reviews Annals of Oncology 25: 763773, 2014

doi:10.1093/annonc/mdu021

Adverse event management in patients with

advanced cancer receiving oral everolimus: focus
on breast cancer
M. Aapro1*, F. Andre2,3, K. Blackwell4, E. Calvo5, M. Jahanzeb6, K. Papazisis7, C. Porta8,
K. Pritchard 9 & A. Ravaud10
1
Multidisciplinary Oncology Institute, Clinique de Genolier, Genolier, Switzerland; 2French National Institute of Health and Medical Research (INSERM), Universit Paris Sud,
Orsay; 3Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; 4Department of Medicine/Medical Oncology, Duke University Medical Center, Durham,
USA; 5Melanoma Program, Centro Integral Oncolgico Clara Campal and Clinical Research, START Madrid, Madrid, Spain; 6Sylvester Comprehensive Cancer Center,
Miller School of Medicine, University of Miami, Miami, USA; 7Department of Medical Oncology, Euromedica General Clinic, Thessaloniki, Greece; 8Department of Medical
Oncology, IRCCS, San Matteo University Hospital Foundation, Pavia, Italy; 9Sunnybrook Odette Cancer Centre and the University of Toronto, Toronto, Canada;
10
Department of Medical Oncology, Hpital Saint-Andre, Bordeaux University Hospital, Bordeaux, France

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Received 13 September 2013; revised 16 December 2013; accepted 18 December 2013

Background: Everolimus, an orally administered rapamycin analogue, inhibits the mammalian target of rapamycin
(mTOR), a highly conserved intracellular serinethreonine kinase that is a central node in a network of signaling pathways
controlling cellular metabolism, growth, survival, proliferation, angiogenesis, and immune function. Everolimus has
demonstrated substantial clinical benet in randomized, controlled, phase III studies leading to approval for the treatment
of advanced renal cell carcinoma, advanced neuroendocrine tumors of pancreatic origin, renal angiomyolipoma and sub-

reviews
ependymal giant-cell astrocytoma associated with tuberous sclerosis complex, as well as advanced hormone-receptor-
positive (HR+) and human epidermal growth factor receptor-2-negative advanced breast cancer.
Materials and methods: We discuss clinically relevant everolimus-related adverse events from the phase III studies, in-
cluding stomatitis, noninfectious pneumonitis, rash, selected metabolic abnormalities, and infections, with focus on ap-
propriate clinical management of these events and specic considerations in patients with breast cancer.
Results: The majority of adverse events experienced during everolimus therapy are of mild to moderate severity. The
safety prole and protocols for toxicity management are well established. The class-effect adverse event prole observed
with everolimus plus endocrine therapy in breast cancer is (as expected) distinct from that of endocrine therapy alone, but
is similar to that observed with everolimus in other solid tumors. Information gained from the experience in other carcin-
omas on prompt diagnosis and treatments to optimize drug exposure, treatment outcomes, and patients quality of life
also applies to the patient population with advanced breast cancer.
Conclusions: As with all orally administered agents, education of both physicians and patients in the management of
adverse events for patients receiving everolimus is critical to achieving optimal exposure and clinical benet. Active moni-
toring for early identication of everolimus-related adverse events combined with aggressive and appropriate intervention
should lead to a reduction in the severity and duration of the event.
Key words: everolimus, stomatitis, pneumonitis, metabolic abnormality, infections, rash

introduction
Everolimus has an established role in the treatment of solid
tumors, including advanced renal cell cancer (RCC), neuroen-
docrine tumors of pancreatic origin ( pNET), and renal angio-
myolipoma and tuberous sclerosis complex (TSC) including
pediatric and adult patients with TSC who have subependymal
* Correspondence to: Dr Matti Aapro, Multidisciplinary Oncology Institute, Clinique de
Genolier, Case Postale, PO Box 100, Route du Muids 3, 1272 Genolier, Switzerland.
Tel: +41-22-3669136; Fax: +41-22-3669207; E-mail: maapro@genolier.net
giant cell astrocytoma (SEGA) [1, 2]. Most recently, everolimus
(in combination with oral exemestane) was approved for the
treatment of postmenopausal patients with hormone-receptor-
positive (HR+), human epidermal growth factor-2-negative
(HER2) advanced breast cancer recurring or progressing
during/after nonsteroidal aromatase inhibitor treatment [2].
Overall, continuous daily dosing with 10-mg oral everolimus is
adequately tolerated, and no evidence of cumulative toxicity has
been observed in clinical trials over median treatment durations
of 2052 weeks [2, 3]. While initiating everolimus treatment at a
dose of 5 mg may decrease the proportion of patients with grade

The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.
reviews Annals of Oncology

