Endocrine treatment constitutes the therapeutic backbone for patients with oestrogen and/or progesterone receptor-positive breast cancer unless there is visceral crisis or suspected or known endocrine resistance. Whether all patients who are suitable for endocrine therapy should receive combination therapy or whether there remains a role for single-agent endocrine therapy is yet to be determined. Cancer biology (ESR1 mutational status) and disease pattern determine the choice of single-agent endocrine treatment. Possibly, patients with low disease burden, slow progression and presumed endocrine sensitivity might still be considered for single-agent endocrine therapy, whereas patients with more aggressive disease including visceral metastases might benefit from combination therapy. Improved guidance on selection and sequencing of treatments should become available once overall survival (OS) and progression-free survival (PFS) data have been reported from the ongoing trials in breast cancer, principally, FALCON (NCT01602380), PALOMA-2 (NCT01740427) and MONALEESA-2 (NCT01958021), which include different patient groups and, probably, different endocrine sensitivity.
Hormone receptor-positive advanced breast cancer, selective oestrogen receptor modulators, aromatase inhibitors, selective oestrogen receptor degrader, endocrine resistance, endocrine sensitivity
Peter Schmid declares personal fees from Pfizer, Boehringer, Bayer, Puma, Eisai, Celgene and Roche/Genetech.
Medical writing support, including preparation of the drafts under the guidance of the author, was provided by Catherine Amey and Janet Manson, Touch Medical Media.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
August 07, 2017 Accepted:
September 20, 2017 Published Online:
October 18, 2017
Peter Schmid, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London Charterhouse Square, London EC1M 6BQ, UK. E: firstname.lastname@example.org
The publication of this article was supported by AstraZeneca. The views and opinions expressed in the article are those of the authors and not necessarily those of AstraZeneca.
The majority (60–75%) of all breast cancers have oestrogen and/or progesterone receptors.1
Endocrine treatment constitutes the therapeutic backbone for patients with this cancer subtype
unless there is a visceral crisis or concern/proof of endocrine resistance,2 as recommended by
the third European School of Oncology (ESO)/European Society for Medical Oncology (ESMO)
international consensus guidelines for Advanced Breast Cancer (ABC 3)3 and the National
Comprehensive Cancer Network (NCCN) guidelines.4 Current endocrine therapy includes: selective
oestrogen receptor modulators, aromatase inhibitors, and selective oestrogen-receptor degraders
(Table 1), and the modes of action of these therapies are outlined in Figure 1. Not all patients have
a response to first-line endocrine therapy (primary or de novo resistance). Such resistance occurs
in approximately 40% of patients with hormone receptor (HR)-positive breast cancer, and even
patients who do respond eventually exhibit acquired resistance.5 Cytotoxic chemotherapy is also
considered a first-line treatment option in patients diagnosed with HR-positive breast cancer. The
decision for chemotherapy or endocrine therapy depends on a number of factors, outlined below,
and there is a wide variation in the use of these treatments.6
Several molecular mechanisms have been proposed to underlie endocrine resistance, including:
loss of oestrogen receptor expression; altered activity of oestrogen-receptor co-regulators;
deregulation of apoptosis and cell cycle signalling; hyperactive receptor tyrosine kinase; and
stress/cell kinase pathways.7 The oestrogen receptor may be activated in a ligand-independent
manner via intracellular signal transduction pathways mediated either by the phosphatidylinositol-
3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway,
(Figure 1) or the mitogen-activated protein kinase (MAPK) pathway which promotes oestrogen
receptor phosphorylation and subsequently, activation.8,9 In addition, mutations in the ESR1
gene have recently attracted attention as an important mechanism for endocrine resistance
in metastatic breast cancer (MBC). These mutations occur in approximately 20–40% of patients
with metastatic oestrogen receptor-positive disease who received endocrine therapies, with the
higher occurrence in more advanced patients.10 Clustered in a ‘hotspot’ within the ligand-binding
domain (LBD) of the oestrogen receptor, these mutations lead to ligand-independent oestrogen
receptor activity that promotes tumour growth, and partial resistance to endocrine therapy, and
potentially enhanced metastatic capacity.10 The purpose of this article is to provide a concise
overview of endocrine therapeutic strategies for MBC, including studies with cohorts in first-line
therapy, second-line and beyond.
