Therapeutic effect of β-blockers in triple-negative breast cancer postmenopausal women

EPIDEMIOLOGY

Therapeutic effect of b-blockers in triple-negative breast cancerpostmenopausal women

Edoardo Botteri • Elisabetta Munzone • Nicole Rotmensz • Carlo Cipolla •

Vincenzo De Giorgi • Barbara Santillo • Arnaldo Zanelotti • Laura Adamoli •

Marco Colleoni • Giuseppe Viale • Aron Goldhirsch • Sara Gandini

Received: 1 July 2013 / Accepted: 26 July 2013 / Published online: 3 August 2013

� Springer Science+Business Media New York 2013

Abstract Beta-blockers (BB) drugs have been used for

decades worldwide, mainly to treat hypertension. However, in

recent epidemiological studies, BBs were suggested to

improve cancer prognosis. In the wake of this evidence, we

evaluated the possible therapeutic effect of BBs in triple-

negative breast cancer (TNBC) patients. We identified 800

postmenopausal women operated between 1997 and 2008 for

early primary TNBC. The effect of BB intake on the risk of

breast cancer (BC) recurrence and death was evaluated

through competing risk and Cox regression survival models.

At cancer diagnosis, 74 (9.3 %) women out of 800 were BBs

users. Median age was 62 years in BB users and 59 years in

non-users (P = 0.02). BB users and non-users were similarly

distributed by all tumor characteristics. The 5-year cumulative

incidence of BC-related events was 13.6 % in BB users and

27.9 % in non-users (P = 0.02). The beneficial impact of BBs

remained statistically significant at multivariable analysis

(HR, 0.52; 95 % CI 0.28–0.97), after the adjustment for age,

tumor stage, and treatment, peritumoral vascular invasion and

use of other antihypertensive drugs, antithrombotics, and

statins. Adjusted HRs for metastases and for BC deaths were

0.32 (95 % CI 0.12–0.90) and 0.42 (95 % CI 0.18–0.97),

respectively, in favor of BBs. Hypertension, other antihyper-

tensive drugs, antithrombotics, and statins did not impact

prognosis. In this series of postmenopausal TNBC patients,

BB intake was associated with a significantly decreased risk of

BC-related recurrence, metastasis, and BC death. Innovative

therapeutic strategies including BBs should be urgently

explored in cancer patients.

Keywords Beta-blockers � Breast cancer �Triple negative � Prognosis

Introduction

Beta-blocker (BB) drugs have been used for decades

worldwide, typically to treat hypertension, coronary artery

Electronic supplementary material The online version of thisarticle (doi:10.1007/s10549-013-2654-3) contains supplementarymaterial, which is available to authorized users.

E. Botteri (&) � N. Rotmensz � B. Santillo � S. Gandini

Division of Epidemiology and Biostatistics, European Institute

of Oncology, Milan, Italy

e-mail: [email protected]

E. Munzone � M. Colleoni

Division of Medical Senology, European Institute of Oncology,

Milan, Italy

C. Cipolla � A. Zanelotti

Division of Cardiology, European Institute of Oncology,

Milan, Italy

V. De Giorgi

Department of Dermatology, University of Florence, Florence,

Italy

L. Adamoli � A. Goldhirsch

Department of Medicine, European Institute of Oncology, Milan,

Italy

G. Viale

Department of Pathology and Laboratory Medicine, European

Institute of Oncology, Milan, Italy

G. Viale

University of Milan, Milan, Italy

123

Breast Cancer Res Treat (2013) 140:567–575

DOI 10.1007/s10549-013-2654-3

http://dx.doi.org/10.1007/s10549-013-2654-3

disease, and arrhythmias [1]. Despite the therapeutic indi-

cations, evidence from recent epidemiological studies

suggested that BB intake might potentially improve prog-

nosis in patients affected by prostate [2, 3], breast [4–7],

lung [8], and ovarian [9] cancer as well as cutaneous

melanoma [10, 11]. Moreover, BB intake was reported to

reduce overall cancer incidence [12] and specific prostate

cancer risk [13]. This observed association is supported by

data coming from preclinical in vivo and in vitro studies,

which showed how b-adrenergic receptors mediate the

effect of stress hormones norepinephrine and epinephrine

on the tumor microenvironment, and how antagonists of

Table 1 Characteristics at

baseline by beta-blocker intake

BB beta-blocker, ACEI

angiotensin-converting enzyme

inhibitor, ARB angiotensin

receptor blocker, CCB calcium

channel blocker, MAST

mastectomy, QUAD

quadrantectomya Clinical stage was used for

patients undergoing

neoadjuvant chemotherapyb Among patients not receiving

neoadjuvant chemotherapy.

