Targeted Therapies in Breast Cancer

61 Pages·2011·0.42 MB·English

by  Harold Burstein

O A P N
OXFORD AMERICAN POCKET NOTES
Targeted Therapies in
Breast Cancer
This material is not intended to be, and should not be
considered, a substitute for medical or other professional
advice. Treatment for the conditions described in this material
is highly dependent on the individual circumstances. While this
material is designed to off er accurate information with respect
to the subject matter covered and to be current as of the time it
was written, research and knowledge about medical and health
issues is constantly evolving, and dose schedules for medications
are being revised continually, with new side eff ects recognized and
accounted for regularly. Readers must therefore always check the
product information and clinical procedures with the most up-to-
date published product information and data sheets provided by
the manufacturers and the most recent codes of conduct and safety
regulation. Oxford University Press and the authors make no rep-
resentations or warranties to readers, express or implied, as to the
accuracy or completeness of this material, including without lim-
itation that they make no representations or warranties as to the
accuracy or effi cacy of the drug dosages mentioned in the material.
The authors and the publishers do not accept, and expressly dis-
claim, any responsibility for any liability, loss, or risk that may be
claimed or incurred as a consequence of the use and/or application
of any of the contents of this material.
The Publisher is responsible for author selection and the Publisher
and the Author(s) make all editorial decisions, including deci-
sions regarding content. The Publisher and the Author(s) are not
responsible for any product information added to this publication
by companies purchasing copies of it for distribution to clinicians.
O A P N
OXFORD AMERICAN POCKET NOTES
Targeted Therapies in
Breast Cancer
Harold J. Burstein, MD, PhD
Associate Professor of Medicine,
Harvard Medical School
Breast Oncology Center,
Dana-Farber Cancer Institute
Boston, Massachusetts
1
1
Oxford University Press, Inc., publishes works that further
Oxford University’s objective of excellence
in research, scholarship, and education.
Oxford New York
Auckland Cape Town Dar es Salaam Hong Kong Karachi
Kuala Lumpur Madrid Melbourne Mexico City Nairobi
New Delhi Shanghai Taipei Toronto
With offi ces in
Argentina Austria Brazil Chile Czech Republic France Greece
Guatemala Hungary Italy Japan Poland Portugal Singapore
South Korea Switzerland Thailand Turkey Ukraine Vietnam
Copyright © 2011 by Oxford University Press, Inc.
Published by Oxford University Press, Inc.
198 Madison Avenue, New York, New York 10016
www.oup.com
Oxford is a registered trademark of Oxford University Press
All rights reserved. No part of this publication may be reproduced,
stored in a retrieval system, or transmitted, in any form or by any
means, electronic, mechanical, photocopying, recording, or
otherwise, without the prior permission of Oxford University Press.
ISBN: 978-0-19-973567-9
9 8 7 6 5 4 3 2 1
Printed in the United States of America
on acid-free paper
TARGETED THERAPIES
IN BREAST CANCER
TABLE OF CONTENTS
Introduction 1
Antiestrogen Therapies 6
Aromatase Inhibitors (AI’s) 6
Selective Estrogen Receptor Modulators (SERM’s) and
Estrogen-Receptor Downregulators (ERD’s) 7
Chemotherapeutic Agents—Microtubule
Targeting Agents 14
Taxanes 14
Ixabepilone 14
Eribulin Mesylate 17
HER2 Directed Therapies for Metastatic
Breast Cancer 19
Trastuzumab 19
Trastuzumab-Refactory Breast Cancer 23
Investigational Agents 26
HER2 Directed Therapy for Early Stage Breast
Cancer 29
Angiogenesis Inhibitors in Breast Cancer 32
Bevacizumab 34
VEGFR Inhibitors 37
PARP Inhibitors 39
Emerging Areas 42
References 43