3/4 adverse events, more complete inhibition of eukaryotic initi-
ation factor 4E binding protein 1 (4E-BP1) and pS6K phosphor-
ylation occurs at the 10-mg dose. This dose has proven clinical
benet in RCC, pNET and HR+, HER2 advanced breast
cancers [46].
Class-effect toxicities during mammalian target of rapamycin
(mTOR) inhibitor therapy are well characterized [7]. Extensive
clinical experience with everolimus, particularly in patients with
RCC, has advanced our understanding of its safety prole [8, 9].
In the phase III BOLERO-2 study of everolimus plus exemestane
in patients with HR+ breast cancer progressing after prior non-
steroidal aromatase inhibitor therapy, the incidence and severity
of class-effect adverse events was comparable with that of phase
III studies of everolimus monotherapy in patients with RCC and
pNET, and no new or unexpected safety signals were identied.
Because everolimus is a new drug class in the breast cancer
arena, many physicians treating such patients may be unfamiliar
with its adverse event prole and appropriate management [10].
In clinical practice, the threshold for change in therapy because
optimal outcomes. This article reviews the clinical management
and monitoring guidelines for class-effect adverse events of ever-
olimus, focusing on the data from HR+ advanced breast cancer.
Practical guidance is also provided, based on clinical experience
across approved oncology indications.
everolimus safety prole: class-effect
toxicities
Adverse events observed in patients undergoing systemic treat-
ment with mTOR inhibitors include epithelia-cutaneous events
(stomatitis, rash), pulmonary dysfunction (noninfectious pneu-
monitis), toxicities related to metabolic dysfunction (elevated
blood levels of glucose and lipids), and immune suppression
(infections) [10]. Metabolic and immune-related adverse events
are clearly associated with on-target effects of mTOR inhibition
[12]. However, skin-cutaneous effects may have a less direct as-
sociation with mTOR inhibition; inhibition of mTOR-mediated
growth and tissue repair and/or immune dysregulation may be a

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of adverse events may be lower in breast cancer compared with
other malignancies because of the availability of multiple
approved treatment options with which physicians have more
experience [11]. As with any drug, the optimal use of everolimus
in breast cancer is contingent upon adequate management of
adverse events, to maximize treatment exposure and facilitate
factor in mucosal epithelia with high turnover (Figure 1) [13, 14].
In general, the incidences of class-effect adverse events in the
large phase III trials of everolimus in RCC (RECORD-1), pNET
(RADIANT-3), and HR+, HER2 advanced breast cancer
(BOLERO-2) were comparable (Table 1) [5, 6, 8, 15]. Therefore,
the addition of exemestane did not alter the adverse event

Growth factors

RTK

PIP2
PI3K
Amino PTEN
acids
Ras PIP3
Cytoskeletal
Raf Mek organization
AGC kinases
Inflammation IKKb
?

Akt SGK1 PKCa

Hypoxia REDD1

Intra lysosomal Cell survival/

amino acids TSC1/2 metabolism
Energy GDP GTP
LKB1 AMPK pras40
deficit
v-ATPase rheb rheb

mTORC1
Translocation to
(Active)
mTORC1 lysosomal surface
(Inactive)

Protein synthesis Autophagy

Lipid synthesis Energy metabolism

Figure 1. Connections of the mTOR signaling pathways to metabolic processes and cellular proliferation. The key signaling nodes that regulate mTORC1 and
mTORC2. Critical inputs regulating mTORC1 include growth factors, amino acids, stress, energy status, and oxygen. When active, mTORC1 promotes protein
synthesis, lipogenesis, and energy metabolism, and inhibits autophagy and lysosome biogenesis. Alternatively, mTORC2 is activated by growth factors and reg-
ulates cell survival/metabolism, immune function, and angiogenesis. Adapted with permission from Laplante and Sabatini [13].