Numbers might not sum up to

totals due to missing values

Variable Category No BB BB P value

No. (%) No. (%)

Total 726 (90.7) 74 (9.3)

Age Median (range) 59 (30–89) 62 (48–80) 0.02

\65 506 (69.7) 42 (56.8) 0.02

C65 220 (30.3) 32 (43.2)

BMI \25 364 (60.2) 35 (52.2) 0.15

25–30 187 (30.9) 23 (34.3)

[30 54 (8.9) 9 (13.4)

Ta 1 321 (45.5) 41 (56.2) 0.34

2 285 (40.4) 22 (30.1)

3 36 (5.1) 3 (4.1)

4 64 (9.1) 7 (9.6)

Na 0 374 (53.5) 42 (57.5) 0.43

1 206 (29.5) 21 (28.8)

2/3 119 (17.0) 10 (13.7)

Ki-67 Median (range) 42 (1–95) 38 (4–90) 0.37

B40 337 (48.6) 40 (54.8) 0.32

[40 356 (51.4) 33 (45.2)

Peritumoral vascular invasion Absent 539 (76.0) 61 (83.6) 0.14

Focal 90 (12.7) 7 (9.6)

Extensive 80 (11.3) 5 (6.9)

Neoadjuvant chemotherapy No 598 (82.4) 61 (82.4) 0.99

Yes 128 (17.6) 13 (17.6)

Type of surgery MAST 168 (23.1) 15 (20.3) 0.58

QUAD 558 (76.9) 59 (79.7)

Radiotherapy No 106 (14.6) 8 (10.8) 0.37

Yes 620 (85.4) 66 (89.2)

Adjuvant chemotherapy No 117 (16.1) 10 (13.5) 0.56

Yes 609 (83.9) 64 (86.5)

Hypertension No 533 (73.4) 1 (1.3) \0.01

Yes 193 (26.6) 73 (98.7)

ACEI No use 640 (88.2) 51 (68.9) \0.01

Use 86 (11.8) 23 (31.1)

ARB No use 686 (94.5) 63 (85.1) \0.01

Use 40 (5.5) 11 (14.9)

CCB No use 677 (93.3) 61 (82.4) \0.01

Use 49 (6.7) 13 (17.6)

Diuretic No use 654 (90.1) 49 (66.2) \0.01

Use 72 (9.9) 25 (33.8)

Antithrombotics No use 710 (97.8) 65 (87.8) \0.01

Use 16 (2.2) 9 (12.1)

Statins No use 680 (93.7) 63 (85.1) \0.01

Use 46 (6.3) 11 (14.9)

568 Breast Cancer Res Treat (2013) 140:567–575

123

b-adrenergic receptors, such as BBs, can interfere with

tumor cell proliferation and migration, as well as tumoral

angiogenesis [14–17]. The general pattern of transcrip-

tional responses induced by b-adrenergic signaling

includes upregulated expression of metastasis-associated

genes involved in inflammation, angiogenesis, tissue

invasion, and epithelial–mesenchymal transition, and

downregulated expression of genes facilitating antitumor

immune responses [16].

On the basis of all this evidence, we decided to examine

the potential benefit of BB use in the subset of women

affected by triple-negative breast cancer (TNBC), which

represents one of the most aggressive and difficult-to-treat

cancers. Should the beneficial impact of BBs on prognosis

be confirmed in this and other series of TNBC patients,

innovative therapeutic strategies involving the use of BBs

are to be urgently explored.

