BY ANTONIO C. WOLFF, MD, FACP, MARY E. CIANFROCCA, DO, AND STEPHEN R. D. JOHNSTON, MA, PHD, FRCP

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Optimizing Endocrine Therapy for
Women with Breast Cancer Regardless
of Menopausal Status

                           By Antonio C. Wolff, MD, FACP, Mary E. Cianfrocca, DO, and
                                     Stephen R. D. Johnston, MA, PhD, FRCP

Overview: Endocrine therapy is now accepted as the most                                           part of endocrine therapy in postmenopausal women, al-
important component of adjuvant therapy for all patients                                          though questions remain about its sequential use with
with hormone receptor-positive breast cancer, regardless                                          tamoxifen and duration of therapy. However, not all patients
of menopausal status. There is now considerable interest in                                       equally benefit from adjuvant endocrine therapy. This article
the role of ovarian suppression/ablation in younger women,                                        reviews the optimal use of adjuvant endocrine therapy in
which is the subject of several large ongoing international                                       breast cancer and the possible strategies to overcome
trials. Aromatase inhibitors are now considered an integral                                       primary or secondary endocrine resistance.

L     EVELS OF estrogen receptor (ER) alpha and proges-
      terone receptor (PR) expression are modest prognos-
tic factors for breast cancer recurrence and survival that
                                                                                                  Rather, these new guidelines reflect the increasing ability
                                                                                                  to move beyond prognostic factors to focus on individual
                                                                                                  predictive factors. In other words, one should first con-
were primarily used for risk stratification. However, the                                         sider those unique features that could potentially deter-
true clinical utility of hormone receptor expression is to                                        mine an individual’s likelihood of benefiting (or not) from
serve as a powerful predictive marker for benefit from                                            specific therapies (e.g., hormone receptor and human
adjuvant endocrine therapy. About three-quarters of all                                           epidermal growth factor receptor 2 [HER2] status), and
patients with invasive tumors and about one-half of those                                         only then should traditional anatomic markers that aid in
who are premenopausal present with hormone receptor-                                              prognostic but not predictive assessment (e.g., tumor size
positive disease. Many of the early adjuvant endocrine                                            and lymph node status) come into play.
trials were small and not powered to detect improvements                                             Patients with hormone receptor-positive disease do not
in specific subsets, and many studies conducted well into                                         have a uniform response to various endocrine therapies.
the 1990s allowed patients with negative or unknown                                               In addition to individual tumor characteristics, individual
receptor status. Therefore, not until the 1995 edition of                                         host factors are likely to also influence response and
the Early Breast Cancer Trialists Collaborative Group                                             toxicity to individual therapies.5 Gene expression profile
systematic review exercise were the notions finally put to                                        assays seem to identify several major breast cancer sub-
rest1 that tamoxifen is ineffective in premenopausal                                              types with prognostic implications, and there appears to
women and potentially effective in those with hormone                                             be at least two major subtypes of ER-positive tumors.6 At
receptor-negative tumors.                                                                         least one commercial assay using formalin-fixed paraffin-
                                                                                                  embedded tissue has undergone strict assay standardiza-
TREATING AN INDIVIDUAL                                                                            tion and was shown in retrospective validation studies to
AND NOT A POPULATION                                                                              have a strong prognostic7 and predictive8 value for pa-
  There is now clear evidence that breast cancer is not one                                       tients with lymph node-negative, ER-positive disease.
but a collection of diseases that share a common name and                                         This assay may in fact discriminate luminal A from the
have an extremely diverse biologic behavior. This is un-                                          luminal B and the ER-positive HER2-positive tumor sub-
questionably a diagnosis where one treatment will not fit                                         types described in gene expression profiles using frozen
all patients,2 a concept that is clearly reflected in the most                                    tissue. A large prospective validation trial of this technol-
recent update of algorithms for adjuvant therapy selection                                        ogy (the TAILORx trial) was activated in North America
issued by the 2005 St. Gallen International Consensus                                             in early 2006. A separate international effort will attempt
Panel and the National Comprehensive Cancer Network                                               to validate gene expression platforms that require fresh
in the United States.3,4 The two groups now place primary                                         frozen tissue.
emphasis on measures of potential response to therapy
rather than measures of risk stratification, and these                                            PREMENOPAUSAL SETTING
seemingly subtle changes must be interpreted as much
                                                                                                    The well entrenched misconception that endocrine ther-
more than a simple switch in their order of consideration.
                                                                                                  apy is ineffective in premenopausal women was perpetu-
                                                                                                  ated by results from trials that were confounded by the
                                                                                                  inclusion of patients with ER-negative disease, the limited
  From The Johns Hopkins Kimmel Cancer Center, Baltimore, MD; Northwestern                        use of tamoxifen, and the indirect endocrine effects of
University Feinberg School of Medicine, Chicago, IL; and The Royal Marsden NHS                    chemotherapy.9 The Early Breast Cancer Trialists’ Col-
Trust, London, UK.
  Authors’ disclosures of potential conflicts of interest are found at the end of this article.
                                                                                                  laborative Group data have now confirmed the survival
  Address reprint requests to Antonio C. Wolff, MD, FACP, The Johns Hopkins Kimmel                benefit offered by adjuvant chemotherapy for the average
Cancer Center, Bunting-Blaustein Cancer Research Building, Room 189, 1650 Orleans                 patient with early-stage disease (especially younger
St, Baltimore, MD 21231-1000; e-mail: awolff@jhmi.edu.
  © 2006 by American Society of Clinical Oncology.                                                women) and by tamoxifen for any patient with ER-positive
  1092-9118/06/22-29                                                                              disease regardless of age.1 Age is, therefore, an incomplete

