Locoregional and distant recurrences after breast conserving therapy in patients with triple-negative breast cancer: A meta-analysis

Surgical Oncology 22 (2013) 247e255

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Surgical Oncology journal homepage: www.elsevier.com/locate/suronc

Review

Locoregional and distant recurrences after breast conserving therapy in patients with triple-negative breast cancer: A meta-analysis Jin Wang a, Xiaoming Xie a, *, Xi Wang a, Jun Tang a, Qingqing Pan b, Yefan Zhang c, Mengyang Di d a Department of Breast Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China b Peking Union Medical College Hospital, Beijing, China c Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China d The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China

a r t i c l e i n f o

a b s t r a c t

Article history: Accepted 3 October 2013

Background: With higher incidence of recurrence, ongoing dispute exists on whether triple-negative breast cancer (TNBC) is a good candidate for breast conserving therapy (BCT). Objective: We aimed to appraise the safety of BCT in treating TNBC, in comparison with modified radical mastectomy. The prognostic effect of TN phenotype in conservatively managed patients was also assessed. Methods: A systematic search for studies regarding recurrences in patients with TNBC or treated by BCT was conducted up to March 2013. Summary relative risks (RRs) for ipsilateral locoregional recurrence (ILRR) and distant metastasis (DM) were calculated in a fixed-effects model. Results: Twenty-two studies concerning 15,312 breast cancer patients were analyzed. In the cohort of TNBC, the patients receiving BCT were less likely to develop ILRR and DM in comparison with mastectomy (RR 0.75, 95% CI 0.65e0.87; RR 0.68, 95% CI 0.60e0.76). In the cohort of BCT, the TN subtype increased the risks of both ILRR and DM than non-TN subtypes (RR 1.88, 95% CI 1.58e2.22; RR 2.12, 95% CI 1.72e2.62). Further subgroup analyses of BCT cohort revealed that the luminal phenotype had the most favorable prognosis. Notably, TN subtype was less likely to develop ILRR than HER-2 subtype (RR 0.69, 95% CI 0.53e0.91), there was no difference in DM rate between them. Conclusions: BCT benefits patients with TNBC than mastectomy does. However, TN subtype predicts a poorer prognosis than non-TN subtype, suggesting more aggressive adjuvant therapy for TNBC be established in future trials. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Triple-negative breast cancer Breast conserving therapy Mastectomy Locoregional recurrence Distant metastasis

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 Selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Study characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Local treatments affect recurrence for TNBC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 Molecular phenotype affect recurrence for BCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

* Corresponding author. Department of Breast Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, No. 651, Dongfeng Road, Yuexiu District, Guangzhou 510060, China. Tel./fax: þ86 20 87343317. E-mail address: [email protected] (X. Xie). 0960-7404/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.suronc.2013.10.001

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Discussions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 Authorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

Introduction With great heterogeneity of pathologic and molecular features [1e3], breast cancer has wide variations in outcomes and response to therapy [4e6]. Since comprehensive molecular subtypes requires whole genome profiling, the expressions of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2/neu), as surrogate markers, are used to categorize breast cancers into luminal A, luminal B, HER-2, and triple-negative subtypes [4,7e11]. The triple-negative tumors are identified to have poorer prognosis, with lower survival and higher recurrence rates [12e16]. With the absence of ER, PR and HER-2, TNBC cannot be treated by either endocrine therapy or targeted therapy to HER-2, which arouses greater emphasis placed on its locoregional treatments [17,18]. The importance of optimal local control is highlighted by meta-analysis, which shows that preventing local recurrence (LR) at year five appears to decrease breast cancer mortality at year fifteen [19]. Regardless of the inoperable or metastatic disease, surgical excision of the breast tumor mass has been the core strategy in treating breast cancer, and comprises simple or radical mastectomy, or breast conserving surgery (lumpectomy or quadranectomy) [20,21]. The equivalence of disease free and overall survival for breast conserving surgery followed by radiotherapy (BCT) and mastectomy for early breast cancer has been established by a number of large randomized-controlled trials and metaanalysis [19,22e24]. However, it is less well-established whether BCT is indicated for TNBC, according to its aggressive biological behavior [25]. Several studies corroborated that the BCT could decreased either local or distant recurrences in patients with TNBC [26e29]. In contrast, Ihemelandu et al. [30] reported that mastectomy would benefit patients with TNBC rather than BCT. Furthermore, conflicting data exit in the prognosis of TN subtype in patients receiving BCT [31e34]. Regarding to the relatively new conception of triple-negative subtype for clinical decision making, there is no large databases concerning locoregional control in patients with TNBC [35]. Hence, this meta-analysis is conducted to compare the impact of BCT and mastectomy on recurrences in TNBC, and then to assess the prognostic effects of TN phenotype in conservatively managed patients.