| Aapro et al. Volume 25 | No. 4 | April 2014

Annals of Oncology
Table 1. Incidence of key class-effect toxicities from phase III studies of everolimus in advanced solid tumors
Metastatic renal cell carcinoma [8]
Everolimus + best supportive care
(n = 274), %
All Grades Grade 3/grade 4
Stomatitis 44 4/<1
Rash 29 1/0
Noninfectious pneumonitis 14 4/0
Hyperglycemia 57b 15/<1b
Infectionsd 37 7/3
a
Breakdown by grade 3 and 4 not reported.
b
Based on laboratory values.
c
Based on investigator-reported adverse events.
d
Incidence based on system organ class (SOC); includes all infections.
e
Data from Anitor prescribing information [2].
prole compared with everolimus monotherapy. However, rates
of treatment discontinuations and dose modications in
BOLERO-2 were slightly higher than that observed in the other
phase III trials of everolimus monotherapy, which may in part
be related to the novelty of everolimus and its safety prole to
clinicians and patients. The median duration of everolimus
treatment was 20.1 weeks in patients with RCC [8], 37.7 weeks
in patients with pNET [6], and 23.9 weeks in HR+ advanced
breast cancer [16].
Most class-effect adverse events are manageable and resolve
without the need for treatment discontinuation. However, active
monitoring and early identication can reduce the rate and se-
verity of specic adverse events. Clinical management informa-
tion and guidelines for adverse events during mTOR therapy
have been published, detailing the strategies for each type of event
[2, 1725]. In both the RCC and pNET phase III trials, 13% of
patients discontinued everolimus treatment because of an adverse
event [6, 8]. In patients with pNET, the most common adverse
events resulting in treatment discontinuation were pneumonitis,
fatigue, and interstitial lung disease. In patients with RCC, these
adverse events were pneumonitis, dyspnea, lung disorders, and
fatigue [9]. In patients with HR+ advanced breast cancer, 26% dis-
continued treatment of one or both study drugs in the everolimus
group because of an adverse event [16]; the most common events
were pneumonitis, stomatitis, dyspnea, rash, and fatigue.
stomatitis
Stomatitis is an adverse event term that encompasses inamma-
tion and ulceration of the oral mucosal lining. Oral mucositis is
the more specic, preferred term used to describe oral inamma-
tion/ulceration observed on nonkeratinized mucosal surfaces.
Preferred terms that are included in stomatitis and related events
include stomatitis, mouth ulceration, aphthous stomatitis, glosso-
dynia, gingival pain, lip ulceration, and glossitis. In general, the
onset of stomatitis with mTOR inhibition is rapid and occurs
within a few weeks of treatment initiation [22, 24]. In patients re-
ceiving everolimus plus exemestane for advanced breast cancer in
Volume 25 | No. 4 | April 2014
reviews
Neuroendocrine tumors of Advanced breast cancer [15]
pancreatic origin [6]
Everolimus (n = 204), % Everolimus + exemestane
(n = 482), %
All grades Grade 3/4a All grades Grade 3/grade 4
64 7 59 8/0
49 <1 39 1/0
17 2 16 3/0
13 5 14c 5/<1
23 2 50e 4/1e
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BOLERO-2, more than a third of stomatitis and related events
(grade 2) were reported in the rst 2 weeks after starting treat-
ment. Furthermore, these events began to plateau at 6 weeks
(Figure 2A) [16, 26]. A similar trend was noted in patients receiving
everolimus monotherapy for RCC in RECORD-1 [20]. After the
initial 2-month treatment period, the probability of stomatitis oc-
curring in patients who have not already experienced this adverse
event is low [20].
The clinical presentation of stomatitis in patients receiving
mTOR inhibitors is distinct from that induced by chemotherapy
in that it is characterized by discrete, supercial, well-demarcated,
aphthous-like ulcers with a grayish-white pseudomembrane [22].
Recent reviews note that the average incidence of stomatitis
during everolimus treatment is 44% [22, 24], making it the most
common treatment-related adverse event.
In phase III studies, the incidence of all-grade stomatitis ( pre-
ferred term) in the everolimus plus exemestane group of the
BOLERO-2 study (advanced HR+ breast cancer) was 59%,
similar to that observed in the everolimus-treated patients with
RCC (44%) and pNET (64%) (Table 1) [6, 8, 15]. The incidence
of grade 3/4 stomatitis was 8% in patients with breast cancer, 4%
in patients with RCC, and 7% in patients with pNET [6, 8, 16].
No dose modications are required for managing grade 1 sto-
matitis (Table 2) [2, 20, 21]. For stomatitis events of grade 2 or
3, treatment interruption is recommended until resolution to
grade 1. The median time to resolution from grade 3 to 1 sto-
matitis following everolimus dose interruption/reduction was 3.1
weeks in 97% of patients with breast cancer (complete resolution
occurred in 82% of patients after a median of 7.4 weeks) [16].
In general, patients should be advised on good oral hygiene,
and to avoid spicy foods and mouthwashes containing debride-
ment agents such as peroxide upon onset of stomatitis. Topical
analgesics can alleviate symptoms such as oral pain. However,
patients should be cautioned regarding the use of topical analge-
sics and ingestion of hot foods, as there is an increased likelihood
of mouth burns from the inability to sense food temperature.
Mouth pain, dysgeusia, and dysphagia in the absence of clinically
apparent lesions may be useful symptoms to monitor to allow for
doi:10.1093/annonc/mdu021 |
reviews Annals of Oncology

A 100

80

Probability of event, %
60
Censoring times
EVE+EXE (n/N = 160/482)
PBO+EXE (n/N = 7/238)
40

20

0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time, months
Number of patients still at risk
EVE+EXE 482 307 233 172 134 99 63 39 25 13 10 5 2 0
PBO+EXE 238 168 115 70 47 33 20 11 7 3 1 1 0 0

B 100

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80
Probability of event, %

60

40 Censoring times
EVE+EXE (n/N = 55/482)
PBO+EXE (n/N = 0/238)
20

0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Time, months
Number of patients still at risk
EVE+EXE 482 417 317 242 184 136 94 59 38 21 15 9 3 1 0
PBO+EXE 238 173 119 72 48 34 21 11 7 3 1 1 0 0 0

C 100

80
Probability of event, %

60 Censoring times
EVE+EXE (n/N = 151/482)
PBO+EXE (n/N = 29/238)
40

20

0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Time, months
Number of patients still at risk
EVE+EXE 482 369 251 187 142 102 68 45 27 16 13 7 3 1 0
PBO+EXE 238 160 109 64 38 27 16 10 7 3 1 1 0 0 0

Figure 2. Cumulative incidence of grade 2 (A) stomatitis, (B) noninfectious pneumonitis, and (C) infections in patients with advanced breast cancer
(BOLERO-2). Infections included all infections and infestations. EVE, everolimus; EXE, exemestane; PBO, placebo. Parts (A) and (B) reprinted with permission
from Rugo et al., OUP, on behalf of the European Society for Medical Oncology [16]. Part (C) reprinted with permission from Rugo et al. [26].

| Aapro et al. Volume 25 | No. 4 | April 2014

Annals of Oncology reviews
Table 2. Recommendations for clinical management of key adverse events by symptom severity

Grade
1 2 3 4

Stomatitis
Symptoms/ Minimal symptoms (normal
description diet)
Treatment Alcohol-free mouthwash
or saline several times per
day
Cooling with ice, frozen
pineapple chunks, or balls
of frozen pineapple juice
Symptomatic (able to eat and Symptomatic (unable to Symptoms may be
swallow modied diet) properly eat/drink) associated with life-
threatening
consequences
Topical oral treatments
Dobendan Strepsils Dolo lozenges
Lidocaine-containing denture adhesive for denture wearers
Mouthwash with local anesthetic (e.g. benzocaine 15 ml q3h), with or without steroids
Rinse with supersaturated calcium phosphate solution (moistens mouth and makes it
slippery)
Gelclair oral gel (3 daily, or as needed 1 h before next food/drink intake), undiluted or
diluted (15 ml + 40 ml water); rinse mouth thoroughly for 1 min
Rinse with magic mouthwash containing analgesic or anesthetic
Ketamine oral rinse (ketamine 20 mg in 5 ml saliva replacement uid or isotonic saline) q4h