22
OPTIMAL ENDOCRINE THERAPY IN BREAST CANCER                                                                             23

surrogate for the interaction of host and tumor biologic      mors had similar outcomes. Eastern Cooperative Oncology
features (e.g., expression of hormone receptors, tumor        Group 5188 is the largest trial examining the role of
grade, mitotic rate, and lymphatic vascular invasion)         combined endocrine therapy.23 It showed a benefit from
rather than an independent prognostic factor.9                adding goserelin plus tamoxifen (but not just goserelin)
   Similar confounding factors explain the ongoing contro-    after adjuvant anthracycline-based chemotherapy, while
versy on the role of ovarian suppression/ablation (OA) in     suggesting that goserelin alone following chemotherapy
premenopausal women. Following the original reports on        may be of benefit in patients younger than age 40. A
the palliative role of oophorectomy for patients with ad-     tamoxifen-only arm after chemotherapy was unfortu-
vanced disease in the late 19th century and the first         nately not included based on existing knowledge at the
randomized trials of adjuvant ovarian ablation in the late    time.
1940s, accumulated evidence and systematic review exer-         Therefore, these data suggest that optimal endocrine
cises held by the Early Breast Cancer Trialists’ Collabo-     therapy plays an important role in younger premeno-
rative Group every 5 years since 1985 confirmed that          pausal patients with hormone receptor-positive disease
ablation of functioning ovaries significantly improves sur-   are more likely to continue menstruating after adjuvant
vival in patients with breast cancer younger than age 50,     chemotherapy and to benefit less from chemotherapy as
at least in the absence of chemotherapy.10                    compared with patients with hormone-receptor–negative
                                                              disease. However, most of these trials did not use contem-
Ovarian Suppression With and Without                          porary chemotherapy regimens (e.g., anthracyclines or
Chemotherapy                                                  taxanes), allowed patients with hormone receptor-
                                                              negative or unknown status, and used tamoxifen inconsis-
   Several studies that evaluated OA against cyclophosph-
                                                              tently. OA is not devoid of potential toxicities, including
amide, methotrexate, and fluorouracil (CMF) chemother-
                                                              weight gain, diabetes, and hot flashes.23 At present, OA
apy, such as the Zoladex Early Breast Cancer Research
                                                              should not yet be routinely used to replace or to comple-
Association,11 Scottish-Guys,12 Takeda Adjuvant Breast
                                                              ment adjuvant chemotherapy. Several ongoing trials de-
Cancer Study with Leuprolide Acetate, 13 and Interna-
                                                              scribed in Table 1 are expected to address definitively the
tional Breast Cancer Study Group (IBCSG) VIII14 trials,
                                                              various roles of combining chemotherapy, OA, tamoxifen,
showed that OA offered similar outcomes to patients with
                                                              and aromatase inhibitors (AIs) in premenopausal patients
hormone receptor-positive disease but was inferior to
                                                              with early stage hormone receptor-positive breast cancer.
CMF in patients whose tumors did not express hormone
receptors. Studies like the Austrian Breast and Colorectal    POSTMENOPAUSAL SETTING
Study Group 5,15 French Adjuvant Study Group 06,16 and
Gruppo di Ricerca in Oncologia Clinica e Terapie Associ-         Issues surrounding adjuvant endocrine therapy in post-
ate17 showed that combined endocrine therapy with OA          menopausal women are somewhat less controversial. Sev-
and tamoxifen offers similar or improved outcome when         eral AIs offer additional benefit to what was observed with
combined with CMF.                                            just 5 years of tamoxifen, including an overall survival
                                                              benefit in patients with lymph node-positive disease,24
Ovarian Suppression after Chemotherapy                        and aromatase inhibitors are now considered an integral
                                                              part of endocrine therapy in postmenopausal women.25
  Data from the use of OA after chemotherapy are more            Until recently, 5 years of tamoxifen alone was the
limited. Although no significant survival benefit was seen    standard adjuvant endocrine therapy for postmenopausal
with the use of CMF followed by goserelin over CMF in         women. However, tamoxifen is associated with a small
IBCSG VIII, a retrospective subset analysis suggests that     risk of complications (e.g., uterine cancer and thromboem-
any benefit might be restricted to women younger than         bolic disease), and not all patients are helped. The risk of
age 40.14 The Zoladex in Premenopausal Patients four-         recurrence in patients with hormone receptor-positive
arm trial compared 2 years of therapy with tamoxifen          disease is not limited to the first 5 years,26 and the use of
and/or goserelin compared with placebo using a 2 ⫻ 2          tamoxifen beyond 5 years is not routinely recommended.27
factorial design, and showed a survival benefit in the        The clinical activity and safety of AIs in the metastatic
goserelin arm that was less pronounced in patients            setting led to their evaluation in adjuvant setting for
treated with tamoxifen or chemotherapy.18 A French            postmenopausal women (Table 2). These trials used three
study with a mixed hormone receptor population did not        different strategies as follows: replacement of tamoxifen
show a benefit from adding OA after various kinds of          with an AI, sequencing of an AI after 2 years to 3 years of
chemotherapy.19                                               tamoxifen compared with continuation of tamoxifen for a
                                                              total of 5 years of therapy, and sequencing of an AI or
Endocrine Effects of Chemotherapy                             placebo after 5 years of tamoxifen for a total of 10 years of
   Provocative data from international collaborators led by   therapy.
the IBCSG20 and individual trials21,22 suggest that young
women (⬍ 35 years old) with hormone-receptor–positive         Upfront Use of an Aromatase Inhibitor
tumors primarily treated with chemotherapy had a statis-         The Arimidex Versus Tamoxifen Alone or in Combina-
tically significantly higher risk of relapse than older       tion (ATAC) trial28 and the Breast International Group
premenopausal patients, although younger and older pre-       (BIG) 1-98 trial29 compared 5 years of an AI (anastrozole
menopausal patients with hormone-receptor–negative tu-        and letrozole, respectively) to 5 years of tamoxifen as
24                                                                                                                     WOLFF, CIANFROCCA, AND JOHNSTON

                           Table 1. Ongoing Adjuvant Trials of Ovarian Suppression in Premenopausal Women

              Study                             Study Design                                   Patient Population                                 Issues