Methods Search strategy To compare the impact of BCT vs. mastectomy on the recurrences of patients with TNBC, and to evaluate the prognosis of TN subtype in patients receiving BCT, a systematic search for studies published in English was conducted up to March 2013, based on Cochrane Library, Pubmed/Medline and Embase database. The combinations of MeSH terms and text words for the literature searches were browsed as follows: (‘breast neoplasm’ OR ‘breast cancer’ OR ‘breast carcinoma’) AND (‘breast conservative’ OR ‘breast conserving’ OR ‘breast conserved’ OR ‘breast sparing’ OR ‘lumpectomy’) AND (‘triple-negative’ OR ‘basal-like’) AND (‘recurrence’).

Additional sources were performed manually by searching reference lists of the retrieved articles and preceding reviews, including meta-analysis. The authors examined the title and abstract of potentially eligible studies for full text retrieval independently. Disagreements were harmonized by consensus. Selection criteria Studies meeting the following terms were included: (1) Patients with operable breast cancer were treated by BCT or mastectomy with curative intent; (2) Study design is to assess impact of initial surgery type on patients with TNBC; (3) Study design is to assess the prognostic effects of molecular subtype on patients receiving BCT; (4) Standardized adjuvant therapy was administered regardless of the details of chemotherapy regimens or radiotherapy protocols. Studies meeting the following terms were excluded: (1) Study design is to investigate the neoadjuvant chemotherapy; (2) Patients have history of prior cancer or evidence of metastatic disease; (3) Breast cancer subtypes cannot be explicitly defined on the basis of ER, PR, and HER-2 status; (4) Outcomes relating to breast cancer molecular subtype or surgical procedure could not be accurately extracted. We screened titles and looked at abstracts when the title suggested a study possibly meeting the main criteria. If the abstract content was relevant, full text of articles were retrieved and pulled for further consideration. Studies without raw data available for retrieval were not considered eligible. To avoid overlapping data from duplicate publications, only the article with the largest sample size was included. Data extraction The relevant data were extracted from all full text publications using a standardized data abstraction form. They were blinded to the information of journal, investigator and institution. One of our primary endpoints was the ipsilateral locoregional recurrence (ILRR), which included any ipsilateral in-breast recurrence (invasive or noninvasive) and/or regional recurrences in the axilla, chest wall, internal mammary, or supraclavicular fossa lymph nodes. The other endpoint was the distant metastasis (DM) based on clinical and/or radiographical document. The data extraction form comprised the following items: (1) Total number of patients with breast cancer; (2) The number of patients with different molecular subtype; (3) The number of patients receiving either BCT or mastectomy; (4) The events of ILRR or DM associated with surgical type occurred in patients with TNBC; (5) The events of ILRR or DM associated with molecular subtype occurred in patients undergoing BCT. The additional data including pTNM/stage, systemic adjuvant chemotherapy, endocrine therapy and radiotherapy were also extracted where possible. For studies yielding the incidence rate for each arm, the number of events was calculated from percentages at study endpoints or from other information available in the publication. Extracted data were compared at the end for consistency.

