- Email: [email protected]
Patient Case Lessons: Endocrine Management of Advanced Breast Cancer
Accepted Manuscript Patient Case Lessons: Endocrine Management of Advanced Breast Cancer Nicholas J. Robert, MD, Neelima Denduluri, MD PII:
S1526-8209(16)30502-X
DOI:
10.1016/j.clbc.2017.05.014
Reference:
CLBC 627
To appear in:
Clinical Breast Cancer
Received Date: 22 November 2016 Revised Date:
7 April 2017
Accepted Date: 22 May 2017
Please cite this article as: Robert NJ, Denduluri N, Patient Case Lessons: Endocrine Management of Advanced Breast Cancer, Clinical Breast Cancer (2017), doi: 10.1016/j.clbc.2017.05.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Endocrine Management of ABC
1 2 3 4 5
RI PT
Nicholas J. Robert, MD1, and Neelima Denduluri, MD2 1
SC
US Oncology Network, Virginia Cancer Specialists, 8503 Arlington Blvd, Suite 400, Fairfax, VA 22031, USA; 2US Oncology Research Network, 1635 N. George Mason Drive, Suite 170, Arlington, VA 22205, USA
M AN U
6 7 8 9 10 11 12 13
Patient Case Lessons: Endocrine Management of Advanced Breast Cancer
Corresponding Author: Nicholas J. Robert, MD US Oncology Network Virginia Cancer Specialists 8503 Arlington Blvd, Suite 400 Fairfax, VA 22031, USA E-mail: [email protected] Phone: 703-280-5390 Fax: 703-280-9596
24 25 26 27 28 29 30 31 32 33 34 35 36
Type of Manuscript: Review
TE D
14 15 16 17 18 19 20 21 22 23
EP
Key Words: Metastatic breast cancer, Endocrine therapy, Estrogen, Progesterone, Human epidermal growth factor
AC C
Abbreviations not common in the field: None Word Counts: Abstract 178 (limit 250); Text 4,335 (limit 10,000) References: 122 (limit 120) Figures/Tables: 3 (limit 7) 2 tables, 1 figure Conflict of Interest Nicholas J. Robert, MD, and Neelima Denduluri, MD, report no conflicts of interest.
37 38
1
ACCEPTED MANUSCRIPT Endocrine Management of ABC
ABSTRACT
40
Advances in treatment for women with advanced breast cancer (ABC) have led to
41
improvements in survival. While the condition remains incurable, treatment goals focus on
42
stabilizing disease, prolonging life, and maintaining patient quality of life. Hormone receptor-
43
positive subtypes constitute the majority of breast cancers, and an increasing number of
44
effective endocrine therapies are available. Although practice guidelines provide important
45
recommendations and principles for treatment selection, the choice of specific agents from
46
among existing options should be customized to the individual based on patient and disease
47
characteristics, as well as the nature and duration of response to previous treatments. This
48
review examines endocrine and endocrine-based options, including combinations with targeted
49
agents, for hormone receptor-positive and human epidermal growth factor receptor 2-negative
50
(HR-positive and HER2-negative) ABC. It also elaborates on the factors that enter into treatment
51
decision-making, using patient case examples to illustrate how ABC can present and the clinical
52
issues involved in treatment selection. Case examples are included to provide evidence for the
53
clinical scenarios of de novo HR-positive/HER2-negative ABC and progression during adjuvant
54
treatment for early breast cancer.
SC
M AN U
TE D
EP
AC C
55
RI PT
39
2
ACCEPTED MANUSCRIPT Endocrine Management of ABC
56 57 58
Introduction
59
incurable and represents an unmet medical need. While overall mortality rates have declined,
60
median survival for women with ABC is approximately 2 to 3 years, with a 5-year survival rate of
61
25% or less, depending on the database cited and the time during which the data were
62
gathered.1-4 Estrogen receptor (ER)-positive tumors represent up to 80% of all breast cancers.5-7
63
Among US patients with ABC, approximately 60% to 75% have hormone receptor (HR)-positive
64
(i.e., ER-positive and/or progesterone receptor [PgR]-positive) disease.8 The incidence of HR-
65
positive tumors tends to increase with age and vary with ethnicity.7,9
66 67
This review examines available endocrine and endocrine-based treatment options for the
68
management of HR-positive, human epidermal growth factor receptor 2(HER2)-negative ABC,
69
including endocrine therapy (ET) and targeted therapies, as well as newly investigated
70
combinations and monotherapies. It also elaborates on factors that enter into treatment
71
decision-making, using patient case examples to illustrate how ABC can present and the clinical
72
issues involved in treatment selection. Case examples are included to provide evidence for the
73
clinical scenarios of de novo ABC and recurrence during adjuvant treatment for early breast
74
cancer.
75 76
Considerations in Choosing Treatment
77
Advances in endocrine-based therapeutics have improved survival for women with HR-positive
78
ABC.10-13 And because women with HR-positive breast cancer are living longer, patient quality
79
of life has come to the forefront of clinical decision-making.12 The following includes several
AC C
EP
TE D
M AN U
SC
RI PT
Despite advances in medicine and drug development, advanced breast cancer (ABC) remains
3
ACCEPTED MANUSCRIPT Endocrine Management of ABC
80
factors that should be considered when selecting from among available therapies for women
81
with HR-positive ABC11,13-16: •
Minimizing toxicity in keeping with the palliative aim of therapy
83
•
Maintaining and/or improving the patient’s quality of life
84
•
The urgency of the need for treatment based on factors such as symptom severity and the pace of disease progression
85
RI PT
82
•
The duration of prior response to adjuvant ET
87
•
The duration of disease-free interval since last therapy (i.e., early vs late disease
89
M AN U
progression)
88
•
SC
86
The sites of disease (i.e., bone or soft tissue, which may indicate a more indolent disease course; combined bone and soft tissue; or visceral metastases associated
91
with more aggressive phenotype)
TE D
90
92
•
Disease burden (e.g., volume and the number of metastases)
93
•
HER2 status
In addition, the following patient factors also warrant consideration:
EP
94
•
Comorbidities
96
•
Patient performance status
•
Patient preferences
•
Patient access to drug coverage
97 98
AC C
95
99
Several treatment options are available for women with HR-positive ABC. The selective ER
100
modulator (SERM) tamoxifen is one of the earliest forms of ET used in the treatment of HR-
101
positive disease and is the most firmly established ET use as adjuvant therapy for both pre- and 4
ACCEPTED MANUSCRIPT Endocrine Management of ABC
postmenopausal women.12,17 In premenopausal women, ovarian ablation or treatment with
103
luteinizing hormone-releasing hormone analogues such as goserelin and leuprolide11 may be
104
used to suppress ovarian function.12,13 For postmenopausal women, the nonsteroidal
105
aromatase inhibitors (AIs) anastrozole and letrozole,18,19 the steroidal AI exemestane,20 and the
106
selective ER degrader (SERD) fulvestrant21 are established, approved, and effective therapeutic
107
options.
SC
RI PT
102
108
Development of resistance to ET in HR-positive ABC is common, and most patients experience
110
disease progression.22,23 However, the mechanisms underlying disease progression and the
111
development of resistance to ET are complex and not fully understood, but likely resistance
112
pathways differ for AIs versus SERMs/SERDs. In recent years, greater understanding of the
113
molecular pathways of resistance has led to increased investigation of combinations that
114
include ET and targeted agents, such as everolimus, a mammalian target of rapamycin (mTOR)
115
inhibitor, and palbociclib, a cyclin-dependent kinase (CDK) inhibitor. While these novel
116
combinations may provide additional therapeutic options for women with ET-resistant disease,
117
tradeoffs may include increased toxicity and added cost.22,23
TE D
EP
AC C
118
M AN U
109
119
Studies suggest that patients with HR-positive metastatic disease whose disease has progressed
120
during first line ET might still respond to different types of ET in the second line.24,25 These
121
observations support that well-tolerated, sequential ET may slow progression in HR-positive
122
ABC and potentially delay the need for chemotherapy.12,13 Indeed, this approach is
123
recommended in clinical practice guidelines.12,26 The optimal sequencing of ETs, however,
5
ACCEPTED MANUSCRIPT Endocrine Management of ABC
remains unclear, and decisions regarding sequencing approaches may be confounded by clinical
125
variables such as menopausal status or previous treatments.12,27 Careful consideration of
126
factors such as prior ET and the time to progression on that treatment (i.e., early relapse, ≤12
127
months may be indicative of resistance; >12 months may suggest endocrine sensitivity),
128
mechanism of action and the potential for cross-resistance, site of metastasis, whether the
129
patient demonstrated symptoms, and the current clinical evidence are paramount.14
SC
RI PT
124
130
Overview of Treatment Options in HR-Positive ABC: Endocrine Therapies and Targeted Agents
132
An overview of currently available ETs and targeted agents is presented in Table 1.28-40 Data
133
from key phase 3 studies of endocrine and endocrine-based therapies for ABC are presented in
134
Table 2.21,41-61
M AN U
131
TE D
135
Selective Estrogen Receptor Modulators
137
The SERMs tamoxifen and toremifene are competitive inhibitors of estrogen: they bind directly
138
to the ER in breast cancer cells, blocking estrogen binding.30,31,62 In addition to their estrogen
139
antagonist effects in the breast, SERMs also manifest partial estrogen agonist effects on
140
peripheral tissues, with beneficial effects in some sites (e.g., bone)62,63 and unfavorable effects
141
in others (e.g., uterus).30,64 The adverse events (AEs) of SERMs are consistent with those
142
experienced during menopause, and may include hot flashes, night sweats, vaginal dryness,
143
discharge, or bleeding.30,64 More serious AEs associated with prolonged use include an
144
increased risk of endometrial cancer and deep venous thrombosis.12,30,62,65
AC C
EP
136
145
6
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Aromatase Inhibitors
147
Aromatase inhibitors, which include anastrozole, letrozole, and exemestane, decrease the
148
amount of estrogen in postmenopausal women by blocking the enzyme aromatase which
149
converts androgens to estrogen in peripheral tissue, including breast tumor cells.66 Anastrozole
150
and letrozole are nonsteroidal AIs that bind reversibly to aromatase, inhibiting the enzyme.66
151
Exemestane is a steroidal AI and analogue of the endogenous aromatase substrate
152
androstenedione, whose metabolites bind irreversibly to aromatase, causing permanent
153
inactivation of the enzyme.67-70
M AN U
SC
RI PT
146
154
Prior to the approval of palbociclib, single-agent ET was the mainstay therapy for women with
156
HR-positive, recurrent disease in the metastatic setting.11 Aromatase inhibitors remain an
157
important option in first line therapy for postmenopausal women with HR-positive ABC and are
158
generally well tolerated.52,71,72 Adverse events associated with AI monotherapy may include
159
musculoskeletal symptoms, hot flashes, vaginal dryness, and an increased risk of bone
160
fracture.12,32-34 Direct comparative studies of the three AIs in first line therapy of ABC have not
161
been conducted, although results across studies suggest similar efficacy and tolerability. The
162
current National Comprehensive Cancer Network (NCCN) guidelines recommend ovarian
163
suppression plus ET for treating premenopausal women with HR-positive ABC , which could
164
then include an AI.12
AC C
EP
TE D
155
165 166
Based on using a dual-blockade approach, combining ETs with different mechanisms of action,
167
the combination of a SERM with an AI was investigated to assess clinical benefit over either
7
ACCEPTED MANUSCRIPT Endocrine Management of ABC
therapy alone. Early studies with fadrozole and vorozole did not consistently provide additional
169
anti-tumor activity when used in combination with tamoxifen.73,74 Later preclinical studies
170
reported that letrozole alone was superior to tamoxifen and added benefit was not evident
171
with the combination treatment. The findings of studies conducted with anastrozole in
172
combination with tamoxifen were similar to those with letrozole.75
SC
173
RI PT
168
Selective ER Degrader
175
Fulvestrant is a SERD35 that binds competitively to the ER with a higher relative binding affinity
176
than tamoxifen (IC50 0.89 vs 0.025).76-78 In contrast to tamoxifen’s partial agonist activity,
177
fulvestrant inhibits ER dimerization and translocation to the nucleus, effectively targeting and
178
blocking estrogen-sensitive gene transcription and eliminating all known agonist activity.
179
Fulvestrant also accelerates ER degradation, resulting in complete suppression of the estrogenic
180
effects on breast tissue.79 Fulvestrant has received FDA approval for the treatment of HR-
181
positive metastatic breast cancer in postmenopausal women with disease progression following
182
antiestrogen therapy, and for treatment of HR-positive/HER2-negative advanced or metastatic
183
breast cancer in combination with palbociclib in women with disease progression after ET
184
(discussed below).35
TE D
EP
AC C
185
M AN U
174
186
The most frequent AEs observed with fulvestrant (occurring with a frequency of ≥5% of
187
patients) include injection-site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue,
188
pain in extremities, hot flashes, vomiting, anorexia, asthenia, musculoskeletal pain, cough,
189
dyspnea, and constipation.35,79-81
8
ACCEPTED MANUSCRIPT Endocrine Management of ABC
190
Targeted Therapies
192
Treatments for HR-positive/HER2-negative ABC may also include the targeted inhibition of
193
other pathways involved in the promotion of tumor cell proliferation, such as the mTOR82 and
194
CDK4/6 signaling pathways.83-85 Abnormal signaling through the phosphatidylinositol 3-kinase-
195
Akt-mTOR pathway may be a mechanism of resistance to ET, suggesting the potential for
196
mTOR-targeted therapies in patients with endocrine-resistant, HR-positive ABC.52 Everolimus, a
197
derivative of sirolimus (formerly rapamycin), inhibits mTOR signaling through allosteric binding
198
to mTORC1.86,87 Preclinical studies have shown that the use of everolimus in combination with
199
AIs yields synergistic inhibition of cell proliferation and induction of apoptosis.88 Everolimus is
200
FDA-approved in combination with exemestane for treatment of postmenopausal women with
201
HR-positive/HER2-negative ABC after failure of treatment with letrozole or anastrozole.38,52
202
Adverse events associated with everolimus are consistent with those observed for other
203
rapamycin analogues and include stomatitis, infections, rash, fatigue and asthenia, diarrhea,
204
edema, abdominal pain, nausea, cough, headache, and decreased appetite.38,52,89
SC
M AN U
TE D
EP
205
RI PT
191
It is well recognized that cell cycle progression is dysregulated in certain molecular subtypes of
207
breast cancer.83-85 The first FDA-approved CDK4/6 inhibitor, palbociclib,90 blocks progression
208
from G1 into S phase of the cell cycle and represent a new pathway to target in HR-positive
209
ABC.83 It is approved for use in HR-positive/HER2-negative ABC in combination with letrozole
210
for the first line treatment of postmenopausal women, and in combination with fulvestrant for
211
disease progression following ET in both pre- and postmenopausal women.39 The most
AC C
206
9
ACCEPTED MANUSCRIPT Endocrine Management of ABC
common adverse reactions observed in the pivotal studies (incidence ≥10%) were neutropenia,
213
leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea,
214
thrombocytopenia, constipation, alopecia, vomiting, rash, and decreased appetite.39
RI PT
212
215
In March 2017, ribociclib (LEE011) was granted FDA approval as first line treatment for HR-
217
positive/HER2-negative ABC in combination with any AI.40 In the planned interim analysis of the
218
MONALEESA-2 study, which is evaluating ribociclib (600 mg) in combination with letrozole (2.5
219
mg) compared with letrozole plus placebo in postmenopausal women with HR-positive/HER2-
220
negative recurrent or metastatic breast cancer who had not received previous systemic therapy
221
for advanced disease, common grade 3/4 AEs were neutropenia, leukopenia, hypertension,
222
elevated alanine aminotransferase, lymphopenia, and elevated aspartate aminotransferase.56
M AN U
SC
216
TE D
223
An additional CDK4/6 inhibitor, abemaciclib (LY2835219), is under evaluation and may become
225
a future option for treatment. In June 2016, the first interim results were reported from the
226
phase 2, single-arm MONARCH 1 study of 132 patients with HR-positive/HER2-negative ABC
227
who experienced disease progression on or after prior ET and chemotherapy. Patients were
228
treated with 200 mg abemaciclib orally twice daily. The objective response rate (ORR) was
229
19.7% (95% CI, 13.3–27.5) and the clinical benefit rate (CBR) was 42.4%.91 Two phase 3 studies
230
are also being conducted: the MONARCH 2 study in combination with fulvestrant in women
231
with HR-positive/HER2-negative breast cancer,92 and the MONARCH 3 study in postmenopausal
232
women with HR-positive/HER2-negative breast cancer to evaluate abemaciclib 150 mg or
AC C
EP
224
10
ACCEPTED MANUSCRIPT Endocrine Management of ABC
233
placebo given orally every 12 hours continuously until progression, along with anastrozole 1 mg
234
or letrozole 2.5 mg once daily at the investigator’s discretion, with assessments every 28 days.93
RI PT
235
ESR Mutation
237
The emergence of ESR1 mutations occurs primarily in ABC after exposure to AIs,94 resulting in
238
dose-dependent changes in responsiveness to endocrine agents.95-98
SC
236
239
Retrospective analysis of baseline plasma samples from patients enrolled in the phase 3 SoFEA
241
study, which evaluated fulvestrant (500 mg intramuscularly on day 1, followed by 250 mg on
242
days 15 and 29, then every 28 days) with placebo or anastrozole (1 mg) versus exemestane (25
243
mg) in patients with prior sensitivity to AIs, suggests that the presence of ESR1 mutations may
244
impart sensitivity to fulvestrant. Plasma samples from 161 of 723 (22.4%) patients were
245
analysed for ESR1 mutations. Of these, 63 (39%) had ESR1 mutations, and among these, 49.1%
246
(27 of 55) were polyclonal. Patients with ESR1 mutations had improved progression-free
247
survival (PFS) after receiving fulvestrant compared with exemestane (hazard ratio [HR]=0.52;
248
95% CI, 0.30-0.92; P=0.02). However, patients with wild-type ESR1 had similar PFS regardless of
249
treatment (HR=1.07; 95% CI, 0.68-1.67; P=0.77).99
TE D
EP
AC C
250
M AN U
240
251
In the phase 3 PALOMA-3 study, conducted in patients with HER2-negative ABC who had
252
progressed on previous ET, the prevalence of ESR1 mutations was 25.3% (91 of 360). Among
253
those, 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to
254
prior AIs. Improved PFS was observed for the fulvestrant plus palbociclib arm versus the
11
ACCEPTED MANUSCRIPT Endocrine Management of ABC
255
fulvestrant plus placebo arm in both ESR1-mutant (HR=0.43; 95% CI, 0.25-0.74; P=0.002) and
256
ESR1-wild-type patients (HR=0.49; 95% CI, 0.35-0.70; P<0.001).99
RI PT
257
In BOLERO-2, an international, double-blind, randomized, phase 3 study comparing everolimus
259
plus exemestane to placebo plus exemestane in postmenopausal women with HR-
260
negative/HER2-negative ABC who progressed during or following treatment with nonsteroidal
261
AIs, ESR1 mutations in cell-free DNA were detected in baseline plasma samples obtained from
262
541 of 724 patients (74.7%). Of 541 evaluable patients, 156 (28.8%) had the ESR1 mutations
263
D538G (21.1%) and/or Y537S (13.3%), and 30 had both. Shorter overall survival (OS) was
264
associated with these mutations (wild-type, 32.1 months [95% CI, 28.09–36.40 months];
265
D538G, 25.99 months [95% CI, 19.19–32.36 months]; Y537S, .19.98 months [95% CI, 13.01–
266
29.31 months]; both mutations, 15.15 months [95% CI, 10.87–27.43 months]). Patients with the
267
D538G mutation demonstrated a similar PFS benefit (HR=0.34 [95% CI, 0.02–0.57]) from the
268
addition of everolimus to exemestane as did those without D538G or Y537S mutations.98 These
269
studies indicate that ESR1 mutations are prevalent in ER-positive, AI-treated ABC. Both Y537S
270
and D538G mutations are associated with more aggressive disease biology.