SOFT, Suppression of Ovarian       TAM 5 years v OA 5 years ⫹ TAM 5               2,700 premenopausal women with                 Does OA add to chemotherapy in
  Function Trial (IBCSG 24-02/       years v OA 5 years ⫹ EXE 5 years               endocrine-responsive disease treated            premenopausal women? Does OA
  BIG 2-02)                                                                         with no adjuvant chemotherapy or                add to TAM (or EXE) in
                                                                                    remain premenopausal after                      premenopausal women not treated
                                                                                    chemotherapy                                    with chemotherapy?
TEXT (IBCSG 25-02/BIG 3-02)        OA 5 years ⫹ TAM 5 years v OA 5                2,025 premenopausal women with                 Is an AI superior to a SERM in
                                    years ⫹ EXE 5 years                             endocrine-responsive disease who are            premenopausal women treated with
                                                                                    candidates for OA, and who may or               OA?
                                                                                    not receive chemotherapy
PERCHE (IBCSG 26-02/BIG            OA 5 years ⫹ endocrine therapy                 1,750 premenopausal women with                 Is chemotherapy necessary in
  4-02)                             (TAM or EXE) 5 years                            endocrine-responsive disease                    premenopausal women receiving
                                    ⫾ chemotherapy                                                                                  combined endocrine therapy?
ABCSG AU12                         Goserelin 3.6 mg SQ monthly/TAM 1              1,250 premenopausal women with stage           Is OA plus an AI superior to OA plus
                                    mg PO four times a day 3 years v                I/II disease (⬍ 10 positive lymph               TAM? Preliminary data suggest that
                                    Goserelin 3.6 mg SQ monthly/ANZ                 nodes)                                          the osteoporosis risk of OA ⫹ AI
                                                                                                                                                                  56
                                    1 mg PO four times a day 3 years v                                                              combination is reduced by ZOL
                                    same arms ⫾ ZOL 4 mg IV twice a
                                    year (2 ⫻ 2 design)
  Abbreviations: TAM, tamoxifen; AI, aromatase inhibitor; ANZ, anastrozole; ER, estrogen-positive; EXE, exemestane; HR, hazard ratio; LTZ, letrozole; OA,
ovarian suppression/ablation; ZOL, zoledronate. SERM, selective estrogen receptor modulator; IBCSG, International Breast Cancer Study Group; BIG, Breast
International Group; PERCHE, Premenopausal Endocrine Responsive Chemotherapy Study; ABCSC, Austrian Breast and Colorectal Study Group; PO, orally.

adjuvant therapy for postmenopausal women with early-                                    Sequential Therapy
stage breast cancer. The ATAC trial also included a
combination arm (concurrent anastrozole and tamoxifen),                                     The Italian Tamoxifen Anastrozole trial,30 the joint
which was discontinued after the first analysis for lack of                              analysis of the Austrian Breast and Colorectal Cancer
benefit. The BIG 1-98 trial also included two sequential                                 Study Group Trial 8 and the Arimidex-Nolvadex 95 tri-
arms (letrozole followed by tamoxifen and tamoxifen fol-                                 al,31 and the International Exemestane Study32 compared
lowed by letrozole), but these data are not yet available.                               5 years of tamoxifen to a sequential approach using 2
Both trials showed an improvement in disease-free sur-                                   years to 3 years of tamoxifen followed by 2 years to 3 years
vival (DFS) favoring the AI over tamoxifen, but thus far                                 of an AI. All trials showed a benefit in DFS for a sequential
none demonstrated a significant improvement in overall                                   tamoxifen-AI approach compared with 5 years of tamox-
survival.                                                                                ifen, but none other than MA-17 thus far showed a

                                 Table 2. Results from Aromatase Inhibitor Trials in Postmenopausal Women

                                                                                                                                      Results (primary end point ⫽ DFS;
          Study                       Schema                          Eligibility Criteria           n        Median Follow-Up                    IES ⫽ EFS)

