surgical management of breast cancer in brca-mutation ......review surgical management of breast...

REVIEW

Surgical management of breast cancer in BRCA-mutationcarriers: a systematic review and meta-analysis

Antonis Valachis • Andreas D. Nearchou •

Pehr Lind

Received: 14 September 2013 / Accepted: 17 February 2014! Springer Science+Business Media New York 2014

Abstract This meta-analysis investigates the oncologicalsafety of breast-conserving therapy BCT in BRCA-muta-

tion carriers and the risk for contralateral breast cancer

(CBC) compared with non-carriers, potential risk factorsfor ipsilateral breast recurrence (IBR) or CBC and grades

these factors based on the level of evidence. A PubMed

search was conducted through April 2013 to identifystudies that described the risk for IBR and CBC after BCT

in BRCA-mutation carriers versus non-carriers as well as

studies that investigated risk factors for IBR and CBC inBRCA-mutation carriers. Results were summarized using

meta-analysis when sufficient studies were available. Ten

studies investigated the oncological safety of BCT inBRCA-mutation carriers versus non-carriers. There was no

significant difference in IBR between carriers and controls

(RR 1.45, 95 % CI 0.98–2.14). However, a significanthigher risk for IBR in BRCA-mutation carriers was

observed in studies with a median follow-up C7 years (RR

1.51, 95 % CI 1.15–1.98). CBCs were significantly greaterin carriers versus controls (RR 3.56, 95 % CI 2.50–5.08).

Use of adjuvant chemotherapy and oophorectomy wereassociated with a significantly lower risk for IBR in

BRCA-mutation carriers. Three factors were associated

with a lower risk for CBC in BRCA-mutation carriers:oophorectomy, use of tamoxifen, and age at first breast

cancer. Based on current evidence, the use of BCT in

BRCA-mutation carriers can be considered a reasonableoption since it does not seem to increase the risk for IBR.

However, several aspects should be taken into account

before the final decision-making.

Keywords BRCA ! Breast cancer ! Breast-conserving

therapy ! Meta-analysis

Introduction

BRCA-mutation carriers have a lifetime estimate of breast

cancer that ranges from 36 to 90 % [1, 2]. For women

without mutation, breast-conserving therapy (BCT), whichrefers to breast-conserving surgery (BCS) followed by

radiation therapy (RT), is the treatment of choice since itoffers similar survival to that of unilateral mastectomy [3].

However, after a breast cancer diagnosis in BRCA-muta-

tion carriers is established, the optimal local managementremains a matter of debate. These patients are facing the

difficult question to choose among BCS, unilateral mas-

tectomy, or unilateral therapeutic mastectomy with con-comitant contralateral prophylactic mastectomy.

Several aspects should be taken into account before the

decision-making: The risk of ipsilateral breast recurrence(IBR), the risk of contralateral breast cancer (CBC), the

potential survival benefit of prophylactic mastectomy, and

the possible risk factors that could either increase ordecrease the risk for IBR or CBC. Several studies, mostly

Electronic supplementary material The online version of thisarticle (doi:10.1007/s10549-014-2890-1) contains supplementarymaterial, which is available to authorized users.

A. Valachis (&) ! A. D. Nearchou ! P. LindDepartment of Oncology, Malarsjukhuset, 63188 Eskilstuna,Swedene-mail: [email protected];[email protected]

A. ValachisCentre for Clinical Research Sormland, Uppsala University,Uppsala, Sweden

P. LindKarolinska Institute, 11883 Stockholm, Sweden

123

Breast Cancer Res Treat

DOI 10.1007/s10549-014-2890-1

http://dx.doi.org/10.1007/s10549-014-2890-1

retrospective, have tried to clarify these questions but the

results are conflicting and prone to biases due to the natureof such studies and the small sample size [4–16].

The purpose of our study was to gather all the available

evidence on the topic in order to investigate the oncolog-ical safety of BCT in BRCA-mutation carriers, the risk for

CBC, to identify potential risk or protective factors for IBR

or CBC and to grade the factors based on the quality ofevidence.

Materials and methods

Search strategy

This meta-analysis was conducted in accordance with themeta-analysis of observational studies in epidemiology

(MOOSE) guidelines [17].

We conducted a comprehensive systematic electronicsearch through MEDLINE, without year or language

restriction, using the following keywords: ‘‘BRCA’’,

‘‘breast-conserving therapy’’, ‘‘BCT’’, ‘‘radiotherapy’’,‘‘recurrence’’, ‘‘contralateral’’, ‘‘breast cancer’’. The last

search was updated on April 2013.

We also conducted secondary referencing by manuallyreviewing reference lists of potentially eligible articles.

Additionally, the bibliographies of selected review articles

were reviewed to ensure that other relevant publicationswere included.

In studies with multiple publications from the same

patient sample, only data from the most recent publicationwere included in the systematic review and in meta-

analysis.

Study selection

Studies were included in our systematic review if they ful-filled one of the following criteria: (1) cohort or case–control

studies that compared the risk of IBR [as well as breast

cancer-specific survival (BCSS) or overall survival (OS) ifavailable] after BCT in BRCA-mutation carriers versus non-

carriers; (2) cohort or case–control studies that compared the

risk of IBR (as long as BCSS or OS if available) in BRCA-mutation carriers who underwent mastectomy versus BCS;

(3) cohort or case–control studies that compared risk for

CBC after BCT in BRCA-mutation carriers versus non-carriers; (4) cohort or case–control studies that compared the

risk of IBR or CBC in BRCA1-mutation carriers versus

BRCA2-mutation carriers; (5) studies that investigated riskfactors for IBR or CBC after BCT in BRCA-mutation car-

riers; and (6) studies that compared the BCSS or OS in

BRCA-mutation carriers if a contralateral prophylacticmastectomy was performed or not.

