Review

Oncology Received: August 10, 2016

Accepted after revision: May 4, 2017
DOI: 10.1159/000477404
Published online: June 15, 2017

Optimizing Quality of Life in Patients with

Hormone Receptor-Positive Metastatic Breast
Cancer: Treatment Options and Considerations
Pavani Chalasani
University of Arizona Cancer Center, Tucson, AZ, USA

Keywords crucial. This article surveys data relevant to the use of endo-
Quality of life · Metastatic breast cancer · Treatment crine therapy in the setting of hormone receptor-positive
options · Management strategies · Hormonal or endocrine metastatic breast cancer, including key clinical evidence re-
therapy garding approved therapies and the impact of these thera-
pies on patient quality of life. © 2017 S. Karger AG, Basel

Abstract
The treatment landscape for hormone receptor-positive
metastatic breast cancer continues to evolve as the molecu- Current Challenges in Metastatic Breast Cancer
lar mechanisms of this heterogeneous disease are better un-
derstood and targeted treatment strategies are developed. Although metastatic breast cancer (MBC) is consid-
Patients are now living for extended periods of time with this ered incurable, improvements in treatment have resulted
disease as they progress through sequential lines of treat- in more effective disease control. Death rates from breast
ment. With a rapidly expanding therapeutic armamentari- cancer (BC) have declined since 1989 [1], and among
um, the prevalence of metastatic breast cancer patients with more than 3 million survivors of BC in the United States
prolonged survival is expected to increase, as is the duration (US), more than 155,000 patients are living with MBC
of survival. Practice guidelines recommend endocrine ther- [2]. Indeed, data demonstrate statistically and clinically
apy alone as first-line therapy for the majority of patients meaningful improvements in outcome measures such as
with metastatic hormone receptor-positive, human epider- progression-free survival (PFS) and overall survival with-
mal growth factor receptor 2-negative breast cancer. The ap- in some MBC patient subpopulations, including de novo
proval of new agents and expanded combination options MBC, hormone receptor-positive (HR-positive), and hu-
has extended their use beyond first line, but endocrine ther- man epidermal growth factor receptor 2-positive (HER2-
apy is not used as widely in clinical practice as recommend- positive) disease [3–5]. A key management goal and con-
ed. As all treatments are palliative, even as survival is pro- sideration when selecting treatment for patients with
longed, optimizing and maintaining patient quality of life is MBC is to maintain quality of life (QoL). Therefore, it is
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© 2017 S. Karger AG, Basel Dr. Pavani Chalasani

Univ. of California San Diego

University of Arizona Cancer Center

3838 N. Campbell Ave.
E-Mail [email protected]
Tucson, AZ 85719 (USA)
www.karger.com/ocl
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E-Mail PChalasani @ uacc.arizona.edu
Table 1. Key recommendations and principles for treating HR-positive metastatic breast cancer (ASCO) [9]
First line Second line ≥Third line

No prior adjuvant ET (ET-naïve) Fulvestrant ± palbociclib

AI, nonsteroidal Al + everolimus
AI + fulvestrant Al (steroidal)
AI + palbociclib Tamoxifen
AI + ribociclib
Prior treatment with tamoxifen, early relapse
Al (nonsteroidal)
Fulvestrant
Al + palbociclib Fulvestrant ± palbociclib
Al + everolimus
Prior treatment with tamoxifen, late relapse Al (steroidal) Sequential therapy based on prior
Al (nonsteroidal) Tamoxifen exposure and response to ET
Al + fulvestrant
– Estradiol (2 mg 3 times per day)
Al + palbociclib
– Megestrol acetate fluoxymesterone
Tamoxifen
Reintroduction of prior therapy
Prior treatment with an Al, early relapse
Fulvestrant ± palbociclib
Al + everolimus
Al (steroidal) Depending on prior therapy:
Tamoxifen Fulvestrant ± palbociclib
Al + everolimus
Prior treatment with an Al, late relapse Al (steroidal)
Al (nonsteroidal) Tamoxifen
Fulvestrant
Al + palbociclib
Tamoxifen

AI, aromatase inhibitor; ASCO, American Society of Clinical Oncology; ET, endocrine therapy; HR, hormone receptor.

important to discern from among the growing number of Despite the combination of evidence and guidelines,
treatment options those that demonstrate clinical efficacy data suggest that a substantial number of patients with
yet maintain QoL [6, 7]. HR-positive/HER2-negative MBC do not receive the rec-
The majority of BCs (∼75%) are HR-positive (estro- ommended number of lines of ET before initiation of che-
gen receptor-positive [ER+] and/or progesterone recep- motherapy. A retrospective chart review of patients with
tor-positive) tumors [8]. Evidence-based guidelines es- recurrent or de novo HR-positive/HER2-negative MBC,
tablished by the American Society of Clinical Oncology treated at 13 oncology practices in the US, found that ET
recommend endocrine therapy (ET) as first-line treat- was used as first-line treatment in only 68%, and only
ment for HR-positive, HER2-negative MBC except when about 7% received 3 lines of ET before chemotherapy was
the patient is in visceral crisis (Table 1) [9]. The NCCN initiated [11]. Another analysis of 19,120 women with
guidelines also recommend that patients receive 3 se- HR-positive/HER2-negative MBC reported that only
quential lines of ET before chemotherapy, in part to avoid 60% received initial ET and only 26% received second-
toxicities and maintain QoL [6]. Recent data from a large line ET [12]. This article reviews approved and emerging
cross-sectional study (n = 2,352) of patients with HR-pos- ET options and available data regarding their impact on
itive MBC indicated that ET was associated with a sig- QoL in patients with HR-positive MBC, including those
nificantly (p < 0.05) better patient-reported QoL than with visceral disease.
chemotherapy, based on the Functional Assessment of
Cancer Therapy Breast (FACT-B) instrument and its
subscales [10].
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2 Oncology Chalasani
Univ. of California San Diego