ATAC28                   ANZ 5 years v TAM ⫻ 5 years           Postmenopausal; ER-unknown         9,366         68 months         ANZ alone better than TAM alone
                          v ANZ/TAM ⫻ 5 years                    and negative also allowed                                           (DFS HR 0.87, p ⫽ 0.01); Similar
                                                                                                                                     survival in combination arm
                                                                                                                                     (discontinued after 1st analysis)
BIG 1–9829               LTZ ⫻ 5 years v TAM ⫻ 5               Postmenopausal, ER-positive        8,010         25.8 months       First analysis favors LTZ v TAM (DFS
                           years v LTZ ⫻ 2 years 3                                                                                   HR 0.81, p ⫽ 0.003); Cross-over
                           TAM ⫻ 3 years v TAM ⫻ 2                                                                                   results not yet available
                           years 3 LTZ ⫻ 3 years
ITA30                    TAM ⫻ 5 years v TAM ⫻ 2–3             Postmenopausal, ER-positive,       448           36 months         TAM-⬎ ANZ better than TAM (DFS
                           years 3 ANZ ⫻ 3–2 years               node-positive only; Free of                                        HR 0.35, p ⫽0.001)
                                                                 recurrence after 2–3 years
                                                                 of TAM
ABCSG 8/ARNO 9531        TAM ⫻ 5 years v TAM ⫻ 2               Postmenopausal, ER-positive        3,224         28 months         TAM-⬎ ANZ better than TAM ⫻ 5
                           years 3 ANZ ⫻ 3 years                                                                                    years (EFS HR 0.60, p ⫽ 0.0009)
IES32                    TAM ⫻ 5 years v TAM ⫻ 2–3             Postmenopausal, ER-positive or     4,742         30.6 months       TAM-⬎ EXE better than TAM ⫻ 5
                           years 3 EXE ⫻ 3–2 years               unknown, Free of recurrence                                        years (DFS HR 0.68, p ⬍ 0.001)
                                                                 after 2–3 years of TAM
MA-1724                  Years 6–10: LTZ ⫻ 5 years v           Postmenopausal, ER-positive,       5,187         30 months         LTZ better than placebo (DFS
                           Placebo ⫻ 5 years                     free of recurrence after                                           HR ⫽ 0.58, p ⬍ 0.001; DDFS
                                                                 4.5–6 years of TAM                                                 HR ⫽ 0.60, p ⫽ 0.002); Improved
                                                                                                                                    survival in node-positive
                                                                                                                                    (HR ⫽ 0.61, p ⫽ 0.04)
  Abbreviations: ANZ, anastrozole; DFS, disease-free survival; DDFS, distant disease-free survival; EFS, event-free survival; ER, estrogen-receptor; EXE,
exemestane; HR, hazard ratio; LTZ, letrozole; TAM, tamoxifen; ATAC, Arimidex, Tamoxifen, Alone or in combination; BIG, Breast International Group; ITA, Italian
Tamoxifen Anastrozole trial; ABCSG8, Austrian Breast and Colorectal Study Group 8; ARNO, Arimidex-Nolvadex; IES, Intergroup Exemestane Study.
OPTIMAL ENDOCRINE THERAPY IN BREAST CANCER                                                                            25