M AN U
TE D
EP
AC C
271
SC
258
272
Case Studies
273
The following patient-case scenarios provide opportunities to examine factors that may impact
274
therapeutic strategies for postmenopausal patients with HR-positive ABC. Selected treatment
275
recommendations based on available data and the clinical experience of the authors are
276
presented in Figure 1.
12
ACCEPTED MANUSCRIPT Endocrine Management of ABC
277
For any postmenopausal patient with HR-positive disease and bone and/or soft tissue or
279
asymptomatic visceral metastases, the NCCN Clinical Guidelines in Oncology for breast cancer
280
currently recommend 3 lines of ET before considering cytotoxic chemotherapy.12 Optimal
281
sequencing has not yet been determined12,27 and is subject to change with the emergence of
282
new agents.
SC
RI PT
278
283
Case Study 1: De Novo ABC
285
A 67-year-old woman with no history of breast cancer presented with a 3-cm nodule in the
286
left breast and hip pain that had not resolved despite treatment with nonsteroidal anti-
287
inflammatory drugs. Workup revealed bone metastases including the pelvis and low-volume
288
malignant pleural effusion in the right lung. Biopsy and subsequent pathology findings
289
revealed ER-positive, PgR-positive, HER2-negative ABC.
TE D
290
M AN U
284
The overall rate of patients with HR-positive ABC who have not received prior ET is reported to
292
be 3% to 6%,100 and other data suggest that the rate may be higher. The variation in rates may
293
be subject to regional differences in reporting, which are affected by various factors, such as
294
affluence and insurance coverage, that also impact patients’ ability to seek care early in their
295
disease.101,102 This case provides clinical guidance for first line options.
AC C
EP
291
296
13
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Options for Monotherapy
298
Recommended monotherapy options for postmenopausal patients with HR-positive ABC who
299
are ET-naïve or have had no ET for more than 12 months, include a SERM (e.g., tamoxifen) or AI
300
(letrozole, exemestane, or anastrozole).12,26 However, emerging data based on the FALCON
301
study (discussed below) provide evidence for fulvestrant as a potential new option for
302
endocrine-naïve patients.103 Comparative studies of tamoxifen versus AIs support the first line
303
use of third-generation AIs in ABC. The outcomes of several phase 3 studies comparing
304
anastrozole, letrozole, or exemestane with tamoxifen as first line therapy in postmenopausal
305
women with advanced endocrine-sensitive breast cancer indicate that AIs offer a modest, but
306
statistically significant, benefit in comparison with tamoxifen.12,41-44,46 At this time, no head-to-
307
head comparison studies of third-generation AIs in the metastatic setting have been conducted
308
to determine the superiority of one agent over another.27
SC
M AN U
TE D
309
RI PT
297
Clinical Studies of Fulvestrant First Line Monotherapy
311
Fulvestrant has been evaluated thoroughly in clinical studies as a single agent, in first and
312
second line therapy, and in combination with other agents.104
AC C
313
EP
310
314
Although not currently approved for first line treatment, data regarding the use of fulvestrant
315
500 mg in the ET-naïve setting are available. In the phase 2 FIRST study of 205 postmenopausal
316
women with HR-positive ABC who had not received prior ET, fulvestrant 500 mg significantly
317
prolonged time to progression (TTP) versus anastrozole 1 mg. At the follow-up analysis (median
318
duration of follow-up for TTP: 18.8 months in the fulvestrant group and 12.9 months in the
14
ACCEPTED MANUSCRIPT Endocrine Management of ABC
anastrozole group, when 79.5% of patients had discontinued therapy), the median TTP was 23.4
320
months with fulvestrant versus 13.1 months with anastrozole (HR=0.66; 95 % CI, 0.47-0.92;
321
P=0.01). These findings represent a 34% decrease in the risk of progression.105 Fulvestrant was
322
also associated with a significantly greater median OS (54.1 months) than anastrozole (48.4
323
months; HR=0.70; 95% CI, 0.50-0.98; P=0.041).106
SC
324
RI PT
319
The findings from the FIRST study led to the phase 3 confirmatory FALCON study that also
326
compared fulvestrant with anastrozole for first line treatment of ET-naïve patients with HR-
327
positive locally advanced or ABC.103 In total, 462 patients were randomized to receive
328
fulvestrant 500 mg (n=230) or anastrozole 1 mg (n=232). The primary endpoint was met as
329
demonstrated by a significant improvement in PFS with fulvestrant versus anastrozole
330
(HR=0.797; 95% CI, 0.637-0.999; P=0.049; median PFS 16.6 vs 13.8 months, respectively).103
331
While OS data were not yet mature at the time of publication, the PFS data suggest that
332
fulvestrant may soon become a treatment option in the ET-naïve setting.103
TE D
M AN U
325
EP
333
A First Line Option: Palbociclib Plus Letrozole
335
With the approval of palbociclib in combination with letrozole as first line endocrine-based
336
therapy, postmenopausal women with de novo HR-positive ABC have a new option for initial
337
treatment.90,107
AC C
334
338 339
The confirmatory phase 3 study (PALOMA-2) evaluated palbociclib 125 mg/day in 3-week-on, 1-
340
week-off treatment cycles plus letrozole 2.5 mg/day continuously, compared with letrozole
15
ACCEPTED MANUSCRIPT Endocrine Management of ABC
alone every 28 days in 666 postmenopausal patients without prior systemic therapy for ABC. As
342
of February 2016, 331 PFS events were reported with a median PFS for the combination of
343
palbociclib and letrozole of 24.8 versus 14.5 months for letrozole alone (HR=0.58; 95% CI, 0.46-
344
0.72; P<0.001). The ORR was significantly higher in the palbociclib plus letrozole arm (42.1% vs
345
34.7%, P=0.031) than in the letrozole-alone arm. In patients with measureable disease, the ORR
346
was 55.3% and 44.4% for the palbociclib plus letrozole and letrozole-alone arms, respectively
347
(P=0.013). Overall survival was not reported because the data were immature. Common AEs (all
348
grades) for the palbociclib plus letrozole and letrozole-alone arms, respectively, were
349
neutropenia (79.5% vs 6.3%), fatigue (37.4% vs 27.5%), nausea (35.1% vs 26.1%), arthralgia
350
(33.3% vs 33.8%), and alopecia (32.9% vs 15.8%).53
M AN U
SC
RI PT
341
351
The recent FDA approval of ribociclib plus any AI as a first line treatment for HR-positive/HER2-
353
negative ABC, based on the interim analysis of the MONALEESA-2 study, provides another
354
treatment option in this setting.40
EP
355
TE D
352
Other Combination Approaches
357
The combination of fulvestrant plus anastrozole in comparison with anastrozole alone has been
358
the subject of two studies. The SWOG S0226 study evaluated 707 randomized postmenopausal
359
patients with HR-positive ABC to characterize differences in PFS following treatment with the
360
combination of fulvestrant plus anastrozole (fulvestrant 500 mg intramuscularly [IM] on day 1;
361
250 mg on days 14 and 28, then every 4 weeks plus anastrozole, 1 mg/day orally) versus
362
anastrozole alone. The study demonstrated a survival benefit with the addition of fulvestrant to
AC C
356
16
ACCEPTED MANUSCRIPT Endocrine Management of ABC
anastrozole (15.0 months; 95% CI, 13.2-18.4; HR=0.80, P=0.007) compared with anastrozole
364
monotherapy (13.5 months; 95% CI, 12.1-15.1). Among the 414 women naïve to adjuvant ET,
365
median PFS was 17.0 months for combination therapy compared with 12.6 months for
366
anastrozole alone (HR=0.74; 95% CI, 0.59-0.92; P=0.006).51 It should be noted that the
367
250 mg/month fulvestrant dosage administered in S0226 has been shown to be inferior to
368
500 mg/month.48
SC
RI PT
363
369
Another investigation of fulvestrant plus anastrozole as combination therapy was the FACT
371
study.50 This was an open-label, randomized, phase 3 study of fulvestrant and anastrozole in
372
combination (500 mg IM on day 1 and 250 mg on days 15 and 29, and every 4 weeks thereafter
373
plus anastrozole 1 mg/day orally) compared with anastrozole alone (1 mg/day orally) as first
374
line therapy for postmenopausal women with ER-positive and/or PgR-positive breast cancer in
375
first relapse of endocrine-responsive breast cancer. In contrast to SWOG S0226, approximately
376
two-thirds of the 514 randomized patients in this study had previously received adjuvant
377
antiestrogens. Of these, only 8 patients had previously received an AI. The median TTP was 10.8
378
and 10.2 months for fulvestrant plus anastrozole versus anastrozole alone, respectively
379
(HR=0.99; 95% CI, 0.81-1.20; P=0.91); median OS was 37.8 and 38.2 months, respectively
380
(HR=1.0; 95% CI, 0.76-1.32; P=1.00).50
TE D
EP
AC C
381
M AN U
370
382
Case Study 2: Progression During Hormonal Therapy for Early Breast Cancer
383
A 58-year-old woman initially diagnosed with ER-positive, PgR-positive, HER2-negative,
384
lymph-node–negative breast cancer was prescribed a 5-year course of anastrozole after an
17
ACCEPTED MANUSCRIPT Endocrine Management of ABC
initial lumpectomy followed by radiation. During her fourth year of anastrozole treatment,
386
she was diagnosed with multiple bone metastases, but no evidence of visceral disease. A
387
biopsy confirmed that the metastasis had the same biologic profile as the index tumor.
RI PT
385
388
Sequencing Considerations for Progression During or After Endocrine Therapy
390
When progression occurs after ET, as is typical of ABC, it is reasonable to select an ET with a
391
different mechanism of action (e.g., fulvestrant after tamoxifen), an agent of different chemical
392
class (e.g., a steroidal AI such as exemestane after a nonsteroidal AI such as anastrozole), or
393
combination therapy with targeted agents (e.g., palbociclib plus fulvestrant or exemestane with
394
everolimus).26 Other options in this setting include androgens and high-dose ethinyl estradiol.12
M AN U
SC
389
395
In vitro research suggests that primary resistance may emerge from heightened tumor
397
sensitivity to low estrogen levels in situations of prolonged estrogen depletion.108 Therefore,
398
fulvestrant, which promotes degradation of the ER, and thereby complete blockade of ER
399
signaling, may be an option in AI-resistant patients.79
EP
400
TE D
396
The combination of palbociclib and fulvestrant has received FDA approval based on the findings
402
of the phase 3 study, PALOMA-3 (Table 2). This study demonstrated that the combination of
403
palbociclib and fulvestrant resulted in significantly longer PFS than treatment with fulvestrant
404
alone (9.5 vs 4.6 months, respectively; HR=0.46; 95% CI, 0.36-0.59; P<0.001).39,54 The AE profile
405
of the combination regimen was consistent with previously reported data for each agent. The
406
most common AEs of all grades and rates of study discontinuation in the palbociclib/fulvestrant
AC C
401
18
ACCEPTED MANUSCRIPT Endocrine Management of ABC
group were consistent with the CDK4/6 toxicity profile.55 Quality of life measures included the
408
QLQ-C30 and its breast cancer module, QLQ-BR23. Overall global quality of life was maintained
409
over the treatment period in the palbociclib/fulvestrant group compared with fulvestrant
410
monotherapy.55
RI PT
407
411
Earlier phase 3, randomized, clinical studies that led to the approval of fulvestrant
413
demonstrated that the 250 mg dose was as effective as anastrozole in tamoxifen-resistant
414
ABC.21,45 Since fulvestrant degrades the ER in a dose-dependent manner, it was hypothesized
415
that a higher dosage might provide superior benefit,109 leading to the phase 3 CONFIRM study.
416
This study compared the safety and efficacy of fulvestrant 250 mg with fulvestrant 500 mg in
417
postmenopausal women with ER-positive ABC who experienced progression after prior ET. The
418
study demonstrated the superior efficacy of fulvestrant 500 mg, and this dosage has since been
419
approved by the FDA. Progression-free survival was significantly longer for fulvestrant 500 mg
420
over 250 mg (HR=0.80; 95% CI, 0.68-0.94; P=0.006), representing a 20% reduction in the risk of
421
disease progression. Fulvestrant 500 mg was also associated with a clinically relevant 4.1-month
422
increase in median OS, and a 19% reduction in risk of death compared with fulvestrant 250
423
mg.48,49 Toxicity was generally similar between the two doses.35,48,49
M AN U
TE D
EP
AC C
424
SC
412
425
Among AIs, exemestane was shown to provide clinical benefit in a phase 2 clinical study in
426
patients with ABC who had failed up to three lines of nonsteroidal AIs.20 In this open-label,
427
uncontrolled, phase 2 study, exemestane 25 mg was associated with an objective response of
428
6.6% (95% CI, 3.8-10.6) and an overall success rate of 24.3% (95% CI, 19.0-30.2); the median
19
ACCEPTED MANUSCRIPT Endocrine Management of ABC
durations of the objective response and overall success were 58.4 and 37.0 weeks,
430
respectively.20 In a phase 2, sequential, 2-stage, uncontrolled study of second line exemestane
431
in HR-positive or HR-unknown patients (n=50) who had been treated in the first line with
432
anastrozole, exemestane demonstrated clinical benefit. The CBR (i.e., complete response +
433
partial response + stable disease >6 months) for anastrozole and exemestane was 73% and
434
44%, respectively.110 For patients who may have already received first line antiestrogen
435
therapy, letrozole has also been shown to have clinical benefit as second line therapy in
436
ABC.19,111
M AN U
SC
RI PT
429
437
The combination of the mTOR inhibitor everolimus with exemestane has also been approved
439
for the treatment of postmenopausal women with advanced HR-positive/HER2-negative breast
440
cancer in combination with exemestane after treatment failure with letrozole or
441
anastrozole.38,112 The BOLERO-2 study, which led to the approval of this combination regimen,
442
demonstrated that exemestane plus everolimus substantially improved PFS compared with
443
exemestane alone (median PFS on final analysis: 7.8 vs 3.2 months, respectively [HR=0.45; 95%
444
CI, 0.38-0.54]). For patients receiving everolimus plus exemestane, the median OS was 31.0
445
months compared with 26.6 months for placebo plus exemestane (HR=0.89; 95% CI, 0.73-1.10;
446
log-rank P=0.14).113,114 There were, however, more AEs reported in the combination arm,
447
including stomatitis, anemia, dyspnea, hyperglycemia, fatigue, and pneumonitis, and these
448
should be taken into account when selecting therapy.52,113
AC C
EP
TE D
438
449
20
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Supportive Treatment
451
Supportive therapy plays an important role in the management of patients with ABC.12 For
452
example, bisphosphonates and denosumab, in combination with calcium and vitamin D
453
supplementation, are well-established treatments that may be considered to reduce the risk of
454
skeletal-related events in patients with bone metastases.12,115 Management strategies for the
455
other potential side effects of treatment (mucositis, stomatitis, injection-site reactions, nausea,
456
and musculoskeletal pain) have been covered in detail elsewhere in the literature.26,116-122
SC
RI PT
450
M AN U
457
Summary and Conclusions
459
The increase in the number of options for ET and endocrine-based therapy is challenging
460
traditional approaches to therapy sequencing for patients with HR-positive ABC. Strategies are
461
largely based on previous ET exposure, hormone-receptor and HER2 status, menopausal status,
462
and tolerability of therapy. Although current treatments for HR-positive ABC are not curative,
463
clinical evidence indicates that ET can slow disease progression with a low risk of significant
464
AEs. Use of targeted agents to inhibit intracellular pathways important for cell proliferation can
465
significantly enhance the efficacy of currently available endocrine interventions to stabilize
466
disease and delay progression. However, such treatments are associated with a higher
467
incidence of AEs than ET alone and have not yet confirmed an OS benefit.
EP
AC C
468
TE D
458
469
Acknowledgments
470
The authors would like to thank Greg Tardie, PhD and Joan Hudson, The Lockwood Group,
471
Stamford, CT, for medical writing and editorial support (funded by AstraZeneca LP).
21
ACCEPTED MANUSCRIPT Endocrine Management of ABC
AC C
EP
TE D
M AN U
SC
RI PT
472
22
ACCEPTED MANUSCRIPT Endocrine Management of ABC
473 474
References 1.
American Cancer Society. Cancer facts & figures 2017. Available at: http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2017/index. Accessed March 13, 2017.
478 479 480
2.
American Cancer Society. Breast cancer facts & figures 2015-2016. Available at: https://www.cancer.org/research/cancer-facts-statistics/breast-cancer-factsfigures.html. Accessed March 13, 2017.
481 482 483 484
3.
Pal SK, Gupta R, Bernstein L, Mortimer J. Lack of survival benefit in metastatic breast cancer with newer chemotherapy agents: The City of Hope cancer experience. Abstract presented at: American Society of Clinical Oncology Breast Cancer Symposium; September 5-7, 2008; Washington, DC.
485 486 487
4.
National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Fact Sheets: Breast 2016. Available at: http://seer.cancer.gov/statfacts/html/breast.html. Accessed March 13, 2017.
488 489
5.
Pinhel I, Hills M, Drury S, et al. ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer. Breast Cancer Res. 2012;14:R46.
490 491 492
6.
Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999;17:1474-1481.
493 494 495
7.
Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106:doi 10.1093/jnci/dju1055.
496 497
8.
Cancer.net. Breast cancer: overview. Available at: http://www.cancer.net/cancertypes/breast-cancer/overview. Accessed March 13, 2017.
498 499 500
9.
501 502
10.
503 504 505
11.
AC C
EP
TE D
M AN U
SC
RI PT
475 476 477
Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res Treat. 2002;76:27-36.
Luu T, Chung C, Somlo G. Combining emerging agents in advanced breast cancer. Oncologist. 2011;16:760-771. Cardoso F, Fallowfield L, Costa A, Castiglione M, Senkus E, ESMO Guidelines Working Group. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22 Suppl 6:vi25-vi30.
23
ACCEPTED MANUSCRIPT Endocrine Management of ABC
12.
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Breast Cancer. v.1.2017. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed March 13, 2017.
510 511
13.
Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Ann Oncol. 2014;25:1871-1888.
512 513
14.
Beslija S, Bonneterre J, Burstein HJ, et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol. 2009;20:1771-1785.
514 515
15.
Chung CT, Carlson RW. Goals and objectives in the management of metastatic breast cancer. Oncologist. 2003;8:514-520.