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for stomatitis pain
Topical corticosteroids
Antiviral therapy for conrmed HSV infection
Topical antifungal therapy as appropriate (e.g. Ampho-Moronal)
Systemic antifungal therapy for refractory or severe fungal infection
Everolimus dose None Temporary interruption until Temporary interruption Discontinue everolimus
adjustmenta recovery to grade 1; restart at until recovery to grade 1;
same dose restart at reduced dose
If grade 2 stomatitis recurs,
interrupt dose until recovery
to grade 1; restart at reduced
dose
Pneumonitis
Symptoms/ Asymptomatic; radiographic Symptomatic; no impairment of Symptomatic; impairment of Life-threatening; strong
description ndings only ADL ADL, supplemental impairment of ADL,
oxygen required mechanical ventilation
required
Treatment Observation Depending on symptom severity: Consult pulmonologist
Consult pulmonologist Diagnostics to rule out infection
Consider diagnostics to rule Corticosteroids if infectious cause excluded
out infection For impending respiratory distress: concomitant
Consider corticosteroidsa until antibiotics and corticosteroids are recommended
symptoms improve to grade
1
Everolimus dose None Temporary interruption; Interruption until recovery Discontinue everolimus
adjustmenta restart at reduced dose to grade 1; restart at
Discontinue everolimus if reduced dose
failure to recover within 4 If grade 3 pneumonitis
weeks recurs, consider
discontinuation of
everolimus
Hyperglycemia
Glucose level >ULN160 mg/dl >160250 mg/dl >250500 mg/dl >500 mg/dl
(8.9 mmol/l) (>8.913.9 mmol/l) (>13.927.8 mmol/l) (>27.8 mmol/l)
Treatment Nonea Patient self-monitoring of blood glucose
Patient self-monitoring of Treat according to ADA and EASD standard guidelines
blood glucose

Continued

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reviews Annals of Oncology

Table 2. Continued

Grade
1 2 3 4

Everolimus dose None None Temporary interruption; Discontinue everolimus

adjustmentb If intolerable, temporary restart at reduced dose
interruption until recovery to
grade 1, then restart at same
dose

a
Apply more vigorous monitoring strategy.
b
If dose reduction is required, the suggested dose is 50% lower than the dose previously administered.
Data from Anitor prescribing information [2], Porta et al. [20], and Nathan et al. [21].
ADA, American Diabetes Association; ADL, activities of daily living; EASD, European Association for the Study of Diabetes; HSV, herpes simplex
virus; q3h, every 3 h; q4h, every 4 h; ULN, upper limit of normal.

early implementation of preventive measures. In a recent report, desquamative interstitial pneumonia, and vasculitis. Appropriate

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87% of patients had resolution of stomatitis following local or sys-
temic treatment with corticosteroid therapy [27]. Accordingly, an
ongoing study, BOLERO-4, will assess the effectiveness of treating
stomatitis using a 0.5-mg/5-ml dexamethasone mouth rinse [28].
The use of antiseptic and sodium bicarbonate mouth rinses for
stomatitis prevention has yielded inconsistent results [24, 29, 30].
One center was successful in minimizing the rate of stomatitis
using a sodium bicarbonate mouth rinse and a mouth rinse with
Benadryl, tetracycline, hydrocortisone, and nystatin [31].
noninfectious pneumonitis
Noninfectious pneumonitis is a nonmalignant inammatory
inltration of the lungs that is associated with the use of rapa-
mycin derivatives (e.g. current mTOR inhibitors) [20, 25]. The
time to onset for noninfectious pneumonitis has a wide range
over several months [20]. The median time to onset in advanced
breast cancer (BOLERO-2) was not reported, although ap-
proximately half of all events (grade 2) occurred within the
rst 24 weeks of treatment initiation. Cumulative risks of pneu-
monitis and related events (grade 2) in the everolimus plus
exemestane arm were 10% and 16% at weeks 24 and 48, respect-
ively (Figure 2B) [6, 8, 16]. In patients with advanced RCC, the
median times to onset varied between 65 and 108 days in a
retrospective review of patients treated in clinical practice and
phase III trials, respectively [8, 25, 32]. This range is consistent
with previous experience where most cases of noninfectious
pneumonitis were observed within 6 months of treatment initi-
ation [17]. The incidence of pneumonitis may also reect the
variation in the duration of everolimus exposure (20.137.7
weeks) across the tumor types.
Patients with noninfectious pneumonitis may be asymptomatic
or present with nonspecic respiratory symptoms such as cough,
shortness of breath/dyspnea, pleural effusion, or hypoxia.
Radiologic changes such as ground glass opacities and focal con-
solidation may be evident (Figure 3) [33]. Occasionally, patients
may present with systemic symptoms such as fatigue and fever
[17, 20, 25]. Pathologic features of noninfectious pneumonitis
may include nonspecic interstitial pneumonitis, bronchiolitis
obliterans organizing pneumonia, alveolar hemorrhage,
differential diagnosis to exclude alternative causes, including in-
fection, is needed to identify noninfectious pneumonitis.
The incidence of any-grade (16%) and grade 3/4 (3%) non-
infectious pneumonitis ( preferred term) in advanced breast
cancer was similar to that of patients with RCC or pNET
(Table 1) [6, 8, 15]. Radiologic review of everolimus-treated
patients in the RCC study shows that many patients with
changes consistent with pneumonitis (39%) did not exhibit clin-
ical symptoms consistent with pneumonitis during the trial
[25], highlighting the importance of consulting an experienced
radiologist. In an analysis of ve everolimus studies in breast
cancer, the overall rate of noninfectious pneumonitis was 41%
in pretreated metastatic disease, although 35% represented
grade 1/2 and included patients without clinical symptoms [34].
Of the patients with advanced breast cancer enrolled in
BOLERO-2 who developed grade 3 noninfectious pneumonitis
or related events (includes interstitial lung disease, lung inltra-
tion, organizing pneumonia, and pulmonary brosis), the ma-
jority (75%) had complete resolution at a median of 5.4 weeks,
typically after dose adjustments [16]. Similarly, 60% of patients
with RCC and grade 3 noninfectious pneumonitis had complete
resolution following dose adjustments/discontinuation and/or
corticosteroid therapy [20].
Before initiating everolimus therapy, clinicians should evalu-
ate pulmonary history, educate patients on the symptoms of this
potentially serious complication, and caution patients with pre-
existing conditions (e.g. chronic obstructive pulmonary disease)
regarding the potential emergence of noninfectious pneumon-
itis. Patients should be encouraged to seek medical attention
if they develop new or unexplained cough and/or dyspnea. To
facilitate diagnoses, a baseline pretreatment chest X-ray or pref-
erably, a computed tomography (CT) scan, is helpful to distin-
guish onset of drug-associated noninfectious pneumonitis on
subsequent examinations. If the patient presents with clinical
symptoms during treatment with everolimus, prompt referral to
a pulmonologist is recommended, as symptoms (e.g. from grade
3 to 4) may rapidly worsen. In such instances, timely imaging is
needed to exclude differential diagnoses such as tumor progres-
sion or pleural effusion (Table 2) [2, 20, 21]. Bronchoalveolar
lavage is recommended to eliminate the possibility of respiratory