Patients and methods

We retrospectively analyzed data of all consecutive women

diagnosed and operated for early primary TNBC between

1997 and 2008 at the European Institute of Oncology in

Milan (n = 1,464). Patients with history of any previous

invasive cancer or with metastatic disease at diagnosis

(stage IV) were previously excluded. Given the low prev-

alence (1.1 %) of BB users in premenopausal patients, we

decided to limit the analysis to postmenopausal women

only (n = 800) in order to avoid high heterogeneity

between BB users and non-users. Patients were divided

into two groups: the BB users group, which included

patients who were using any BB at the moment of their

diagnosis of TNBC, and the BB non-users group, which

included all the other patients. The data sources were the

institutional Breast Cancer Database, which collects data

on patients’ characteristics, breast cancer (BC) features and

comorbidities such as hypertension and hypercholesterol-

emia, and the Cardiology Division Database, which col-

lects information on patients’ diseases of the circulatory

system and cardiovascular drugs. In addition to BBs, we

analyzed data on statins, antithrombotics, and other anti-

hypertensive drugs such as angiotensin-converting enzyme

inhibitors, angiotensin receptor blocker, calcium channel

blocker, and diuretics. If a patient took one single drug

containing two or more different antihypertensive agents

(e.g., angiotensin-converting enzyme inhibitor plus diure-

tic), she was considered as taking two or more different

antihypertensive drugs. Use of the data for the present

study was approved by the Institutional Review Board.

TNBC was defined as a BC with negative estrogen and

progesterone receptor expression (i.e., \1 % immunore-

active tumor cells) and without overexpression of HER2/

neu. Immunohistochemical expression of HER2/neu was

scored as follows: 0 (no staining or faint membrane

staining), 1? (faint membrane staining in[10 % of tumor

cells, incomplete membrane staining), 2? (weak to mod-

erate membrane staining in[10 % of tumor cells), and 3?

(intense circumferential membrane staining in [10 % of

tumor cells). For this analysis, we included patients with

negative estrogen and progesterone receptor tumors char-

acterized by HER2/neu scores of 0 and 1?, as well as 2?

resulting negative for gene amplification by fluorescence

in situ hybridization (FISH; Vysis PathVysion; Abbott,

Chicago, IL).

For all the patients receiving pre-surgical chemotherapy

(CT) we reported the clinical stage (T and N). When

pathological complete response was obtained, pathological

data such as ER, PgR, HER2/neu, and Ki-67 were retrieved

from the initial breast lesion biopsy. Responses to pre-

surgical CT were evaluated using the Response Evaluation

Criteria in Solid Tumors (RECIST) guidelines.

Statistical analysis

Association between categorical variables and BB use was

evaluated by the Chi square test, the Fisher exact test and

Table 2 Events and follow-up by beta-blocker intake

Event No BB BB P value

No. (%) No. (%)