516 517
16.
Sanchez-Munoz A, Perez-Ruiz E, Jimenez B, et al. Targeted therapy of metastatic breast cancer. Clin Transl Oncol. 2009;11:643-650.
518 519
17.
Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN. Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol. 1995;13:513-529.
520 521 522 523
18.
Buzdar AU, Jones SE, Vogel CL, Wolter J, Plourde P, Webster A. A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Arimidex Study Group. Cancer. 1997;79:730-739.
524 525 526 527
19.
Gershanovich M, Chaudri HA, Campos D, et al. Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3). Ann Oncol. 1998;9:639-645.
528 529 530
20.
Lonning PE, Bajetta E, Murray R, et al. Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial. J Clin Oncol. 2000;18:2234-2244.
531 532 533 534
21.
Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol. 2002;20:3386-3395.
535 536 537
22.
538 539
23.
AC C
EP
TE D
M AN U
SC
RI PT
506 507 508 509
Bedard PL, Freedman OC, Howell A, Clemons M. Overcoming endocrine resistance in breast cancer: are signal transduction inhibitors the answer? Breast Cancer Res Treat. 2008;108:307-317. Miller WR, Larionov AA. Understanding the mechanisms of aromatase inhibitor resistance. Breast Cancer Res. 2012;14:201.
24
ACCEPTED MANUSCRIPT Endocrine Management of ABC
24.
Buzdar AU. Sequence of hormonal treatments in breast cancer. Semin Breast Dis. 1999;2:167-179.
542 543
25.
Hayes DF, Henderson IC, Shapiro CL. Treatment of metastatic breast cancer: present and future prospects. Semin Oncol. 1995;22:5-19; discussion 19-21.
544 545 546
26.
Rugo HS, Rumble RB, Macrae E, et al. Endocrine Therapy for Hormone Receptor-Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline. J Clin Oncol. 2016;34:3069-3103.
547 548
27.
Bertelli G, Paridaens R. Optimal sequence of hormonotherapy in advanced breast cancer. Curr Opin Oncol. 2006;18:572-577.
549
28.
Zoladex (goserelin acetate) [package insert]. Wilmington, DE: AstraZeneca; 2016.
550
29.
Lupron (leuprolide acetate) [package insert]. North Chicago, IL: AbbVie Inc.; 2016.
551
30.
Tamoxifen citrate [package insert]. Parsippany, NJ: Actavis Pharma, Inc.; 2015.
552
31.
Fareston (toremifene) [package insert]. Bedminster, NJ: Kyowa Kirin, Inc.; 2017.
553 554
32.
Arimidex (anastrozole) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2016.
555 556
33.
Femara (letrozole) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.
557
34.
Aromasin (exemestane) [package insert]. New York, NY: Pfizer Inc.; 2016.
558 559
35.
Faslodex (fulvestrant) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2016.
560 561
36.
Herceptin (trastuzumab) [package insert]. South San Francisco, CA: Genentech, Inc.; 2016.
562
37.
563 564
38.
565
39.
566 567 568 569 570
40.
AC C
EP
TE D
M AN U
SC
RI PT
540 541
Perjeta (pertuzumab) [package insert]. South San Francisco, CA: Genentech, Inc.; 2016. Afinitor (everolimus) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2016. Ibrance (palbociclib) [package insert]. New York, NY: Pfizer Inc.; 2016. Novartis Global. Novartis Kisqali® (ribociclib, LEE011) receives FDA approval as first-line treatment for HR+/HER2- metastatic breast cancer in combination with any aromatase inhibitor (press release March 13, 2017). Available at: https://www.novartis.com/news/media-releases/novartis-kisqalir-ribociclib-lee011receives-fda-approval-first-line-treatment. Accessed March 14, 2017. 25
ACCEPTED MANUSCRIPT Endocrine Management of ABC
41.
Bonneterre J, Thurlimann B, Robertson JF, et al. Anastrozole versus tamoxifen as firstline therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol. 2000;18:3748-3757.
575 576 577 578
42.
Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol. 2001;19:2596-2606.
579 580 581 582
43.
Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003;21:2101-2109.
583 584 585 586
44.
Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol. 2000;18:3758-3767.
587 588 589
45.
Howell A, Robertson JF, Quaresma Albano J, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002;20:3396-3403.
590 591 592 593
46.
Paridaens RJ, Dirix LY, Beex LV, et al. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 2008;26:4883-4890.
594 595 596 597
47.
Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008;26:1664-1670.
598 599 600
48.
601 602 603
49.
604 605
50.
AC C
EP
TE D
M AN U
SC
RI PT
571 572 573 574
Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol 2010;28:4594-4600. Di Leo A, Jerusalem G, Petruzelka L, et al. Final analysis of overall survival for the Phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg [abstract]. Cancer Res. 2012;72:S14. Bergh J, Jonsson P-E, Lidbrink EK, et al. FACT: An open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-
26
ACCEPTED MANUSCRIPT Endocrine Management of ABC
line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012;30:1919-1925.
606 607
51.
Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. New Engl J MEd. 2012;367:435-444.
610 611
52.
Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormonereceptor-positive advanced breast cancer. New Engl J Med. 2012;366:520-529.
612 613 614 615
53.
Finn RS, Martin M, Rugo HS, et al. PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2– advanced breast cancer (ABC). J Clin Oncol. 2016;34 (suppl):abstr 507.
616 617 618 619 620
54.
Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17:425-439.
621 622
55.
Turner NC, Ro J, Andre F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373:209-219.
623 624
56.
Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HRpositive, advanced breast cancer. N Engl J Med. 2016;375:1738-1748.
625 626 627 628
57.
Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009;27:5529-5537.
629 630 631
58.
Johnston S, Pippen J, Jr., Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptorpositive metastatic breast cancer. J Clin Oncol. 2009;27:5538-5546.
632 633 634 635
59.
636 637 638 639 640
60.
AC C
EP
TE D
M AN U
SC
RI PT
608 609
Huober J, Fasching PA, Barsoum M, et al. Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer - results of the eLEcTRA trial. Breast. 2012;21:27-33. Johnston SR, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol. 2013;14:989-998.
27
ACCEPTED MANUSCRIPT Endocrine Management of ABC
61.
Burstein HJ, Cirrincione CT, Barry WT, et al. Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: a randomized, double-blind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced breast cancer-CALGB 40302 (Alliance). J Clin Oncol. 2014;32:3959-3966.
646 647
62.
Harwood KV. Advances in endocrine therapy for breast cancer: considering efficacy, safety, and quality of life. Clin J Oncol Nurs. 2004;8:629-637.
648 649
63.
Hadji P. Cancer Treatment-Induced Bone Loss in women with breast cancer. Bonekey Rep. 2015;4:692.
650 651
64.
Bissett D, Davis JA, George WD. Gynaecological monitoring during tamoxifen therapy. Lancet. 1994;344:1244.
652 653 654 655
65.
Bergman L, Beelen ML, Gallee MP, Hollema H, Benraadt J, van Leeuwen FE. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres' ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen. Lancet. 2000;356:881-887.
656 657
66.
Lake DE, Hudis C. Aromatase inhibitors in breast cancer: an update. Cancer Control. 2002;9:490-498.
658 659 660
67.
Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM. An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane. Cancer. 2002;95:2006-2016.
661 662 663
68.
Miller WR, Bartlett J, Brodie AM, et al. Aromatase inhibitors: are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter? Oncologist. 2008;13:829-837.
664 665
69.
Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol. 2001;19:881-894.
666 667 668
70.
Hong Y, Yu B, Sherman M, Yuan YC, Zhou D, Chen S. Molecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase. Mol Endocrinol. 2007;21:401-414.
669 670
71.
671 672
72.
AC C
EP
TE D
M AN U
SC
RI PT
641 642 643 644 645
Johnston SR. Enhancing the efficacy of hormonal agents with selected targeted agents. Clin Breast Cancer. 2009;9 Suppl 1:S28-36. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003;348:2431-2442.
28
ACCEPTED MANUSCRIPT Endocrine Management of ABC
73.
Brodie AMH, Brodie HJ, Romanoff L, Williams JG, Williams KIH, Wu JT. Inhibition of Estrogen Biosynthesis and Regression of Mammary Tumors by Aromatase Inhibitors. In: Leavitt WW, ed. Hormones and Cancer. Boston, MA: Springer US; 1982:179-190.
676 677 678 679
74.
Van Ginckel R, Janssens B, Callens M, Goeminne N, Wouters L, De Coster R. Effects of combined and sequential treatment with tamoxifen and the aromatase inhibitor vorozole on 7,12-dimethylbenz(a) anthracene-induced mammary carcinoma in the rat. Cancer Chemother Pharmacol. 1996;38:21-28.
680 681 682
75.
Lu Q, Liu Y, Long BJ, Grigoryev D, Gimbel M, Brodie A. The effect of combining aromatase inhibitors with antiestrogens on tumor growth in a nude mouse model for breast cancer. Breast Cancer Res Treat. 1999;57:183-192.
683
76.
Wakeling AE, Bowler J. Steroidal pure antioestrogens. J Endocrinol. 1987;112:R7-10.
684 685
77.
Wakeling AE. Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr Relat Cancer. 2000;7:17-28.
686 687
78.
Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res. 1991;51:3867-3873.
688 689
79.
Morris C, Wakeling A. Fulvestrant ('Faslodex')--a new treatment option for patients progressing on prior endocrine therapy. Endocr Relat Cancer. 2002;9:267-276.
690 691
80.
Cruz Jurado J, Richart Aznar P, Garcia Mata J, et al. Management of patients with metastatic breast cancer. Adv Ther. 2011;28 Suppl 6:50-65.
692 693 694
81.
Howell A, Pippen J, Elledge RM, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer. 2005;104:236-239.
695 696 697
82.
Villarreal-Garza C, Cortes J, Andre F, Verma S. mTOR inhibitors in the management of hormone receptor-positive breast cancer: the latest evidence and future directions. Ann Oncol. 2012;23:2526-2535.
698 699 700
83.
701 702
84.
703 704 705 706
85.
AC C
EP
TE D
M AN U
SC
RI PT
673 674 675
Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11:R77.
Caldon CE, Daly RJ, Sutherland RL, Musgrove EA. Cell cycle control in breast cancer cells. J Cell Biochem. 2006;97:261-274. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16:25-35. 29
ACCEPTED MANUSCRIPT Endocrine Management of ABC
86.
Efeyan A, Sabatini DM. mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol. 2010;22:169-176.
709 710 711 712 713
87.
United States Food and Drug Administration. Center for Drug Evaluation and Research Application Number 21-110: Approved draft labeling Rapamune® (sirolimus) oral solution and tablets. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21110_Rapamune_prntlbl. pdf. Accessed March 13, 2017.
714 715 716
88.
Boulay A, Rudloff J, Ye J, et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res. 2005;11:53195328.
717 718 719
89.
Beaver JA, Park BH. The BOLERO-2 trial: the addition of everolimus to exemestane in the treatment of postmenopausal hormone receptor-positive advanced breast cancer. Future Oncol. 2012;8:651-657.
720 721 722 723
90.
Pfizer Inc. 2015 press release: Pfizer receives U.S. FDA accelerated approval of IBRANCE® (palbociclib) Available at: http://www.pfizer.com/news/press-release/press-releasedetail/pfizer_receives_u_s_fda_accelerated_approval_of_ibrance_palbociclib. Accessed March 13, 2017.
724 725 726 727
91.
Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2breast cancer, after chemotherapy for advanced disease. J Clin Oncol. 2016;34 (suppl):abstr 510.
728 729 730
92.
Eli Lilly and Company. A study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive HER2 negative breast cancer (MONARCH 2). Available at: https://clinicaltrials.gov/ct2/show/NCT02107703. Accessed March 8, 2017.
731 732 733
93.
Eli Lilly and Company. A study of nonsteroidal aromatase inhibitors plus abemaciclib (LY2835219) in postmenopausal women with breast cancer (MONARCH 3). Available at: https://clinicaltrials.gov/ct2/show/NCT02246621. Accessed April 3, 2017.
734 735
94.
736 737 738
95.
739 740
96.
AC C
EP
TE D
M AN U
SC
RI PT
707 708
Alluri PG, Speers C, Chinnaiyan AM. Estrogen receptor mutations and their role in breast cancer progression. Breast Cancer Res. 2014;16:494. Jeselsohn R, Yelensky R, Buchwalter G, et al. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014;20:1757-1767. Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormoneresistant breast cancer. Nat Genet. 2013;45:1439-1445.
30
ACCEPTED MANUSCRIPT Endocrine Management of ABC
97.
Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45:1446-1451.
743 744 745
98.
Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial. JAMA Oncol. 2016;2:1310-1315.
746 747
99.
Fribbens C, O'Leary B, Kilburn L, et al. Plasma ESR1 Mutations and the Treatment of Estrogen Receptor-Positive Advanced Breast Cancer. J Clin Oncol. 2016;34:2961-2968.
748 749
100.
Lee T, Isaacs C. Treatment of primary breast tumors in de novo metastatic breast cancer. Clin Adv Hematol Oncol. 2014;12:820-827.
750 751 752
101.
Dawood S, Broglio K, Ensor J, Hortobagyi GN, Giordano SH. Survival differences among women with de novo stage IV and relapsed breast cancer. Ann Oncol. 2010;21:21692174.
753 754 755
102.
Lobbezoo DJ, van Kampen RJ, Voogd AC, et al. Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer? Br J Cancer. 2015;112:1445-1451.
756 757 758
103.
Robertson JF, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016;388:2997-3005.
759 760
104.
Al-Mubarak M, Sacher AG, Ocana A, Vera-Badillo F, Seruga B, Amir E. Fulvestrant for advanced breast cancer: a meta-analysis. Cancer Treat Rev. 2013;39:753-758.
761 762 763
105.
Robertson JF, Lindemann JP, Llombart-Cussac A, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized 'FIRST' study. Breast Cancer Res Treat. 2012;136:503-511.
764 765 766
106.
Ellis MJ, Llombart-Cussac A, Feltl D, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: Overall survival analysis from the phase II FIRST study. J Clin Oncol. 2015;33:3781-3787.
767 768 769 770
107.
771 772
108.
AC C
EP
TE D
M AN U
SC
RI PT
741 742
United States Food and Drug Administration. Approval letter NDA 207103/S-002 (dated February 19, 2016). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/207103Orig1s002ltr.p df. Accessed March 8, 2017. Hayes EL, Lewis-Wambi JS. Mechanisms of endocrine resistance in breast cancer: an overview of the proposed roles of noncoding RNA. Breast Cancer Res. 2015;17:40.
31
ACCEPTED MANUSCRIPT Endocrine Management of ABC
109.
Kuter I, Gee JM, Hegg R, et al. Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study. Breast Cancer Res Treat. 2012;133:237-246.
776 777 778
110.
Iaffaioli RV, Formato R, Tortoriello A, et al. Phase II study of sequential hormonal therapy with anastrozole/exemestane in advanced and metastatic breast cancer. Br J Cancer. 2005;92:1621-1625.
779 780 781 782
111.
Dombernowsky P, Smith I, Falkson G, et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol. 1998;16:453-461.
783 784 785 786
112.
United States Food and Drug Administration. Approval letter NDA 022334/S-016 (dated August 20, 2012). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/022334Orig1s016ltrR epl.pdf. Accessed March 8, 2017.
787 788 789
113.
Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30:870-884.
790 791 792
114.
Piccart M, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane for hormonereceptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol. 2014;25:2357-2362.
793 794
115.
Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. 2012;2:CD003474.
795 796
116.
Aapro MS. Challenges in clinical patient management. Cancer Invest. 2010;28 (Suppl 1):14-27.
797 798 799
117.
Bryce J, Bauer M, Hadji P. Managing arthralgia in a postmenopausal woman taking an aromatase inhibitor for hormonesensitive early breast cancer: a case study. Cancer Manag Res. 2012;4:105-111.
800 801
118.
802 803
119.
804 805
120.
AC C
EP
TE D
M AN U
SC
RI PT
773 774 775
Hopkins U, Arias CY. Large-volume IM injections: A review of best practices. ONA. 2013;Jan/Feb:32-37. Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev (Orlando). 2014;28:126-133. Leclerc AF, Jerusalem G, Devos M, Crielaard JM, Maquet D. Multidisciplinary management of breast cancer. Arch Public Health. 2016;74:50.
32
ACCEPTED MANUSCRIPT Endocrine Management of ABC
121.
Roberts K, Rickett K, Greer R, Woodward N. Management of aromatase inhibitor induced musculoskeletal symptoms in postmenopausal early Breast cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2017;111:66-80.
809 810 811
122.
Versea L, Rosenzweig M. Hormonal therapy for breast cancer: focus on fulvestrant. Clin J Oncol Nurs. 2003;7:307-311.
AC C
EP
TE D
M AN U
SC
RI PT
806 807 808
33
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Figure Legend
EP
TE D
M AN U
SC
RI PT
Figure 1. Treatment recommendations for postmenopausal ABC based on clinical presentation. Abbreviations: ABC = advanced breast cancer; AI = aromatase inhibitor; HR+ = hormone receptor-positive; ; ± = with/without.
AC C
812 813 814 815 816 817
34
ACCEPTED MANUSCRIPT Endocrine Management of ABC
TE D
EP
•
Tumor flare can occur on the initiation of goserelin for both men and women being treated for cancer. Not indicated for breast cancer, but included Reported in ≥5% of patients with endometriosis or fibroids and thought to be potentially related in the guidelines11,12 to drug: asthenia, general pain, headache,b hot flashes/sweats,b nausea/vomiting, gastrointestinal disturbances,b edema, weight gain/loss, acne, joint disorder,b depression/emotional lability,b dizziness, decreased libido,b nervousness,b neuromuscular disorders,b paresthesias, skin reactions, breast changes/tenderness/pain,b vaginitis.29
AC C
Leuprolide29
M AN U
SC
RI PT
Table 1. Available Endocrine and Targeted Agents for Hormone Receptor (HR)-Positive Advanced Breast Cancer (ABC)a Class/Mechanism of Action Luteinizing hormone-releasing hormone analogues Agents Indications Adverse Events (AEs) 28 Goserelin The AE profile was similar for women treated for • Use in the palliative treatment of advanced breast cancer, dysfunctional uterine bleeding, or breast cancer in premenopausal and endometriosis and included (>20%): hot flushes, perimenopausal women headache, sweating, acne, emotional lability, depression, decreased libido, vaginitis, breast atrophy, seborrhea, and peripheral edema.
35
ACCEPTED MANUSCRIPT Endocrine Management of ABC
RI PT
AEs MBC: increased bone and tumor pain along with local disease flare have occurred, which are sometimes associated with a good tumor response. Patients with increased bone pain may require additional analgesics. Patients with soft tissue disease may have sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions.
Toremifene31
•
AC C
EP
TE D
M AN U
SC
Selective estrogen-receptor modulators (SERMs) Agents Indications Tamoxifen30 • Metastatic breast cancer (MBC) in women and men • Adjuvant treatment of breast cancer – Treatment of node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation – Treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation
The treatment of MBC in postmenopausal women with estrogen receptor (ER)-positive or ER-unknown tumors
36
When they occur, the bone pain or disease flare is evident shortly after starting tamoxifen and generally subsides rapidly. In patients treated with tamoxifen for MBC, the most frequent AE was hot flashes. Other AEs seen infrequently were hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, lightheadedness, headache, hair thinning and/or partial hair loss, and vaginal dryness. Most common adverse reactions are hot flashes, sweating, nausea and vaginal discharge.