DOI: 10.1159/000477404
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Table 2. Agents used in endocrine-based treatments of metastatic breast cancer (FDA-approved indications)

Agents Indications in breast cancer (FDA approved) General dosing and administration guidelines

SERMs
Tamoxifen [13] MBC in males and pre- and postmenopausal females 20-mg tablet once daily to 20-mg tablet
twice daily
Toremifene [14] MBC in postmenopausal women with ER-positive or 60-mg tablet once daily
unknown tumors
Aromatase inhibitors
Anastrozole [15] First-line treatment of postmenopausal women with 1-mg tablet once daily
HR-positive or HR unknown locally advanced cancer or MBC
Treatment of advanced breast cancer in postmenopausal
women with disease progression following tamoxifen therapy
Letrozole [16] First- and second-line treatment of postmenopausal women 2.5-mg tablet once daily; patients with
with HR-positive or unknown advanced breast cancer cirrhosis or severe hepatic impairment:
2.5 mg every other day
Exemestane [17] The treatment of advanced breast cancer in postmenopausal 25-mg tablet once daily after a meal
women whose disease has progressed following tamoxifen
therapy
SERD
Fulvestrant [18] Treatment of HR-positive MBC in postmenopausal women 500 mg intramuscularly into the buttocks
with disease progression following antiestrogen therapy slowly (1 – 2 min per injection) as two 5-mL
Treatment of HR-positive, HER2-negative advanced or injections, one in each buttock, on days 1,
metastatic breast cancer in combination with palbociclib in 15, 29, and once monthly thereafter
women with disease progression after endocrine therapy
mTOR inhibitor
Everolimus [19] Treatment of postmenopausal women with advanced 10 mg once daily with or without food
HR-positive, HER2-negative breast cancer in combination
with exemestane after failure of treatment with letrozole or
anastrozole
CDK4/6 inhibitor
Palbociclib [20] A kinase inhibitor indicated for the treatment of HR-positive, Recommended starting dose: 125 mg once
HER2-negative advanced or MBC in combination with an daily taken with food for 21 days followed
aromatase inhibitor as initial endocrine-based therapy in by 7 days off treatment
postmenopausal women or with fulvestrant in women with
disease progression following ET
Ribociclib [21] A kinase inhibitor indicated in combination with an Recommended starting dose: 600 mg orally
aromatase inhibitor as initial endocrine-based therapy for (three 200 mg tablets) taken once daily with or
the treatment of postmenopausal women with HR-positive, without food for 21 consecutive days
HER2-negative advanced or MBC followed by 7 days off treatment

CDK, cyclin-dependent kinase; ER, estrogen receptor; ET, endocrine therapy; FDA, US Food and Drug Administration; HER, hu-
man epidermal growth factor receptor; HR, hormone receptor; MBC, metastatic breast cancer; mTOR, mammalian target of rapamycin;
SERM, selective estrogen receptor modulator.

Endocrine-Based Treatment Options for HR-Positive ET. These agents and their US Food and Drug Adminis-
MBC tration (FDA)-approved indications, dosage, and admin-
istration guidelines are summarized in Table 2 [13–21].
Several ET options are currently approved for use in In real-world clinical oncology practice, the use of these
the US, including selective ER modulators (SERMs), a se- agents may vary somewhat from the labeled indications.
lective ER degrader (SERD), aromatase inhibitors (AIs), Tamoxifen is a nonsteroidal agent with potent anties-
androgens, low-dose and high-dose estrogen, progestins, trogenic effects that generate metabolites with up to 100
and targeted nonendocrine agents in combination with times greater affinity for ER than tamoxifen itself [13, 22,
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Optimizing Quality of Life in Patients Oncology 3