At risk 726 74

First events

Locala 52 (7.2) 6 (8.1) 0.77

Regionala 28 (3.9) 1 (1.3) 0.51

Distanta,b 110 (15.2) 3 (4.1) \0.01

Contralateral breast tumor 21 (2.9) 3 (4.1) 0.48

Other non-breast primary

tumor

27 (3.7) 4 (5.4) 0.52

Death from breast cancera,b 9 (1.2) 1 (1.4) 1.00

Death from other cancer 0 (0.0) 0 (0.0) –

Death from other causes 8 (1.1) 3 (4.1) 0.07

Death from missing causes 16 (2.2) 2 (2.7) 0.68

Overall mortality

Death from breast cancerc 141 (19.4) 6 (8.1) 0.02

Death from other cancerd 8 (1.1) 4 (5.4) \0.01

Death from other causesd 9 (1.2) 3 (4.1) 0.09

Death from missing causesd 17 (2.3) 2 (2.7) 0.69

Follow-up

Months, median (Q1–Q3) 68 (43–98) 72 (52–100) 0.62

Events were used for the calculation of cumulative incidence of

(a) breast cancer related events; (b) metastases; (c) breast-related

deaths; (d) deaths from causes other than breast cancer. Association

between number of events and BB use was tested by the Chi square or

the Fisher exact test, and the corresponding P value was reported

BB beta-blocker, Q1 lower quartile, Q3 upper quartile

Breast Cancer Res Treat (2013) 140:567–575 569

123

the Chi square test for trend, as appropriate. Differences in

median age and Ki-67 were tested using the non-parametric

median two sample test. Ki-67 was also dichotomized

using the median value of 40 % as cutpoint. For the cal-

culation of cumulative incidences, only first events of

interest were considered. For the cumulative incidence of

BC-related events, BC-related recurrences, and deaths

from BC were counted as events, while contralateral

tumors, non-breast primary tumors, and deaths from other

causes were considered as competing events. For the

cumulative incidence of metastases, metastases and deaths

from BC were counted as events, while loco-regional

events, contralateral tumors, non-breast primary tumors,

and deaths from other causes were considered as compet-

ing events. For the cumulative incidence BC-related

deaths, we considered deaths from other causes as com-

peting events. For the cumulative incidence non-BC

deaths, we considered deaths from BC as competing

events. Cumulative incidences were compared across dif-

ferent subgroups by means of the Gray test. Multivariable

Cox proportional hazards models were applied to evaluate

BB intake as independent prognostic factor, adjusting the

YearsYears

Years

Cum

ulat

ive

Inci

denc

e

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7

Gray test P-value: 0.017

HR* Beta-Blockers vs Beta-Blocker: 1.79 (95% CI 0.82-3.90; P-value 0.146)

* From multivariable analysis

At risk

BB 74 71 67 67 59 50 37 29

No BB 726 702 646 583 513 427 341 257

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7




At risk

BB 74 71 67 67 59 50 37 29

No BB 726 702 646 583 513 427 341 257

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7




At risk

BB 74 70 65 60 51 43 31 24

No BB 726 659 654 512 434 349 271 201

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7

Beta-Blockers



*From multivariable analysis

At risk

BB 74 70 65 60 51 43 31 24

No BB 726 659 654 512 434 349 271 201

No Beta-Blockers

Years

Cum

ulat

ive

Inci

denc

eC

umul

ativ

e In

cide

nce

Cum

ulat

ive

Inci

denc

e

Beta-BlockersNo Beta-Blockers



a b

c d

Fig. 1 a Cumulative incidence of breast cancer related events by use

of beta-blockers, b cumulative incidence of distant metastases by use

of beta-blockers, c cumulative incidence of deaths from breast cancer

by use of beta-blockers, d cumulative incidence of deaths from causes

other than breast cancer by use of beta-blockers


123

effect of BB for all the variables that were associated in

univariate analysis with BB use or with the event of

interest. Hypertension was excluded from the multivariable

models in order to avoid multicollinearity with the use of

antihypertensive drugs. Adjusted hazard ratios (HR) with

95 % confidence intervals (CIs) were reported. All analy-

ses were carried out with SAS software (SAS Institute,

Cary, NC) and R software, version 2.12.2 (http://www.r-

project.org). Results associated with P values \0.05 were

considered statistical significant. All reported P values

were two-sided.

Results

At the time of cancer diagnosis, 74 women (9.3 %) out of

800 postmenopausal women were using BBs, while 726

(90.7 %) were not. Among the 74 users, 11 were taking

Carvedilol, 3 Sotalol, 27 Atenolol, 1 Betaxolol, 11 Biso-

prolol, 8 Metoprolol, and 13 Nebivolol. In Table 1 we

reported baseline characteristics in association with BB

use, as well as information on hypertension and use of

statins, antithrombotics and antihypertensive drugs other

than BBs. Median age was 62 years for the BB users and

59 years for the non-users (P = 0.015). BB users and non-

users were similarly distributed by body mass index, cancer

characteristics, and cancer treatments. Quadrantectomy

was performed in 617 (77.1 %) cases, 33 (5.3 %) of which

without radiotherapy. Details of adjuvant CT were as fol-

lows, respectively for BB users and non-users: 23 (31.1 %)

and 199 (27.4 %) received an anthracycline containing

regimen, 26 (35.1 %) and 283 (39.0 %) classical CMF, 15

(20.3 %) and 127 (17.5 %) another regimen, while 10

(13.5 %) and 117 (16.1 %) received no CT (P = 0.763).

As expected, the presence of hypertension and the use of

other antihypertensive drugs, antithrombotics and statins

were significantly more frequent in BBs users (P \ 0.01).