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Results Study characteristics

Figure 1. Flow diagram of eligible studies selection.

Statistical analysis We calculated the summary relative risk (RR) and 95% CI for ILRR and DM as dichotomous data using the general inverse variance fixed-effects model with a Z-statistic test for overall effect. By convention, an observed RR > 1 or <1 implied a hazard or protective effect and would be considered statistically significant if the 95% CI did not overlap with 1. The heterogeneity among the included studies was evaluated with the chi-square test and the I2 statistic. I2 values of less than 25%, 25%e50%, and more than 50% represent low, moderate, and high inconsistency [36]. In the absence of observed heterogeneity, an overall effect was calculated in fixed-effect models, otherwise random effects model was applied [37]. Sensitivity analyses were carried out to evaluate the influence of each study on the overall estimate by omitting them from the meta-analysis (leave-oneout analysis) [38]. All statistical analyses were conducted using the Review Manager software (RevMan, version 5.2.3) provided by the Cochrane Collaboration (www.cochrane.org). All statistical tests were two-tailed, a P value <0.05 was considered statistically significant.

According to the search strategy, 184 unique publications were identified potentially relevant. After preliminary review of the title and abstract from each, 82 articles were retrieved for full text examination. Additional 11 articles were obtained by manually searching reference lists of the retrieved articles. Of these, 71 studies were excluded according to the selection criteria, which left 22 studies for evaluation [26e34,39,40e51]. Fig. 1 describes the flow diagram of the process of study selection and the reasons for exclusion of studies. The characteristics of included studies are delineated in Table 1. The twenty-two studies included in the meta-analysis were published between 2006 and 2012 and originated from the United States, Canada, Korea, Italy, Singapore, Finland and Australia. Except one RCT study [32], the remains are all retrospective observational studies. Sample size ranges from 77 to 1443 breast cancer cases, with a median number of 508. The included studies presented data for a total of 15,312 breast cancer patients, 11,678 of which underwent BCT, and the other 3634 patients underwent mastectomy. In terms of the negative expressions of ER, PR, and HER-2/neu, 4364 cases were identified as TNBC. The median follow-up period was 70 months and the median age was 55 years old. There were 97% of patients undergoing BCT and 21% of patients undergoing mastectomy treated by radiotherapy defined as the irradiation to the whole breast/chest wall with or without the elective irradiation to the locoregional lymph nodes. For systemic therapy, 36% of patients had adjuvant chemotherapy, and 46% of patients received endocrine therapy, only 48 patients were treated by Trastuzumab. The majority of chemotherapy regimens delivered was administered according to the guidelines as per published recommendations. Quality assessment Since the majority of the included studies were retrospective cohort design, the quality of these studies was appraised by

Table 1 Characteristics of included studies. Author

Ho et al. [27] Han et al. [42] Pashtan et al. [43] Hattangadi-Gluth et al. [44] Arvold et al. [45] Noh et al. [46] Barbieri et al. [47] Zaky et al. [48] Wong et al. [49] Siponen et al. [50] Abdulkarim et al. [39] Adkins et al. [29] Parker et al. [26] Dragun et al. [40] Voduc et al. [28] Gabos et al. [41] Freedman et al. [33] Solin et al. [51] Millar et al. [32] Nguyen et al. [31] Ihemelandu et al. [30] Haffty et al. [34]

Country of origin

USA Canada USA USA USA Korea Italy USA Singapore Finland Canada USA USA USA Canada Canada USA USA Australia USA USA USA

Year

2012 2012 2012 2012 2011 2011 2011 2011 2011 2011 2011 2011 2010 2010 2010 2010 2009 2009 2009 2008 2008 2006

ILRR: ipsilateral locoregional recurrence; DM: distant metastasis.