ACCEPTED MANUSCRIPT Endocrine Management of ABC
RI PT
AEs In the advanced breast cancer studies, the most common (occurring with an incidence of >10%) AEs occurring in women taking anastrozole included hot flashes, nausea, asthenia, pain, headache, back pain, bone pain, increased cough, dyspnea, pharyngitis, and peripheral edema.
The most common adverse reactions (>20%) were hot flashes, arthralgia; flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, bone pain, and musculoskeletal.
AC C
EP
TE D
M AN U
SC
Third-generation aromatase inhibitors (AIs) Nonsteroidal AIs Agents Indications 32 Anastrozole • Adjuvant treatment of postmenopausal women with HR-positive early breast cancer • First-line treatment of postmenopausal women with HR-positive or HR-unknown locally advanced breast cancer or MBC • Treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy Letrozole33 • Adjuvant treatment of HR-positive earlystage breast cancer • Extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy • First- and second-line treatment of postmenopausal women with HR-positive or HR-unknown advanced breast cancer Steroidal AIs Agents Indications 34 Exemestane • Adjuvant treatment of postmenopausal women with ER-positive early-stage breast cancer who have received 2 to 3 years of tamoxifen and are switched to exemestane for completion of a total of 5 consecutive years of adjuvant hormonal therapy • The treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy 37
AEs Advanced breast cancer: Most common AEs were mild to moderate and included hot flashes, nausea, fatigue, increased sweating, and increased appetite.
ACCEPTED MANUSCRIPT Endocrine Management of ABC
RI PT
AEs The most common adverse reactions occurring in ≥5% of patients receiving fulvestrant 500 mg were injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation. Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX patients and were not dose-dependent.
Indications Approved in combination with paclitaxel for first-line treatment of HER2-overexpressing MBC, and as a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease
EP
TE D
•
AC C
TARGETED AGENTS HER2-targeted antibody Agents Trastuzumab36
M AN U
SC
Selective estrogen-receptor degrader (SERD) Agents Indications Fulvestrant35 • HR-positive MBC in postmenopausal women with disease progression following antiestrogen therapy • HR-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with palbociclib in women with disease progression after endocrine therapy.
38
AEs MBC: Most common AEs (incidence ≥10%) were fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash.
ACCEPTED MANUSCRIPT Endocrine Management of ABC
•
Most common AEs (incidence ≥10%) were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, peripheral neuropathy, decreased appetite, mucosal inflammation, asthenia, vomiting, anemia, peripheral edema, myalgia, nail disorder headache, stomatitis, pyrexia, dysgeusia, leukopenia, upper respiratory tract infection, arthralgia, constipation, increased lacrimation, dyspnea, pruritus, febrile neutropenia, insomnia, dizziness, nasopharyngitis, dry skin.
EP
Indications • Postmenopausal women with advanced HR-positive/HER2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole
AC C
mTOR inhibitor Agents Everolimus38
TE D
M AN U
SC
•
Use in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive MBC who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease Use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either >2 cm in diameter or node-positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival.
RI PT
Pertuzumab37
39
AEs Most common AEs (incidence ≥10%) were stomatitis, infections, rash, diarrhea, fatigue, decreased appetite, nausea, cough, dysgeusia, weight decreased, arthralgia, headache, dyspnea, edema peripheral, pneumonitis, vomiting, epistaxis, pyrexia, constipation, hyperglycemia, back pain, insomnia, pruritus, asthenia, dry mouth, and alopecia.
ACCEPTED MANUSCRIPT Endocrine Management of ABC
AC C
EP
TE D
M AN U
SC
RI PT
Cyclin-dependent kinase (CDK4/6) inhibitor Agents Indications AEs Palbociclib39 Most common adverse reactions (incidence ≥ • Indicated for the treatment of HRpositive/HER2-negative advanced or 10%) were neutropenia, leukopenia, infections, metastatic breast cancer in combination fatigue, nausea, anemia, stomatitis, headache, with letrozole as initial endocrine based diarrhea, thrombocytopenia, constipation, therapy in postmenopausal women, or alopecia, vomiting, rash, and decreased appetite. fulvestrant in women with disease progression following endocrine therapy. • The indication in combination with letrozole is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 40 Ribociclib • Indicated in combination with an aromatase Most common adverse reactions (incidence ≥20%) are neutropenia, nausea, fatigue, diarrhea, inhibitor as initial endocrine-based therapy leukopenia, alopecia, vomiting, constipation, for the treatment of postmenopausal headache, and back pain. women with HR-positive/HER2-negative advanced or metastatic breast cancer. a Note that AE rates should not be compared across studies because these were not head-to-head studies and rates selected as “most common” differed as well. b Possible effect of decreased estrogen.
40
ACCEPTED MANUSCRIPT Endocrine Management of ABC
AC C
EP
TE D
M AN U
SC
RI PT
Table 2. Phase 3 Trials of Endocrine Therapy in Postmenopausal Women With Hormone Receptor (HR)-Positive Recurrent or Advanced Breast Cancer (ABC): Efficacy Results Secondary Efficacy Treatments, Dose, Regimen Primary Efficacy Endpoint: Study/Patient Population Endpoints: (Arm 1 vs Arm 2) Results (Arm 1 vs Arm 2) Results (Arm 1 vs Arm 2) Trials in Patients Without Prior or Recent (Within 12 months) Endocrine Therapy Bonneterre et al 200041 Arm 1: anastrozole, Median time to progression Clinical benefit rate (CBR): (TTP): 8.2 vs 8.3 months 56.2% vs 55.5% • Postmenopausal women with 1 mg/day orally (hazard ratio [HR]=0.99; locally advanced or ABC Arm 2: tamoxifen, 20 mg/day 2-sided P=0.941) Overall survival (OS): not • No prior tamoxifen within orally reported (NR) 12 months Objective response rate • HR-positive or HR-unknown (ORR): 32.9% vs 32.6% tumors (2-sided P=0.787) Mouridsen et al 2001, 200342,43 Arm 1: letrozole, 2.5 mg/day Median TTP: 9.4 vs 6 months ORR: 32% vs 21% (P=0.002) (P<0.001) • Postmenopausal women with orally CBR: 50% vs 38% (P=0.004) locally advanced, Arm 2: tamoxifen, 20 mg/day locoregionally recurrent, or orally OS: 34 vs 30 months (P=NS) ABC • HR-positive or HR-unknown tumors Nabholtz et al 200044 Arm 1: anastrozole, Median TTP: 11.1 vs 5.6 CBR: 59% vs 46% months (2-sided P=0.005) (2-sided P=0.010) • Postmenopausal women with 1 mg/day orally locally advanced or ABC Arm 2: tamoxifen, 20 mg/day ORR: 21% vs 17% OS: NR • No prior tamoxifen within orally 12 months • HR-positive or HR-unknown tumors
41
ACCEPTED MANUSCRIPT Endocrine Management of ABC
CBR: 42.2% vs 36.1% (P=0.26)
AC C
EP
TE D
M AN U
SC
RI PT
Trials in Patients With HR-Positive Recurrent or ABC Who Progressed on Endocrine Therapy Monotherapy Osborne et al 200221 Arm 1: fulvestrant 250 mg TTP: 5.4 vs 3.4 months (HR=0.92 [95.14% CI, 0.74• Postmenopausal women with once monthly intramuscularly (IM) 1.14]; P=0.43) locally advanced or ABC that had progressed on adjuvant antiestrogen therapy or first- Arm 2: anastrozole 1 mg/day orally line therapy for advanced disease Howell et al 200245 Arm 1: fulvestrant 250 mg Median TTP: 5.5 vs 5.1 months (HR=0.98 [95.14% CI, • Postmenopausal women with once monthly IM 0.80-1.21]; P=0.84) locally advanced or ABC that Arm 2: anastrozole 1 mg/day had progressed on adjuvant antiestrogen therapy or first- orally line therapy for advanced disease • All patients had tumors with hormone sensitivity Paridaens et al 200846 Arm 1: exemestane, 25 Median PFS: 9.9 vs 5.8 months (P=0.028) • Postmenopausal women with mg/day orally locally recurrent inoperable Arm 2: tamoxifen, 20 mg/day PFS: (HR=0.84 [95% CI, 0.67or ABC 1.05]; log-rank P=0.121) • Prior tamoxifen therapy with orally 6-month recurrence-free interval allowed • No previous hormone therapy for ABC • HR-positive or HR-unknown
42
Median duration of response (DOR): 19.0 vs 10.8 months
CBR=44.6% vs 45.0% (P=0.85) Median DOR: 15.0 vs 14.5 months
ORR: 46% vs 31% (P=0.005) OS: not significant (NS)
ACCEPTED MANUSCRIPT Endocrine Management of ABC
ORR: 7.4% vs 6.7%; P=0.736 CBR: 32.2% vs 31.5%; P=0.853
RI PT
Median TTP: 3.7 months in both groups (HR=0.963 [95% CI, 0.819-1.133]; P=0.653)
OS: NR
M AN U
SC
Arm 2: exemestane 25 mg/day orally
Arm 1: fulvestrant 500 mg IM Median PFS: 6.5 vs 5.5 on days 0, 14, 28, then every months (HR=0.80 [95% CI, 4 weeks 0.68-0.94]; P=0.006)
TE D
Arm 2: fulvestrant 250 mg IM on days 0, 14, and 28, then every 4 weeks Arm 1: fulvestrant 500 mg IM on day 1; 250 mg on days 15, 29, then every 4 weeks plus anastrozole 1 mg/day orally
EP
Combination Therapy FACT Bergh et al 201250 • Postmenopausal women or premenopausal women receiving a gonadotropinreleasing hormone, with HRpositive breast cancer that relapsed after or during primary treatment • Patients on adjuvant AI had to be relapse-free for >1 year after treatment completion
Arm 1: fulvestrant 500 mg IM on day 0, 250 mg on days 14 and 28, then every 4 weeks
Median TTP: 10.8 vs 10.2 months (HR=0.99 [95% CI, 0.81-1.20]; P=0.91)
ORR: 9.1% vs 10.2%; P=0.795 CBR: 45.6% vs 39.6%; P=0.100 OS: 26.4 vs 22.3 months; nominal P=0.016 ORR: 31.8% vs 33.6%; P=0.76 CBR: 55.0 % vs 55.1%; P=0.99 Median OS: 37.8 vs 38.2 months; P=1.00
AC C
EFECT Chia et al 200847 • Postmenopausal women with locally advanced or ABC who had relapsed on treatment with (or within 6 months of discontinuation of) an adjuvant nonsteroidal AI or who had disease progression during treatment with a nonsteroidal AI CONFIRM Di Leo et al 2010, 201248,49 • Postmenopausal women with locally advanced or ABC who had progressed on prior endocrine therapy
Arm 2: anastrozole 1 mg/day orally
43
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Arm 1: fulvestrant 500 mg IM on day 1; 250 mg on days 14, 28, then every 4 weeks plus anastrozole 1 mg/day orally
BOLERO-2 Baselga et al 201252 • Postmenopausal women with ER-positive, HER2nonamplified advanced breast cancer refractory to prior nonsteroidal AI treatment PALOMA-2 Finn et al 201653 • Postmenopausal women with ER-positive/HER2-negative ABC
Arm 1: everolimus 10 mg/day orally plus exemestane 25 mg/day orally
Median PFS: 15.0 vs 13.5 months (HR=0.80 [95% CI, 0.68-0.94]; log-rank P=0.007)
SC
Arm 2: anastrozole 1 mg/day orally
Median PFS: 6.9 vs 2.8 months (HR=0.43 [95% CI, 0.35-0.54]; P<0.001)
ORR: 9.5% vs 0.4%; P<0.001
Median PFS: 24.8 vs 14.5 months (HR=0.58 [95% CI, 0.46-0.72]; P<0.001)
ORR: 42.1% vs 34.7%; P=0.031
M AN U
Arm 2: exemestane 25 mg/day orally
EP
TE D
Arm 1: palbociclib 125 mg/day orally for 3 weeks on, 1 week off plus letrozole 2.5 mg/day orally continuously
Median OS: 47.7 vs 41.3 months; log-rank P=0.05
RI PT
SWOG S0226 Mehta et al 201251 • Postmenopausal women with HR-positive ABC • Previously untreated for metastatic disease
AC C
Arm 2: matched placebo once-daily orally plus letrozole 2.5 mg/day orally every 28 days
44
OS: NR
CBR: 84.9% vs 70.3%; P<0.001
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Arm 1: palbociclib 125 mg/day orally for 3 weeks then 1 week off plus fulvestrant 500 mg IM every 14 days for 3 injections, then every 28 days
MONALEESA-2 Hortobagyi et al 201656 • Postmenopausal women with HR-positive/HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease.
Arm 1: ribociclib 600 mg/day on a 3-weekson, 1-week-off schedule plus letrozole 2.5 mg/day
Median PFS: 9.5 vs 4.6 months (HR=0.46 [95% CI, 0.36-0.59]; P<0.001)54
ORR: 10.4% vs 6.3%; P=0.16 CBR: 34.0% vs 19.0%; P<0.00155
RI PT
PALOMA-3 Cristofanilli et al 201654 Turner et al 201555 • Pre- or postmenopausal women with HER2negative/HR-positive ABC • Relapsed or progressed during prior endocrine therapy
M AN U
SC
Arm 2: matching placebo plus fulvestrant
AC C
EP
TE D
Arm 2: placebo plus letrozole
Median PFS was not reached in the ribociclib group (95% CI, 19.3 to not reached) vs 14.7 months (95% CI, 13.016.5) in the placebo group (HR=0.56; [95% CI, 0.430.72]; P=3.29×10−6 for superiority)
45
Overall response rate (ORR + complete response + partial response): 40.7% vs 27.5%; (P<0.001) CBR: 79.6% vs 72.8% (P<0.02)
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Median PFS: 8.2 vs 3.0 months (HR=0.71 [95% CI, 0.53-0.96]; P=0.019)
M AN U
Arm 1: letrozole 2.5 mg/day orally with lapatinib 1500 mg/day orally Arm 2: letrozole 2.5 mg/day
Median TTP: 14.1 vs 3.3 months (HR=0.67 [95% CI, 0.35-1.29]; P=0.23)
EP
TE D
Arm 1: letrozole 2.5 mg/day plus trastuzumab 4 mg/kg IV loading dose, then 2 mg/kg weekly until progression (trastuzumab subsequently allowed as a 6 mg/kg dose every 3 weeks following 8 mg/kg loading dose
AC C
Johnston et al 200958 • Postmenopausal women with HR-positive/HER2-positive ABC • No prior therapy for advanced or ABC allowed eLEcTRA Huober et al 201259 • Postmenopausal women with newly diagnosed HRpositive/HER2-positive ABC or locally advanced breast cancer • No prior treatment for ABC or locally advanced breast cancer
SC
RI PT
Trials of Combination Therapy in Postmenopausal Women With HR-Positive/HER2-Positive Recurrent or ABC TTP: 4.8 vs 2.4 months; TAnDEM Arm 1: anastrozole 1 mg/day Median PFS: 4.8 vs 2.4 months (HR=0.63 [95% CI, log rank P=0.007 Kaufman et al 200957 orally with trastuzumab, 0.47-0.84]; log rank P=0.002) • Postmenopausal women with 4 mg/kg intravenous (IV) on day 1, then 2 mg/kg weekly CBR(ITT): 42.7% vs 27.9%; HR-positive/HER2-positive P=0.026 until progression ABC • Prior endocrine treatment Arm 2: anastrozole 1 mg/day Median OS: 28.5 vs 23.9 allowed if begun up to 4 months; log rank P=0.325 weeks before randomization orally
Arm 2: letrozole 2.5 mg/day until disease progression
46
ORR: 28% vs 15%; P=0.021 CBR: 48% vs 29%; P=0.003 OS: 33.3 vs 32.3 months; P=0.113 ORR: 27% vs 13%; P=0.312 CBR: 65% vs 39%; P=0.064
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Arm 2: fulvestrant plus anastrozole-matched placebo
Arm 1 vs Arm 2(HR=1.00 [95% CI, 0.83-1.21]; log-rank P=0.98)
Arm 3: 21.6 months (19.423.9)
Arm 3: oral exemestane 25 mg daily
Arm 2 vs. Arm 3 (HR=0.95 [95% CI, 0.79-1.14]; log-rank P=0.56)
Arm 1 vs. Arm 2 (HR=0.95 [95% CI, 0.76-1.17]; log-rank P=0.61)
M AN U
SC
RI PT
Median PFS: Arm 1: 4.4 months (95% CI, 3.4-5.4) Arm 2: 4.8 months (3.6-5.5) Arm 3: 3.4 months (3.0-4.6)
Median PFS: All patients: 4.7 vs 3.8 months (HR=1.04; 95% CI, 0.82-1.33; P=0.37)
Arm 2: fulvestrant (as above) plus placebo
HER2-negative: 4.1 vs 3.8 months (HR=1.00; 95% CI, 0.76-1.30)
TE D
Arm 1: fulvestrant 500 mg IM day 1; 250 mg days 15 and 28, then every 28 days; lapatinib 1500 mg/day orally
EP
CALGB 40302 Burstein et al 201461 • Postmenopausal women with stage III/IV breast cancer • ER- and/or PgR-positive • HER2-positive or negative • Previous endocrine treatment allowed, but no prior treatment with fulvestrant, lapatinib, erlotinib, cetuximab, or gefitinib
Median OS: Arm 1: 20.2 months (17.222.5)
Arm 1: fulvestrant 500 mg IM on day 1, followed by 250 mg doses on days 15 and 29, then every 28 days plus oral anastrozole 1 mg daily
AC C
SoFEA Johnston et al 201360 • Postmenopausal patients with HR-positive locally advanced or ABC (HER2positive, negative, or unknown) • Relapsed or progressed with locally advanced or metastatic disease on a nonsteroidal AI
HER2-positive: 5.9 vs 3.3 months (HR=1.23; 95% CI, 0.69-2.18)
47
Arm 2: 19.4 months (16.822.8)
Arm 2 vs. Arm 3 (HR=1.05 [0.84-1.29]; log-rank P=0.68) Median OS: 30 vs 26.4 months (HR=0.91; 95% CI, 0.68-1.21; P=0.25)
ACCEPTED MANUSCRIPT
RI PT
Recurrence during adjuvant AI
Palbociclib + letrozole Ribociclib + any AI
Palbociclib + fulvestrant
Alternatives
Alternatives
M AN U
First-line
SC
De novo HR+ ABC
Everolimus + Exemestane
EP
Second-line
TE D
• AI • Tamoxifen • Fulvestrant + AI
Alternatives
AC C
• Fulvestrant ± palbociclib • Al (steroidal) • Tamoxifen
Third-line
Any of the above, not previously used
• Different AI • Tamoxifen • Fulvestrant
Everolimus + Exemestane Alternatives • Fulvestrant ± palbociclib • Al (steroidal) • Tamoxifen (late relapse) Any of the above, not previously used
S1526-8209(16)30502-X
DOI:
10.1016/j.clbc.2017.05.014
Reference:
CLBC 627
To appear in:
Clinical Breast Cancer
Received Date: 22 November 2016 Revised Date:
7 April 2017
Accepted Date: 22 May 2017
Please cite this article as: Robert NJ, Denduluri N, Patient Case Lessons: Endocrine Management of Advanced Breast Cancer, Clinical Breast Cancer (2017), doi: 10.1016/j.clbc.2017.05.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Endocrine Management of ABC
1 2 3 4 5
RI PT
Nicholas J. Robert, MD1, and Neelima Denduluri, MD2 1
SC
US Oncology Network, Virginia Cancer Specialists, 8503 Arlington Blvd, Suite 400, Fairfax, VA 22031, USA; 2US Oncology Research Network, 1635 N. George Mason Drive, Suite 170, Arlington, VA 22205, USA
M AN U
6 7 8 9 10 11 12 13
Patient Case Lessons: Endocrine Management of Advanced Breast Cancer
Corresponding Author: Nicholas J. Robert, MD US Oncology Network Virginia Cancer Specialists 8503 Arlington Blvd, Suite 400 Fairfax, VA 22031, USA E-mail: [email protected] Phone: 703-280-5390 Fax: 703-280-9596
24 25 26 27 28 29 30 31 32 33 34 35 36
Type of Manuscript: Review
TE D
14 15 16 17 18 19 20 21 22 23
EP
Key Words: Metastatic breast cancer, Endocrine therapy, Estrogen, Progesterone, Human epidermal growth factor
AC C
Abbreviations not common in the field: None Word Counts: Abstract 178 (limit 250); Text 4,335 (limit 10,000) References: 122 (limit 120) Figures/Tables: 3 (limit 7) 2 tables, 1 figure Conflict of Interest Nicholas J. Robert, MD, and Neelima Denduluri, MD, report no conflicts of interest.