Median follow-up was 72 months (interquartile range

52–100) and 68 months (48–93) in BB users and non-users,

respectively (P = 0.62). Details on first events and

Table 3 Multivariable survival analysis

BC events Metastases BC deaths

HR (95 % CI) HR (95 % CI) HR (95 % CI)

Beta-blockers Use versus No use 0.52 (0.28–0.97) 0.32 (0.12–0.90) 0.42 (0.18–0.97)

Age 1-year increase 1.00 (0.99–1.02) 0.99 (0.97–1.02) 1.01 (0.99–1.03)

Primary tumor (T) 2 versus 1 1.37 (0.96–1.95) 1.28 (0.81–2.03) 1.26 (0.80–1.96)

3/4 versus 1 2.08 (1.11–3.91) 2.53 (1.13–5.63) 2.01 (0.95–4.23)

Positive lymph nodes 1–3 versus 0 1.20 (0.80–1.80) 1.47 (0.88–2.45) 1.77 (1.08–2.90)

[3 versus 0 2.49 (1.64–3.78) 2.33 (1.33–4.07) 2.91 (1.73–4.90)

Peritumoral vascular invasion Present versus absent 1.96 (1.41–2.73) 1.88 (1.22–2.89) 1.99 (1.35–2.94)

Antihypertensive drugs other than Beta-blockers Use versus No use 0.97 (0.69–1.38) 0.83 (0.51–1.35) 0.86 (0.56–1.32)

Antithrombotics Use versus No use 1.02 (0.46–2.28) 1.60 (0.60–4.22) 1.17 (0.45–3.05)

Statins Use versus No use 1.11 (0.66–1.88) 1.12 (0.55–2.24) 0.89 (0.43–1.85)

Response to neoadjuvant chemotherapy CR/PR versus No use 1.11 (0.65–1.90) 1.08 (0.56–2.1) 1.51 (0.81–2.83)

SD/PD versus No use 2.57 (1.49–4.45) 1.30 (0.61–2.76) 2.29 (1.21–4.34)

Loco-regional treatment QUAD versus QUART 3.29 (1.89–5.74) 3.34 (1.59–6.99) 2.99 (1.59–5.66)

MAST versus QUART 1.10 (0.75–1.61) 1.25 (0.76–2.05) 1.37 (0.87–2.14)

BC breast cancer, CR complete response after neoadjuvant chemotherapy, PR partial response after neoadjuvant chemotherapy, SD stable disease

after neoadjuvant chemotherapy, PD progressive disease after neoadjuvant chemotherapy, QUAD quadrantectomy, QUART quadrantectomy and

radiotherapy, MAST mastectomy

Cum

ulat

ive

Inci

denc

e

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7

No hypertensionHypertension


Hypertension 266 249 214 190 157 125 95 70

No Hypertension 534 480 415 382 328 267 207 155

YearsAtrisk

Fig. 2 Cumulative incidence of breast cancer related events by

hypertension


123

http://www.r-project.org

http://www.r-project.org

No StatinsAny Statins


At risk

Any Statins 57 55 49 45 38 29 24 21

No Statins 743 675 580 528 449 363 278 205

No Antithrombotics Any Antithrombotics


At risk

Any Antithrombotics 25 21 21 16 14 10 7 3

No Antithrombotics 608 557 473 382 295 222

No Diuretics Any Diuretics


At risk

Any Diuretics 97 94 80 68 58 48 40 29

No Diuretics 703 635 549 505 429 344 262 196

No CCB Any CCB


At risk

Any CCB 62 58 51 44 38 24 18 16

No CCB 738 671 578 529 447 367 284 209

Years

Cum

ulat

ive

Inci

denc

e

0.0

0.1

0.2

0.3

0.4

0.5No ARBAny ARB


At risk

Any ARB 51 49 40 36 26 21 15 9

No ARB 749 680 589 537 459 371 287 216

Years

Cum

ulat

ive

Inci

denc

e

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 70 1 2 3 4 5 6 7

No ACEIAny ACEI


At risk

Any ACEI 109 101 89 80 66 56 48 37

No ACEI 691 628 540 493 419 336 254 188

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7 0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7

Cum

ulat

ive

Inci

denc

e

Cum

ulat

ive

Inci

denc

eC

umul

ativ

e In

cide

nce

Cum

ulat

ive

Inci

denc

e

Years Years

YearsYears

775 708

a b

c d

e f


123

mortality were reported in Table 2. Six (8.1 %) local

recurrences were observed in BB users and 52 (7.2 %) in

non-users (P = 0.77), while 1 (1.3 %) regional recurrence

in BB users and 28 (3.9 %) in non-users (P = 0.51). Three

(4.1 %) distant metastases were observed in BB users and

110 (15.2 %) non-users (P \ 0.01).