OAPN
DISCLOSURES
The author has no fi nancial confl icts of interest to disclose.
TARGETED THERAPIES
IN BREAST CANCER
INTRODUCTION
Breast cancer is a heterogeneous disease. Recently, it has
become apparent that clinically important subsets can be
identifi ed using traditional pathology markers, and also by
using newer molecular diagnostic assays. These diff erences
are clinically signifi cant, as they often relate to expression of
important biological markers such as the hormone receptors
(estrogen receptor and progesterone receptor) and the HER2
growth factor receptor—markers that are the target of impor-
tant therapies. However, it is also apparent that these diff erent
cancer subsets can be distinguished not just by the expression of
a single marker, but rather by broad patterns of gene expression
aff ecting hundreds of genes throughout the cancer genome.1,2
In clinical practice, three major subsets of breast cancer can
readily be recognized. These are: hormone receptor positive
breast cancers; HER2-overexpressing breast cancers; and
so-called “triple-negative” breast cancers, tumors that lack
expression of ER, PR, and HER2 (Figure 1). In the US and
other developed nations, particularly those with widespread
screening mammography programs, hormone receptor posi-
tive breast cancers constitute the large majority of all tumors,
and are particularly prevalent in postmenopausal and older
women. HER2-overexpressing breast cancers account for ap-
proximately 20% of all tumors. About half of HER2 positive
breast cancers will also express estrogen receptor or proges-
terone receptor, though frequently such tumors express lower
levels of the hormone receptors than tumors that are other-
wise HER2 negative.3 Triple-negative breast cancers account
for approximately 15% to 20% of all cases. Triple-negative
and HER2 positive breast cancer subtypes are found more
commonly among younger women. Furthermore, triple-neg-
ative breast cancers have additional unique epidemiological
1
OAPN
ER and/or PR +
65%–75%
All Breast Cancer
HER2+
15%–20%
“Triple
Neg”
15%
Figure 1 Breast Cancer Subsets.
features. They are found more commonly in younger women,
in women with hereditary BRCA1 mutations, and in women
of African or African American ancestry.4,5
Importantly, diff erent treatment paradigms are emerg-
ing for management of each of the major clinical subsets of
breast cancer. For women with hormone receptor positive
breast cancer, endocrine therapy remains the mainstay of
treatment for both early and advanced stage cancers. In addi-
tion, these women may receive chemotherapy on a selective
basis in the adjuvant setting, or as treatment for metastatic
disease if the tumor becomes resistant to endocrine therapy.
Patients with HER2 positive breast cancers will typically be
candidates for anti-HER2 therapy with trastuzumab, the
anti-HER2 directed monoclonal antibody. This drug is most
frequently given in combination with chemotherapy. Finally,
women with triple-negative cancers will be candidates for
chemotherapy. Chemotherapeutic (i.e. cytotoxic) agents in-
cluding anthracyclines (e.g. doxorubicin and epirubicin) and
those that inhibit the microtubule pathway (see Figure 2),
2
Stabilizing Destabilizing Dynamic
factors factors instability
Folding factors
Severing GTP
Cap
MAPs Catastrophe
Nucleation GTRP Teucbauplin
GDP Tubulin
Depolymerizing
kinesin
End-binding MAPs
Tubulin sequestering
Co-polymerizing factors T
or GTP hydrolysis A
IN RG
B E
R T
γ-TURC Dis1p, TOG, EA ED
αβ-TubulinCCT coFAfoa ltcdotio nErgs: γG-Triupbsulin TauM, MAPA4P2, SXZtYMuG2Ap-P,92, 1M5s,ps CBILKIP1p1,7 E0,B1ALIPSC1/, dCyLnAeiSnP-sdynactKinatanin XMKCCAMK1, OStapt1h8m/in ST C THE
A R
N A
Figure 2 Microtubule Dynamics C P
3 Reprinted with permission from Heald R, Nogales E. Microtubule Dynamics. J Cell Sci. 2002;15:3–4. ER IES