For the criterion (5), we included only studies that

identified risk factors obtained from multivariable analysesthat were adjusted for at least 1 potential confounder.

However, we included studies that calculated the cumula-

tive risk for CBC according to age to first breast cancerdiagnosis (age as risk factor for CBC) even if a multivar-

iable analysis was not perform.

We excluded case reports and studies that only includedBRCA-mutation carriers without control group and did not

investigate risk factors for IBR or CBC. In addition, weexcluded studies that have been presented at scientific

meetings only and have not been published in full-text.

Data extraction and quality assessment

For the included studies, two reviewers (AV, AN)abstracted the data independently on a predefined form.

Differences between reviewers were resolved by discus-

sion. The following data were collected from each study;first author’s last name, year of publication, country of

origin, type of study (retrospective/prospective, cohort/

case–control), matching criteria (in case of case–controlstudy), years of follow-up, number of patients, median age,

T status, N status, ER status, tumor grade, type of adjuvant

therapy, number of IBR, number of true recurrences, i.e.,defined as recurrence with same histology with primary

breast cancer and located to the same quadrant, number of

new primary cancer, i.e., defined as breast cancer in dif-ferent quadrant than the one in primary cancer or with

different histology, number of CBC, number of deaths, risk

factors with adjustment for at least 1 potential confounderin multivariate analysis, for IBR or CBC.

Two investigators (AV, AN) independently assessed

each eligible study for methodological quality using a16-item checklist that selected from a bank of items for

evaluating the risk of bias of observational studies [18]

(ESM Appendix Table). Each item of a selected study wasassigned one point, with the highest possible score for any

one study being 16. Studies scoring more than 12 points,

i.e.,[75 % or more of the maximum attainable score, wererated as high quality, studies scoring 8–11 points were

rated as moderate quality, and studies scoring 7 or fewer

points (lower than 50 % of maximum attainable score)were regarded as low quality.

Furthermore, we categorized the risk factors into four

levels of evidence, i.e., high, moderate, low, or inconclusive,depending on consistency of findings, i.e., the degree of

similarity in the effect sizes of the different studies, and

quality and quantity of studies contributing to findings.Level of evidence for risk factors was defined as follows:

High, in case of consistent findings including at least two

high-quality studies; moderate, in case of consistent findingsincluding one high-quality study; low, in case of inconsistent


123

result or consistent results without a high-quality study;

inconclusive, if there is only one eligible study.

Data synthesis and analysis

We calculated the pooled rate for each outcome (number of

IBR or CBC) along with the corresponding 95 % confi-

dence intervals (CI). We proceeded to the calculation ofpooled effect estimates and their 95 % CI if there were at

least two studies with sufficient data in each outcome ofinterest.

The number of IBR or CBC in BRCA-mutation carriers

and non-carriers were retrieved from each primary studyand 2 9 2 tables were constructed. We calculated an

overall effect estimate for all dichotomous data as a risk

ratio (RR) with 95 % CI. We assessed the presence ofstatistical heterogeneity among the studies using the Q

statistics and the magnitude of heterogeneity using the I2

statistic. We considered a p value \0.10 or an I2 value ofgreater than 50 % as indicative of substantial heterogene-

ity. When substantial heterogeneity was not observed, the

pooled RR calculated based on the fixed-effects modelusing the Mantel–Haenszel method. When substantial

heterogeneity was observed, the pooled RR calculated

based on the random-effects model was reported using theDerSimonian and Laird method.

For the time-to-event outcomes (BCSS, OS), we per-

formed a meta-analysis first by transforming the hazardratio (HR) and their errors into their log counterparts, and

then using the inverse variance method and then trans-

formed back into the HR scale.For each risk factor, we abstracted odds ratios (ORs),

HRs, or RRs and associated 95 % CIs, based only on

factors obtained from multivariable analyses that wereadjusted for at least 1 potential confounder. Results were

summarized using meta-analysis when at least two studies

were available.We performed the following subgroup analyses in the

meta-analysis of IBR: by study design (case–control vs.

cohort studies); by median follow-up time (C7 vs.\7 years). We chose this follow-up cut-off because it has

been shown in large series that the median time to breast

relapse due to new primary cancer is about 7 years [19–21]. Thus, we hypothesized that if we observed a higher

rate of IBR for BRCA-mutation carriers in studies with

longer than those with shorter follow-up, this could beindirect evidence that BRCA-mutation carriers are at

higher risk for new primary cancer after BCT rather than a

true breast cancer recurrence. In addition, two separatepooled estimates have been calculated for new primary

cancer and true recurrence, respectively. Regarding the

meta-analysis of CBC, we performed a subgroup analysisbased on the study design (case–control vs. cohort studies).

The presence of publication bias was evaluated quali-

tatively using a funnel plot. All reported p values are2-sided, with significance set at p \ 0.05. All statistical

analyses were performed with RevMan 5.0.

Results

Eligible studies

A total of 755 abstracts were identified with the search

criteria; of these, 36 full-text articles were reviewed as

potentially eligible and 23 met the inclusion criteria(Fig. 1). Of the 23 eligible studies, 11 met the criterion (1)

[4–10, 14, 15, 22, 23], 11 the criterion (3) [4–10, 14–16,

23], eight the criterion (4) [4, 7, 12, 15, 24–27], 10 thecriterion (5) [11, 12, 14, 15, 24, 25, 28–31], and two the

criterion (6) [4, 32] (Fig. 1).