37 38
1
ACCEPTED MANUSCRIPT Endocrine Management of ABC
ABSTRACT
40
Advances in treatment for women with advanced breast cancer (ABC) have led to
41
improvements in survival. While the condition remains incurable, treatment goals focus on
42
stabilizing disease, prolonging life, and maintaining patient quality of life. Hormone receptor-
43
positive subtypes constitute the majority of breast cancers, and an increasing number of
44
effective endocrine therapies are available. Although practice guidelines provide important
45
recommendations and principles for treatment selection, the choice of specific agents from
46
among existing options should be customized to the individual based on patient and disease
47
characteristics, as well as the nature and duration of response to previous treatments. This
48
review examines endocrine and endocrine-based options, including combinations with targeted
49
agents, for hormone receptor-positive and human epidermal growth factor receptor 2-negative
50
(HR-positive and HER2-negative) ABC. It also elaborates on the factors that enter into treatment
51
decision-making, using patient case examples to illustrate how ABC can present and the clinical
52
issues involved in treatment selection. Case examples are included to provide evidence for the
53
clinical scenarios of de novo HR-positive/HER2-negative ABC and progression during adjuvant
54
treatment for early breast cancer.
SC
M AN U
TE D
EP
AC C
55
RI PT
39
2
ACCEPTED MANUSCRIPT Endocrine Management of ABC
56 57 58
Introduction
59
incurable and represents an unmet medical need. While overall mortality rates have declined,
60
median survival for women with ABC is approximately 2 to 3 years, with a 5-year survival rate of
61
25% or less, depending on the database cited and the time during which the data were
62
gathered.1-4 Estrogen receptor (ER)-positive tumors represent up to 80% of all breast cancers.5-7
63
Among US patients with ABC, approximately 60% to 75% have hormone receptor (HR)-positive
64
(i.e., ER-positive and/or progesterone receptor [PgR]-positive) disease.8 The incidence of HR-
65
positive tumors tends to increase with age and vary with ethnicity.7,9
66 67
This review examines available endocrine and endocrine-based treatment options for the
68
management of HR-positive, human epidermal growth factor receptor 2(HER2)-negative ABC,
69
including endocrine therapy (ET) and targeted therapies, as well as newly investigated
70
combinations and monotherapies. It also elaborates on factors that enter into treatment
71
decision-making, using patient case examples to illustrate how ABC can present and the clinical
72
issues involved in treatment selection. Case examples are included to provide evidence for the
73
clinical scenarios of de novo ABC and recurrence during adjuvant treatment for early breast
74
cancer.
75 76
Considerations in Choosing Treatment
77
Advances in endocrine-based therapeutics have improved survival for women with HR-positive
78
ABC.10-13 And because women with HR-positive breast cancer are living longer, patient quality
79
of life has come to the forefront of clinical decision-making.12 The following includes several
AC C
EP
TE D
M AN U
SC
RI PT
Despite advances in medicine and drug development, advanced breast cancer (ABC) remains
3
ACCEPTED MANUSCRIPT Endocrine Management of ABC
80
factors that should be considered when selecting from among available therapies for women
81
with HR-positive ABC11,13-16: •
Minimizing toxicity in keeping with the palliative aim of therapy
83
•
Maintaining and/or improving the patient’s quality of life
84
•
The urgency of the need for treatment based on factors such as symptom severity and the pace of disease progression
85
RI PT
82
•
The duration of prior response to adjuvant ET
87
•
The duration of disease-free interval since last therapy (i.e., early vs late disease
89
M AN U
progression)
88
•
SC
86
The sites of disease (i.e., bone or soft tissue, which may indicate a more indolent disease course; combined bone and soft tissue; or visceral metastases associated
91
with more aggressive phenotype)
TE D
90
92
•
Disease burden (e.g., volume and the number of metastases)
93
•
HER2 status
In addition, the following patient factors also warrant consideration:
EP
94
•
Comorbidities
96
•
Patient performance status
•
Patient preferences
•
Patient access to drug coverage
97 98
AC C
95
99
Several treatment options are available for women with HR-positive ABC. The selective ER
100
modulator (SERM) tamoxifen is one of the earliest forms of ET used in the treatment of HR-
101
positive disease and is the most firmly established ET use as adjuvant therapy for both pre- and 4
ACCEPTED MANUSCRIPT Endocrine Management of ABC
postmenopausal women.12,17 In premenopausal women, ovarian ablation or treatment with
103
luteinizing hormone-releasing hormone analogues such as goserelin and leuprolide11 may be
104
used to suppress ovarian function.12,13 For postmenopausal women, the nonsteroidal
105
aromatase inhibitors (AIs) anastrozole and letrozole,18,19 the steroidal AI exemestane,20 and the
106
selective ER degrader (SERD) fulvestrant21 are established, approved, and effective therapeutic
107
options.
SC
RI PT
102
108
Development of resistance to ET in HR-positive ABC is common, and most patients experience
110
disease progression.22,23 However, the mechanisms underlying disease progression and the
111
development of resistance to ET are complex and not fully understood, but likely resistance
112
pathways differ for AIs versus SERMs/SERDs. In recent years, greater understanding of the
113
molecular pathways of resistance has led to increased investigation of combinations that
114
include ET and targeted agents, such as everolimus, a mammalian target of rapamycin (mTOR)
115
inhibitor, and palbociclib, a cyclin-dependent kinase (CDK) inhibitor. While these novel
116
combinations may provide additional therapeutic options for women with ET-resistant disease,
117
tradeoffs may include increased toxicity and added cost.22,23
TE D
EP
AC C
118
M AN U
109
119
Studies suggest that patients with HR-positive metastatic disease whose disease has progressed
120
during first line ET might still respond to different types of ET in the second line.24,25 These
121
observations support that well-tolerated, sequential ET may slow progression in HR-positive
122
ABC and potentially delay the need for chemotherapy.12,13 Indeed, this approach is
123
recommended in clinical practice guidelines.12,26 The optimal sequencing of ETs, however,
5
ACCEPTED MANUSCRIPT Endocrine Management of ABC
remains unclear, and decisions regarding sequencing approaches may be confounded by clinical
125
variables such as menopausal status or previous treatments.12,27 Careful consideration of
126
factors such as prior ET and the time to progression on that treatment (i.e., early relapse, ≤12
127
months may be indicative of resistance; >12 months may suggest endocrine sensitivity),
128
mechanism of action and the potential for cross-resistance, site of metastasis, whether the
129
patient demonstrated symptoms, and the current clinical evidence are paramount.14
SC
RI PT
124
130
Overview of Treatment Options in HR-Positive ABC: Endocrine Therapies and Targeted Agents
132
An overview of currently available ETs and targeted agents is presented in Table 1.28-40 Data
133
from key phase 3 studies of endocrine and endocrine-based therapies for ABC are presented in
134
Table 2.21,41-61
M AN U
131
TE D
135
Selective Estrogen Receptor Modulators
137
The SERMs tamoxifen and toremifene are competitive inhibitors of estrogen: they bind directly
138
to the ER in breast cancer cells, blocking estrogen binding.30,31,62 In addition to their estrogen
139
antagonist effects in the breast, SERMs also manifest partial estrogen agonist effects on
140
peripheral tissues, with beneficial effects in some sites (e.g., bone)62,63 and unfavorable effects
141
in others (e.g., uterus).30,64 The adverse events (AEs) of SERMs are consistent with those
142
experienced during menopause, and may include hot flashes, night sweats, vaginal dryness,
143
discharge, or bleeding.30,64 More serious AEs associated with prolonged use include an
144
increased risk of endometrial cancer and deep venous thrombosis.12,30,62,65
AC C
EP
136
145
6
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Aromatase Inhibitors
147
Aromatase inhibitors, which include anastrozole, letrozole, and exemestane, decrease the
148
amount of estrogen in postmenopausal women by blocking the enzyme aromatase which
149
converts androgens to estrogen in peripheral tissue, including breast tumor cells.66 Anastrozole
150
and letrozole are nonsteroidal AIs that bind reversibly to aromatase, inhibiting the enzyme.66
151
Exemestane is a steroidal AI and analogue of the endogenous aromatase substrate
152
androstenedione, whose metabolites bind irreversibly to aromatase, causing permanent
153
inactivation of the enzyme.67-70
M AN U
SC
RI PT
146
154
Prior to the approval of palbociclib, single-agent ET was the mainstay therapy for women with
156
HR-positive, recurrent disease in the metastatic setting.11 Aromatase inhibitors remain an
157
important option in first line therapy for postmenopausal women with HR-positive ABC and are
158
generally well tolerated.52,71,72 Adverse events associated with AI monotherapy may include
159
musculoskeletal symptoms, hot flashes, vaginal dryness, and an increased risk of bone
160
fracture.12,32-34 Direct comparative studies of the three AIs in first line therapy of ABC have not
161
been conducted, although results across studies suggest similar efficacy and tolerability. The
162
current National Comprehensive Cancer Network (NCCN) guidelines recommend ovarian
163
suppression plus ET for treating premenopausal women with HR-positive ABC , which could
164
then include an AI.12
AC C
EP
TE D
155
165 166
Based on using a dual-blockade approach, combining ETs with different mechanisms of action,
167
the combination of a SERM with an AI was investigated to assess clinical benefit over either
7
ACCEPTED MANUSCRIPT Endocrine Management of ABC
therapy alone. Early studies with fadrozole and vorozole did not consistently provide additional
169
anti-tumor activity when used in combination with tamoxifen.73,74 Later preclinical studies
170
reported that letrozole alone was superior to tamoxifen and added benefit was not evident
171
with the combination treatment. The findings of studies conducted with anastrozole in
172
combination with tamoxifen were similar to those with letrozole.75
SC
173
RI PT
168
Selective ER Degrader
175
Fulvestrant is a SERD35 that binds competitively to the ER with a higher relative binding affinity
176
than tamoxifen (IC50 0.89 vs 0.025).76-78 In contrast to tamoxifen’s partial agonist activity,
177
fulvestrant inhibits ER dimerization and translocation to the nucleus, effectively targeting and
178
blocking estrogen-sensitive gene transcription and eliminating all known agonist activity.
179
Fulvestrant also accelerates ER degradation, resulting in complete suppression of the estrogenic
180
effects on breast tissue.79 Fulvestrant has received FDA approval for the treatment of HR-
181
positive metastatic breast cancer in postmenopausal women with disease progression following
182
antiestrogen therapy, and for treatment of HR-positive/HER2-negative advanced or metastatic
183
breast cancer in combination with palbociclib in women with disease progression after ET
184
(discussed below).35
TE D
EP
AC C
185
M AN U
174
186
The most frequent AEs observed with fulvestrant (occurring with a frequency of ≥5% of
187
patients) include injection-site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue,
188
pain in extremities, hot flashes, vomiting, anorexia, asthenia, musculoskeletal pain, cough,
189
dyspnea, and constipation.35,79-81
8
ACCEPTED MANUSCRIPT Endocrine Management of ABC
190
Targeted Therapies
192
Treatments for HR-positive/HER2-negative ABC may also include the targeted inhibition of
193
other pathways involved in the promotion of tumor cell proliferation, such as the mTOR82 and
194
CDK4/6 signaling pathways.83-85 Abnormal signaling through the phosphatidylinositol 3-kinase-
195
Akt-mTOR pathway may be a mechanism of resistance to ET, suggesting the potential for
196
mTOR-targeted therapies in patients with endocrine-resistant, HR-positive ABC.52 Everolimus, a
197
derivative of sirolimus (formerly rapamycin), inhibits mTOR signaling through allosteric binding
198
to mTORC1.86,87 Preclinical studies have shown that the use of everolimus in combination with
199
AIs yields synergistic inhibition of cell proliferation and induction of apoptosis.88 Everolimus is
200
FDA-approved in combination with exemestane for treatment of postmenopausal women with
201
HR-positive/HER2-negative ABC after failure of treatment with letrozole or anastrozole.38,52
202
Adverse events associated with everolimus are consistent with those observed for other
203
rapamycin analogues and include stomatitis, infections, rash, fatigue and asthenia, diarrhea,
204
edema, abdominal pain, nausea, cough, headache, and decreased appetite.38,52,89
SC
M AN U
TE D
EP
205
RI PT
191
It is well recognized that cell cycle progression is dysregulated in certain molecular subtypes of
207
breast cancer.83-85 The first FDA-approved CDK4/6 inhibitor, palbociclib,90 blocks progression
208
from G1 into S phase of the cell cycle and represent a new pathway to target in HR-positive
209
ABC.83 It is approved for use in HR-positive/HER2-negative ABC in combination with letrozole
210
for the first line treatment of postmenopausal women, and in combination with fulvestrant for
211
disease progression following ET in both pre- and postmenopausal women.39 The most
AC C
206
9
ACCEPTED MANUSCRIPT Endocrine Management of ABC
common adverse reactions observed in the pivotal studies (incidence ≥10%) were neutropenia,
213
leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea,
214
thrombocytopenia, constipation, alopecia, vomiting, rash, and decreased appetite.39
RI PT
212
215
In March 2017, ribociclib (LEE011) was granted FDA approval as first line treatment for HR-
217
positive/HER2-negative ABC in combination with any AI.40 In the planned interim analysis of the
218
MONALEESA-2 study, which is evaluating ribociclib (600 mg) in combination with letrozole (2.5
219
mg) compared with letrozole plus placebo in postmenopausal women with HR-positive/HER2-
220
negative recurrent or metastatic breast cancer who had not received previous systemic therapy
221
for advanced disease, common grade 3/4 AEs were neutropenia, leukopenia, hypertension,
222
elevated alanine aminotransferase, lymphopenia, and elevated aspartate aminotransferase.56
M AN U
SC
216
TE D
223
An additional CDK4/6 inhibitor, abemaciclib (LY2835219), is under evaluation and may become
225
a future option for treatment. In June 2016, the first interim results were reported from the
226
phase 2, single-arm MONARCH 1 study of 132 patients with HR-positive/HER2-negative ABC
227
who experienced disease progression on or after prior ET and chemotherapy. Patients were
228
treated with 200 mg abemaciclib orally twice daily. The objective response rate (ORR) was
229
19.7% (95% CI, 13.3–27.5) and the clinical benefit rate (CBR) was 42.4%.91 Two phase 3 studies
230
are also being conducted: the MONARCH 2 study in combination with fulvestrant in women
231
with HR-positive/HER2-negative breast cancer,92 and the MONARCH 3 study in postmenopausal
232
women with HR-positive/HER2-negative breast cancer to evaluate abemaciclib 150 mg or
AC C
EP
224
10
ACCEPTED MANUSCRIPT Endocrine Management of ABC
233
placebo given orally every 12 hours continuously until progression, along with anastrozole 1 mg
234
or letrozole 2.5 mg once daily at the investigator’s discretion, with assessments every 28 days.93
RI PT
235
ESR Mutation
237
The emergence of ESR1 mutations occurs primarily in ABC after exposure to AIs,94 resulting in
238
dose-dependent changes in responsiveness to endocrine agents.95-98
SC
236
239
Retrospective analysis of baseline plasma samples from patients enrolled in the phase 3 SoFEA
241
study, which evaluated fulvestrant (500 mg intramuscularly on day 1, followed by 250 mg on
242
days 15 and 29, then every 28 days) with placebo or anastrozole (1 mg) versus exemestane (25
243
mg) in patients with prior sensitivity to AIs, suggests that the presence of ESR1 mutations may
244
impart sensitivity to fulvestrant. Plasma samples from 161 of 723 (22.4%) patients were
245
analysed for ESR1 mutations. Of these, 63 (39%) had ESR1 mutations, and among these, 49.1%
246
(27 of 55) were polyclonal. Patients with ESR1 mutations had improved progression-free
247
survival (PFS) after receiving fulvestrant compared with exemestane (hazard ratio [HR]=0.52;
248
95% CI, 0.30-0.92; P=0.02). However, patients with wild-type ESR1 had similar PFS regardless of
249
treatment (HR=1.07; 95% CI, 0.68-1.67; P=0.77).99
TE D
EP
AC C
250
M AN U
240
251
In the phase 3 PALOMA-3 study, conducted in patients with HER2-negative ABC who had
252
progressed on previous ET, the prevalence of ESR1 mutations was 25.3% (91 of 360). Among
253
those, 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to
254
prior AIs. Improved PFS was observed for the fulvestrant plus palbociclib arm versus the
11
ACCEPTED MANUSCRIPT Endocrine Management of ABC
255
fulvestrant plus placebo arm in both ESR1-mutant (HR=0.43; 95% CI, 0.25-0.74; P=0.002) and
256
ESR1-wild-type patients (HR=0.49; 95% CI, 0.35-0.70; P<0.001).99
RI PT
257
In BOLERO-2, an international, double-blind, randomized, phase 3 study comparing everolimus
259
plus exemestane to placebo plus exemestane in postmenopausal women with HR-
260
negative/HER2-negative ABC who progressed during or following treatment with nonsteroidal
261
AIs, ESR1 mutations in cell-free DNA were detected in baseline plasma samples obtained from
262
541 of 724 patients (74.7%). Of 541 evaluable patients, 156 (28.8%) had the ESR1 mutations
263
D538G (21.1%) and/or Y537S (13.3%), and 30 had both. Shorter overall survival (OS) was
264
associated with these mutations (wild-type, 32.1 months [95% CI, 28.09–36.40 months];
265
D538G, 25.99 months [95% CI, 19.19–32.36 months]; Y537S, .19.98 months [95% CI, 13.01–
266
29.31 months]; both mutations, 15.15 months [95% CI, 10.87–27.43 months]). Patients with the
267
D538G mutation demonstrated a similar PFS benefit (HR=0.34 [95% CI, 0.02–0.57]) from the
268
addition of everolimus to exemestane as did those without D538G or Y537S mutations.98 These
269
studies indicate that ESR1 mutations are prevalent in ER-positive, AI-treated ABC. Both Y537S
270
and D538G mutations are associated with more aggressive disease biology.
