REVIEW Surgical management of breast cancer in BRCA-mutation carriers: a systematic review and meta-analysis Antonis Valachis • Andreas D. Nearchou • Pehr Lind Received: 14 September 2013 / Accepted: 17 February 2014 Ó Springer Science+Business Media New York 2014 Abstract This meta-analysis investigates the oncological safety of breast-conserving therapy BCT in BRCA-muta- tion carriers and the risk for contralateral breast cancer (CBC) compared with non-carriers, potential risk factors for 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 identify studies 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 in BRCA-mutation carriers. Results were summarized using meta-analysis when sufficient studies were available. Ten studies investigated the oncological safety of BCT in BRCA-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 significant higher 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 greater in carriers versus controls (RR 3.56, 95 % CI 2.50–5.08). Use of adjuvant chemotherapy and oophorectomy were associated 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 reasonable option 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 Á Breast cancer Á Breast-conserving therapy Á 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), which refers to breast-conserving surgery (BCS) followed by radiation therapy (RT), is the treatment of choice since it offers similar survival to that of unilateral mastectomy [3]. However, after a breast cancer diagnosis in BRCA-muta- tion carriers is established, the optimal local management remains 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 or decrease the risk for IBR or CBC. Several studies, mostly Electronic supplementary material The online version of this article (doi:10.1007/s10549-014-2890-1) contains supplementary material, which is available to authorized users. A. Valachis (&) Á A. D. Nearchou Á P. Lind Department of Oncology, Ma ¨larsjukhuset, 63188 Eskilstuna, Sweden e-mail: [email protected]; [email protected]A. Valachis Centre for Clinical Research So ¨rmland, Uppsala University, Uppsala, Sweden P. Lind Karolinska Institute, 11883 Stockholm, Sweden 123 Breast Cancer Res Treat DOI 10.1007/s10549-014-2890-1
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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
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
Breast Cancer Res Treat
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
Breast Cancer Res Treat
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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