The characteristics of the eligible studies, including thequality assessment, are listed in Table 1.

Risk for IBR after BCT: BRCA-mutation carriersversus non-carriers

Ten studies (6 cohort and 4 case–control studies) investi-gated the risk for IBR after BCT in BRCA-mutation car-

riers versus non-carriers. In total, 526 patients with BRCA-

mutation and 2320 controls were included in the meta-analysis. The pooled rates of IBR for BRCA-mutation and

controls were 17.3 % (95 % CI 11.4–24.2 %) and 11 %

755 potentially relevant studiesidentified and screened for retrieval from electronic search

36 studies retrieved in full text

719 studies excluded on basis of title or abstract

23 eligible studies included in systematic review and meta-analysis according to inclusion criteria:

Criterion 1: 11 studies Criterion 2: 1 study Criterion 3: 11 studies Criterion 4: 8 studies Criterion 5: 10 studies Criterion 6: 2 studies

13 studies excluded based on exclusion criteria: 7 with duplicate results 3 without separate data for BCT 3 reviews

Fig. 1 Flow chart diagram of study selection


123

Tab

le1

Ch

arac

teri

stic

so

fel

igib

lest

ud

ies

Au

tho

r(y

ear)

Stu

dy

des

ign

Co

un

try

/et

hn

icit

yS

tud

ied

po

pu

lati

on

Mu

tati

on

No

of

pat

ien

ts(B

RC

A-

carr

iers

/no

n-

carr

iers

)

Ou

tco

me

mea

sure

sF

oll

ow

-up

,y

ears

Ris

kfa

cto

rsa

Stu

dy

Qu

alit

y

Bre

kel

man

set

al.

[4]

Ret

rosp

ecti

ve

case

–co

ntr

ol

Th

eN

eth

erla

nd

sP

atie

nts

wit

hb

reas

tca

nce

ran

dB

RC

A-

mu

tati

on

fro

mR

ott

erd

amF

amil

yC

ance

rC

lin

icv

ersu

sco

ho

rto

fsp

ora

dic

case

sm

atch

edfo

rag

ean

dy

ear

of

dia

gn

osi

s

BR

CA

1an

dB

RC

A2

26

0/7

59

IBR

,C

BC

,B

CS

Saf

ter

pro

ph

yla

ctic

ver

sus

ther

apeu

tic

mas

tect

om

y

4.3

(BR

CA

1),

4.3

(BR

CA

2),

5.1

(sp

ora

dic

)

NP

Mo

der

ate

Ch

app

uis

etal

.[5

]R

etro

spec

tiv

eco

ho

rtC

anad

a/A

shk

enaz

iJe

wis

h

Co

nse

cuti

ve

Ash

ken

azi

Jew

ish

wo

men

wit

hp

rim

ary

bre

ast

can

cer

trea

ted

ato

ne

Gen

eral

Ho

spit

al

BR

CA

1an

dB

RC

A2

32

/17

0IB

R,

CB

C6

.4N

PM

od

erat

e

El-

Tam

er[7

]R

etro

spec

tiv

eco

ho

rtU

SA

/Jew

ish

US

AC

olu

mb

ia-P

resb

yte

rian

Co

mp

reh

ensi

ve

Bre

ast

Cen

tre,

pat

ien

tsy

ou

ng

erth

an6

5y

ears

of

age

and

of

Jew

ish

des

cen

t

BR

CA

1an

dB

RC

A2

51

/43

6IB

R,

CB

C4

.2N

PL

ow

Gar

cia-

Eti

enn

eet

al.

[8]

Ret

rosp

ecti

ve

case

–co

ntr

ol

Ital

yA

llp

atie

nts

wit

hB

RC

A-m

uta

tio

nfo

llo

wed

atth

eE

uro

pea

nIn

stit

ute

of

on

colo

gy

,M

ilan

,It

aly

ver

sus

spo

rad

icca

sed

trea

ted

atth

esa

me

inst

itu

tio

n(m

atch

ing

for

age,

size

of

tum

or,

yea

ro

fsu

rger

y)

BR

CA

1an

dB

RC

A2

54

/16

2IB

R,

CB

C4

NP

Mo

der

ate

Gra

eser

[24]

Ret

rosp

ecti

ve

coh

ort

Ger

man

yP

atie

nts

wit

hu

nil

ater

alb

reas

tca

nce

rfr

om

fam

ilie

sw

ith

kn

ow

nB

RC

A-

mu

tati

on

sfr

om

the

Ger

man

Co

nso

rtiu

mfo

rH

ered

itar

yB

reas

tan

dO

var

ian

Can

cer

BR

CA

1an

dB

RC

A2

1,0

42

CB

C,

risk

fact

ors

for

CB

C

NR

Ag

eat

dia

gn

osi

sL

ow

Gro

nw

ald

etal

.[2

8]R

etro

spec

tiv

eca

se–

con

tro

l1

0co

un

trie

sA

llp

atie

nts

wit

hu

nil

ater

alan

db

ilat

eral

bre

ast

can

cer

and

kn

ow

nB

RC

A-

mu

tati

on

BR

CA

1an

dB

RC

A2

28

5(b

ilat

eral

bre

ast

can

cer)

/75

1(u

nil

ater

alb

reas

tca

nce

r

Ris

kfa

cto

rsfo

rC

BC

7.4

No

tu

sin

gad

juv

ant

tam

ox

ifen

Mo

der

ate

Haf

fty

[9]

Ret

rosp

ecti

ve

coh

ort

US

AA

llp

atie

nts

wit

hb

reas

tca

nce

rd

iag

no

sed

atag

e4

2y

ears

or

yo

un

ger

fro

mo

ne

Un

iver

sity

Ho

spit

al

BR

CA

1an

dB

RC

A2

22

/10

5IB

R,

CB

C1

4.0

(BR

CA

),1

2.8

(sp

ora

dic

)

NP

Mo

der

ate

Kir

ov

aet

al.