significant improvement in overall survival. The MA-17        first report from BIG 1-98.29 It is also not unreasonable to
trial randomly assigned patients who had completed 5          use tamoxifen first in a low-risk patient with ER-positive/
years of tamoxifen to 5 years of letrozole compared with      PR-positive, HER2-negative disease at low risk for recur-
placebo.24 DFS was improved for the letrozole group           rence, especially if lymph node-negative.7,8
compared with placebo, and an overall survival benefit           It is now common practice to consider a switch from
was seen in the subgroup of lymph node-positive patients.     tamoxifen to an AI after 2 years to 5 years, although
Patients completing 10 years of therapy are now being         individual preferences and safety issues must be ad-
offered a second random assignment to 5 more years of         dressed. There are no compelling safety or efficacy data to
letrozole compared with placebo.                              differentiate among the three approved AIs (anastrozole,
                                                              exemestane, and letrozole) in the United States. It is
Safety Profile                                                important to emphasize, however, that AIs should only be
   These studies also addressed safety and tolerability.      considered in the postmenopausal setting, and caution is
Adjuvant AIs compared with tamoxifen result in fewer          advised when offering AIs to women with chemotherapy-
endometrial malignancies and thromboembolic events.           induced amenorrhea who may still have residual ovarian
However, they are consistently associated with a higher       function, and some may resume menses even years later.
risk of osteoporosis and related complications and muscu-
                                                              MECHANISMS OF ENDOCRINE RESISTANCE
loskeletal complaints. Concerns about cardiovascular risk
are also being assessed. Long-term follow-up is needed to       Resistance to endocrine therapy in ER-positive tumors
assess their safety in a population likely to survive a       can be intrinsic occurring at first exposure (de novo) or
breast cancer diagnosis.                                      develop over time after an initial response to endocrine
                                                              therapy (acquired). Identification of the key mechanisms
Aromatase Inhibitors in Clinical Practice                     involved is important to help predict response or resis-
   The American Society of Clinical Oncology convened an      tance to specific treatments, and to facilitate development
AI Technology Assessment Panel to review the available        of new pharmaceutical agents targeted at the various
data and make recommendations regarding AIs optimal           molecular components of endocrine resistance pathways.
use in the adjuvant setting.25 In the panel’s most recent
update, they concluded that optimal adjuvant endocrine        De Novo Resistance in ER-positive Breast Cancer
therapy for a postmenopausal woman with hormone                  The expression of ER in breast cancer cells has always
receptor-positive breast cancer should include an AI either   been perceived to be the single most important determi-
as initial therapy or after a period of treatment with        nant for endocrine response in breast cancer. Tumors that
tamoxifen. Several issues regarding AIs await further         do not express any ER are unable to respond to endocrine
evaluation. These include the optimal duration of total       therapies and thus exhibit primary resistance. However,
endocrine therapy, optimal sequencing with tamoxifen,         expression of ER alone is insufficient to accurately predict
efficacy in premenopausal women whether combined              response to endocrine therapy in the clinical setting. For