Univ. of California San Diego

with HR+ Metastatic Breast Cancer DOI: 10.1159/000477404

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23]. Tamoxifen metabolites compete with estrogen for al specified combination with letrozole [20]. In March
the ER ligand-binding domain, leading to ER dimeriza- 2017, a second CDK4/6 inhibitor, ribociclib (LEE011),
tion and subsequent binding to specific estrogen response was granted FDA approval as first-line treatment for HR-
elements, DNA alterations, and changes in gene tran- positive/HER2-negative advanced BC in combination
scription [22, 23]. The agonist or antagonist effects of with any AI [21].
tamoxifen have been reported to vary depending upon Persistent estrogen deprivation therapy has been hy-
the tissue [24]. pothesized to sensitize HR-positive, yet endocrine-resis-
Fulvestrant, the only available agent classified as a tant, BC to estradiol-induced tumoricidal effects termed
SERD, is an analog of 17β-estradiol that binds competi- the “estrogen paradox.” In preclinical models, exposure
tively to the ER with a similar affinity as estradiol, and to low-dose or high-dose estrogen after prolonged estro-
higher affinity than tamoxifen [25–27]. It inhibits recep- gen deprivation induced tumor regression [42, 43]. Clin-
tor dimerization, reduces translocation of receptor to the ical studies have reported clinical benefit rates between 26
nucleus, and accelerates degradation of the ER, account- and 55% among patients receiving low-dose or high-dose
ing for its pure antiestrogenic effects [25, 28]. estrogen after prolonged treatment with an AI [44–48].
The AIs inhibit aromatase, the enzyme responsible for Although estrogen therapy did not seem to reverse endo-
conversion of androgens into estrogen, resulting in de- crine resistance, there was evidence of clinical benefit
creased concentrations of serum estrogens in postmeno- with low-dose estradiol treatment by itself, suggesting it
pausal women. The class includes the nonsteroidal AIs, might be an option for treatment of hormone-refractory
anastrozole and letrozole, which bind reversibly to aro- MBC. These studies, however, are limited by their small
matase, and the steroidal agent, exemestane, which binds sample size, and larger studies are needed to confirm the
irreversibly [29]. results [44].
Three targeted nonendocrine therapies, everolimus,
palbociclib, and ribociclib, are now approved by the FDA Treatment in the Setting of Visceral Disease
[21, 30, 31] and/or the European Medicines Agency [32, Patients with bone as a single metastatic site demon-
33] for use in HR-positive/HER2-negative BC in combi- strate a better prognosis than those with visceral or both
nation with ET (Table 2) [19–21]. Their use is based on bone and visceral disease [49]. Visceral metastases, those
increased understanding of the molecular mechanisms of occurring in the soft internal organs of the body, includ-
ER signaling, mediated by both ligand-dependent and li- ing the lungs, heart, and organs of the digestive, excretory,
gand-independent pathways, and mechanisms of endo- reproductive, and circulatory systems, portend a poor
crine resistance [34–36]. The complex biology of ER sig- prognosis [2, 50]. One recent study of 886 patients re-
naling and mechanisms of endocrine resistance have ported that the intrinsic and histological subtypes of MBC
been reviewed comprehensively elsewhere [35, 37]. significantly correlate with the presence of visceral metas-
Everolimus is currently the only FDA-approved drug tases, which were detected in 48.3% of patients with sub-
for treatment of HR-positive/HER2-negative MBC that class luminal A (HR-positive/HER2-negative; grade 1 or
targets the mTOR pathway. Everolimus binds to the 2), in 57.5% with luminal-B (HR-positive/HER2-nega-
FKBP-12 protein, which subsequently binds mTOR to tive; grade 3), and in 68.1% with triple-negative BC and
form an inhibitory complex, resulting in inhibition of overexpressing HER2 [50]. The presence of visceral me-
mTOR signaling and tumor cell proliferation [19, 34]. tastases poses a major challenge to the selection of treat-
Cyclin-dependent kinases (CDKs; serine threonine ki- ments with optimal efficacy, minimal toxicity, and mini-
nases) are cell cycle regulators that may become dysregu- mal impact on QoL.
lated in cancer cells, resulting in unchecked tumor cell For patients with HR-positive MBC in visceral crisis,
proliferation [38–40]. During the cell cycle, cyclin D current NCCN guidelines recommend that chemothera-
binds to CDKs 4 and 6 to form a complex that phosphor- py may be considered as a first-line treatment option.
ylates retinoblastoma proteins (pRb), leading to their in- However, ET may still be used effectively in patients with
activation and the promotion of cell cycle progression. visceral disease, barring a visceral crisis, where a rapid re-
Inhibition of CDK4/6 blocks pRb hyperphosphorylation, sponse is required [6]. Evidence from key ET studies, in-
leading to G1 arrest in BC cells lines [38, 41]. Palbociclib, cluding efficacy data and sites of metastatic disease, is
an orally administered, FDA-approved selective CDK4/6 summarized in Table 3 [38, 51–60]. While bone is regard-
inhibitor targeting this pathway, is now approved for use ed as the most common site of distant spread in HR-pos-
in combination with an AI, whereas the previous approv- itive MBC [61], many ET studies in MBC have includ-
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4 Oncology Chalasani
Univ. of California San Diego

DOI: 10.1159/000477404
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 Table 3. Studies of endocrine-based therapies in women with HR-positive advanced and metastatic breast cancer

Study, phase, patient population Treatment Main metastatic sites at baseline, % of patients Median PFS/ Hazard ratio (95% CI), Median Hazard ratio (95% CI),
arms TTP, months p value OS, p value
bone visceral liver lung soft tissue months
or node/
nonvisceral

SoFEA study, phase 3, postmenopausal, HR+, Fulvestrant + 16 62 – – 22 4.8 F alone vs. F + A: 1.00 19.4 F + P alone vs. F + A: 0.95
MBC w/progression on NSAI (n = 723) [51]a placebo (0.83 – 1.21), p = 0.98 (0.76 – 1.17) p = 0.61
Fulvestrant + 15 57 – – 28 4.4 F alone vs. E alone: 0.95 20.2 F alone vs. E alone: 1.05
anastrozole (0.79 – 1.14), p = 0.56 (0.84 – 1.29) p = 0.68
Exemestane 13 58 – – 29 3.4 21.6
alone
SWOG study, phase 3, postmenopausal, HR+, Anastrozole 22.0 48.4 – – 29.6 13.5 0.80 (0.68 – 0.94) 41.3 0.81 (0.65 – 1.00)