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Annals of Oncology reviews
A B
L L

Figure 3. Radiographic scans of (A) pneumonitis and (B) improvement. This patient had metastatic renal cell carcinoma in the lower right lobe. After 8 weeks

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of everolimus treatment, the chest X-ray shows patch consolidation and ground glass opacity (A). Everolimus was discontinued; 2 weeks later, improvement
was noted on the follow-up X-ray (B). Reprinted with permission from Lee et al. [33].

infection that could not otherwise be diagnosed and may also be
useful in differentiation from neoplastic lymphangitis. The sub-
sequent monitoring schedule depends on the grade and clinical
course, and has been reviewed in detail [10, 17]. Treatment with
corticosteroids and everolimus dose adjustments, if necessary, is
presented in Table 2.
infections
The immunosuppressive properties of mTOR inhibitors may
predispose patients to localized and systemic infections such as
candidiasis, pneumonia, other bacterial infections, and invasive
fungal infections [20]. In phase III studies of everolimus, infec-
tion rates are generally similar across the entire treatment period
[8, 20], and in patients with advanced breast cancer (BOLERO-
2), the incidence of infections grade 2 had no noticeable
plateau (Figure 2C) [26]. The most common types of infections
reported for patients with advanced breast cancer were naso-
pharyngitis (10%), urinary tract infection (10%), upper respira-
tory tract infection (6%), and pneumonia (4%) [2]. In patients
with RCC, the infections included pneumonia, sepsis, and
fungal infections, and in some populations, reactivation of latent
hepatitis viral infections [20]. No cases of tuberculosis reactiva-
tion in everolimus-treated patients have been reported.
The incidence of overall infections was higher in patients with
advanced breast cancer (50%) [2] compared with RCC (37%)
[8] and pNET (23%) [6]; however, the incidence of infections in
the advanced breast cancer placebo group was also higher (25%)
compared with RCC (18%) and pNET (6%). Thus, rates of
all-grade infections could vary by setting, potentially because of
differences in the background infection rates in control arms
and possibly from differences in reporting. The proportion of
patients with infections and longer everolimus exposure (pNET)
was lower (23%) compared with that of patients who had a
shorter exposure (RCC; 37%), suggesting that risk of infection
does not directly correlate with treatment duration. Overall, the
incidence rates of grade 3/4 infection are low (6%), and
infections were not reported as being a major cause for dose
adjustments or discontinuations across these phase III studies
[26].
All infections require prompt diagnosis and treatment with
antibiotic, antifungal, or antiviral agents, and interruption or dis-
continuation of everolimus therapy should be considered [1, 2,
20]. Consideration of drug interactions with everolimus should be
taken into account when treating infections; several drugs are
CYP3A4 inhibitors or inducers to various degrees necessitating
an everolimus dose adjustment, and concomitant strong inhibi-
tors of CYP3A4 should not be used (Table 3) [2]. For grade 2 or 3
infections, treatment with everolimus should be interrupted until
improvement to grade 1; treatment may be reinitiated at the
same dose for grade 2 events and at a lower dose for grade 3
events.
The importance of hygiene should be stressed, and patients
should be encouraged to seek medical attention for infection-
related signs and symptoms (e.g. fever, cough, etc.) [18]. Overall,
vigilance for infections is standard practice during chemotherapy
for metastatic breast cancer (because of potential myelosuppres-
sive effects), and this should be incorporated as a component of
patient care during everolimus-based treatment. In areas with a
high prevalence of hepatitis, physicians may consider a compre-
hensive baseline medical history that includes an antibody
immune status (hepatitis B virus) to identify high-risk patients
(see Supplementary Appendix, available at Annals of Oncology
online for details) [20].
metabolic adverse events
Hyperglycemia and hyperlipidemia are potential metabolic dys-
functions that can arise from mTOR inhibition [13]. In muscle
tissue, mTOR inhibition can lead to a reduction in glucose
uptake and contribute to systemic glucose intolerance. In the
liver, inhibition of the PI3K/Akt/mTOR pathway promotes glu-
coneogenesis, thus contributing to hyperglycemia. In adipose
tissue, mTOR inhibition can reduce lipid uptake, leading to