with OA or in patients with chemotherapy-induced              example, a second ER has been cloned (ERbeta) that has
amenorrhea, and long-term safety.25 BIG 1-98 is examin-       different transcriptional activity compared with ERalpha
ing sequential therapy with an up-front AI followed by        and has been implicated in tamoxifen resistance.36 In
tamoxifen.29                                                  addition to the classical model of liganded ER that binds
   It has been noted that the trials using the sequential     DNA at defined estrogen-response elements upstream of
approach (tamoxifen followed by an AI) yielded larger         ER-regulated genes, ER may also activate alternative
proportional benefits than trials using 5 years of mono-      DNA sequences such as AP-1-response elements that
therapy with an AI. It is unfair, however, to compare the     regulate genes involved in cell proliferation, motility, and
results of these trials for many reasons, including differ-   apoptosis. Enhanced AP-1 activation has been associated
ences in populations studied and differences in the defini-   with tamoxifen resistance both in models of breast cancer
tion of end points. For example, patients in the              and in human tumors.37 Likewise, the relative balance of
International Exemestane Study and MA-17 trials had           coactivator and corepressor proteins in a cell may deter-
completed 2 years to 5 years of tamoxifen without a           mine response of ER to a particular ligand; overexpression
recurrence and were, therefore, more likely to truly have     of the coactivator SRC-1 enhanced the agonist response to
endocrine-responsive disease than patients in the ATAC        tamoxifen,38 whereas reduced nuclear receptor corepres-
and BIG 1-98 trials who started an AI up front. One           sor N expression was associated with development of
theoretical model was proposed to select patients for the     tamoxifen resistance in breast cancer xenografts.39
use of up-front AI compared with a sequential approach,33        More recently, the presence of nongenomic mechanisms
but its generalizability is not certain.                      for ER action has been postulated as an alternative
   Data from the sequential arms of BIG 1-98 trial com-       mechanism for endocrine resistance in ER-positive breast
paring 5 years of an AI to a sequential AI followed by        cancers. Membrane-initiated signaling involves ER inter-
tamoxifen are awaited with interest.29 In the absence of      acting with and/or activating several kinases, including
direct comparative data, an AI up front may be considered     the insulin-like growth factor-1 receptor and the p85
for many patients such as those with HER2-positive34 or       regulatory subunit of phosphatidylinositol 3-kinase via
ER-positive/progesterone receptor (PR)-negative dis-          adaptor proteins Src and Shc, resulting in different cell
ease,35 although these patterns were not observed in the      survival and proliferative signals via the AKT (protein
26                                                                                          WOLFF, CIANFROCCA, AND JOHNSTON

  Fig 1. Bidirectional crosstalk pathways that may be active in endocrine-resistant breast cancer; liganded estrogen receptor can
interact at the plasma membrane with adaptor proteins (ie, Shc) and growth factor receptors, whereas epidermal growth factor
receptor/HER2 or insulin-like growth factor receptor can activate downstream of MEK/MAPK, pp90rsk, or the phosphatidylinositol
3-kinase-AKT pathways to phosphorylate nuclear coactivators/estrogen receptor to initiate hormone-dependent gene transcription, with
tamoxifen/estrogen functioning as agonist ligands. Abbreviations: IGFR, insulin-like growth factor receptor; EGFR, epidermal growth
factor receptor; HER2, human epidermal growth factor receptor2; ER, estrogen receptor.