[10

]R

etro

spec

tiv

eca

se–

con

tro

lF

ran

ceW

om

enw

ith

afa

mil

yh

isto

ryo

fb

reas

tan

d/o

ro

var

ian

can

cer,

trea

ted

wit

hB

CT

ato

ne

Inst

itu

tev

ersu

sco

ntr

ol

(mat

chin

gfo

rag

eat

dia

gn

osi

s,y

ear

of

trea

tmen

t,an

dp

erio

do

ffo

llo

w-u

p)

BR

CA

1an

dB

RC

A2

27

/26

1IB

R,

CB

C,

OS

13

.4N

PL

ow


123

Tab

le1

con

tin

ued

Au

tho

r(y

ear)

Stu

dy

des

ign

Co

un

try

/et

hn

icit

yS

tud

ied

po

pu

lati

on

Mu

tati

on

No

of

pat

ien

ts(B

RC

A-

carr

iers

/no

n-

carr

iers

)

Ou

tco

me

mea

sure

sF

oll

ow

-up

,y

ears

Ris

kfa

cto

rsa

Stu

dy

Qu

alit

y

Mal

on

eet

al.

[29]

Ret

rosp

ecti

ve

case

–co

ntr

ol

5d

iffe

ren

tca

nce

rre

gis

trie

sfr

om

Den

mar

kan

dU

SA

Pat

ien

tsw

ith

un

ilat

eral

and

bil

ater

alb

reas

tca

nce

rb

efo

reth

eag

eo

f5

5.

All

pat

ien

tste

sted

for

BR

CA

-mu

tati

on

BR

CA

1an

dB

RC

A2

18

1/1

,92

2R

isk

fact

ors

for

CB

CN

RA

ge

atd

iag

no

sis

Mo

der

ate

Mav

add

atet

al.

[25]

Pro

spec

tiv

eco

ho

rtU

KP

rosp

ecti

ve

reg

iste

ro

fm

uta

tio

nca

rrie

rsre

ferr

edfo

rg

enet

icte

stin

gat

clin

ical

gen

etic

sce

nte

rsin

the

Un

ited

Kin

gd

om

and

Irel

and

BR

CA

1an

dB

RC

A2

34

0(B

RC

A1

)/3

09

(BR

CA

2)

Ris

kfa

cto

rsfo

rC

BC

2.1

(BR

CA

1),

1.8

(BR

CA

2)

No

tp

erfo

rmin

go

op

ho

rect

om

yH

igh

Met

calf

eet

al.

[11]

Ret

rosp

ecti

ve

coh

ort

Can

ada

Pat

ien

tsw

ith

stag

eI

or

IIb

reas

tca

nce

r,fo

rw

ho

ma

BR

CA

1o

rB

RC

A2

mu

tati

on

had

bee

nid

enti

fied

inth

efa

mil

yfr

om

10

par

tici

pat

ing

can

cer

gen

etic

scl

inic

s

BR

CA

1an

dB

RC

A2

81

0R

isk

fact

ors

for

CB

C1

1.5

Ag

eat

dia

gn

osi

s\

50

yea

rso

ld,

no

tp

erfo

rmin

go

op

ho

rect

om

y

Hig

h

Met

calf

eet

al.

[12]

Ret

rosp

ecti

ve

coh

ort

Can

ada

Pat

ien

tsw

ith

stag

eI

or

stag

eII

bre

ast

can

cer

wit

hip

sila

tera

lb

reas

tan

dfo

rw

ho

ma

BR

CA

1o

rB

RC

A2

mu

tati

on

had

bee

nid

enti

fied

inth

efa

mil

yfr

om

10

par

tici

pat

ing

can

cer

gen

etic

scl

inic

s

BR

CA

1an

dB

RC

A2

39

6R

isk

fact

ors

for

IBR

10

.5N

ot

per

form

ing

oo

ph

ore

cto

my

,n

ot

per

form

ing

rad

ioth

erap

yaf

ter

BC

S

Hig

h

Pie

rce

etal

.[1

3]

Ret

rosp

ecti

ve

coh

ort

9in

stit

uti

on

sfr

om

5co

un

trie

s(U

SA

,Is

rael

,S

pai

n,

Au

stra

lia,

New

Zea

lan

d)

Pat

ien

tsw

ith

aB

RC

A1

or

BR

CA

2m

uta

tio

nan

dst

ages

I–II

Ib

reas

tca

nce

rtr

eate

dw

ith

eith

erB

CT

or

mas

tect

om

y

BR

CA

1an

dB

RC

A2

30

2(B

CT

)/3

53

(mas

tect

om

y)

IBR

,C

BC

,B

CS

S,

OS

8.2

(BC

T),

8.9

(mas

tect

om

y)

NP

Mo

der

ate

Pie

rce

etal

.[1

4]

Ret

rosp

ecti

ve

case

–co

ntr

ol

11

inst

itu

tio

ns

fro

m3

cou

ntr

ies

(US

A,

Can

ada,

Isra

el)