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reviews Annals of Oncology

Table 3. Known drug interactions with everolimus

Among the patients with advanced breast cancer who had
grade 3/4 hyperglycemia or new-onset diabetes mellitus, 46%
Reason for interaction experienced resolution to grade 1 after a median of 29.1 weeks.
Increased everolimus concentration
During the study, more patients (5%) in the everolimus arm
Ketoconazole, itraconazole, Strong CYP3A4 inhibitora used insulin or its analogues compared with the control (exe-
voriconazole mestane only) arm (2%) [16]. In patients with pre-existing dys-
Clarithromycin, telithromycin Strong CYP3A4 inhibitora function in sugar metabolism, it is necessary to monitor fasting
Atazanavir, saquinavir, ritonavir, Strong CYP3A4 inhibitora serum glucose levels and manage the patient to optimal glycemic
indinavir, nelnavir control before initiating everolimus (see Supplementary Appendix,
Nefazodone Strong CYP3A4 inhibitora available at Annals of Oncology online for details) [2, 37].
Fluconazole Moderate CYP3A4 inhibitor
and/or PgP inhibitorb hyperlipidemia. Hyperlipidemia is also well dened by elevated
Erythromycin Moderate CYP3A4 inhibitor blood cholesterol and/or triglyceride levels [38]. Before
and/or PgP inhibitorb
initiating everolimus therapy, patients should have a fasting
Amprenavir, fosamprenavir Moderate CYP3A4 inhibitor
serum cholesterol 300 mg/dl or 7.75 mmol/l and fasting
and/or PgP inhibitorb
triglycerides 2.5 ULN (data in Baselga et al., Supplementary
Verapamil Moderate CYP3A4 inhibitor
Appendix, available at Annals of Oncology online [5]). If one or
and/or PgP inhibitorb
both of these thresholds are exceeded, adequate control should
Aprepitant Moderate CYP3A4 inhibitor
be achieved before initiation of therapy. The time to onset of

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and/or PgP inhibitorb
Diltiazem Moderate CYP3A4 inhibitor hyperlipidemia was not reported in phase III everolimus
and/or PgP inhibitorb studies.
Decreased everolimus concentration The incidences of elevated cholesterol and triglyceride levels
Rifampin Strong CYP3A4 inducerc were 2444% higher in patients treated with everolimus com-
Rifabutin, rifapentine Strong CYP3A4 inducerc pared with the respective control arms of the phase III oncology
Phenytoin Strong CYP3A4 inducerc trials [2]. As with hyperglycemia, patients with elevated lipids at
Phenobarbital Strong CYP3A4 inducerc baseline should have their lipid panels screened frequently and
Carbamazepine Strong CYP3A4 inducerc managed to stable levels. However, intervention for elevated
Increased drug concentration lipid levels should be adapted to the overall concern for the
Midazolam Sensitive CYP3A4 substrate extent of cancer disease, the individuals cardiovascular risk
factor, and the expected survival (which may exceed 2 years in
Data from Anitor prescribing information [2]. advanced breast cancer) [39]. In individual cases, it may be ac-
a
Concomitant strong inhibitors of CYP3A4 should not be used. ceptable to tolerate lipid elevations to grade 1 and perhaps even
b
If alternative treatment cannot be administered, reduce the grade 2 because lipid abnormalities do not have the same clinic-
everolimus dose to 2.5 mg daily. al impact as hyperglycemia.
c
If alternative treatment cannot be administered, increase the
Hyperlipidemia can also be treated per guidelines [20, 38, 40,
everolimus dose up to 20 mg daily using 5-mg increments.
41], with monitoring for possible interactions between statins
and CYP3A4 enzymes. High triglyceride levels (500 mg/dl)
should be lowered promptly with brates because of the risk of
acute pancreatitis [20, 23, 37, 42].
hyperlipidemia. A reduction in muscle mass has been also
described as a consequence of everolimus treatment [35].
rash
Rash is a typical class-effect of mTOR inhibitors, and usually mani-
hyperglycemia. Hyperglycemia is well dened by elevated fests as an acneiform dermatitis that starts as an inammatory
blood glucose levels [36]. Patients with uncontrolled diabetes lesion (papule or pustule), with comedones (blackheads) some-
(fasting serum glucose >1.5 upper limit of normal [ULN]) times appearing thereafter [43, 44]. Similar to stomatitis, rash
should not receive everolimus therapy. Although the time to usually develops soon after initiating everolimus treatment. This
onset of hyperglycemia or new-onset diabetes was not reported rash is distinguished by its wide and unusual distributiontypically
for advanced breast cancer, approximately half of these events found in areas not acne prone such as the upper extremities or
(grade 2) occurred within the rst 6 weeks of treatment neck [43, 44].
initiation [16]. Median time to onset of hyperglycemia was also The incidence of rash in the phase III trials of everolimus
not reported for RCC and pNET. monotherapy ranged from 29% to 49% [6, 8]. The incidence of
The incidence of hyperglycemia ( preferred term) in advanced rash for everolimus plus exemestane in BOLERO-2 was 39%
breast cancer was 14%, with a similar rate reported in pNET [26]. A meta-analysis of rash incidence in 13 everolimus trials
(13%) [6]. The incidence of hyperglycemia traditionally dened (N = 2242) reported an all-grade incidence of 29% and a grade
as an adverse event was 8% in RCC, and there was one case of 3/4 incidence of 1% [45].
new-onset diabetes [20]. However, the incidence of hypergly- Because there are so few high-grade events, the majority of
cemia in RCC reported on the basis of laboratory tests was 57% rash events typically resolve without therapeutic intervention.
(Table 1) [6, 8, 15, 20]. Topical application of cortisone creams and moisturizers may