Tamoxifen, first described in the treatment of advanced breast cancer
in 1971,11 is the oldest selective oestrogen receptor modulator in clinical
use. In the 1990s, tamoxifen became standard first-line treatment based
on randomised, controlled trials, demonstrating comparable efficacy to
megestrol acetate or aminoglutethimide, but with superior tolerability.
Subsequently, tamoxifen was replaced by third-generation aromatase
inhibitors (letrozole, anastrozole, exemestane), which have demonstrated
3–4 months improvement in progression-free survival (PFS) in a range of
randomised, controlled trials, for example, in postmenopausal women
with oestrogen synthesis occurring mainly in peripheral tissues, but do
not benefit in overall survival (OS) (Table 1).12-16
Fulvestrant is a selective oestrogen receptor degrader that blocks
oestrogen receptor dimerisation and DNA binding, inhibiting nuclear
translocation while increasing turnover of the oestrogen receptor
(Figure 1). This leads to inhibition of oestrogen signalling via a reduction
of oestrogen receptor expression and accelerated oestrogen receptor
degradation.17 A multicentre, double-blind, randomised trial, in patients
with metastatic/locally advanced breast cancer comparing treatment
with fulvestrant (250 mg/month) versus tamoxifen (20 mg/day) found no
significant difference between fulvestrant and tamoxifen for the primary
end point of time to progression (TTP).18 Similarly, in a double-blind,
randomised trial comparing the efficacy and tolerability of fulvestrant
versus anastrozole in postmenopausal women with advanced breast
cancer progressing on prior endocrine therapy, fulvestrant was found to
be at least as effective as anastrozole, with efficacy endpoints slightly
Initial investigation of fulvestrant in breast cancer used a dose of 250 mg,
which the latest evidence suggests is suboptimal. Whereas fulvestrant
250 mg is sufficient to competitively inhibit binding of oestradiol to
the oestrogen receptor, oestrogen receptor downregulation is a dosedependent
process.20 At this dose, inhibition of oestrogen receptor
transcription may occur but with incomplete oestrogen receptor
degradation, i.e., so that both mechanisms of action of fulvestrant are
not being utilised fully. This might explain why initial trials investigating fulvestrant at the 250 mg dose showed only comparable efficacy to
anastrozole or tamoxifen.18,19 The open-label, randomised, phase III
Fulvestrant and Anastrozole Combination Therapy (FACT) trial found
no clinical advantage with the combination of fulvestrant 250 mg plus
anastrozole versus anastrozole alone.21 In contrast, the Southwest
Oncology Group (SWOG), in another open-label, randomised, phase
III trial, reported results favouring this combination approach over
anastrozole alone (Table 2).22 In this study, among women who had not
received prior tamoxifen therapy, the median PFS was 12.6 months with
anastrozole alone versus 17.0 months with fulvestrant plus anastrozole
(hazard ratio, 0.74; 95% confidence interval [CI], 0.59–0.92; p=0.006),
suggesting an increased clinical benefit in patients who were endocrine
therapy-naïve. A potential drug interaction has also been reported with
fulvestrant plus anastrozole, resulting in a decrease in trough anastrozole
concentration in patients in this study.23
Further supporting the effect of fulvestrant dose on efficacy, fulvestrant
500 mg/month versus 250 mg/month was compared in the Comparison
of Faslodex in Recurrent or MBC (CONFIRM), a randomised, doubleblind,