M AN U
TE D
EP
AC C
271
SC
258
272
Case Studies
273
The following patient-case scenarios provide opportunities to examine factors that may impact
274
therapeutic strategies for postmenopausal patients with HR-positive ABC. Selected treatment
275
recommendations based on available data and the clinical experience of the authors are
276
presented in Figure 1.
12
ACCEPTED MANUSCRIPT Endocrine Management of ABC
277
For any postmenopausal patient with HR-positive disease and bone and/or soft tissue or
279
asymptomatic visceral metastases, the NCCN Clinical Guidelines in Oncology for breast cancer
280
currently recommend 3 lines of ET before considering cytotoxic chemotherapy.12 Optimal
281
sequencing has not yet been determined12,27 and is subject to change with the emergence of
282
new agents.
SC
RI PT
278
283
Case Study 1: De Novo ABC
285
A 67-year-old woman with no history of breast cancer presented with a 3-cm nodule in the
286
left breast and hip pain that had not resolved despite treatment with nonsteroidal anti-
287
inflammatory drugs. Workup revealed bone metastases including the pelvis and low-volume
288
malignant pleural effusion in the right lung. Biopsy and subsequent pathology findings
289
revealed ER-positive, PgR-positive, HER2-negative ABC.
TE D
290
M AN U
284
The overall rate of patients with HR-positive ABC who have not received prior ET is reported to
292
be 3% to 6%,100 and other data suggest that the rate may be higher. The variation in rates may
293
be subject to regional differences in reporting, which are affected by various factors, such as
294
affluence and insurance coverage, that also impact patients’ ability to seek care early in their
295
disease.101,102 This case provides clinical guidance for first line options.
AC C
EP
291
296
13
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Options for Monotherapy
298
Recommended monotherapy options for postmenopausal patients with HR-positive ABC who
299
are ET-naïve or have had no ET for more than 12 months, include a SERM (e.g., tamoxifen) or AI
300
(letrozole, exemestane, or anastrozole).12,26 However, emerging data based on the FALCON
301
study (discussed below) provide evidence for fulvestrant as a potential new option for
302
endocrine-naïve patients.103 Comparative studies of tamoxifen versus AIs support the first line
303
use of third-generation AIs in ABC. The outcomes of several phase 3 studies comparing
304
anastrozole, letrozole, or exemestane with tamoxifen as first line therapy in postmenopausal
305
women with advanced endocrine-sensitive breast cancer indicate that AIs offer a modest, but
306
statistically significant, benefit in comparison with tamoxifen.12,41-44,46 At this time, no head-to-
307
head comparison studies of third-generation AIs in the metastatic setting have been conducted
308
to determine the superiority of one agent over another.27
SC
M AN U
TE D
309
RI PT
297
Clinical Studies of Fulvestrant First Line Monotherapy
311
Fulvestrant has been evaluated thoroughly in clinical studies as a single agent, in first and
312
second line therapy, and in combination with other agents.104
AC C
313
EP
310
314
Although not currently approved for first line treatment, data regarding the use of fulvestrant
315
500 mg in the ET-naïve setting are available. In the phase 2 FIRST study of 205 postmenopausal
316
women with HR-positive ABC who had not received prior ET, fulvestrant 500 mg significantly
317
prolonged time to progression (TTP) versus anastrozole 1 mg. At the follow-up analysis (median
318
duration of follow-up for TTP: 18.8 months in the fulvestrant group and 12.9 months in the
14
ACCEPTED MANUSCRIPT Endocrine Management of ABC
anastrozole group, when 79.5% of patients had discontinued therapy), the median TTP was 23.4
320
months with fulvestrant versus 13.1 months with anastrozole (HR=0.66; 95 % CI, 0.47-0.92;
321
P=0.01). These findings represent a 34% decrease in the risk of progression.105 Fulvestrant was
322
also associated with a significantly greater median OS (54.1 months) than anastrozole (48.4
323
months; HR=0.70; 95% CI, 0.50-0.98; P=0.041).106
SC
324
RI PT
319
The findings from the FIRST study led to the phase 3 confirmatory FALCON study that also
326
compared fulvestrant with anastrozole for first line treatment of ET-naïve patients with HR-
327
positive locally advanced or ABC.103 In total, 462 patients were randomized to receive
328
fulvestrant 500 mg (n=230) or anastrozole 1 mg (n=232). The primary endpoint was met as
329
demonstrated by a significant improvement in PFS with fulvestrant versus anastrozole
330
(HR=0.797; 95% CI, 0.637-0.999; P=0.049; median PFS 16.6 vs 13.8 months, respectively).103
331
While OS data were not yet mature at the time of publication, the PFS data suggest that
332
fulvestrant may soon become a treatment option in the ET-naïve setting.103
TE D
M AN U
325
EP
333
A First Line Option: Palbociclib Plus Letrozole
335
With the approval of palbociclib in combination with letrozole as first line endocrine-based
336
therapy, postmenopausal women with de novo HR-positive ABC have a new option for initial
337
treatment.90,107
AC C
334
338 339
The confirmatory phase 3 study (PALOMA-2) evaluated palbociclib 125 mg/day in 3-week-on, 1-
340
week-off treatment cycles plus letrozole 2.5 mg/day continuously, compared with letrozole
15
ACCEPTED MANUSCRIPT Endocrine Management of ABC
alone every 28 days in 666 postmenopausal patients without prior systemic therapy for ABC. As
342
of February 2016, 331 PFS events were reported with a median PFS for the combination of
343
palbociclib and letrozole of 24.8 versus 14.5 months for letrozole alone (HR=0.58; 95% CI, 0.46-
344
0.72; P<0.001). The ORR was significantly higher in the palbociclib plus letrozole arm (42.1% vs
345
34.7%, P=0.031) than in the letrozole-alone arm. In patients with measureable disease, the ORR
346
was 55.3% and 44.4% for the palbociclib plus letrozole and letrozole-alone arms, respectively
347
(P=0.013). Overall survival was not reported because the data were immature. Common AEs (all
348
grades) for the palbociclib plus letrozole and letrozole-alone arms, respectively, were
349
neutropenia (79.5% vs 6.3%), fatigue (37.4% vs 27.5%), nausea (35.1% vs 26.1%), arthralgia
350
(33.3% vs 33.8%), and alopecia (32.9% vs 15.8%).53
M AN U
SC
RI PT
341
351
The recent FDA approval of ribociclib plus any AI as a first line treatment for HR-positive/HER2-
353
negative ABC, based on the interim analysis of the MONALEESA-2 study, provides another
354
treatment option in this setting.40
EP
355
TE D
352
Other Combination Approaches
357
The combination of fulvestrant plus anastrozole in comparison with anastrozole alone has been
358
the subject of two studies. The SWOG S0226 study evaluated 707 randomized postmenopausal
359
patients with HR-positive ABC to characterize differences in PFS following treatment with the
360
combination of fulvestrant plus anastrozole (fulvestrant 500 mg intramuscularly [IM] on day 1;
361
250 mg on days 14 and 28, then every 4 weeks plus anastrozole, 1 mg/day orally) versus
362
anastrozole alone. The study demonstrated a survival benefit with the addition of fulvestrant to
AC C
356
16
ACCEPTED MANUSCRIPT Endocrine Management of ABC
anastrozole (15.0 months; 95% CI, 13.2-18.4; HR=0.80, P=0.007) compared with anastrozole
364
monotherapy (13.5 months; 95% CI, 12.1-15.1). Among the 414 women naïve to adjuvant ET,
365
median PFS was 17.0 months for combination therapy compared with 12.6 months for
366
anastrozole alone (HR=0.74; 95% CI, 0.59-0.92; P=0.006).51 It should be noted that the
367
250 mg/month fulvestrant dosage administered in S0226 has been shown to be inferior to
368
500 mg/month.48
SC
RI PT
363
369
Another investigation of fulvestrant plus anastrozole as combination therapy was the FACT
371
study.50 This was an open-label, randomized, phase 3 study of fulvestrant and anastrozole in
372
combination (500 mg IM on day 1 and 250 mg on days 15 and 29, and every 4 weeks thereafter
373
plus anastrozole 1 mg/day orally) compared with anastrozole alone (1 mg/day orally) as first
374
line therapy for postmenopausal women with ER-positive and/or PgR-positive breast cancer in
375
first relapse of endocrine-responsive breast cancer. In contrast to SWOG S0226, approximately
376
two-thirds of the 514 randomized patients in this study had previously received adjuvant
377
antiestrogens. Of these, only 8 patients had previously received an AI. The median TTP was 10.8
378
and 10.2 months for fulvestrant plus anastrozole versus anastrozole alone, respectively
379
(HR=0.99; 95% CI, 0.81-1.20; P=0.91); median OS was 37.8 and 38.2 months, respectively
380
(HR=1.0; 95% CI, 0.76-1.32; P=1.00).50
TE D
EP
AC C
381
M AN U
370
382
Case Study 2: Progression During Hormonal Therapy for Early Breast Cancer
383
A 58-year-old woman initially diagnosed with ER-positive, PgR-positive, HER2-negative,
384
lymph-node–negative breast cancer was prescribed a 5-year course of anastrozole after an
17
ACCEPTED MANUSCRIPT Endocrine Management of ABC
initial lumpectomy followed by radiation. During her fourth year of anastrozole treatment,
386
she was diagnosed with multiple bone metastases, but no evidence of visceral disease. A
387
biopsy confirmed that the metastasis had the same biologic profile as the index tumor.
RI PT
385
388
Sequencing Considerations for Progression During or After Endocrine Therapy
390
When progression occurs after ET, as is typical of ABC, it is reasonable to select an ET with a
391
different mechanism of action (e.g., fulvestrant after tamoxifen), an agent of different chemical
392
class (e.g., a steroidal AI such as exemestane after a nonsteroidal AI such as anastrozole), or
393
combination therapy with targeted agents (e.g., palbociclib plus fulvestrant or exemestane with
394
everolimus).26 Other options in this setting include androgens and high-dose ethinyl estradiol.12
M AN U
SC
389
395
In vitro research suggests that primary resistance may emerge from heightened tumor
397
sensitivity to low estrogen levels in situations of prolonged estrogen depletion.108 Therefore,
398
fulvestrant, which promotes degradation of the ER, and thereby complete blockade of ER
399
signaling, may be an option in AI-resistant patients.79
EP
400
TE D
396
The combination of palbociclib and fulvestrant has received FDA approval based on the findings
402
of the phase 3 study, PALOMA-3 (Table 2). This study demonstrated that the combination of
403
palbociclib and fulvestrant resulted in significantly longer PFS than treatment with fulvestrant
404
alone (9.5 vs 4.6 months, respectively; HR=0.46; 95% CI, 0.36-0.59; P<0.001).39,54 The AE profile
405
of the combination regimen was consistent with previously reported data for each agent. The
406
most common AEs of all grades and rates of study discontinuation in the palbociclib/fulvestrant
AC C
401
18
ACCEPTED MANUSCRIPT Endocrine Management of ABC
group were consistent with the CDK4/6 toxicity profile.55 Quality of life measures included the
408
QLQ-C30 and its breast cancer module, QLQ-BR23. Overall global quality of life was maintained
409
over the treatment period in the palbociclib/fulvestrant group compared with fulvestrant
410
monotherapy.55
RI PT
407
411
Earlier phase 3, randomized, clinical studies that led to the approval of fulvestrant
413
demonstrated that the 250 mg dose was as effective as anastrozole in tamoxifen-resistant
414
ABC.21,45 Since fulvestrant degrades the ER in a dose-dependent manner, it was hypothesized
415
that a higher dosage might provide superior benefit,109 leading to the phase 3 CONFIRM study.
416
This study compared the safety and efficacy of fulvestrant 250 mg with fulvestrant 500 mg in
417
postmenopausal women with ER-positive ABC who experienced progression after prior ET. The
418
study demonstrated the superior efficacy of fulvestrant 500 mg, and this dosage has since been
419
approved by the FDA. Progression-free survival was significantly longer for fulvestrant 500 mg
420
over 250 mg (HR=0.80; 95% CI, 0.68-0.94; P=0.006), representing a 20% reduction in the risk of
421
disease progression. Fulvestrant 500 mg was also associated with a clinically relevant 4.1-month
422
increase in median OS, and a 19% reduction in risk of death compared with fulvestrant 250
423
mg.48,49 Toxicity was generally similar between the two doses.35,48,49
M AN U
TE D
EP
AC C
424
SC
412
425
Among AIs, exemestane was shown to provide clinical benefit in a phase 2 clinical study in
426
patients with ABC who had failed up to three lines of nonsteroidal AIs.20 In this open-label,
427
uncontrolled, phase 2 study, exemestane 25 mg was associated with an objective response of
428
6.6% (95% CI, 3.8-10.6) and an overall success rate of 24.3% (95% CI, 19.0-30.2); the median
19
ACCEPTED MANUSCRIPT Endocrine Management of ABC
durations of the objective response and overall success were 58.4 and 37.0 weeks,
430
respectively.20 In a phase 2, sequential, 2-stage, uncontrolled study of second line exemestane
431
in HR-positive or HR-unknown patients (n=50) who had been treated in the first line with
432
anastrozole, exemestane demonstrated clinical benefit. The CBR (i.e., complete response +
433
partial response + stable disease >6 months) for anastrozole and exemestane was 73% and
434
44%, respectively.110 For patients who may have already received first line antiestrogen
435
therapy, letrozole has also been shown to have clinical benefit as second line therapy in
436
ABC.19,111
M AN U
SC
RI PT
429
437
The combination of the mTOR inhibitor everolimus with exemestane has also been approved
439
for the treatment of postmenopausal women with advanced HR-positive/HER2-negative breast
440
cancer in combination with exemestane after treatment failure with letrozole or
441
anastrozole.38,112 The BOLERO-2 study, which led to the approval of this combination regimen,
442
demonstrated that exemestane plus everolimus substantially improved PFS compared with
443
exemestane alone (median PFS on final analysis: 7.8 vs 3.2 months, respectively [HR=0.45; 95%
444
CI, 0.38-0.54]). For patients receiving everolimus plus exemestane, the median OS was 31.0
445
months compared with 26.6 months for placebo plus exemestane (HR=0.89; 95% CI, 0.73-1.10;
446
log-rank P=0.14).113,114 There were, however, more AEs reported in the combination arm,
447
including stomatitis, anemia, dyspnea, hyperglycemia, fatigue, and pneumonitis, and these
448
should be taken into account when selecting therapy.52,113
AC C
EP
TE D
438
449
20
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Supportive Treatment
451
Supportive therapy plays an important role in the management of patients with ABC.12 For
452
example, bisphosphonates and denosumab, in combination with calcium and vitamin D
453
supplementation, are well-established treatments that may be considered to reduce the risk of
454
skeletal-related events in patients with bone metastases.12,115 Management strategies for the
455
other potential side effects of treatment (mucositis, stomatitis, injection-site reactions, nausea,
456
and musculoskeletal pain) have been covered in detail elsewhere in the literature.26,116-122
SC
RI PT
450
M AN U
457
Summary and Conclusions
459
The increase in the number of options for ET and endocrine-based therapy is challenging
460
traditional approaches to therapy sequencing for patients with HR-positive ABC. Strategies are
461
largely based on previous ET exposure, hormone-receptor and HER2 status, menopausal status,
462
and tolerability of therapy. Although current treatments for HR-positive ABC are not curative,
463
clinical evidence indicates that ET can slow disease progression with a low risk of significant
464
AEs. Use of targeted agents to inhibit intracellular pathways important for cell proliferation can
465
significantly enhance the efficacy of currently available endocrine interventions to stabilize
466
disease and delay progression. However, such treatments are associated with a higher
467
incidence of AEs than ET alone and have not yet confirmed an OS benefit.
EP
AC C
468
TE D
458
469
Acknowledgments
470
The authors would like to thank Greg Tardie, PhD and Joan Hudson, The Lockwood Group,
471
Stamford, CT, for medical writing and editorial support (funded by AstraZeneca LP).
21
ACCEPTED MANUSCRIPT Endocrine Management of ABC
AC C
EP
TE D
M AN U
SC
RI PT
472
22
ACCEPTED MANUSCRIPT Endocrine Management of ABC
473 474
References 1.
American Cancer Society. Cancer facts & figures 2017. Available at: http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2017/index. Accessed March 13, 2017.
478 479 480
2.
American Cancer Society. Breast cancer facts & figures 2015-2016. Available at: https://www.cancer.org/research/cancer-facts-statistics/breast-cancer-factsfigures.html. Accessed March 13, 2017.
481 482 483 484
3.
Pal SK, Gupta R, Bernstein L, Mortimer J. Lack of survival benefit in metastatic breast cancer with newer chemotherapy agents: The City of Hope cancer experience. Abstract presented at: American Society of Clinical Oncology Breast Cancer Symposium; September 5-7, 2008; Washington, DC.
485 486 487
4.
National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Fact Sheets: Breast 2016. Available at: http://seer.cancer.gov/statfacts/html/breast.html. Accessed March 13, 2017.
488 489
5.
Pinhel I, Hills M, Drury S, et al. ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer. Breast Cancer Res. 2012;14:R46.
490 491 492
6.
Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999;17:1474-1481.
493 494 495
7.
Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106:doi 10.1093/jnci/dju1055.
496 497
8.
Cancer.net. Breast cancer: overview. Available at: http://www.cancer.net/cancertypes/breast-cancer/overview. Accessed March 13, 2017.
498 499 500
9.
501 502
10.
503 504 505
11.
AC C
EP
TE D
M AN U
SC
RI PT
475 476 477
Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res Treat. 2002;76:27-36.
Luu T, Chung C, Somlo G. Combining emerging agents in advanced breast cancer. Oncologist. 2011;16:760-771. Cardoso F, Fallowfield L, Costa A, Castiglione M, Senkus E, ESMO Guidelines Working Group. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22 Suppl 6:vi25-vi30.
23
ACCEPTED MANUSCRIPT Endocrine Management of ABC
12.
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Breast Cancer. v.1.2017. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed March 13, 2017.
510 511
13.
Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Ann Oncol. 2014;25:1871-1888.
512 513
14.
Beslija S, Bonneterre J, Burstein HJ, et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol. 2009;20:1771-1785.
514 515
15.
Chung CT, Carlson RW. Goals and objectives in the management of metastatic breast cancer. Oncologist. 2003;8:514-520.
516 517
16.
Sanchez-Munoz A, Perez-Ruiz E, Jimenez B, et al. Targeted therapy of metastatic breast cancer. Clin Transl Oncol. 2009;11:643-650.