| Aapro et al. Volume 25 | No. 4 | April 2014

Annals of Oncology
provide symptomatic relief, although caution is recommended
for symptomatic treatment of rash with steroids in patients
prone to infection and/or hyperglycemia [46].
specic considerations for management
of everolimus-related adverse events
in patients with breast cancer
While large phase III trials have established that there are no
signicant differences in the safety prole of everolimus across
various indications, there are issues specic to population,
disease, and concomitant treatment that are particularly relevant
in patients with breast cancer. For breast cancer, everolimus has
a specic indication in combination with exemestane [1, 2];
consequently, patients with advanced breast cancer who receive
everolimus will be postmenopausal and possibly already experi-
enced or will be at risk for certain adverse events. In one data-
base review of patients with breast cancer (N = 64 034) who were
diagnosed at a median age of 75 years, 42% had one or more co-
morbid conditions, often diabetes and/or chronic obstructive
pulmonary disease [47]. Correspondingly, concurrent medica-
tions for the comorbid conditions should be reviewed for the
potential to inuence the risk of adverse events such as im-
munosuppression and resulting infections, as well as for drug
interactions (Table 3).
Patients with advanced breast cancer who receive everolimus
may also have received other prior therapies, the effects of which
may inuence patient perception of everolimus. For example the
safety prole of everolimus may be favorably perceived by the
patient after receiving intravenous chemotherapy. In contrast,
patients who have only received prior hormonal therapy will
need education on the benet-to-risk ratio of everolimus and
adverse event management. Adherence to dened thresholds for
dose reductions per management guidelines is critical to maxi-
mize treatment exposure and clinical benet. Patient education
on class-effects of mTOR inhibitors is, therefore, also critical.
Further, physicians may also have a low threshold for opting to
change treatment because of potential increases in adverse event
incidence or severity versus prior hormonal therapies. For
example in BOLERO-2, study treatment was discontinued for
grade 1/2 pneumonitis in 18 patients (3.7%) and for grade 1/2
stomatitis in 9 patients (1.9%) [26].
Many patients will receive bone-conserving therapies (e.g.
bisphosphonates or denosumab) to prevent skeletal-related
events or to treat osteoporosis related to the use of an aromatase
inhibitor. Although relatively infrequent, certain adverse events
during bone-conserving therapy, including renal impairment
and osteonecrosis of the jaw (ONJ), may present additional
management/monitoring considerations in patients with breast
cancer. For example grade 3/4 creatinine increase was observed
in 2% of patients with breast cancer receiving everolimus
therapy, and this may affect the usage of bisphosphonates or
denosumab. In theory, ONJ is part of the differential diagnosis
at the presentation of a stomatitis event. Although the denuded
bone area is easily distinguished from supercial mucosal lesions
on the gum, preliminary symptoms such as pain are observed in
both clinical conditions. Preventive measures and patient educa-
tion are critical to reduce rates of ONJ and stomatitis.
Volume 25 | No. 4 | April 2014
reviews
Special consideration/monitoring for metabolic abnormalities
may be required for perimenopausal women. Recent oophorec-
tomy or use of luteinizing hormone-releasing hormone agonists
may predispose them to metabolic dysfunction [48]. Accordingly,
the metabolic prole of these patients needs to be monitored
regularly to minimize the risk of adverse events associated with
severe metabolic dysfunction.
Finally, all patients with cough or dyspnea should seek medical
attention to rule out noninfectious pneumonitis. Notably, 24%
and 21% of patients enrolled in BOLERO-2 had cough and
dyspnea, respectively (all-grade) [2]. In particular, patients with
breast cancer who have had prior radiation therapy should have a
baseline CT scan or X-ray to evaluate for pre-existing radiograph-
ic pneumonitis resulting from radiotherapy.
conclusions
The adverse event prole of everolimus is broadly similar across
various approved indications, and no new safety signals were
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observed in combining everolimus with hormonal therapy in
patients with breast cancer. Clinical management protocols for
everolimus-related adverse events are well established and applic-
able across all oncology settings. Many adverse events begin as
minor issues, and patient education may encourage early report-
ing, which allows for prompt intervention and mitigation of the
adverse events severity and duration. It may be advisable to see or
contact the patients after 2 weeks of treatment in order to elicit
signs/symptoms of early toxicity. Overall, everolimus is an effective
treatment option, with manageable toxicity, among patients with
HR+ advanced breast cancer who have recurring or progressing
disease during/after nonsteroidal aromatase inhibitor therapy.
acknowledgements
We thank Tamalette Loh, PhD, and Jerome F. Sah, ProEd
Communications, Inc., for their medical editorial assistance with
this manuscript.
funding
This work was supported by Novartis Pharmaceuticals in the
form of nancial support for medical editorial assistance [no
grant number].
disclosure
MA is a consultant to Novartis, AstraZeneca, Celgene Pzer,
Pierre Fabre, and Roche. He has received research funding from
Pierre Fabre and Novartis and has received honoraria or been
part of speakers bureaus from all of the above. FA is an advisor
to Novartis and has received honoraria and research grants from
Novartis. KB is a consultant to Novartis and Genentech. EC is a
consultant or has received honoraria for serving on advisory
boards of Novartis, Pzer, Roche/Genentech, GlaxoSmithKline
(GSK), and Astellas. MJ has received honoraria for serving on
advisory boards of Genentech, Eisai, Novartis, GSK, Bayer/
Onyx, Oxigene, and Roche; has received honoraria or been part
of speakers bureaus from Genentech, Roche, and GSK; and has
received research grants from Genentech and Oxigene. KP is a
doi:10.1093/annonc/mdu021 |
reviews
consultant with Novartis and GSK; has been a member on an
advisory committee for Roche, Pzer, Novartis, and GSK; has
received honoraria or been part of speakers bureaus from
Roche, Novartis, GSK, and Amgen. CP acted as a consultant
and/or speaker for Novartis, Pzer, GSK, Bayer-Schering, Astellas,
Aveo, and Boehringer-Ingelheim; he also received research grants
from Novartis and Bayer-Schering. KP is a consultant with sano-
aventis, AstraZeneca, Roche, Pzer, Novartis, Abraxis, Amgen,
and GSK; has received research funding either directly through
per-case funding for studies or indirectly through the National
Cancer Institute of Canada Clinical Trials Group; contracted with
pharmaceutical companies including AstraZeneca, Bristol-Myers
Squibb, sano-aventis, Amgen, Pzer, Novartis, and GSK; has
received honoraria or been part of speakers bureaus from
sano-aventis, AstraZeneca, Pzer, Roche, Novartis, GSK, and
Amgen; has given paid expert testimony for sano-aventis,
AstraZeneca, and GSK; and has been a member on an advisory
committee for sano-aventis, AstraZeneca, Roche, Pzer, Novartis,
GSK, and Amgen. AR is a member of Global, European, and/or
French advisory boards in renal cell cancer for Pzer, Novartis,
Bayer-Schering, GSK, Astellas, Aveo, and Bristol-Myers Squibb;
has received institutional grant support from Pzer, Novartis, and
Roche; has been an international principal investigator for trials
sponsored by Novartis and Pzer; has been a member of steering
committees of trials for Pzer, Novartis, and Bristol-Myers Squibb;
and has received travel and housing support for meetings from
Novartis and Pzer.
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Annals of Oncology 25: 773780, 2014
doi:10.1093/annonc/mdt531
Published online 18 December 2013