phase III trial.24 Fulvestrant 500 mg was associated with a 19%
reduction in the risk of death and a 4.1 month difference in median
OS compared with fulvestrant 250 mg (Median OS 26.4 months versus
22.3 months, respectively; hazard ratio, 0.81; 95% CI, 0.69–0.96; nominal
p=0.02). Fulvestrant 500 mg regimens therefore offer the possibility of greater antitumour activity than the 250 mg regimen.25,26 Comparison
of the fulvestrant high-dose 500 mg regimen versus anastrozole in the
Fulvestrant fIRst-line Study comparing endocrine Treatments (FIRST) trial
showed a 34% reduction in the risk of progression in patients treated
with fulvestrant (hazard ratio, 0.66; 95% CI, 0.47–0.92; p=0.01).27
To investigate further the potential benefits of fulvestrant 500 mg/
month, and expand upon earlier data suggesting an increased clinical
benefit for fulvestrant in patients who were endocrine therapy naïve,22
the Fulvestrant and AnastrozoLe COmpared in hormonal therapy-
Naïve advanced breast cancer (FALCON) first-line therapy cohort only
randomised, double-blind, multicentre phase III trial was initiated.28 In
this study, there was a statistically significant 21% reduction in the risk
of disease progression or death in women with HR-positive advanced
breast cancer who had been treated with fulvestrant 500 mg (n=230)
compared with those who had received anastrozole 1 mg/day (n=232).
The median PFS was 16.6 months with fulvestrant versus 13.8 months
with anastrozole (hazard ratio, 0.797; 95% CI, 0.637–0.999; p=0.0486).29
Subgroup analysis showed improved PFS in fulvestrant-treated patients
whose disease had not spread to the liver or lungs at baseline, indicating
that fulvestrant would be a particularly advantageous option for patients
with non-visceral disease whereas, for patients with visceral disease,
outcomes were similar.
1. Cancer.Net. Available from: www.cancer.net/cancer-types/
breast-cancer/overview (accessed 21 September 2017).
2. Hammond ME, Hayes DF, Dowsett M, et al., American Society
of Clinical Oncology/College of American Pathologists
guideline recommendations for immunohistochemical testing
of estrogen and progesterone receptors in breast cancer
(unabridged version), Arch Pathol Lab Med, 2010;134:e48–72.
3. Cardoso F, Costa A, Senkus E, et al., 3rd ESO-ESMO
international consensus guidelines for Advanced Breast Cancer
(ABC 3), Breast, 2017;31:244–59.
4. National Comprehensive Cancer Network (NCCN) Clinical
Practice Guidelines in Oncology. Breast Cancer version 2/, 2016.
available at: www.nccn.org/professionals/physician_gls/pdf/
breast.pdf (accessed 3 October 2017).
5. Angus L, Beije N, Jager A, et al., ESR1 mutations: Moving
towards guiding treatment decision-making in metastatic
breast cancer patients, Cancer Treat Rev, 2017;52:33–40.
6. DeVita VT Jr., Lawrence TS, Rosenberg SA, DeVita, Hellman, and
Rosenberg’s Cancer: Principles and Practice of Oncology, 8th
edn., Philadelphia: PA Lippincott Williams & Wilkins and Wolters
7. Giuliano M, Schifp R, Osborne CK, et al., Biological mechanisms
and clinical implications of endocrine resistance in breast
cancer, Breast, 2011;20 Suppl 3:S42–9.
8. McGlynn LM, Tovey S, Bartlett JM, et al., Interactions between
MAP kinase and oestrogen receptor in human breast cancer,
Eur J Cancer, 2013;49:1176–86.
9. Osborne CK, Schiff R, Mechanisms of endocrine resistance in
breast cancer, Annu Rev Med, 2011;62:233–47.
10. Jeselsohn R, Buchwalter G, De Angelis C, et al., ESR1
mutations-a mechanism for acquired endocrine resistance in
breast cancer, Nat Rev Clin Oncol, 2015;12:573–83.