Pat

ien

tsw

ith

stag

eI/

IIb

reas

tca

nce

ran

dB

RC

A1

/2m

uta

tio

ns

trea

ted

wit

hB

CT

ver

sus

spo

rad

icco

ntr

ols

fro

mth

esa

me

inst

itu

tio

ns

(mat

chin

gb

yag

e,d

ate

of

dia

gn

osi

s,

BR

CA

1an

dB

RC

A2

16

0/4

45

IBR

,C

BC

,ri

skfo

rIB

R,

risk

for

CB

C

7.9

(BR

CA

),6

.7(s

po

rad

ic)

Ag

e(I

BR

),n

ot

usi

ng

adju

van

tch

emo

ther

apy

(IB

R),

no

tu

sin

gad

juv

ant

tam

ox

ifen

(CB

C)

Lo

w

Pie

rce

etal

.[2

2]

Ret

rosp

ecti

ve

case

–co

ntr

ol

9in

stit

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123

(95 % CI 6.5–15.4 %), respectively. We found no signifi-

cant difference in IBR between carriers and controls (RR1.45, 95 % CI 0.98–2.14, p value = 0.07) (Fig. 2).

Only two studies (893 patients) presented separate data

on true recurrences and new primary cancer. We found nosignificant increase in true recurrences (RR 1.37, 95 % CI

0.44–4.21, p value = 0.59) but a trend for higher new pri-

mary cancers (RR 2.07, 95 % CI 0.99–4.36, p value = 0.05)in BRCA-mutation carriers versus non-carriers.

We performed a subgroup analysis based on the median

follow-up time and found that there was no difference inIBR risk for BRCA-mutation carriers versus non-carriers in

studies with a median follow-up\7 years (6 studies; 1,212

patients) (11.7 % for BRCA-mutation carriers with 95 %CI 8.2–15.6 and 8.9 % for controls with 95 % CI

4.8–14.2 %, RR 1.38, 95 % CI 0.53–3.60, p value = 0.51)

while a significant higher risk for IBR in BRCA-mutationcarriers was observed in studies a with median follow-up

C7 years (5 studies; 1,634 patients) (23.7 % for BRCA-

mutation carriers with 95 % CI 12.1–37.8 and 15.9 % forcontrols with 95 % CI 8.7–24.8 %, RR 1.51, 95 % CI

1.15–1.98, p value = 0.003) (p value for interaction 0.09).

Risk for IBR: BRCA1-mutation carriers

versus BRCA2-mutation carriers

Four studies (405 BRCA1-mutation and 203 BRCA2-

mutation carriers) [4, 7, 12, 26] included in the meta-

analysis of risk for IBR according to type of gene mutation.

No difference was observed in risk for IBR betweenBRCA1 and BRCA2 mutation carriers (RR 0.76, 95 % CI

0.49–1.16, p value = 0.20).

BCSS and OS after BCT: BRCA-mutation carriers

versus non-carriers

Two studies [10, 22] investigated the OS after BCT

between BRCA-mutation carriers and non-carriers and two

the BCSS [15, 22]. However, it was unable to perform ameta-analysis on this question due to the lack of sufficient

data from primary studies.

Regarding OS, no difference between carriers and non-carriers was observed in the two eligible studies. The first

study [10] had the longest follow-up (161 months) and

revealed no difference in OS using Kaplan–Meier curve(no p value or survival rates were reported). The other

study [22], with a median follow-up of 5.3 years for the

mutation-carriers, found that the 5-year overall survivalrate was 86 % for carriers and 91 % for non-carriers but

this was not statistically significant.

Regarding BCSS, conflicted results were observed in thetwo eligible studies. The first study [22] (median follow-

up: 5.3 years) found no difference in the 5-year BCSS rate

between the two groups (92 % for carriers versus 91 % fornon-carriers) while the second one [15] (median follow-up

116 months) revealed a significantly higher risk for death

Fig. 2 Forest plot of risk for ipsilateral breast recurrence: BRCA mutation carriers versus non-carriers


123

due to breast cancer in patients with BRCA-mutation (HR

on multivariable analysis: 2.39, 95 % CI 1.20–4.75).

Risk for IBR in BRCA mutation carriers: Mastectomy

versus BCT

Only one study [13] investigated the risk for IBR in BRCA

mutation carriers after mastectomy versus BCT. Patientswho underwent BCT had higher risk for IBR than patients

with mastectomy (15-year cumulative estimated risk 23.5vs. 5.5 %). However, both BCSS and OS were similar

between the two groups at 15 years (93.5 vs. 92.8 and 91.8

and 89.8 %, respectively).

Risk factors for IBR after BCT in BRCA-mutation

carriers

Two studies [12, 14] (556 BRCA-mutation carriers)

investigated potential risk factors for IBR after BCT inBRCA-mutation carriers and fulfilled our criteria as eligi-

ble studies for the meta-analysis. Of these studies, one was

high quality [12] and the other moderate quality [14]. Twofactors were found to be protective against IBR and were

supported by a moderate level of evidence; the use of

adjuvant chemotherapy (RR 0.51, 95 % CI 0.31–0.84), andto undergo oophorectomy (RR 0.42, 95 % CI 0.22–0.81).

The use of adjuvant tamoxifen was not significantly asso-

ciated with IBR (level of evidence: moderate). We identi-fied inconclusive evidence to lend support to other risk

factors (Table 2).