518 519
17.
Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN. Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol. 1995;13:513-529.
520 521 522 523
18.
Buzdar AU, Jones SE, Vogel CL, Wolter J, Plourde P, Webster A. A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Arimidex Study Group. Cancer. 1997;79:730-739.
524 525 526 527
19.
Gershanovich M, Chaudri HA, Campos D, et al. Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3). Ann Oncol. 1998;9:639-645.
528 529 530
20.
Lonning PE, Bajetta E, Murray R, et al. Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial. J Clin Oncol. 2000;18:2234-2244.
531 532 533 534
21.
Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol. 2002;20:3386-3395.
535 536 537
22.
538 539
23.
AC C
EP
TE D
M AN U
SC
RI PT
506 507 508 509
Bedard PL, Freedman OC, Howell A, Clemons M. Overcoming endocrine resistance in breast cancer: are signal transduction inhibitors the answer? Breast Cancer Res Treat. 2008;108:307-317. Miller WR, Larionov AA. Understanding the mechanisms of aromatase inhibitor resistance. Breast Cancer Res. 2012;14:201.
24
ACCEPTED MANUSCRIPT Endocrine Management of ABC
24.
Buzdar AU. Sequence of hormonal treatments in breast cancer. Semin Breast Dis. 1999;2:167-179.
542 543
25.
Hayes DF, Henderson IC, Shapiro CL. Treatment of metastatic breast cancer: present and future prospects. Semin Oncol. 1995;22:5-19; discussion 19-21.
544 545 546
26.
Rugo HS, Rumble RB, Macrae E, et al. Endocrine Therapy for Hormone Receptor-Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline. J Clin Oncol. 2016;34:3069-3103.
547 548
27.
Bertelli G, Paridaens R. Optimal sequence of hormonotherapy in advanced breast cancer. Curr Opin Oncol. 2006;18:572-577.
549
28.
Zoladex (goserelin acetate) [package insert]. Wilmington, DE: AstraZeneca; 2016.
550
29.
Lupron (leuprolide acetate) [package insert]. North Chicago, IL: AbbVie Inc.; 2016.
551
30.
Tamoxifen citrate [package insert]. Parsippany, NJ: Actavis Pharma, Inc.; 2015.
552
31.
Fareston (toremifene) [package insert]. Bedminster, NJ: Kyowa Kirin, Inc.; 2017.
553 554
32.
Arimidex (anastrozole) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2016.
555 556
33.
Femara (letrozole) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.
557
34.
Aromasin (exemestane) [package insert]. New York, NY: Pfizer Inc.; 2016.
558 559
35.
Faslodex (fulvestrant) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2016.
560 561
36.
Herceptin (trastuzumab) [package insert]. South San Francisco, CA: Genentech, Inc.; 2016.
562
37.
563 564
38.
565
39.
566 567 568 569 570
40.
AC C
EP
TE D
M AN U
SC
RI PT
540 541
Perjeta (pertuzumab) [package insert]. South San Francisco, CA: Genentech, Inc.; 2016. Afinitor (everolimus) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2016. Ibrance (palbociclib) [package insert]. New York, NY: Pfizer Inc.; 2016. Novartis Global. Novartis Kisqali® (ribociclib, LEE011) receives FDA approval as first-line treatment for HR+/HER2- metastatic breast cancer in combination with any aromatase inhibitor (press release March 13, 2017). Available at: https://www.novartis.com/news/media-releases/novartis-kisqalir-ribociclib-lee011receives-fda-approval-first-line-treatment. Accessed March 14, 2017. 25
ACCEPTED MANUSCRIPT Endocrine Management of ABC
41.
Bonneterre J, Thurlimann B, Robertson JF, et al. Anastrozole versus tamoxifen as firstline therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol. 2000;18:3748-3757.
575 576 577 578
42.
Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol. 2001;19:2596-2606.
579 580 581 582
43.
Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003;21:2101-2109.
583 584 585 586
44.
Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol. 2000;18:3758-3767.
587 588 589
45.
Howell A, Robertson JF, Quaresma Albano J, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002;20:3396-3403.
590 591 592 593
46.
Paridaens RJ, Dirix LY, Beex LV, et al. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 2008;26:4883-4890.
594 595 596 597
47.
Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008;26:1664-1670.
598 599 600
48.
601 602 603
49.
604 605
50.
AC C
EP
TE D
M AN U
SC
RI PT
571 572 573 574
Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol 2010;28:4594-4600. Di Leo A, Jerusalem G, Petruzelka L, et al. Final analysis of overall survival for the Phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg [abstract]. Cancer Res. 2012;72:S14. Bergh J, Jonsson P-E, Lidbrink EK, et al. FACT: An open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-
26
ACCEPTED MANUSCRIPT Endocrine Management of ABC
line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012;30:1919-1925.
606 607
51.
Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. New Engl J MEd. 2012;367:435-444.
610 611
52.
Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormonereceptor-positive advanced breast cancer. New Engl J Med. 2012;366:520-529.
612 613 614 615
53.
Finn RS, Martin M, Rugo HS, et al. PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2– advanced breast cancer (ABC). J Clin Oncol. 2016;34 (suppl):abstr 507.
616 617 618 619 620
54.
Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17:425-439.
621 622
55.
Turner NC, Ro J, Andre F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373:209-219.
623 624
56.
Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HRpositive, advanced breast cancer. N Engl J Med. 2016;375:1738-1748.
625 626 627 628
57.
Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009;27:5529-5537.
629 630 631
58.
Johnston S, Pippen J, Jr., Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptorpositive metastatic breast cancer. J Clin Oncol. 2009;27:5538-5546.
632 633 634 635
59.
636 637 638 639 640
60.
AC C
EP
TE D
M AN U
SC
RI PT
608 609
Huober J, Fasching PA, Barsoum M, et al. Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer - results of the eLEcTRA trial. Breast. 2012;21:27-33. Johnston SR, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol. 2013;14:989-998.
27
ACCEPTED MANUSCRIPT Endocrine Management of ABC
61.
Burstein HJ, Cirrincione CT, Barry WT, et al. Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: a randomized, double-blind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced breast cancer-CALGB 40302 (Alliance). J Clin Oncol. 2014;32:3959-3966.
646 647
62.
Harwood KV. Advances in endocrine therapy for breast cancer: considering efficacy, safety, and quality of life. Clin J Oncol Nurs. 2004;8:629-637.
648 649
63.
Hadji P. Cancer Treatment-Induced Bone Loss in women with breast cancer. Bonekey Rep. 2015;4:692.
650 651
64.
Bissett D, Davis JA, George WD. Gynaecological monitoring during tamoxifen therapy. Lancet. 1994;344:1244.
652 653 654 655
65.
Bergman L, Beelen ML, Gallee MP, Hollema H, Benraadt J, van Leeuwen FE. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres' ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen. Lancet. 2000;356:881-887.
656 657
66.
Lake DE, Hudis C. Aromatase inhibitors in breast cancer: an update. Cancer Control. 2002;9:490-498.
658 659 660
67.
Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM. An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane. Cancer. 2002;95:2006-2016.
661 662 663
68.
Miller WR, Bartlett J, Brodie AM, et al. Aromatase inhibitors: are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter? Oncologist. 2008;13:829-837.
664 665
69.
Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol. 2001;19:881-894.
666 667 668
70.
Hong Y, Yu B, Sherman M, Yuan YC, Zhou D, Chen S. Molecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase. Mol Endocrinol. 2007;21:401-414.
669 670
71.
671 672
72.
AC C
EP
TE D
M AN U
SC
RI PT
641 642 643 644 645
Johnston SR. Enhancing the efficacy of hormonal agents with selected targeted agents. Clin Breast Cancer. 2009;9 Suppl 1:S28-36. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003;348:2431-2442.
28
ACCEPTED MANUSCRIPT Endocrine Management of ABC
73.
Brodie AMH, Brodie HJ, Romanoff L, Williams JG, Williams KIH, Wu JT. Inhibition of Estrogen Biosynthesis and Regression of Mammary Tumors by Aromatase Inhibitors. In: Leavitt WW, ed. Hormones and Cancer. Boston, MA: Springer US; 1982:179-190.
676 677 678 679
74.
Van Ginckel R, Janssens B, Callens M, Goeminne N, Wouters L, De Coster R. Effects of combined and sequential treatment with tamoxifen and the aromatase inhibitor vorozole on 7,12-dimethylbenz(a) anthracene-induced mammary carcinoma in the rat. Cancer Chemother Pharmacol. 1996;38:21-28.
680 681 682
75.
Lu Q, Liu Y, Long BJ, Grigoryev D, Gimbel M, Brodie A. The effect of combining aromatase inhibitors with antiestrogens on tumor growth in a nude mouse model for breast cancer. Breast Cancer Res Treat. 1999;57:183-192.
683
76.
Wakeling AE, Bowler J. Steroidal pure antioestrogens. J Endocrinol. 1987;112:R7-10.
684 685
77.
Wakeling AE. Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr Relat Cancer. 2000;7:17-28.
686 687
78.
Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res. 1991;51:3867-3873.
688 689
79.
Morris C, Wakeling A. Fulvestrant ('Faslodex')--a new treatment option for patients progressing on prior endocrine therapy. Endocr Relat Cancer. 2002;9:267-276.
690 691
80.
Cruz Jurado J, Richart Aznar P, Garcia Mata J, et al. Management of patients with metastatic breast cancer. Adv Ther. 2011;28 Suppl 6:50-65.
692 693 694
81.
Howell A, Pippen J, Elledge RM, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer. 2005;104:236-239.
695 696 697
82.
Villarreal-Garza C, Cortes J, Andre F, Verma S. mTOR inhibitors in the management of hormone receptor-positive breast cancer: the latest evidence and future directions. Ann Oncol. 2012;23:2526-2535.
698 699 700
83.
701 702
84.
703 704 705 706
85.
AC C
EP
TE D
M AN U
SC
RI PT
673 674 675
Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11:R77.
Caldon CE, Daly RJ, Sutherland RL, Musgrove EA. Cell cycle control in breast cancer cells. J Cell Biochem. 2006;97:261-274. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16:25-35. 29
ACCEPTED MANUSCRIPT Endocrine Management of ABC
86.
Efeyan A, Sabatini DM. mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol. 2010;22:169-176.
709 710 711 712 713
87.
United States Food and Drug Administration. Center for Drug Evaluation and Research Application Number 21-110: Approved draft labeling Rapamune® (sirolimus) oral solution and tablets. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21110_Rapamune_prntlbl. pdf. Accessed March 13, 2017.
714 715 716
88.
Boulay A, Rudloff J, Ye J, et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res. 2005;11:53195328.
717 718 719
89.
Beaver JA, Park BH. The BOLERO-2 trial: the addition of everolimus to exemestane in the treatment of postmenopausal hormone receptor-positive advanced breast cancer. Future Oncol. 2012;8:651-657.
720 721 722 723
90.
Pfizer Inc. 2015 press release: Pfizer receives U.S. FDA accelerated approval of IBRANCE® (palbociclib) Available at: http://www.pfizer.com/news/press-release/press-releasedetail/pfizer_receives_u_s_fda_accelerated_approval_of_ibrance_palbociclib. Accessed March 13, 2017.
724 725 726 727
91.
Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2breast cancer, after chemotherapy for advanced disease. J Clin Oncol. 2016;34 (suppl):abstr 510.
728 729 730
92.
Eli Lilly and Company. A study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive HER2 negative breast cancer (MONARCH 2). Available at: https://clinicaltrials.gov/ct2/show/NCT02107703. Accessed March 8, 2017.
731 732 733
93.
Eli Lilly and Company. A study of nonsteroidal aromatase inhibitors plus abemaciclib (LY2835219) in postmenopausal women with breast cancer (MONARCH 3). Available at: https://clinicaltrials.gov/ct2/show/NCT02246621. Accessed April 3, 2017.
734 735
94.
736 737 738
95.
739 740
96.
AC C
EP
TE D
M AN U
SC
RI PT
707 708
Alluri PG, Speers C, Chinnaiyan AM. Estrogen receptor mutations and their role in breast cancer progression. Breast Cancer Res. 2014;16:494. Jeselsohn R, Yelensky R, Buchwalter G, et al. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014;20:1757-1767. Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormoneresistant breast cancer. Nat Genet. 2013;45:1439-1445.
30
ACCEPTED MANUSCRIPT Endocrine Management of ABC
97.
Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45:1446-1451.
743 744 745
98.
Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial. JAMA Oncol. 2016;2:1310-1315.
746 747
99.
Fribbens C, O'Leary B, Kilburn L, et al. Plasma ESR1 Mutations and the Treatment of Estrogen Receptor-Positive Advanced Breast Cancer. J Clin Oncol. 2016;34:2961-2968.
748 749
100.
Lee T, Isaacs C. Treatment of primary breast tumors in de novo metastatic breast cancer. Clin Adv Hematol Oncol. 2014;12:820-827.
750 751 752
101.
Dawood S, Broglio K, Ensor J, Hortobagyi GN, Giordano SH. Survival differences among women with de novo stage IV and relapsed breast cancer. Ann Oncol. 2010;21:21692174.
753 754 755
102.
Lobbezoo DJ, van Kampen RJ, Voogd AC, et al. Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer? Br J Cancer. 2015;112:1445-1451.
756 757 758
103.
Robertson JF, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016;388:2997-3005.
759 760
104.
Al-Mubarak M, Sacher AG, Ocana A, Vera-Badillo F, Seruga B, Amir E. Fulvestrant for advanced breast cancer: a meta-analysis. Cancer Treat Rev. 2013;39:753-758.
761 762 763
105.
Robertson JF, Lindemann JP, Llombart-Cussac A, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized 'FIRST' study. Breast Cancer Res Treat. 2012;136:503-511.
764 765 766
106.
Ellis MJ, Llombart-Cussac A, Feltl D, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: Overall survival analysis from the phase II FIRST study. J Clin Oncol. 2015;33:3781-3787.
767 768 769 770
107.
771 772
108.
AC C
EP
TE D
M AN U
SC
RI PT
741 742
United States Food and Drug Administration. Approval letter NDA 207103/S-002 (dated February 19, 2016). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/207103Orig1s002ltr.p df. Accessed March 8, 2017. Hayes EL, Lewis-Wambi JS. Mechanisms of endocrine resistance in breast cancer: an overview of the proposed roles of noncoding RNA. Breast Cancer Res. 2015;17:40.
31
ACCEPTED MANUSCRIPT Endocrine Management of ABC
109.
Kuter I, Gee JM, Hegg R, et al. Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study. Breast Cancer Res Treat. 2012;133:237-246.
776 777 778
110.
Iaffaioli RV, Formato R, Tortoriello A, et al. Phase II study of sequential hormonal therapy with anastrozole/exemestane in advanced and metastatic breast cancer. Br J Cancer. 2005;92:1621-1625.
779 780 781 782
111.
Dombernowsky P, Smith I, Falkson G, et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol. 1998;16:453-461.
783 784 785 786
112.
United States Food and Drug Administration. Approval letter NDA 022334/S-016 (dated August 20, 2012). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/022334Orig1s016ltrR epl.pdf. Accessed March 8, 2017.
787 788 789
113.
Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30:870-884.
790 791 792
114.
Piccart M, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane for hormonereceptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol. 2014;25:2357-2362.
793 794
115.
Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. 2012;2:CD003474.
795 796
116.
Aapro MS. Challenges in clinical patient management. Cancer Invest. 2010;28 (Suppl 1):14-27.
797 798 799
117.
Bryce J, Bauer M, Hadji P. Managing arthralgia in a postmenopausal woman taking an aromatase inhibitor for hormonesensitive early breast cancer: a case study. Cancer Manag Res. 2012;4:105-111.
800 801
118.
802 803
119.
804 805
120.
AC C
EP
TE D
M AN U
SC
RI PT
773 774 775
Hopkins U, Arias CY. Large-volume IM injections: A review of best practices. ONA. 2013;Jan/Feb:32-37. Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev (Orlando). 2014;28:126-133. Leclerc AF, Jerusalem G, Devos M, Crielaard JM, Maquet D. Multidisciplinary management of breast cancer. Arch Public Health. 2016;74:50.
32
ACCEPTED MANUSCRIPT Endocrine Management of ABC
121.
Roberts K, Rickett K, Greer R, Woodward N. Management of aromatase inhibitor induced musculoskeletal symptoms in postmenopausal early Breast cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2017;111:66-80.
809 810 811
122.
Versea L, Rosenzweig M. Hormonal therapy for breast cancer: focus on fulvestrant. Clin J Oncol Nurs. 2003;7:307-311.
AC C
EP
TE D
M AN U
SC
RI PT
806 807 808
33
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Figure Legend
EP
TE D
M AN U
SC
RI PT
Figure 1. Treatment recommendations for postmenopausal ABC based on clinical presentation. Abbreviations: ABC = advanced breast cancer; AI = aromatase inhibitor; HR+ = hormone receptor-positive; ; ± = with/without.
AC C
812 813 814 815 816 817
34
ACCEPTED MANUSCRIPT Endocrine Management of ABC
TE D
EP
•
Tumor flare can occur on the initiation of goserelin for both men and women being treated for cancer. Not indicated for breast cancer, but included Reported in ≥5% of patients with endometriosis or fibroids and thought to be potentially related in the guidelines11,12 to drug: asthenia, general pain, headache,b hot flashes/sweats,b nausea/vomiting, gastrointestinal disturbances,b edema, weight gain/loss, acne, joint disorder,b depression/emotional lability,b dizziness, decreased libido,b nervousness,b neuromuscular disorders,b paresthesias, skin reactions, breast changes/tenderness/pain,b vaginitis.29
AC C
Leuprolide29
M AN U
SC
RI PT
Table 1. Available Endocrine and Targeted Agents for Hormone Receptor (HR)-Positive Advanced Breast Cancer (ABC)a Class/Mechanism of Action Luteinizing hormone-releasing hormone analogues Agents Indications Adverse Events (AEs) 28 Goserelin The AE profile was similar for women treated for • Use in the palliative treatment of advanced breast cancer, dysfunctional uterine bleeding, or breast cancer in premenopausal and endometriosis and included (>20%): hot flushes, perimenopausal women headache, sweating, acne, emotional lability, depression, decreased libido, vaginitis, breast atrophy, seborrhea, and peripheral edema.
35
ACCEPTED MANUSCRIPT Endocrine Management of ABC
RI PT
AEs MBC: increased bone and tumor pain along with local disease flare have occurred, which are sometimes associated with a good tumor response. Patients with increased bone pain may require additional analgesics. Patients with soft tissue disease may have sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions.
Toremifene31
•
AC C
EP
TE D
M AN U
SC
Selective estrogen-receptor modulators (SERMs) Agents Indications Tamoxifen30 • Metastatic breast cancer (MBC) in women and men • Adjuvant treatment of breast cancer – Treatment of node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation – Treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation
The treatment of MBC in postmenopausal women with estrogen receptor (ER)-positive or ER-unknown tumors
36
When they occur, the bone pain or disease flare is evident shortly after starting tamoxifen and generally subsides rapidly. In patients treated with tamoxifen for MBC, the most frequent AE was hot flashes. Other AEs seen infrequently were hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, lightheadedness, headache, hair thinning and/or partial hair loss, and vaginal dryness. Most common adverse reactions are hot flashes, sweating, nausea and vaginal discharge.