with HR+ Metastatic Breast Cancer

w/previously untreated metastatic alone p = 0.007 p = 0.049

Optimizing Quality of Life in Patients

disease (n = 707) [52]a Fulvestrant + 21.5 51.9 – – 26.6 15.0 47.7
anastrozole
FACT study phase 3, postmenopausal or Anastrozole 27.7 48.4 15.6 26.6 – 10.2 0.99 (0.81 – 1.20) 38.2 1.00 (0.76 – 1.32)
premenopausal women receiving a gonado- alone p = 0.91 p = 1.00
tropin-releasing hormone agonist, HR+ Fulvestrant + 24.4 51.9 22.1 25.6 – 10.8 37.8
disease at first relapse after primary treatment anastrozole
of localized disease (n = 514) [53]a
TAMRAD study, phase 2, postmenopausal, Tamoxifen 79 (25 49 n.a. n.a. n.a. 4.5 0.54 (0.36 – 0.81) 32.9 0.45 (0.24 – 0.81)
HR+, HER2–, AI-resistant MBC (n = 111) alone bone only) p = 0.002 p = 0.007
[54] Tamoxifen + 76 (30 57 n.a. n.a. n.a. 8.6 Not
everolimus bone only) reached
BOLERO-2 study, phase 3, postmenopausal, Everolimus + 76 n.a. 33 29 n.a. 7.8 0.45 (0.38 – 0.54) 31.0 0.89 (0.73 – 1.10)
HR+, w/recurrence or progression on NSAI exemestane p < 0.001) p = 0.143
(n = 724) [55, 56] Exemestane + 77 n.a. 30 33 n.a. 3.2 26.6
placebo
PALOMA-1/TRIO-18 study, phase 2, post- Palbociclib + 20 44 n.a. n.a. n.a. 20.2 0.49 (0.32 – 0.75) n.a. –

Oncology
menopausal, ER+/HER2–, w/no systemic letrozole p = 0.004
treatment for advanced disease (n = 165) [38] Letrozole 15 53 n.a. n.a. n.a. 10.2 n.a.
alone
PALOMA-2 study, phase 3, postmenopausal, Palbociclib + 23 48 n.a. n.a. 52 (non- 24.8 0.58 (0.46 – 0.72) n.a. –
ER+/HER2–, w/no prior treatment for letrozole visceral) p < 0.001

DOI: 10.1159/000477404
advanced disease (n = 666) [57] Letrozole + 22 50 n.a. n.a. 51 (non- 14.5 n.a.
placebo visceral)
PALOMA 3 study, phase 3, pre/postmeno- Palbociclib + 22 59 37 29 Perito- 9.5 0.46 (0.36 – 0.59) n.a. –
pausal, HR+/HER2– MBC w/progression on fulvestrant neal: 1 p < 0.001
ET (n = 521) [58] 500 mg
Fulvestrant + 21 60 47 26 Perito- 4.6
placebo neal: 1
FALCON study, phase 3, postmenopausal, Fulvestrant 10 59 n.a. n.a. 29 16.6 0.797 (0.637 – 0.999) n.a. –
HR+, w/locally advanced or MBC and ET naïve 500 mg p = 0.049
(n = 462) [59] Anastrozole 10 51 n.a. n.a. 38 13.8 n.a. –

MONALEESA-2 study, phase 3, postmeno- Ribociclib + 74 59 n.a. n.a. n.a. 63.0 0.56 (0.43 – 0.72) n.a. –
pausal with locally confirmed, HR+/HER2– letrozole p < 0.001
recurrent or MBC w/no prior systemic Letrozole + 73 59 n.a. n.a. n.a. 42.2 n.a. –
treatment for advanced disease [60] placebo

A, anastrozole; AI, aromatase inhibitor; E, exemestane; ER+, estrogen-receptor-positive; ET, endocrine therapy; F, fulvestrant; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive;
MBC, metastatic breast cancer; n.a., not available; NSAI, nonsteroidal aromatase inhibitor; OS, overall survival; PFS, progression-free survival; SWOG, Southwest Oncology Group; TTP, time to progression; w/, with. a Used a
fulvestrant loading dose regimen (500 mg day 1, 250 mg day 14 or 15, then day 28/29, every 28 days thereafter; anastrozole, 1 mg oral daily; exemestane dose: 25 mg oral daily).