Risk for CBC: BRCA-mutation carriers versus non-

carriers

Eleven studies (7 cohort and 4 case–control studies) pre-

sented data on the risk for CBC between BRCA-mutation

carriers and non-carriers (807 carriers and 3,163 non-car-riers). The pooled rates of CBC for BRCA-mutation and

controls were 23.7 % (95 % CI 17.6–30.5 %) and 6.8 %

(95 % CI 4.2–10 %), respectively. Patients with BRCA-mutation had a higher risk for CBC compared with non-

carriers (RR 3.56, 95 % CI 2.50–5.08, p value \0.001)

(Fig. 3).

Risk for CBC: BRCA1-mutation versus BRCA2-

mutation carriers

Seven studies [4, 7, 15, 24–27] investigated the risk for

CBC between BRCA1-mutation and BRCA2-mutationcarriers (1,532 BRCA1-mutation carriers, 950 BRCA2-

mutation carriers). BRCA1-mutation carriers had an

increased risk for CBC compared to BRCA2-mutationcarriers (21.1 % for BRCA1-mutation carriers with 95 %

CI 15–28.2 % and 15.1 % for controls with 95 % CI

10–21 %, RR 1.42, 95 % CI 1.01–1.99, p value = 0.04).

Risk factors for CBC in BRCA-mutation carriers

Six studies [11, 14, 15, 25, 28, 30] investigated potential

risk factors for CBC in BRCA-mutation carriers and ful-

filled the criteria for inclusion in the meta-analysis. Apartfrom these studies, three additional studies [24, 29, 31]

Table 2 Summary of risk factors from multivariable analyses for ipsilateral breast recurrence after breast-conserving therapy in BRCA-mutationcarriers

Risk factors No ofstudies(patients)

IBR hazard ratio(95 % CI)

Heterogeneity Studies by quality Consistency Level ofevidence

I2

(%)p value High Moderate Low

Age (continuous) 1 (160) 0.96 (0.92–0.99) – – 0 1 0 – Inconclusive

Age [50 years old 1 (396) 0.69 (0.27–1.77) – – 1 0 0 –

Positive margins 1 (160) 0.76 (0.18–3.19) – – 1 0 0 – Inconclusive

Positive ER-status 1 (396) 1.74 (0.71–4.25) – – 1 0 0 – Inconclusive

Grade III 1 (396) 0.95 (0.35–2.59) – – 1 0 0 – Inconclusive

T status (C T2) 1 (396) 0.76 (0.37–1.53) – – 1 0 0 – Inconclusive

Stage II 1 (160) 0.69 (0.36–1.33) – – 1 0 0 – Inconclusive

Positive nodal status 1 (396) 0.86 (0.39–1.89) – – 1 0 0 – Inconclusive

Tamoxifen use 2 (556) 0.73 (0.39–1.39) 0 0.58 1 1 0 Consistent Moderate

Tamoxifen use (patients who did notundergo bilateral oophorectomy)

1 (160) 0.39 (0.09–1.69) – – 0 1 0 – Inconclusive

Chemotherapy 2 (556) 0.51 (0.31–0.84) 0 0.86 1 1 0 Consistent Moderate

Oophorectomy 2 (556) 0.42 (0.22–0.81) 0 0.43 1 1 0 Consistent Moderate

IBR ipsilateral breast cancer, CI confidence interval, ER estrogen-receptors


123

investigated the role of age as risk factor for CBC by

calculating the cumulative risk for CBC according to age atfirst breast cancer diagnosis without performing multivar-

iate analysis. However, we decided to perform a qualitative

evaluation of all studies investigating the role of age as riskfactor for CBC because of the significance of this factor.

Two factors were associated with decreased risk for

CBC and were supported by a high level of evidence:oophorectomy (RR 0.52, 95 % CI 0.37–0.74) and increased

age (qualitative evaluation of 5 studies) (Table 3). Oneadditional factor that reduced the risk for CBC was the use

of adjuvant tamoxifen (RR 0.57, 95 % CI 0.43–0.75)

(moderate level of evidence). This protective effect oftamoxifen seems to be stronger in patients who did not

undergo oophorectomy (RR 0.42, 95 % CI 0.27–0.63),

however, the level of evidence for this observation waslow. Use of adjuvant chemotherapy did not alter the risk

for CBC (RR 0.90, 95 % CI 0.66–1.22) (moderate level of

evidence). We identified inconclusive evidence to lendsupport for other risk factors (Table 3).

BCSS and OS after contralateral prophylacticmastectomy versus therapeutic mastectomy

Two studies [4, 32] presented data on BCSS in patients withBRCA-mutation after prophylactic mastectomy versus ther-

apeutic mastectomy while only one [32] presented data on OS.

The median follow-up time for the two eligible studies

was 4.3 and 3.4 years, respectively. There was no differ-ence in BCSS between patients with BRCA-mutation who

underwent contralateral prophylactic mastectomy and

patients with BRCA-mutation who did not undergo pro-phylactic mastectomy (HR 0.78, 95 % CI 0.44–1.39,

p value = 0.40).

Only one study presented data on OS [32]. This studyfound that OS was 94 % for the prophylactic mastectomy

group versus 77 % for the non-prophylactic mastectomygroup (p value = 0.03). However, when an adjustment for

prophylactic oophorectomy was performed, women in the

mastectomy group did not significantly have better survivalthan those without mastectomy (HR 0.35, p value = 0.14)

[32].