11. Cole MP, Jones CT, Todd ID, A new anti-oestrogenic agent in
late breast cancer. An early clinical appraisal of ICI46474, Br J
12. Bonneterre J, Buzdar A, Nabholtz JM, et al., Anastrozole is
superior to tamoxifen as first-line therapy in hormone receptor
positive advanced breast carcinoma, Cancer, 2001;92:2247–58.
13. Bonneterre J, Thurlimann B, Robertson JF, et al., Anastrozole
versus tamoxifen as first-line 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;18:3748–57.
14. Lonning PE, Eikesdal HP, Aromatase inhibition 2013: clinical
state of the art and questions that remain to be solved, Endocr
Relat Cancer, 2013;20:R183–201.
15. Mouridsen HT, Aromatase inhibitors in advanced breast cancer,
Semin Oncol, 2004;31:3–8.
16. 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
17. Osborne CK, Wakeling A, Nicholson RI, Fulvestrant: an
oestrogen receptor antagonist with a novel mechanism of
action, Br J Cancer, 2004;90 Suppl 1:S2–6.
18. Howell A, Robertson JF, Abram P, et al., Comparison of
fulvestrant versus tamoxifen for the treatment of advanced
breast cancer in postmenopausal women previously untreated
with endocrine therapy: a multinational, double-blind,
randomized trial, J Clin Oncol, 2004;22:1605–13.
19. 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,
20. Robertson JF, Nicholson RI, Bundred NJ, et al., Comparison
of the short-term biological effects of 7alpha-[9-(4,4,5,5,5-
(Faslodex) versus tamoxifen in postmenopausal women
with primary breast cancer, Cancer Res, 2001;61:6739–46.
21. Bergh J, Jonsson PE, Lidbrink EK, et al., FACT: an open-label
randomized phase III study of fulvestrant and anastrozole in
combination compared with anastrozole alone as first-line
therapy for patients with receptor-positive postmenopausal
breast cancer, J Clin Oncol, 2012;30:1919–25.
22. Mehta RS, Barlow WE, Albain KS, et al., Combination
anastrozole and fulvestrant in metastatic breast cancer, N Engl
J Med, 2012;367:435–44.
23. Hertz DL, Barlow WE, Kidwell KM, et al., Fulvestrant decreases
anastrozole drug concentrations when taken concurrently by
patients with metastatic breast cancer treated on SWOG study
S0226, Br J Clin Pharmacol, 2016;81:1134–41.
24. 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,
25. 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;133:237–46.
26. Robertson JF, Fulvestrant (Faslodex) -- how to make a good
drug better, Oncologist, 2007;12:774–84.
27. 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,
28. Ellis MJ, Bondarenko I, Trishkina E, et al., FALCON: A phase
III randomised trial of fulvestrant 500 mg vs. anastrozole for
hormone receptor-positive advanced breast cancer, Annals of
29. 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.
30. Thangavel C, Dean JL, Ertel A, et al., Therapeutically activating
RB: reestablishing cell cycle control in endocrine therapyresistant
breast cancer, Endocr Relat Cancer, 2011;18:333–45.
31. 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.
32. Kim S, Loo A, Chopra R, et al., LEE011: An orally bioavailable,
selective small molecule inhibitor of CDK4/6– Reactivating Rb
in cancer, Presented at: Proceedings of the AACR-NCI-EORTC
International Conference: Molecular Targets and Cancer
Therapeutics; Boston, MA Oct 19–23 October, 2013, Abstr #PR02.
33. Miller TW, Hennessy BT, Gonzalez-Angulo AM, et al.,
Hyperactivation of phosphatidylinositol-3 kinase promotes
escape from hormone dependence in estrogen receptorpositive
human breast cancer, J Clin Invest, 2010;120:2406–13.