5
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ed patients with visceral and nonvisceral metastases. It is warming or rolling the product between the fingers, the
important that treating oncologists consider these data Z-track injection method, warm compresses, and topical
when selecting therapies for patients with visceral disease. anesthetics may also reduce pain and injection-site reac-
tions [66–68].
Loss of bone mineral density (BMD) is experienced
Safety and Tolerability Profiles of Endocrine-Based frequently by postmenopausal patients with MBC under-
Therapies in MBC going AI therapy, occurring at a 2- to 3-fold higher rate
than among healthy, age-matched, postmenopausal
Given that treatment of MBC remains palliative, with women, and is associated with a higher incidence of frac-
the goals of prolonging survival and optimizing QoL [62], tures [69]. Bone-targeting agents such as bisphospho-
consideration of the safety and tolerability of available nates and denosumab can help prevent loss of BMD and
regimens is paramount in treatment decision-making. improve QoL in patients being treated with AIs [69]. A
The safety profiles of approved endocrine-based thera- randomized, double-blind study comparing subcutane-
pies are well-characterized (Table 4) [13–21] and should ous injections of denosumab with placebo injections in
be evaluated in the context of individual disease-related women with BC found denosumab had a significant ef-
issues, personal preferences/needs, and QoL concerns. fect on BMD [70]. Another study in patients with BC and
Although the safety profiles of various endocrine agents bone metastases found monthly subcutaneous denosum-
are similar, they are not identical, and individuals may ab injections were superior to monthly intravenous zole-
tolerate one better than another. If one agent is not well- dronic acid treatments in delaying or preventing skeletal-
tolerated, a study with another is warranted. Safety and related events. Denosumab treatment also resulted in sig-
tolerability profiles of targeted drugs such as everolimus nificant benefit in bone morphology, reflected by greater
and palbociclib reflect their use as monotherapy and in suppression of bone turnover markers [71].
combination with other agents [63]. It is also important The frequencies of AEs reported in clinical studies for
to understand that for some individuals, extended PFS targeted agents used in endocrine-based treatments have
may ameliorate the experience of adverse events (AEs). been published in the literature, as well as in product’s
The results of one study indicated that evidence of re- prescribing information (for approved agents). However,
sponse to treatment or extended PFS contributed to a because of differences in study designs and patient popu-
higher perceived QoL [64]. lations, direct comparisons of the AE profiles of these
agents are not possible (except when clinical studies have
AEs Associated with ET and Endocrine-Based been comparative).
Therapies in Patients with HR-Positive MBC Interventions for managing AEs associated with dif-
Antiestrogen therapy is generally well-tolerated (Ta- ferent types of ET continue to be assessed. Stomatitis/oral
ble 4) and not generally associated with toxicities com- mucositis are among the most common AEs associated
mon to chemotherapeutic agents [24]. with everolimus therapy [19, 72]. In the BOLERO-2
As stated previously, SERMs can exert both estrogenic study, the incidence of all-grade stomatitis was 67% in the
and antiestrogenic effects depending on the tissue, and exemestane plus everolimus group [73]. In a study to
these differential effects influence the safety profiles. For evaluate 2 steroid-based mouth rinses, patients were ran-
example, SERMs such as tamoxifen are associated with an domized to receive a “miracle mouthwash” containing
increased risk of endometrial tumors, deep vein throm- benadryl, tetracycline, hydrocortisone, nystatin, and wa-
bosis, thromboembolic events, and uterine malignancies, ter (or another oral rinse containing prednisolone and
but may have protective effects on bone. Hot flashes, nau- alcohol) to prevent or ameliorate these oral symptoms.
sea, and bone, back, or musculoskeletal pain may be as- The incidence of stomatitis and related oral AEs (any
sociated with AIs and fulvestrant [15, 17, 18]. grade) during the first 12 weeks was 29 and 27.5% in the
A common AE associated with fulvestrant therapy is miracle mouthwash and prednisolone-based rinse
injection-site pain. Because fulvestrant is administered as groups, respectively [74]. The benefit of oral care inter-
a large volume (2 × 5 mL) injection, it may cause localized ventions is further supported by the BRAWO study, in
injection-site pain or reactions. In the CONFIRM study, which there was a lower (41.5%) incidence of stomatitis
13.6% of patients receiving fulvestrant 500 mg monthly among the first 1,300 documented patients, as 85.5% of
reported injection-site reactions [65]. These reactions stomatitis patients used at least one therapeutic interven-
may be ameliorated by alternating injection sites. Passive tion, including nondrug mouthwash solution, cooling, or
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Table 4. Most common adverse events associated with endocrine-based treatments in advanced or metastatic breast cancer

Agent AEs Warnings and precautions

Tamoxifen [13] Rates not stated: hot flashes; infrequent: hypercalcemia, Hypercalcemia, uterine malignancies, nonmalignant uterine
peripheral edema, distaste for food, pruritus vulvae, depression, effects, thromboembolic events (deep vein thrombosis, pulmonary
dizziness, lightheadedness, headache, hair thinning/partial hair embolism, stroke)
loss, vaginal dryness
Toremifene [14] >10%: hot flashes, sweating, nausea, vaginal discharge Boxed warning: prolongation of the QT interval and ventricular
tachycardia; not to be used in patients with congenital or acquired
QT prolongation, uncorrected hypokalemia or uncorrected
hypomagnesemia; drugs that prolong the QT interval and CYP3A4
inhibitors are to be avoided; hypercalcemia and tumor flare,
tumorigenicity, fetal harm may occur when administered to a
pregnant woman, use effective nonhormonal contraception
Anastrozole [15] >10%: hot flashes, nausea, asthenia, pain, headache, back pain, Increased incidence (compared with tamoxifen) of ischemic
bone pain, increased cough, dyspnea, pharyngitis, peripheral cardiovascular events in women with preexisting ischemic heart
edema disease
Letrozole [16] >10%: bone pain, hot flushes, back pain, dyspnea, nausea, Decreases in bone mineral density and increases in total
arthralgia, cough, fatigue; headache cholesterol; monitor for both; fatigue, dizziness and sleepiness
Exemestane [17] >10%: hot flushes; >3%: nausea, fatigue, increased sweating Decreases in bone mineral density, assessment of 25-hydroxy
vitamin D prior to start of aromatase inhibitor treatment should be
performed embryo-fetal toxicity
Fulvestrant [18] >10%: injection site pain; ≥5% (and clinically significant) Risk of bleeding; use with caution in patients with bleeding
nausea, bone pain, arthralgia, headache, back pain, fatigue, diatheses, thrombocytopenia, or anticoagulant use; reduce dose in
pain in extremity, hot flash, vomiting, anorexia, asthenia, hepatic impairment; potential for fetal harm; increased exposure in
musculoskeletal pain, cough, constipation patients with hepatic impairment; injection site reactions, embryo-
fetal toxicity; fulvestrant can interfere with estradiol measurement
by immunoassay, resulting in falsely elevated estradiol levels
Everolimus [19] ≥30%: stomatitis, infections, rash, fatigue, diarrhea, edema, Noninfectious pneumonitis, infections, angioedema, oral
abdominal pain, nausea, fever, asthenia, cough, headache, ulceration, renal failure, laboratory test alterations, vaccinations
decreased appetite (live vaccines), embryo-fetal toxicities, impaired wound healing
Palbociclib [20] ≥10%: neutropenia, infections, leukopenia, fatigue, nausea, Neutropenia, embryo-fetal toxicities
stomatitis, anemia, alopecia, diarrhea, thrombocytopenia,
rash, vomiting, decreased appetite, asthenia, and pyrexia
Ribociclib [21] ≥20%: neutropenia, nausea, fatigue, diarrhea, leukopenia, QT interval prolongation: monitor electrocardiograms (ECGs) and
alopecia, vomiting, constipation, headache, back pain electrolytes before initiation of treatment with ribociclib; repeat
ECGs at approximately day 14 of the first cycle and at the
beginning of the second cycle, and as clinically indicated; monitor
electrolytes at the beginning of each cycle for 6 cycles, and as
clinically indicated
Hepatobiliary toxicity: increases in serum transaminase levels have
been observed; perform liver function tests before initiating
treatment, and monitor every 2 weeks for the first 2 cycles, at the
beginning of each subsequent 4 cycles, and as clinically indicated