ACCEPTED MANUSCRIPT Endocrine Management of ABC
RI PT
AEs In the advanced breast cancer studies, the most common (occurring with an incidence of >10%) AEs occurring in women taking anastrozole included hot flashes, nausea, asthenia, pain, headache, back pain, bone pain, increased cough, dyspnea, pharyngitis, and peripheral edema.
The most common adverse reactions (>20%) were hot flashes, arthralgia; flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, bone pain, and musculoskeletal.
AC C
EP
TE D
M AN U
SC
Third-generation aromatase inhibitors (AIs) Nonsteroidal AIs Agents Indications 32 Anastrozole • Adjuvant treatment of postmenopausal women with HR-positive early breast cancer • First-line treatment of postmenopausal women with HR-positive or HR-unknown locally advanced breast cancer or MBC • Treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy Letrozole33 • Adjuvant treatment of HR-positive earlystage breast cancer • Extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy • First- and second-line treatment of postmenopausal women with HR-positive or HR-unknown advanced breast cancer Steroidal AIs Agents Indications 34 Exemestane • Adjuvant treatment of postmenopausal women with ER-positive early-stage breast cancer who have received 2 to 3 years of tamoxifen and are switched to exemestane for completion of a total of 5 consecutive years of adjuvant hormonal therapy • The treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy 37
AEs Advanced breast cancer: Most common AEs were mild to moderate and included hot flashes, nausea, fatigue, increased sweating, and increased appetite.
ACCEPTED MANUSCRIPT Endocrine Management of ABC
RI PT
AEs The most common adverse reactions occurring in ≥5% of patients receiving fulvestrant 500 mg were injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation. Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX patients and were not dose-dependent.
Indications Approved in combination with paclitaxel for first-line treatment of HER2-overexpressing MBC, and as a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease
EP
TE D
•
AC C
TARGETED AGENTS HER2-targeted antibody Agents Trastuzumab36
M AN U
SC
Selective estrogen-receptor degrader (SERD) Agents Indications Fulvestrant35 • HR-positive MBC in postmenopausal women with disease progression following antiestrogen therapy • HR-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with palbociclib in women with disease progression after endocrine therapy.
38
AEs MBC: Most common AEs (incidence ≥10%) were fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash.
ACCEPTED MANUSCRIPT Endocrine Management of ABC
•
Most common AEs (incidence ≥10%) were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, peripheral neuropathy, decreased appetite, mucosal inflammation, asthenia, vomiting, anemia, peripheral edema, myalgia, nail disorder headache, stomatitis, pyrexia, dysgeusia, leukopenia, upper respiratory tract infection, arthralgia, constipation, increased lacrimation, dyspnea, pruritus, febrile neutropenia, insomnia, dizziness, nasopharyngitis, dry skin.
EP
Indications • Postmenopausal women with advanced HR-positive/HER2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole
AC C
mTOR inhibitor Agents Everolimus38
TE D
M AN U
SC
•
Use in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive MBC who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease Use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either >2 cm in diameter or node-positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival.
RI PT
Pertuzumab37
39
AEs Most common AEs (incidence ≥10%) were stomatitis, infections, rash, diarrhea, fatigue, decreased appetite, nausea, cough, dysgeusia, weight decreased, arthralgia, headache, dyspnea, edema peripheral, pneumonitis, vomiting, epistaxis, pyrexia, constipation, hyperglycemia, back pain, insomnia, pruritus, asthenia, dry mouth, and alopecia.
ACCEPTED MANUSCRIPT Endocrine Management of ABC
AC C
EP
TE D
M AN U
SC
RI PT
Cyclin-dependent kinase (CDK4/6) inhibitor Agents Indications AEs Palbociclib39 Most common adverse reactions (incidence ≥ • Indicated for the treatment of HRpositive/HER2-negative advanced or 10%) were neutropenia, leukopenia, infections, metastatic breast cancer in combination fatigue, nausea, anemia, stomatitis, headache, with letrozole as initial endocrine based diarrhea, thrombocytopenia, constipation, therapy in postmenopausal women, or alopecia, vomiting, rash, and decreased appetite. fulvestrant in women with disease progression following endocrine therapy. • The indication in combination with letrozole is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 40 Ribociclib • Indicated in combination with an aromatase Most common adverse reactions (incidence ≥20%) are neutropenia, nausea, fatigue, diarrhea, inhibitor as initial endocrine-based therapy leukopenia, alopecia, vomiting, constipation, for the treatment of postmenopausal headache, and back pain. women with HR-positive/HER2-negative advanced or metastatic breast cancer. a Note that AE rates should not be compared across studies because these were not head-to-head studies and rates selected as “most common” differed as well. b Possible effect of decreased estrogen.
40
ACCEPTED MANUSCRIPT Endocrine Management of ABC
AC C
EP
TE D
M AN U
SC
RI PT
Table 2. Phase 3 Trials of Endocrine Therapy in Postmenopausal Women With Hormone Receptor (HR)-Positive Recurrent or Advanced Breast Cancer (ABC): Efficacy Results Secondary Efficacy Treatments, Dose, Regimen Primary Efficacy Endpoint: Study/Patient Population Endpoints: (Arm 1 vs Arm 2) Results (Arm 1 vs Arm 2) Results (Arm 1 vs Arm 2) Trials in Patients Without Prior or Recent (Within 12 months) Endocrine Therapy Bonneterre et al 200041 Arm 1: anastrozole, Median time to progression Clinical benefit rate (CBR): (TTP): 8.2 vs 8.3 months 56.2% vs 55.5% • Postmenopausal women with 1 mg/day orally (hazard ratio [HR]=0.99; locally advanced or ABC Arm 2: tamoxifen, 20 mg/day 2-sided P=0.941) Overall survival (OS): not • No prior tamoxifen within orally reported (NR) 12 months Objective response rate • HR-positive or HR-unknown (ORR): 32.9% vs 32.6% tumors (2-sided P=0.787) Mouridsen et al 2001, 200342,43 Arm 1: letrozole, 2.5 mg/day Median TTP: 9.4 vs 6 months ORR: 32% vs 21% (P=0.002) (P<0.001) • Postmenopausal women with orally CBR: 50% vs 38% (P=0.004) locally advanced, Arm 2: tamoxifen, 20 mg/day locoregionally recurrent, or orally OS: 34 vs 30 months (P=NS) ABC • HR-positive or HR-unknown tumors Nabholtz et al 200044 Arm 1: anastrozole, Median TTP: 11.1 vs 5.6 CBR: 59% vs 46% months (2-sided P=0.005) (2-sided P=0.010) • Postmenopausal women with 1 mg/day orally locally advanced or ABC Arm 2: tamoxifen, 20 mg/day ORR: 21% vs 17% OS: NR • No prior tamoxifen within orally 12 months • HR-positive or HR-unknown tumors
41
ACCEPTED MANUSCRIPT Endocrine Management of ABC
CBR: 42.2% vs 36.1% (P=0.26)
AC C
EP
TE D
M AN U
SC
RI PT
Trials in Patients With HR-Positive Recurrent or ABC Who Progressed on Endocrine Therapy Monotherapy Osborne et al 200221 Arm 1: fulvestrant 250 mg TTP: 5.4 vs 3.4 months (HR=0.92 [95.14% CI, 0.74• Postmenopausal women with once monthly intramuscularly (IM) 1.14]; P=0.43) locally advanced or ABC that had progressed on adjuvant antiestrogen therapy or first- Arm 2: anastrozole 1 mg/day orally line therapy for advanced disease Howell et al 200245 Arm 1: fulvestrant 250 mg Median TTP: 5.5 vs 5.1 months (HR=0.98 [95.14% CI, • Postmenopausal women with once monthly IM 0.80-1.21]; P=0.84) locally advanced or ABC that Arm 2: anastrozole 1 mg/day had progressed on adjuvant antiestrogen therapy or first- orally line therapy for advanced disease • All patients had tumors with hormone sensitivity Paridaens et al 200846 Arm 1: exemestane, 25 Median PFS: 9.9 vs 5.8 months (P=0.028) • Postmenopausal women with mg/day orally locally recurrent inoperable Arm 2: tamoxifen, 20 mg/day PFS: (HR=0.84 [95% CI, 0.67or ABC 1.05]; log-rank P=0.121) • Prior tamoxifen therapy with orally 6-month recurrence-free interval allowed • No previous hormone therapy for ABC • HR-positive or HR-unknown
42
Median duration of response (DOR): 19.0 vs 10.8 months
CBR=44.6% vs 45.0% (P=0.85) Median DOR: 15.0 vs 14.5 months
ORR: 46% vs 31% (P=0.005) OS: not significant (NS)
ACCEPTED MANUSCRIPT Endocrine Management of ABC
ORR: 7.4% vs 6.7%; P=0.736 CBR: 32.2% vs 31.5%; P=0.853
RI PT
Median TTP: 3.7 months in both groups (HR=0.963 [95% CI, 0.819-1.133]; P=0.653)
OS: NR
M AN U
SC
Arm 2: exemestane 25 mg/day orally
Arm 1: fulvestrant 500 mg IM Median PFS: 6.5 vs 5.5 on days 0, 14, 28, then every months (HR=0.80 [95% CI, 4 weeks 0.68-0.94]; P=0.006)
TE D
Arm 2: fulvestrant 250 mg IM on days 0, 14, and 28, then every 4 weeks Arm 1: fulvestrant 500 mg IM on day 1; 250 mg on days 15, 29, then every 4 weeks plus anastrozole 1 mg/day orally
EP
Combination Therapy FACT Bergh et al 201250 • Postmenopausal women or premenopausal women receiving a gonadotropinreleasing hormone, with HRpositive breast cancer that relapsed after or during primary treatment • Patients on adjuvant AI had to be relapse-free for >1 year after treatment completion
Arm 1: fulvestrant 500 mg IM on day 0, 250 mg on days 14 and 28, then every 4 weeks
Median TTP: 10.8 vs 10.2 months (HR=0.99 [95% CI, 0.81-1.20]; P=0.91)
ORR: 9.1% vs 10.2%; P=0.795 CBR: 45.6% vs 39.6%; P=0.100 OS: 26.4 vs 22.3 months; nominal P=0.016 ORR: 31.8% vs 33.6%; P=0.76 CBR: 55.0 % vs 55.1%; P=0.99 Median OS: 37.8 vs 38.2 months; P=1.00
AC C
EFECT Chia et al 200847 • Postmenopausal women with locally advanced or ABC who had relapsed on treatment with (or within 6 months of discontinuation of) an adjuvant nonsteroidal AI or who had disease progression during treatment with a nonsteroidal AI CONFIRM Di Leo et al 2010, 201248,49 • Postmenopausal women with locally advanced or ABC who had progressed on prior endocrine therapy
Arm 2: anastrozole 1 mg/day orally
43
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Arm 1: fulvestrant 500 mg IM on day 1; 250 mg on days 14, 28, then every 4 weeks plus anastrozole 1 mg/day orally
BOLERO-2 Baselga et al 201252 • Postmenopausal women with ER-positive, HER2nonamplified advanced breast cancer refractory to prior nonsteroidal AI treatment PALOMA-2 Finn et al 201653 • Postmenopausal women with ER-positive/HER2-negative ABC
Arm 1: everolimus 10 mg/day orally plus exemestane 25 mg/day orally
Median PFS: 15.0 vs 13.5 months (HR=0.80 [95% CI, 0.68-0.94]; log-rank P=0.007)
SC
Arm 2: anastrozole 1 mg/day orally
Median PFS: 6.9 vs 2.8 months (HR=0.43 [95% CI, 0.35-0.54]; P<0.001)
ORR: 9.5% vs 0.4%; P<0.001
Median PFS: 24.8 vs 14.5 months (HR=0.58 [95% CI, 0.46-0.72]; P<0.001)
ORR: 42.1% vs 34.7%; P=0.031
M AN U
Arm 2: exemestane 25 mg/day orally
EP
TE D
Arm 1: palbociclib 125 mg/day orally for 3 weeks on, 1 week off plus letrozole 2.5 mg/day orally continuously
Median OS: 47.7 vs 41.3 months; log-rank P=0.05
RI PT
SWOG S0226 Mehta et al 201251 • Postmenopausal women with HR-positive ABC • Previously untreated for metastatic disease
AC C
Arm 2: matched placebo once-daily orally plus letrozole 2.5 mg/day orally every 28 days
44
OS: NR
CBR: 84.9% vs 70.3%; P<0.001
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Arm 1: palbociclib 125 mg/day orally for 3 weeks then 1 week off plus fulvestrant 500 mg IM every 14 days for 3 injections, then every 28 days
MONALEESA-2 Hortobagyi et al 201656 • Postmenopausal women with HR-positive/HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease.
Arm 1: ribociclib 600 mg/day on a 3-weekson, 1-week-off schedule plus letrozole 2.5 mg/day
Median PFS: 9.5 vs 4.6 months (HR=0.46 [95% CI, 0.36-0.59]; P<0.001)54
ORR: 10.4% vs 6.3%; P=0.16 CBR: 34.0% vs 19.0%; P<0.00155
RI PT
PALOMA-3 Cristofanilli et al 201654 Turner et al 201555 • Pre- or postmenopausal women with HER2negative/HR-positive ABC • Relapsed or progressed during prior endocrine therapy
M AN U
SC
Arm 2: matching placebo plus fulvestrant
AC C
EP
TE D
Arm 2: placebo plus letrozole
Median PFS was not reached in the ribociclib group (95% CI, 19.3 to not reached) vs 14.7 months (95% CI, 13.016.5) in the placebo group (HR=0.56; [95% CI, 0.430.72]; P=3.29×10−6 for superiority)
45
Overall response rate (ORR + complete response + partial response): 40.7% vs 27.5%; (P<0.001) CBR: 79.6% vs 72.8% (P<0.02)
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Median PFS: 8.2 vs 3.0 months (HR=0.71 [95% CI, 0.53-0.96]; P=0.019)
M AN U
Arm 1: letrozole 2.5 mg/day orally with lapatinib 1500 mg/day orally Arm 2: letrozole 2.5 mg/day
Median TTP: 14.1 vs 3.3 months (HR=0.67 [95% CI, 0.35-1.29]; P=0.23)
EP
TE D
Arm 1: letrozole 2.5 mg/day plus trastuzumab 4 mg/kg IV loading dose, then 2 mg/kg weekly until progression (trastuzumab subsequently allowed as a 6 mg/kg dose every 3 weeks following 8 mg/kg loading dose
AC C
Johnston et al 200958 • Postmenopausal women with HR-positive/HER2-positive ABC • No prior therapy for advanced or ABC allowed eLEcTRA Huober et al 201259 • Postmenopausal women with newly diagnosed HRpositive/HER2-positive ABC or locally advanced breast cancer • No prior treatment for ABC or locally advanced breast cancer
SC
RI PT
Trials of Combination Therapy in Postmenopausal Women With HR-Positive/HER2-Positive Recurrent or ABC TTP: 4.8 vs 2.4 months; TAnDEM Arm 1: anastrozole 1 mg/day Median PFS: 4.8 vs 2.4 months (HR=0.63 [95% CI, log rank P=0.007 Kaufman et al 200957 orally with trastuzumab, 0.47-0.84]; log rank P=0.002) • Postmenopausal women with 4 mg/kg intravenous (IV) on day 1, then 2 mg/kg weekly CBR(ITT): 42.7% vs 27.9%; HR-positive/HER2-positive P=0.026 until progression ABC • Prior endocrine treatment Arm 2: anastrozole 1 mg/day Median OS: 28.5 vs 23.9 allowed if begun up to 4 months; log rank P=0.325 weeks before randomization orally
Arm 2: letrozole 2.5 mg/day until disease progression
46
ORR: 28% vs 15%; P=0.021 CBR: 48% vs 29%; P=0.003 OS: 33.3 vs 32.3 months; P=0.113 ORR: 27% vs 13%; P=0.312 CBR: 65% vs 39%; P=0.064
ACCEPTED MANUSCRIPT Endocrine Management of ABC
Arm 2: fulvestrant plus anastrozole-matched placebo
Arm 1 vs Arm 2(HR=1.00 [95% CI, 0.83-1.21]; log-rank P=0.98)
Arm 3: 21.6 months (19.423.9)
Arm 3: oral exemestane 25 mg daily
Arm 2 vs. Arm 3 (HR=0.95 [95% CI, 0.79-1.14]; log-rank P=0.56)
Arm 1 vs. Arm 2 (HR=0.95 [95% CI, 0.76-1.17]; log-rank P=0.61)
M AN U
SC
RI PT
Median PFS: Arm 1: 4.4 months (95% CI, 3.4-5.4) Arm 2: 4.8 months (3.6-5.5) Arm 3: 3.4 months (3.0-4.6)
Median PFS: All patients: 4.7 vs 3.8 months (HR=1.04; 95% CI, 0.82-1.33; P=0.37)
Arm 2: fulvestrant (as above) plus placebo
HER2-negative: 4.1 vs 3.8 months (HR=1.00; 95% CI, 0.76-1.30)
TE D
Arm 1: fulvestrant 500 mg IM day 1; 250 mg days 15 and 28, then every 28 days; lapatinib 1500 mg/day orally
EP
CALGB 40302 Burstein et al 201461 • Postmenopausal women with stage III/IV breast cancer • ER- and/or PgR-positive • HER2-positive or negative • Previous endocrine treatment allowed, but no prior treatment with fulvestrant, lapatinib, erlotinib, cetuximab, or gefitinib
Median OS: Arm 1: 20.2 months (17.222.5)
Arm 1: fulvestrant 500 mg IM on day 1, followed by 250 mg doses on days 15 and 29, then every 28 days plus oral anastrozole 1 mg daily
AC C
SoFEA Johnston et al 201360 • Postmenopausal patients with HR-positive locally advanced or ABC (HER2positive, negative, or unknown) • Relapsed or progressed with locally advanced or metastatic disease on a nonsteroidal AI
HER2-positive: 5.9 vs 3.3 months (HR=1.23; 95% CI, 0.69-2.18)
47
Arm 2: 19.4 months (16.822.8)
Arm 2 vs. Arm 3 (HR=1.05 [0.84-1.29]; log-rank P=0.68) Median OS: 30 vs 26.4 months (HR=0.91; 95% CI, 0.68-1.21; P=0.25)
ACCEPTED MANUSCRIPT
RI PT
Recurrence during adjuvant AI
Palbociclib + letrozole Ribociclib + any AI
Palbociclib + fulvestrant
Alternatives
Alternatives
M AN U
First-line
SC
De novo HR+ ABC
Everolimus + Exemestane
EP
Second-line
TE D
• AI • Tamoxifen • Fulvestrant + AI
Alternatives
AC C
• Fulvestrant ± palbociclib • Al (steroidal) • Tamoxifen
Third-line
Any of the above, not previously used
• Different AI • Tamoxifen • Fulvestrant
Everolimus + Exemestane Alternatives • Fulvestrant ± palbociclib • Al (steroidal) • Tamoxifen (late relapse) Any of the above, not previously used