34. Xu H, Yu S, Liu Q, et al., Recent advances of highly selective
CDK4/6 inhibitors in breast cancer, J Hematol Oncol, 2017;10:97.
35. 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 receptorpositive,
HER2-negative, advanced breast cancer (PALOMA-1/
TRIO-18): a randomised phase 2 study, Lancet Oncol,
36. Finn RS, Martin M, Rugo HS, et al., Palbociclib and Letrozole in
Advanced Breast Cancer, N Engl J Med, 2016;375:1925–36.
37. Verma S, Bartlett CH, Schnell P, et al., Palbociclib in Combination
With Fulvestrant in Women With Hormone Receptor-Positive/
HER2-Negative Advanced Metastatic Breast Cancer:
Detailed Safety Analysis From a Multicenter, Randomized,
Placebo-Controlled, Phase III Study (PALOMA-3), Oncologist,
38. 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;17:425–39.
39. 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,
40. Hortobagyi GN, Stemmer SM, Burris HA et al., First-line
ribociclib + letrozole for postmenopausal women with
hormone receptor-positive (HR+), HER2-negative (HER2–),
advanced breast cancer (ABC), Presented at: European Society
for Medical Oncology (ESMO), Copenhagen, Denmark, 8–11
October, 2016, Abstract 1038.
41. Fasching PAJ, Pivot X, Martin M, et al., Phase III study of
ribociclib (LEE011) plus fulvestrant for the treatment of
postmenopausal patients with hormone receptor-positive
(HR+), human epidermal growth factor receptor 2-negative
(HER2–) advanced breast cancer (aBC) who have received no or
only one line of prior endocrine treatment (ET): MONALEESA-3,
Presented at: 2016 American Society Of Clinical Oncology
(ASCO) Annual Meeting, Chicago, IL, US, 3–7 June, Abstract
42. Gelbert LM, Cai S, Lin X, et al., Preclinical characterization of
the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/
independent anti-tumor activities alone/in combination with
gemcitabine, Invest New Drugs, 2014;32:825–37.
43. Sledge GW Jr, Toi M, Neven P, et al., MONARCH 2: Abemaciclib
in combination with fulvestrant in women with HR+/HER2-
advanced breast cancer who had progressed while receiving
endocrine therapy, J Clin Oncol, 2017;35:2875–84.
44. Di Leo A, Toi M, Campone M, et al., MONARCH 3: Abemaciclib
as initial therapy for patients with HR+/HER2- advanced breast
cancer, Presented at: ESMO 2017 Congress, Madrid, Spain, 8–12
September 2017, Abstract #236O_PR.
45. LoPiccolo J, Blumenthal GM, Bernstein WB, et al., Targeting the
PI3K/Akt/mTOR pathway: effective combinations and clinical
considerations, Drug Resist Updat, 2008;11:32–50.
46. Zardavas D, Fumagalli D, Loi S, Phosphatidylinositol 3-kinase/
AKT/mammalian target of rapamycin pathway inhibition: a
breakthrough in the management of luminal (ER+/HER2-)
breast cancers?, Curr Opin Oncol, 2012;24:623–34.
47. Lau CE, Tredwell GD, Ellis JK, et al., Metabolomic
characterisation of the effects of oncogenic PIK3CA
transformation in a breast epithelial cell line, Sci Rep,
48. Yu K, Toral-Barza L, Discafani C, et al., mTOR, a novel target
in breast cancer: the effect of CCI-779, an mTOR inhibitor,
in preclinical models of breast cancer, Endocr Relat Cancer,
49. Wolff AC, Lazar AA, Bondarenko I, et al., Randomized phase III
placebo-controlled trial of letrozole plus oral temsirolimus as
first-line endocrine therapy in postmenopausal women with
locally advanced or metastatic breast cancer, J Clin Oncol,
50. Baselga J, Campone M, Piccart M, et al., Everolimus in
postmenopausal hormone-receptor-positive advanced breast
cancer, N Engl J Med, 2012;366:520–9.