Rates cannot be compared among drugs or across studies because of differences in trial conditions, designs, and patient populations as well as the ways
in which data are presented. AEs, adverse events; MBC, metastatic breast cancer; SERM, selective estrogen-receptor modulator.

drug intervention [75]. In the SWISH study, the inci- Combination therapies evaluating palbociclib plus le-
dence of all-grade stomatitis was 21.2%, with use of a trozole (PALOMA-2), palbociclib plus fulvestrant (PA-
dexamethasone oral solution [76]. Therefore, it appears LOMA-3), and ribociclib plus letrozole (MONALEESA-
that appropriate oral care can prevent or partially amelio- 2) have been associated with neutropenia, leukopenia,
rate the occurrence of oral-related AEs. and anemia. In the PALOMA-2 study, the most common
grade 3 or 4 AEs for palbociclib plus letrozole versus pla-
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cebo plus letrozole were neutropenia (66.4%; 1.4%), leu- functional well-being, physical well-being, and BC sub-
kopenia (24.8%; 0%), anemia (5.4%; 1.8%), and fatigue scales of the questionnaire [65, 88–90]. In an early study
(1.8%; 0.5%) [57]. In the PALOMA-3 study, grade 3 or 4 of postmenopausal women with HR-positive MBC or lo-
AEs occurred in 73% of patients in the palbociclib plus cally advanced BC who had received no endocrine or cy-
fulvestrant group and 22% of patients in the placebo plus totoxic chemotherapy for advanced disease, or adjuvant
fulvestrant group [58]. The most common grade 3 or 4 ET within 12 months, fulvestrant 250 mg was compared
AEs for palbociclib plus fulvestrant versus placebo plus with tamoxifen 20 mg. No significant differences in QoL
fulvestrant were neutropenia (65%; 1%), anemia (3%; were detected, and the TOI remained constant over time,
2%), and leukopenia (28%; 1%) [58]. For the MONALEE- indicating that QoL did not deteriorate [88]. The QoL of
SA-2 study, grade 3 or 4 AEs in >10% of the patients for postmenopausal women with HR-positive MBC or local-
the ribociclib plus letrozole versus placebo plus letrozole ly advanced BC whose disease had progressed during ad-
groups were neutropenia (59.3%; 0.9%) and leukopenia juvant ET or first-line ET for advanced disease was evalu-
(21.0%; 0.6%) [60]. Therefore, management strategies ated in 3 studies. In two comparisons of fulvestrant 250
should consider these hematologic effects of therapy. mg with anastrozole 1 mg, similar mean TOI scores were
reported over the course of the study, indicating that re-
gardless of treatment, QoL was maintained up to the time
Patient QoL in ET Studies of disease progression [89, 90]. In the CONFIRM study,
the TOI score remained stable at approximately 60 in
As previously mentioned, because of improvements in both treatment groups throughout the duration of the
available treatment options and increasing understand- study [65]. The FALCON study compared fulvestrant
ing of the benefits of therapy sequencing, patients with with anastrozole in postmenopausal women with HR-
HR-positive MBC are living longer with their disease, positive locally advanced or MBC who had not received
making QoL a key priority when selecting treatments. previous ET. While fulvestrant 500 mg monotherapy is
Among the most frequently used QoL measures in clini- not yet approved for this patient population, early QoL
cal studies of ET in BC are the Functional Assessment of data have been reported and are consistent with reports
Cancer Therapy (FACT)-Breast questionnaire, compris- from earlier studies [91].
ing the FACT-General QoL instrument plus the BC sub-
scale; and the European Organization for Research and QoL with Endocrine-Based Targeted Combination
Treatment of Cancer Quality of Life Questionnaire-Core Therapy
30 (EORTC QLQ-C-30) [77, 78]. The validity, reliability, Everolimus Combinations
and relevance of these scales for patients with cancer have Endocrine-based treatments combine various ETs
been clearly demonstrated [78, 79]. Examples of assess- with targeted agents that may help overcome endocrine
ments in these QoL scales include the ability to perform resistance, allowing additional lines of ET-based treat-
physical activities; need for help with activities of daily ment and avoidance of cytotoxic chemotherapy that may
living; extent of symptoms such as pain, fatigue, weak- result in considerably more toxicities and provide no
ness, gastrointestinal issues, sleep disturbances, sexual overall survival advantage [92].
dysfunction, and degree of emotional and psychological In the phase 3 BOLERO 2 study, which compared
well-being and their impact on QoL [78–80]. Findings everolimus plus exemestane with exemestane plus pla-
from select clinical studies that included assessment of cebo in postmenopausal women with HR-positive MBC
patient QoL are summarized in Table 5 [65, 77, 81–86]. that had recurred or progressed on a nonsteroidal AI (Ta-
ble 3), QoL was measured using the EORTC-QLQ-30 [55,
QoL with ET Alone 77]. Time to definitive deterioration (TDD) in global
The efficacy and tolerability profiles of the most wide- health-related QoL was defined as a 5% decrease from
ly used ETs, such as tamoxifen, AIs, and fulvestrant, are baseline with no subsequent increase above this level,
well documented (Table 2). based on established criteria for minimally important dif-
Fulvestrant has been studied extensively in clinical ferences from a patient perspective. The median TDD for
studies as a single agent, as first- and second-line treat- a 5% change from baseline was 8.3 months (95% CI, 7.0–
ment, and in combination with other agents [87]. In ful- 9.7) in the everolimus + exemestane arm compared with
vestrant studies, QoL was assessed with the FACT-B us- 5.8 months (95% CI, 4.2–7.2) in the placebo + exemestane
ing the trial outcome index (TOI) [88], which evaluates arm. Despite a higher incidence of AEs in the combina-
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8 Oncology Chalasani
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DOI: 10.1159/000477404
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Table 5. Quality of life assessments of endocrine-based treatments