Discussion

This is, to the best of our knowledge, the first study that

systematically investigated the question of the most

appropriate surgical management of unilateral breast can-cer in BRCA-mutation carriers and also tried to quantify

the several aspects of this complicated question with meta-

analyses as well as categorizing the level of evidence.There are three main questions that need to be answered in

order to aid both clinicians and patients to make a wise

Fig. 3 Forest plot of risk for contralateral breast cancer: BRCA-mutation carriers versus non-carriers


123

decision: Is the BCT option worse than unilateral mastec-

tomy? Does bilateral mastectomy offer some additionaladvantages compared to BCT or unilateral mastectomy?

Are there any risk factors that determine subgroups of

patients that will gain more benefit with more aggressivesurgical management?

Regarding the first question, our meta-analysis found

that BCT does not increase the risk for IBR in BRCA-mutation carriers compared to non-carriers. This finding is

indicating that radiotherapy in carriers is at least as effec-tive as in non-carriers. However, an increased risk for IBR

in carriers was observed in studies with longer follow-up.

This occurrence may be explained by a higher risk for newprimary cancers in carriers, since their mutation-related

risks continue to affect the residual breast tissue after

removal of the first lesion. The data were not sufficient toreach statistical significance in our separate meta-analysis

of new primary cancer (only 2 studies presented separate

data on new primary cancer [10, 14]) but a trend toward ahigher risk for new primary cancers in carriers was also

observed.

Few data were available about the prognosis of carriersversus non-carriers after BCT since only three studies

presented survival data [10, 15, 22]. Of these studies, two

found no survival difference between carriers and non-carriers [10, 22] while one found decreased BCSS for

carriers [15]. However, all studies included a limited

number of patients and events and their results cannot beconsidered fully reliable. Taking into account the compa-

rable IBR rates after BCT between carriers and non-carri-

ers as well as the similar survival outcomes (irrespective ofthe type of surgical management) of breast cancer in car-

riers and non-carriers that have been observed in large,

well-designed studies [33, 34], we can hypothesize that nosurvival difference between carriers and non-carriers after

BCT is expected.Only one study [13] performed a direct comparison of

mastectomy versus BCT in carriers with unilateral breast

cancer. Despite the increased risk for IBR following BCTcompared with mastectomy observed in this study, no

differences in BCSS or OS were found. When the pattern

of IBR in each group is analyzed, IBRs in BCT-groupconsisted mostly of new primary cancers while in mas-

tectomy-group of true recurrences. The lack of survival

difference between mastectomy and BCT may reflect thedifferences in the type of IBRs between the two groups

since new primary cancers have biologically less aggres-

sive phenotype than true recurrences [19, 21].If BCT and unilateral mastectomy are comparable, as

our results indicated and as we discussed above, could

bilateral mastectomy offer some advantages that wouldmake this treatment option more attractive? Our meta-

Table 3 Summary of risk factors from multivariable analyses for contralateral breast cancer in BRCA-mutation carriers

Risk factors No of studies(patients)

CBC hazardratio (95 % CI)

Heterogeneity Studies by quality Consistency Level ofevidence

I2 (%) p value High Moderate Low

Age (continuous) 1 (160) 0.98 (0.95–1.02) – – 0 1 0 Consistenta High

Age [50 years old 1 (810) 0.47 (0.27–0.82) – – 1 0 0

Age (qualitative evaluationof studies)

3 (1386) NC NC NC 0 1 2

Positive ER-status 1 (810) 1.02 (0.64–1.62) – – 1 0 0 – Inconclusive

Grade III 1 (810) 0.84 (0.50–1.41) – – 1 0 0 – Inconclusive

Positive nodal status 1 (810) 0.76 (0.51–1.12) – – 1 0 0 – Inconclusive

Tamoxifen use 5 (1492) 0.57 (0.43–0.75) 0 0.5 1 3 1 Consistent Moderate

Tamoxifen use (patients whodid not undergo bilateraloophorectomy)

2 (445) 0.42 (0.27–0.63) 44 0.18 0 2 0 Consistent Low

Tamoxifen use (patients whohave undergone bilateraloophorectomy)

1 (149) 0.83 (0.24–2.89) – – 0 1 0 – Inconclusive

Chemotherapy 3 (1151) 0.90 (0.66–1.22) 15 0.31 1 2 0 Consistent Moderate

Oophorectomy 3 (1621) 0.52 (0.37–0.74) 0 0.83 2 1 0 Consistent High

CBC contralateral breast cancer, CI confidence interval, ER estrogen-receptora All 3 studies included in the qualitative evaluation have shown that the cumulative incidence of CBC decreased with increased age (lowerincidence for age[50 years old in two studies (Graeser et al. [24], Verhoog et al. [31]) and[45–54 years old in the other (Malone et al. [29]).The quality of evidence has been derived from all the five studies (including three with qualitative evaluation). All studies are consideredconsistent. However, no cumulative hazard ratio has been calculated due to the differences in the use of age as variable as long as the lack ofmultivariable analysis in the three studies with qualitative evaluation


123

analysis found that BRCA-mutation carriers had a 3.5-fold

increased risk for CBC compared with non-carriers. Con-sequently, bilateral mastectomy will prevent the increased

risk for CBC in carriers [35]. However, no difference in

survival was found in our meta-analysis whether a contralat-eral prophylactic mastectomy was performed or not, though

the number of women studied was small and the median fol-

low-up relatively short. The largest study so far, with thelongest follow-up, on this topic was reported at the American

Society of Clinical Oncology Annual meeting in 2013. Theauthors reported a statistically significant improved survival in

patients who underwent prophylactic mastectomy compared

with those without mastectomy (10 year OS 90 versus 80 %,respectively) [36]. This study was not included in the meta-

analysis because of our exclusion criterion to rule out studies

that have not been published in fulltext, due to inability toadequately investigate the methodological quality of these

studies. An important drawback of this study was the imbal-

ance between the two study groups, i.e., more patients in theprophylactic mastectomy group received adjuvant chemo-

therapy. This difference may account for the improved OS,

especially considering the potential enhanced sensitivity tochemotherapy in BRCA-associated breast cancers [37, 38].