51. 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;30:870–84.
52. Piccart M, Hortobagyi GN, Campone M, et al., Everolimus
plus exemestane for hormone-receptor-positive, human
epidermal growth factor receptor-2-negative advanced breast
cancer: overall survival results from BOLERO-2, Ann Oncol,
53. Hortobagyi GN, Chen D, Piccart M, et al., Correlative Analysis
of Genetic Alterations and Everolimus Benefit in Hormone
Receptor-Positive, Human Epidermal Growth Factor Receptor
2-Negative Advanced Breast Cancer: Results From BOLERO-2,
J Clin Oncol, 2016;34:419–26.
54. Royce M, Villanueva C, Ozguroglu M, et al., BOLERO-4: Phase 2
trial of first-line everolimus (EVE) plus letrozole (LET) in estrogen
receptor–positive (ER+), human epidermal growth factor
receptor 2–negative (HER2−) advanced breast cancer (BC),
Ann Oncol, 2016;27:222O.
55. Krop IE, Mayer IA, Ganju V, et al., Pictilisib for oestrogen
receptor-positive, aromatase inhibitor-resistant, advanced
or metastatic breast cancer (FERGI): a randomised, doubleblind,
placebo-controlled, phase 2 trial, Lancet Oncol,
56. Baselga J, Im S-A, Iwata H, et al., PIK3CA status in circulating
tumor DNA predicts efficacy of buparlisib plus fulvestrant in
postmenopausal women with endocrine-resistant HER+/HER2-
advanced breast cancer: First results from the randomized,
phase III BELLE-2 trial, Presented at: 2015 San Antonio Breast
Cancer Symposium, San Antonio, TX, US, 11 December 2015,
57. Di Leo A, Seok Lee K, Ciruelos E, et al., BELLE-3: A Phase III
study of buparlisib + fulvestrant in postmenopausal women
with HR+, HER2-, aromatase inhibitor-treated, locally advanced
or metastatic breast cancer, who progressed on or after mTOR
inhibitor-based treatment. Presented at: 2015 San Antonio
Breast Cancer Symposium, San Antonio, TX, US, 11 December
58. 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;34:2961–8.
59. Spoerke JM, Gendreau S, Walter K, et al., Heterogeneity and
clinical significance of ESR1 mutations in ER-positive metastatic
breast cancer patients receiving fulvestrant, Nat Commun,
60. 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;20:1757–67.
61. Li S, Shen D, Shao J, et al., Endocrine-therapy-resistant ESR1
variants revealed by genomic characterization of breastcancer-
derived xenografts, Cell Rep, 2013;4:1116–30.
62. Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, et al., D538G
mutation in estrogen receptor-alpha: A novel mechanism for
acquired endocrine resistance in breast cancer, Cancer Res,
63. Robinson DR, Wu YM, Vats P, et al., Activating ESR1 mutations
in hormone-resistant metastatic breast cancer, Nat Genet,
64. Toy W, Shen Y, Won H, et al., ESR1 ligand-binding domain
mutations in hormone-resistant breast cancer, Nat Genet,
65. 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;33:3781–7.
66. 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;19:2596–606.
67. 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,
68. Robertson JF, Llombart-Cussac A, Rolski J, et al., Activity of
fulvestrant 500 mg versus anastrozole 1 mg as first-line
treatment for advanced breast cancer: results from the FIRST
study, J Clin Oncol, 2009;27:4530–5.
69. Di Leo A, Jerusalem G, Petruzelka L, et al., Final overall survival:
fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial,
J Natl Cancer Inst, 2014;106:djt337.
70. 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 receptorpositive,
advanced breast cancer: results from EFECT, J Clin
71. 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,
72. Turner NC, Ro J, Andre F, et al., Palbociclib in Hormone-
Receptor-Positive Advanced Breast Cancer, N Engl J Med,