kinase B) and mitogen-activated protein kinase (MAPK)              signaling pathway.45,46 More recently, changes have been
pathways.40-43 Tamoxifen may also exert agonist effects            reported in intracellular signaling in clinical samples from
via the interaction of membrane ER with peptide growth             patients with breast cancer taken at diagnosis and then
factor signaling (epidermal growth factor receptor (EGFR)          subsequently at the time of relapse on adjuvant tamoxifen
or HER2).44 Likewise, crosstalk may occur in ER-positive           several years later.47 In tumors with retained ER expres-
tumors with HER2 amplification additional by down-                 sion (the majority), there was enhanced expression of
stream activation from various HER2-driven intracellular           HER2 in some patients and evidence that expression of
kinases (eg, p38 MAPK and ERK1/2), which in tamoxifen-             the stress-activated kinase p38 MAPK was also enhanced.
treated tumors may result in the phosphorylation of                These data support a concept that breast cancer cells use
nuclear tamoxifen-liganded ER and its associated coacti-           alternative intracellular signaling pathways over time to
vators. As such, existence of these bi-directional crosstalk       enhance and activate ER signaling and that this allows
pathways can result in tamoxifen stimulating (rather               cells to escape from their initial endocrine therapy with
than inhibiting) the growth of ER-positive breast cancer           tamoxifen.
(Fig 1).                                                              To date there have been fewer clinical or laboratory
                                                                   studies of resistance to aromatase inhibition. Laboratory
Acquired Endocrine Resistance                                      data from several groups support a concept of adaptation
   Several experimental models and clinical studies have           to a low estrogen environment with an enhanced sensitiv-
suggested that peptide growth factor receptor pathways             ity to estrogen as a means of escape from estrogen depri-
(e.g., EGFR and HER2) become selectively upregulated in            vation therapies.48,49 In part, this may be because of an
breast cancer cells that acquire resistance to tamoxifen           increase in ER protein but may also relate to relocation of
during prolonged exposure. Enhanced expression of EGFR             ER to the plasma membrane in association with Shc and
and subsequent downstream MAPK activation have been                insulin-like growth factor-1 receptor together with in-
found in MCF-7 breast cancer cells that become resistant           creased activation of Src and RAS/RAF/MEK/MAPK
over time to tamoxifen, and there is evidence that cotreat-        signaling.40 Treatment with fulvestrant blocked MAPK ac-
ment with the EGFR receptor tyrosine kinase inhibitor              tivation suggesting that ER-alpha is functioning upstream
gefitinib may prevent or delay resistance by blocking this         of MAPK in a nongenomic membrane-associated fashion.
OPTIMAL ENDOCRINE THERAPY IN BREAST CANCER                                                                              27