The 5-year cumulative incidence of BC-related events

was 13.6 % in BB users and 27.9 % in non-users

(P = 0.015; Fig. 1a). Multivariable analysis was reported

in Table 3. After adjusting for age, tumor stage, peritu-

moral vascular invasion, use of other antihypertensive

drugs, antithrombotics and statins, use of and response to

neoadjuvant chemotherapy, and loco-regional BC treat-

ment, the beneficial impact of BB use remained statistically

significant, with a HR of 0.52 (95 % CI 0.28–0.97;

P = 0.041). When analyzing the risk of distant metastases,

the HR adjusted for the same variables was 0.32 (95 % CI

0.12–0.90; P = 0.031; Fig. 1b) in favor of BBs. With

regard to mortality, 6 (8.1 %) BC-related deaths were

observed in BB users and 141 (19.4 %) in non-users, with a

corresponding adjusted HR of 0.42 (95 % CI 0.18–0.97;

P = 0.042; Fig. 1c). Causes of death other than cancer

were as follows: 2 circulatory system disease and 1

myelodysplastic syndrome in BB users; 2 circulatory sys-

tem disease, 1 pulmonary embolism, 1 head trauma, 1 old

age, 1 renal failure, and 3 causes different from BC not

better specified in BB non-users. At univariate analysis, the

risk of death from causes other than BC (other cancer,

other cause and missing cause) was higher in BB users

compared with non-users, but the difference was not sta-

tistically significant after the adjustment for age, antihy-

pertensive and antithrombotic drugs (HR: 1.79; 95 % CI

0.82–3.90; P value 0.146; Fig. 1d). Hypertension, antihy-

pertensive drugs other than BBs, antithrombotics, and

statins did not have any significant effect on the risk of BC-

related events (Figs. 2, 3).

In Supplementary Figure 1 we reported the effect of BB

use on BC-related events in various subgroups of patients.

BBs showed a protective effect in all subgroups (HR \ 1),

even if some HR estimates were not statistically significant,

possibly due to reduced numbers of events. No significant

interaction between BB use and any of the reported vari-

ables was identified. Finally, as shown in Supplementary

Table 1, in the subgroup of patients receiving neoadjuvant

CT, response to therapy was not statistically different by

BB intake.

Discussion

In this large series of postmenopausal women affected by

TNBC, we found that BB intake was associated with a

significantly decreased risk of BC recurrence and death.

Being the TNBC one of the most aggressive and difficult-

to-treat cancers, these findings might be of major clinical

relevance.

Mechanisms through which BB drugs could enhance

cancer patients’ prognosis were explained in preclinical

studies, through in vitro and in vivo models [18–22]. The

sympathetic nervous system mediates the acute stress

response by regulating levels of norepinephrine and epi-

nephrine in organ tissues and circulating blood. Those two

stress hormones interfere with the tumor microenvironment

by modulating the function of several cancer-relevant cell

types, such as epithelial, myocytes and pericytes, adipo-

cytes, fibroblasts, neural and glial cells, and most lym-

phoid, and myeloid immune cells [22]. Ligation of

b-receptors by norepinephrine and epinephrine leads to

activation of Protein kinase A (PKA) which in turn regu-

lates a wide variety of cellular processes by activating

transcription factors and downstream kinases with conse-

quent modulation of cell trafficking and motility as well as

cellular resistance to apoptosis. In a preclinical study on

BC, norepinephrine was shown to be a potent inducer of

migratory activity [21]. Also, b-adrenergic antagonists

have been found to block stress-induced enhancement of

tumor progression and metastasis, while b-adrenergic

agonists have also been found to accelerate in vivo tumor

progression and metastasis in the absence of stress [22].

Therefore, BB drugs might have a role in weakening the

pro-migratory and pro-metastatic effects induced by stress

hormones.