Therefore, the question whether contralateral prophylactic

mastectomy confers a survival benefit in carriers with breastcancer still remains open and a prospective randomized study

is certainly needed.

A different but important aspect concerning the decisionfor prophylactic mastectomy is the potential psychosocial

and emotional impact of such intervention. Although

studies have shown that psychosocial outcomes and qualityof life are similar between women at increased risk of

breast cancer who choose prophylactic mastectomy and

those who do not [39–42], negative effects on body imageand sexuality have also been reported [39, 41, 42].

Therefore, an adequate discussion and counseling of car-

riers with unilateral breast cancer about the most appro-priate surgical management should also include the

psychosocial dimension of each surgical intervention.

An interesting finding of the meta-analysis is thatBRCA1-mutation carriers had an increased risk for CBC

than BRCA2-mutation carriers. Although the reason for

this observation is unknown, one could speculate that thisdifference in CBC reflects the distinct morphological types

of breast cancer caused by BRCA1 and BRCA2 gene

mutations [43]. Indeed, BRCA1-associated cancers showoften a ‘‘basal’’ phenotype (and consequently a more

‘‘aggressive’’ phenotype), but this is not the case for

BRCA2-associated cancers that do not appear to exhibit aspecific morphological phenotype compared to sporadic

breast cancer [43]. In addition, a stronger protective effect

of tamoxifen or prophylactic oophorectomy in BRCA2-carriers compared to BRCA1-carriers, given the higher rate

of estrogen-receptor negative disease in BRCA1-carriers

[43], could also partially explain this observation.The third question is whether there are risk factors that

could identify subgroups of patients with higher risk for

IBR or CBC and could justify a more aggressive surgicalapproach. The following two factors were associated with a

50 % decreased risk for IBR: use of adjuvant chemother-

apy and performing oophorectomy. As mentioned above,BRCA1/2-related breast tumor may have enhanced sensi-

tivity to chemotherapy, and this could explain why adju-vant chemotherapy decreased the risk for IBR in our meta-

analysis. In addition, the risk reduction of IBR that we

observed in carriers who underwent oophorectomy wassimilar to the reduction in risk of breast cancer observed in

carriers without prior history of breast cancer after ooph-

orectomy [44]. As a result, in carriers who have notundergone oophorectomy, a more aggressive surgical

approach (unilateral mastectomy or unilateral therapeutic

mastectomy with concomitant contralateral prophylacticmastectomy) might be more appropriate.

Two risk factors were associated with nearly 50 %

decreased risk for CBC: the use of adjuvant tamoxifen andperforming oophorectomy. Age at first breast cancer

diagnosis is another risk factor for CBC. Indeed, the risk

for CBC significantly decreased with increased age, withan age of 50 years old to be the cut-off that was used in

most of the studies. However, we were unable to quantify

this relation due to the differences in the use of age asvariable among studies [11, 14] as well as the lack of

multivariable analysis in three studies [24, 29, 31]. As a

result, younger patients that have not undergone oopho-rectomy and have not received adjuvant tamoxifen might

constitute a subgroup of patients that might benefit most

from unilateral therapeutic mastectomy with concomitantcontralateral prophylactic mastectomy.

There are several potential limitations of the eligible

studies (and therefore our systematic review and meta-analysis) that deserve comment. Many studies [4–6, 8, 10,

14–16] assessed patients selected from Family Cancer

Clinics and this could lead to selection bias by includingwomen who are alive and have consented to undergo

genetic testing, as compared with women who died early

before undergoing genetic analysis. Potential risk forascertainment bias was also observed in some studies [5, 6,

8–10, 15, 16, 26] with the inclusion of only patients

undergoing DNA testing more than 2 years after theirbreast cancer diagnosis and therefore selecting the longer

living patients for DNA testing. Furthermore, potential risk

for misclassification of mutation carriers in the controlsporadic cohort was possible in some studies [4, 6, 8, 10,

14] in which DNA testing was not performed in all the

patients. Finally, one should also note the absence ofadequate data regarding the effect of systemic adjuvant


123

therapy on IBR in mutation carriers in some studies [8, 16,

26]. To address these issues, we assessed each eligiblestudy for methodological quality using 16 questions

adapted to the special characteristics of the eligible studies,

and we then categorized the risk factors into four levels ofevidence. Publication bias and selective reporting are also

potential limitations but are difficult to assess.

Obviously, the nature of the current evidence does notpermit the creation of clinical guidelines for all the BRCA-

mutation carriers regarding the surgical management ofunilateral breast cancer. At this time, carriers with unilat-

eral breast cancer should be handled on a case-by-case

basis. This meta-analysis could serve as a helpful guide forclinicians during the discussion with their patients before

the final surgical decision is made. The discussion should

include several issues including the current evidence ofadequate oncological safety of BCT, the 3.5-fold increased

risk for CBC, the psychosocial aspects after prophylactic

mastectomy and the presence of any identified factors thatalter risks of IBR and CBC.

Acknowledgments This study has been funded by the Centre forClinical Research Sormland, Uppsala University.

Conflict of interest The authors have no conflict of interest todeclare.

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