Source Intervention Treatment Sample QoL assessment Results/interpretation

line size

Endocrine monotherapy
Phase 3, Di Leo, Fulvestrant Second- 374 FACT-B, NR, NR; p = NS; QoL was similar in both arms at all study
CONFIRM [65] 250 mg line TOI visits
Fulvestrant 362
500 mg
Phase 3, Chia, Fulvestrant Second- 351 FACT-ES, The mean difference across both instruments was not
EFECT [81] Exemestane line 342 TOI significant, p = NS
Phase 3, Lemieux, Letrozole Second- 344 SF-36, No differences were seen between groups in mean change
MA.17R [82] Placebo or third- MENQoL scores for SF-36 PCS, SF-36 MCS, and the other 8 QoL
line 323 domains; patients randomized to letrozole reported worse
vasomotor symptoms (12 months p = 0.02, 36 months p =
0.03) and worse sexual functioning (12 months p = 0.01,
36 months p = 0.01); no differences observed in overall QoL
as measured by SF-36 no difference in MENQOL domains
Observational, Tamoxifen 66 SF-36 Lower PCS scores for AI than the no ET group at 12 months
Ganz, Mind-Body AI 60 (p = 0.05); no significant differences in MCS scores across
Study (MBS) [83] No ET 60 treatment groups
Combination therapy
Endocrine therapy Placebo + Second- 239 EORTC QLQ-C30 Baseline global health status scores were similar between
with mTOR inhibitors exemestane line treatment groups (64.7 vs. 65.3); median TDD in health-
Phase 3, Burris, (EXE) related QoL was 8.3 months for EVE + EXE vs. 5.8 months
BOLERO-2 [77] Everolimus 485 for placebo + EXE (hazard ratio: 0.74; p = 0.008); median
(EVE) + EXE TDD with EVE + EXE was 11.7 vs. 8.4 months for placebo +
EXE (hazard ratio: 0.80; p = 0.102); minimal important
difference = 10 points
Endocrine therapy Palbociclib + 444 FACT-B, No significant differences between 2 treatment arms for
with CDK4/6 inhibitors letrozole FACT-G, FACT-B (102 vs. 103), FACT G, TOI, and each of the
Phase 3, Rugo TOI subscale scores; palbociclib plus letrozole maintained HRQoL
PALOMA-2 [84] Letrozole + 222 in treatment-naïve postmenopausal women with ER+/
placebo HER2– MBC
Phase 3 Fulvestrant + Third- 174 EQ-5D, Global QoL was significantly higher for fulvestrant +
Turner/Harbeck, placebo line or EORTC QLQ-C30, palbociclib vs. fulvestrant + placebo (66.1 and 63.0,
PALOMA-3 [85, 86] greater EORTC QLQ-BR23 respectively; p = 0.031), but this was not clinically relevant;
Fulvestrant + 347 fulvestrant + palbociclib demonstrated significantly greater
palbociclib improvement from baseline in emotional functioning (2.7
vs. −1.9; p = 0.002); mean overall change from baseline in
QLQ-C30 score was −0.9 vs. −4.0 points; p = 0.03; differences
in EQ-5D (0.0037) were not clinically relevant

AI, aromatase inhibitor; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality-of-Life questionnaire; EORTC QLQ-
BR23, EORTC QLQ breast cancer module; ET, endocrine therapy; FACT-B, Functional Assessment of Cancer Therapy-Breast; FACT-ES, Functional
Assessment of Cancer Therapy-Endocrine Symptom; MCS, Short Form (36 Questions) of Health Survey, mental domain; MENQol, Menopause-Specific
Quality of Life Questionnaire; NR, not reported; NS, not significant; QoL, quality of life; PCS, Short Form (36 Questions) of Health Survey, physical domain;
SF-36, Short Form (36 Questions) of Health Survey; TOI, Trial Outcome Index; TTD, time to definitive deterioration.