Our findings on BB use in TNBC patients are in

agreement with studies reporting a beneficial prognostic

role of BBs in patients with prostate [2, 3], breast [4–7],

lung [8], and ovarian [9] cancer as well as cutaneous

melanoma [10, 11]. One study reported a null association

between BB use and risk of developing colorectal cancer

[23]. A very recent large study [24] reporting data from the

Danish Breast Cancer Cooperative Group registry showed

a protective effect of BB use on BC recurrence in univar-

iate analysis and a detrimental effect in multivariable

analysis. The switch from protective to detrimental effect

was mainly due to the adjustments for use of simvastatin

and ARB in the multivariable model. That switch was not

observed in our analysis. Unfortunately, the authors did not

Fig. 3 a Cumulative incidence of breast cancer related events by use

of angiotensin-converting enzyme inhibitor, b cumulative incidence

of breast cancer related events by use of angiotensin receptor blocker,

c cumulative incidence of breast cancer related events by use of

calcium channel blocker, d cumulative incidence of breast cancer

related events by use of diuretics, e cumulative incidence of breast

cancer related events by use of antithrombotics, f cumulative

incidence of breast cancer related events by use of statins. ACEI

angiotensin-converting enzyme inhibitor, ARB angiotensin receptor

blocker, CCB calcium channel blocker

b


123

report results for the subgroups of TNBC patients. Since

the effect of BB on BC prognosis was reported to vary

according to BC molecular subtypes [4], the stratification

according to ER/PgR status as well as HER/neu status

might have possibly led to different conclusions. Finally, of

particular interest, Melhem-Bertrandt et al. [4] showed a

significant protective effect of BB use on relapse-free

survival in a series of 377 TNCB patients, with an adjusted

HR of 0.30 in favor of BB use. That finding was obtained

from a subgroup analysis performed on patients with

TNBC treated with neoadjuvant CT. In accordance to that

finding, when we limited the analysis to TNBC patients

who underwent neoadjuvant CT, we obtained an adjusted

HR of 0.36 in favor of BB (Supplementary Fig. 1). The

authors did not find any potential beneficial effect of BB on

prognosis in estrogen receptor-positive breast cancer

patients. The observed null effect could be due to the

presence of the ER and the use of ER targeting drugs that

may modulate the response to BB.

Interestingly, we did not observe fewer loco-regional

recurrences in BB users in comparison with non-users,

while we found a protective effect of BBs on the risk of

distant metastases and breast-specific mortality. This dif-

ferential effect of BBs on different types of recurrence

could be due to the fact that stress hormone norepinephrine

was shown to be a potent inducer of migratory activity,

with no or little effect on primary tumor growth [21].

Hypothetically, this mechanism might also explain why we

did not find any significant difference between BB users

and non-users in the response to pre-surgical CT. Our

findings on response to pre-surgical CT are consistent with

those reported in the paper by Melhem-Bertrandt et al. [4].

The main strengths of our study are the large size of the

population and its homogeneity, given by the selection of

early primary TNBC diagnosed and operated in one single

institution. An additional strong point of the study was that

BB users and non-users were uniformly distributed by

tumor characteristics and cancer treatments. Also, the

inclusion of TNBC only prevented possible biases due to

interaction between BBs and hormone or anti-HER2/neu

therapies. Moreover, for the analyses of events, we used

competing risk models to take into account the different

types of recurrences as well as the different causes of

death, and these analyses allowed us to highlight the dif-

ferential effect of BBs on different types of recurrence and

the specific effect of BBs on deaths due to BC rather than

deaths due to other causes.

Despite these strengths, the present study has some clear

limitations, apart from the ones linked to the retrospective

design. First of all, we could not retrieve information on

BB use before and after the diagnosis of TNBC. Therefore,

patients that were using BBs at the time of diagnosis might

have quit the medication after BC diagnosis, possibly

switching to different antihypertensive drugs; on the other

hand, patients who were not currently using BB at TNBC

diagnosis, could have started after. Also, the association

between duration of BB use and prognosis could not be

determined. Moreover, possibly not all the patients

receiving BBs at BC diagnosis were correctly identified,

and this would likely have lead to a dilution of the risk

estimates. However, our proportion of BB users was sim-

ilar to the ones reported in other groups of postmenopausal

BC patients [4–6]. Another potential flaw is that BB users

were older than non-users. It is to say, though, that 3 years

difference in median age has no or little clinical relevance

and that all the reported analyses were adjusted for age.

In conclusion, in this series of women affected by

TNBC, BB intake was associated with a significantly

decreased risk of BC recurrence and death. On the basis of

all the extensive preclinical and clinical evidence, and

given the limited number of treatment options in TNBC

patients, we believe that innovative therapeutic strategies,

including BBs, should be urgently explored.

Conflict of interest None.

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Therapeutic effect of β-blockers in triple-negative breast cancer postmenopausal women

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