improve response to therapy
`by combining hormones and chemotherapy
`began in the 1970s (96). A number of ran-
`domized trials comparing tamoxifen alone
`with tamoxifen plus chemotherapy have
`been carried out (97—l0l). In most of these
`studies, an increased response rate was seen
`when chemotherapy was added to tamoxifen,
`but in only one was this increase statistically
`
`significant (97). In addition, a large number
`of trials have compared chemotherapy alone
`with the same chemotherapy plus tamoxifen
`(102-108).
`In several of these trials,
`the
`combination provided a significantly higher
`response rate than the chemotherapy alone.
`(102,103,l08—110). Careful examination of
`additive versus sequential overall response
`rates to the chemotherapy followed by the
`same hormone were not made in most of
`these trials, however, so that the appropriate
`comparisons cannot be made. There was no
`trial in which the combination produced a
`statistically significant improvement in sur-
`vival, although one produced a prolonged
`median survival rate that came close to sig-
`nificance (19 months VS 24 months; P=0.07)
`when tamoxifen was added to chemotherapy
`with cyclophosphamide methotrexate and 5-
`flurouracil
`(CMF)
`(108). One large Aus-
`tralian trial randomized patients to receive
`tamoxifen only, cyclophosphamide and adri-
`amycin (CA), or both tamoxifen and CA con-
`currently. The initial response to tamoxifen
`alone (22%) was significantly lower than that
`to either CA (45%, P<0.00l) or to tamoxifen
`plus CA (51%, P<0.00l). Patients on tamox-
`ifen were given CA after progression, how-
`ever, and additive response rates and overall
`survival
`time on all study regimens were
`similar (97). Until chemotherapy and tamox-
`ifen used concurrently produce clear prolon-
`gation of survival or increased response rates
`and prolonged response durations, accompa-
`nied by improved quality of life, in compari-
`son to the additive response rates and dura-
`tions seen with the two modalities used
`sequentially,
`it seems more prudent to use
`tamoxifen followed by other hormonal ther-
`apy first in appropriate patients, followed by
`chemotherapy when the tumor becomes
`resistant to sequential endocrine maneuvers.
`To improve the effectiveness of phase-spe-
`cific cytotoxic agents,
`studies have been
`designed to exploit cell cycle arrest by using
`tamoxifen to synchronize tumor cells and
`then estrogen to prime the cells in S-phase.
`Although it
`is theoretically interesting to
`attempt this type of approach, trials of this
`
`'
`
`AstraZeneca Ex. 2014 p. ll
`
`

`
`BREAST CANCER: CLINICAL ASPECTS
`
`18]
`
`type have not consistently produced higher
`response rates, much less improved survival
`time (111-114). Further exploration of these
`approaches may be warranted, however.
`
`Use in Premenopausal Women
`
`Initially, tamoxifen was not tested in pre-
`menopausal women, but, by the early 1980s, a
`number of phase II studies ‘had been carried
`out in this group of patients (115-120). There
`have been four randomized trials of tamoxifen
`
`compared with ovarian ablation in pre-
`menopausal
`‘women (121-123)
`(personal
`communication, J. Forbes, Newcastle, Aus-
`tralia). The results of these trials as well as of
`a recent meta—analysis (124) suggest no dif-
`ference in response rate, response duration, or
`survival
`time between the two modalities.
`
`Tamoxifen does not
`
`act
`
`as
`
`a medical
`
`oophorectomy, in that, estrogen levels in pre-
`menopausal women given tamoxifen actually
`increase dramatically, whereas gonadotropin
`levels remain within the premenopausal range
`(125-127). Also, women who respond to
`tamoxifen but in whom progressive disease
`later develops may go on to have subsequent
`responses to ooph