Molecularly Targeted Therapies to Treat                        nists with an AI. Cotreatment with temsirolimus (CCI-
or Prevent Endocrine Resistance                                779) inhibited mTOR activity and restored sensitivity to
                                                               tamoxifen primarily through induction of apoptosis, sug-
   Emerging data suggest that endocrine resistance (either
                                                               gesting that AKT-induced tamoxifen resistance may in
de novo or acquired) may involve bidirectional interaction
                                                               part be mediated by signaling through the mTOR path-
between ER and growth factor signaling, either via non-
                                                               way.54 Preliminary data from randomized phase II trials
genomic ER activation of growth factor receptors at the
                                                               showed higher clinical benefit rates for temsirolimus com-
plasma membrane or via intracellular activation of clas-
                                                               bined with letrozole compared with letrozole alone,55 and
sical genomic ER in the nucleus by various intracellular
                                                               a larger randomized placebo-controlled efficacy study is
kinases driven by upstream growth factor pathways. Hope
                                                               underway. Similarly, preoperative studies are addressing
now exists that by learning which intracellular signaling
                                                               whether everolimus (RAD-001) can enhance the efficacy of
pathways are operative, logical combinations of signal
                                                               4 months of preoperative letrozole.
transduction inhibitors (STIs) can be devised to target key
molecular pathways implicated in development of resis-
                                                               CONCLUSION
tance.50 In particular, EGFR- and HER2-targeted thera-
pies have been used in preclinical models to overcome            Endocrine therapy is the most important treatment for
endocrine resistance by blocking upregulated signaling         patients with hormone-receptor–positive breast cancer,
pathways. In MCF-7 cells that developed resistance to          regardless of menopausal status. Questions about the role
tamoxifen, both gefitinib and trastuzumab were effective       of OA in premenopausal women and optimal schedule of
at reducing downstream ERK1/2 MAPK signaling and               AIs in postmenopausal women remain. Endocrine therapy
inhibiting cell growth.                                        alone will not be enough for many patients. Those with
   Of note, hormone-sensitive cells (in which neither recep-   larger tumors and lymph node involvement often receive
tors are overexpressed) are unaffected by either gefitinib     chemotherapy, but many are potentially overtreated. New
or trastuzumab therapy. However, because adaptive              molecular assays and the resulting refinement of risk
changes in growth factor signaling occur during prolonged      stratification and predictive models will help further dis-
endocrine therapy, strategies to combine endocrine with        criminate those with endocrine-responsive compared with
STI therapies may prevent development of resistance and        nonresponsive disease within the group of patients with
improve therapeutic efficacy. In vitro combination of ta-      hormone-receptor–positive disease.
moxifen and gefitinib prevented the acquired expression of       Substantial progress has been made in recent years to
EGFR/MAPK signaling and the subsequent resistance              better understand some of the molecular mechanisms
that occurred after 5 weeks in tamoxifen-alone treated         involved in both de novo and acquired endocrine resis-
cells,51 and this concept is now being tested in a random-     tance. Laboratory and clinical data support the concept
ized phase II trial. Combined STIs and endocrine therapy       that over time breast cancer cells utilize alternative intra-
may also be more effective than using STIs alone in            cellular signaling pathways to enhance and activate ER,
hormone-resistant HER2-positive/ER-positive breast can-        which then allow cells to escape from their initial endo-
cer cells. For example, the dual EGFR/HER2 inhibitor           crine therapy. As these pathways are elucidated, strate-
lapatinib cooperates with tamoxifen to provide more rapid      gies are emerging to block these signaling pathways from
and profound cell cycle arrest than either therapy alone in    the outset by cotreatment with various STIs. Both in vitro
acquired hormone-resistant cells,52 and a large phase III      and in vivo data now exist to show that this approach may
clinical trial in ER-positive advanced breast cancer is now    delay resistance, and this is being tested in ongoing
in progress to see whether lapatinib combined with letro-      randomized controlled trials in both the metastatic and
zole can prolong time to disease progression compared          preoperative settings.
with letrozole alone.                                            The identification of candidates for adjuvant endocrine
   Other STIs may also be more effective when combined         therapy relies heavily on the accuracy of laboratory assays
with endocrine therapy. The farnesyltransferase inhibitor      for ER and PR. These assays serve as predictive markers
tipifarnib when combined with tamoxifen or estrogen            of response and sole determinants of therapy selection,
deprivation induced greater tumor regression than either       and pathologists and laboratories share responsibility
endocrine therapy alone. However, a randomized phase II        with clinicians regarding patient outcome. Therefore, it is
trial in 120 patients that compared letrozole and tipi-        crucial that all involved (including patients) understand
farnib with letrozole alone showed a longer duration of        the nuances of these assays to avoid the risk of denying
objective response for the combination (23 months vs. 16       adjuvant endocrine therapy to a patient with a false-
months) but no actual improvement in response rate.53 A        negative hormone receptor test. Our ability to identify
similar rationale has emerged to support the combination       optimal candidates for various endocrine therapy ap-
of the mammalian target of rapamycin (mTOR) antago-            proaches will continue to be refined in the years to come.
28                                                                                                               WOLFF, CIANFROCCA, AND JOHNSTON

Authors’ Disclosures of Potential Conflicts of Interest
                                        Employment or
                                          Leadership
                                           Positions       Consultant or      Stock                           Research           Expert           Other
          Author                      (Commercial Firms)   Advisory Role    Ownership        Honoraria         Funding         Testimony       Remuneration
 Mary Cianfrocca                                                                         Pfizer Oncology;
                                                                                          AstraZeneca;
                                                                                          Bristol-Meyers
                                                                                         Squibb; Novartis
                                                                                         Oncology; sanofi-
                                                                                             aventis US
 Stephen R. D. Johnston                                                                                      AstraZeneca;
                                                                                                             OrthoBiotech
 Antonio C. Wolff*
 *No significant financial relationships to disclose.

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