Present and future breast cancer managementbench

to bedside and back: a positioning paper of academia,
regulatory authorities and pharmaceutical industry
R. Bartsch1,2, S. Frings3, M. Marty4, A. Awada5, A. S. Berghoff1,2, P. Conte6, S. Dickin7,
H. Enzmann8, M. Gnant2,9, M. Hasmann10, H. R. Hendriks11, A. Llombart12, C. Massacesi13,
G. von Minckwitz14,15, F. Penault-Llorca16,17, M. Scaltriti18, Y. Yarden19, H. Zwierzina20 &
C. C. Zielinski1,2* for the Biotherapy Development Association (BDA)
1
Clinical Division of Oncology/Department of Medicine I; 2Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria; 3Hoffmann-La Roche, Basel,
Switzerland; 4Centre for Therapeutic Innovations in Oncology and Haematology, Saint Louis University Hospital, Paris, France; 5Institut Jules Bordet/Medical Oncology
Clinic, Universit Libre de Bruxelles, Brussels, Belgium; 6Department of Surgery/Oncology and Gastroenterology, University of Padova, Padova, Italy; 7Eli-Lilly and
Company, Basingstoke, UK; 8BfArM Bundesinstitut fr Arzneimittel und Medizinprodukte, Bonn, Germany; 9Department of Surgery, Medical University of Vienna, Vienna,
Austria; 10Roche Diagnostics GmbH, pRED Penzberg, Penzberg, Germany; 11Hendriks Pharmaceutical Consulting, Purmerend, The Netherlands; 12Medical Oncology
Department, Arnau Vilanova Hospital, Valencia, Spain; 13Novartis, Rueil-Malmaison Cedex, France; 14German Breast Group, Neu-Isenburg; 15University Womens Hospital
Frankfurt, Frankfurt, Germany; 16Department of Pathology, Centre Jean-Perrin, Clermont-Ferrand; 17Department of Pathology, University of Auvergne, Clermont-Ferrand,
France; 18Human Oncology & Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, USA; 19Department of Biological Regulation,
Weizmann Institute of Science, Rehovot, Israel; 20Medical University of Innsbruck, Innsbruck, Austria

Received 12 April 2013; revised 29 September 2013; accepted 24 October 2013

Insights into tumour biology of breast cancer have led the path towards the introduction of targeted treatment
approaches; still, breast cancer-related mortality remains relatively high. Efforts in the eld of basic research revealed new
druggable targets which now await validation within the context of clinical trials. Therefore, questions concerning the
optimal design of future studies are becoming even more pertinent. Aspects such as the ideal end point, availability of pre-
dictive markers to identify the optimal cohort for drug testing, or potential mechanisms of resistance need to be resolved.
An expert panel representing the academic community, the pharmaceutical industry, as well as European Regulatory

*Correspondence to: Dr Christoph C. Zielinski, Clinical Division of Oncology, Department

of Medicine I, and Comprehensive Cancer Center Vienna, Medical University Vienna
General Hospital, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel: +43-1-40400-
4445; Fax: +43-1-40400-6081; E-mail: christoph.zielinski@meduniwien.ac.at

The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.