tion arm, QoL analysis concluded that the treatment arm ceived prior treatment for advanced disease, were ran-
was associated with a longer TDD in global health-related domized to receive palbociclib plus letrozole or letrozole
QoL when compared with exemestane alone [77]. plus placebo [57]. The study also evaluated QoL as a sec-
ondary outcome using the FACT-B questionnaire. Re-
Palbociclib Combinations sults of the full analysis of QoL data are not yet available;
In the PALOMA-2 study, postmenopausal women however, an abstract was presented at the 2016 European
with ER-positive/HER2-negative BC, who had not re- Society for Medical Oncology meeting. Groups did not
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differ at baseline or in change from baseline in any of the no longer effective, for treating rapidly progressive dis-
FACT-B subscales or the TOI. These results indicated ease, or for when endocrine resistance has been proven.
that patients maintained their health-related QoL when Optimal duration is hard to characterize; longer duration
treated with the combination of palbociclib plus letrozole chemotherapy prolongs disease control compared with
in the first-line setting [84]. shorter therapy, but progressive toxicity must be consid-
The phase 3 PALOMA-3 study compared palbociclib ered [97]. Limited data are available to guide sequencing
plus fulvestrant with placebo plus fulvestrant in women and many variables influence treatment choice. These
of any menopausal status with HR-positive/HER2-nega- variables include menopausal status, disease characteris-
tive MBC that had progressed on previous ET [86]. Qual- tics, tumor-related symptoms, other health-related issues
ity-of-life measures included the EORTC-QLQ-30 and such as performance status and comorbidities, response
TTD in pain scores, with deterioration defined as a de- to and tolerability of previous treatment, access to and
crease of at least 10 points from baseline. Patients who suitability for clinical studies, treatment setting, and pa-
received palbociclib plus fulvestrant experienced signifi- tient preference [98]. HR status is universally recognized
cantly higher but not clinically relevant overall global as a critical prognostic and predictive factor. Patients with
QoL scores (66.1 [95% CI, 64.5–67.7] vs. 63.0 [95% CI, HR-positive/HER2-negative MBC tend to have higher 5-
60.6–65.3]; p = 0.031), and longer delays in deterioration and 10-year survival rates and a less aggressive course of
of QoL than those who received fulvestrant alone. They disease than patients with HR-negative disease [4, 99,
also had significantly better change from baseline scores 100]. The biology of these and other BC subtypes contin-
for emotional functioning (2.7 [95% CI, 1.1–4.3] vs. −1.9 ues to be elucidated, and new information may provide
[95% CI, −4.2 to 0.5]; p = 0.002), but not for other mea- additional guidance on treatment selection and sequenc-
sures on the functional scales. In addition, patients who ing. Other important factors informing treatment selec-
received palbociclib plus fulvestrant had significantly tion include duration of relapse-free interval since pri-
greater decrease from baseline in pain (–3.3 [95% CI, –5.1 mary diagnosis or since the completion of adjuvant ther-
to –1.5] vs. 2.0 [–0.6–4.6]; p = 0.001) with a longer esti- apy, and location and extent of metastases [98, 101].
mated median TTD in pain (8 months [95% CI, 5.6 to not
estimable] vs. 2.8 months [2.3–5.4]; p < 0.001). Of note,
the majority of patients (60%) in this study had visceral The Future: The Research Pipeline in HR-Positive
metastases, and a post hoc analysis was conducted for this MBC
subgroup. Results were consistent with those for the over-
all population: the palbociclib plus fulvestrant group had The development of new targeted agents and combi-
significantly improved global QoL, emotional function- nation therapies based on novel MOAs, specific muta-
ing, nausea/vomiting, and pain as compared to the fulves- tions, and pathologic mechanisms in individuals contin-
trant plus placebo group. These results showed that pa- ues to be an exciting area of research; findings from many
tients who experienced disease progression can maintain of these studies have been reviewed in detail [102]. Phase
their QoL when treated with the combination of palboci- 2 and 3 studies include but are not limited to studies
clib plus fulvestrant [86]. of ET in combination with a variety of other agents, in-
Several other studies in progress, including BELLE-3 cluding histone deacetylase inhibitors (e.g., entinostat
(buparlisib plus/minus fulvestrant) [93], BOLERO-6 (ev- with or without exemestane [ECOG E2112 study; NCT-
erolimus plus exemestane) [94], SANDPIPER (taselisib 02115282]), new approaches to antiestrogen treatment
plus fulvestrant) [95], and SOLAR-1 (alpelisib plus ful- (e.g., A011203 study [NCT02311933] comparing ta-
vestrant) [96] are currently assessing QoL with endo- moxifen citrate with its active metabolite, z-endoxifen
crine-based targeted combination therapy. hydrochloride), new SERD agents (e.g., GDC-0810
[NCT02569801]), novel CDK4/6 inhibitors (e.g., abe-
maciclib [103]), and alpha-specific PI3K inhibitors (e.g.,
Considerations for Treatment Selection in MBC BYL719 [NCT01791478] and GDC0032 [LORELEI
study; NCT02273973]). It can be anticipated that addi-
As stated in treatment guidelines, endocrine-based op- tional QoL data will emerge from many of these studies.
tions are the preferred first-line treatment for patients The knowledge accumulated from these types of stud-
with HR-positive/HER-2 negative MBC [6, 9, 63]. Cyto- ies will further enable clinicians to personalize treatment
toxic chemotherapy should be reserved until after ET is to a greater extent than previously possible. In the mean-
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10 Oncology Chalasani
Univ. of California San Diego

DOI: 10.1159/000477404
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time, patients with MBC have an increasing array of op- underutilized in patients with HR-positive MBC. Se-
tions to help prolong survival while maintaining an opti- quencing of endocrine-based regimens over multiple
mal QoL. lines of therapy may allow patients with HR-positive dis-
ease to derive maximum clinical benefit from ET while
optimizing QoL.
Conclusions

The range of treatment options for patients with HR- Acknowledgements

positive MBC continues to expand, with clinical data
Writing and/or editorial assistance was provided by Paula G.
demonstrating increased PFS, and in some cases overall
Davis, PhD, Greg Tardie, PhD, and Joan Hudson, The Lockwood
survival, with new therapeutic approaches. Consequent- Group, Stamford, CT, and funded by AstraZeneca LP.
ly, the prevalence of women living longer with BC is in-
creasing. Existing NCCN Clinical Guidelines in Oncolo-
gy for BC emphasize that ET is not only the recommend- Disclosure Statement
ed first line of therapy, but that it should be continued for
3 lines before chemotherapy is initiated [6]. Nevertheless, Dr. Chalasani reports no conflicts of interest.
real-world evidence suggests that sequential ET may be

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