Number of patients (n) Total number

BCT

Mastectomy

TN

Non-TN

194 180 98 1223 1434 596 387 193 413 1281 768 1325 202 77 2985 602 753 519 498 793 309 482

129 180 98 1223 1434 596 387 193 413 1281 319 651 61 33 1271 233 753 519 498 793 131 482

65 0 0 0 0 0 0 0 0 0 449 674 141 44 1714 369 0 0 0 0 178 0

194 13 10 136 171 105 36 33 56 80 768 1325 202 77 556 72 98 90 68 89 68 117

0 167 88 1087 1263 491 351 160 357 1201 0 0 0 0 2429 530 655 429 430 704 241 365

Outcomes

Anatomic stage

ILRR, ILRR ILRR ILRR ILRR ILRR, ILRR, ILRR, ILRR, ILRR ILRR, ILRR, ILRR ILRR, ILRR ILRR ILRR, ILRR, ILRR, ILRR, ILRR, ILRR,

Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage

DM

DM DM DM DM DM DM DM

DM DM DM DM DM DM

I 0 I IeIII IeIII IeII IeIII IeIII IeII IeIII IeIII IeIII IeIII IeIII IeIII IeIII IeIII IeIII IeIII IeIII IeIV IeIII

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Table 2 Quality of the studies based on the NewcastleeOttawa quality assessment scale for cohort studies. Author

Selection Represent the exposed cohort

Ho et al. [27] Han et al. [42] Pashtan et al. [43] Hattangadi-Gluth et al. [44] Arvold et al. [45] Noh et al. [46] Barbieri et al. [47] Zaky et al. [48] Wong et al. [49] Siponen et al. [50] Abdulkarim et al. [39] Adkins et al. [29] Parker et al. [26] Dragun et al. [40] Voduc et al. [28] Gabos et al. [41] Freedman et al. [33] Solin et al. [51] Nguyen et al. [31] Ihemelandu et al. [30] Haffty et al. [34]

*

* *

* * * *

* *

Comparability

Outcome

Selection of the non- exposed cohort

Ascertainment of exposure

Demonstration that outcome of interest was not present at start of study

Comparability of cohorts on the basis of the design or analysis

Assessment of outcome

Was follow-up long enough

Adequacy of follow-up of cohorts

* * * * * * * * * * * * * * * * * * * * *

* * * * * * * * * * * * * * * * * * * * *

* *

** ** ** * ** **

* * *

* * * * * * * * * * * * *

* * * * * * * * * * * * * * * * * * * * *

*

*

* *

* * *

utilizing the NewcastleeOttawa quality assessment scale (NOS) for cohort studies. A study can obtain 9 stars at most based on criteria. A threshold of 6 stars or above is considered as indicative for high quality [52]. The quality of included studies ranged from 6 to 9 stars, with a median score of 7 (Table 2). Furthermore, the funnel plots of studies were approximately symmetrical indicating no obvious publication bias. Local treatments affect recurrence for TNBC There were eight studies comparing the recurrence rates between BCT group and mastectomy group in patients with TNBC [26e30,39e41]. The overall ILRR rate in this cohort was 19.6% (639/ 3262), and the patients receiving BCT were less likely to develop ILRR than those receiving mastectomy (16.9% vs. 21.9%, RR 0.75, 95% CI 0.65e0.87, P < 0.0001), without statistically significant heterogeneity observed (I2 ¼ 49%, P ¼ 0.06) (Fig. 2(A)). The overall DM rate in this cohort was 29.2% (711/2432), and the patients receiving BCT were less likely to develop DM than those receiving mastectomy (23.6% vs. 34.4%, RR 0.68, 95% CI 0.60e0.76, P < 0.00001), without significant heterogeneity as well (I2 ¼ 32%, P ¼ 0.21) (Fig. 2(B)). The sensitivity analysis (leaving one out at a time) produced no significantly increased or decreased summary relative risk. Hence it follows that the breast conserving surgery plus radiotherapy could benefit patients with TNBC in decreasing both the ILRR and DM, compared to the mastectomy. Molecular phenotype affect recurrence for BCT There were seventeen studies comparing the recurrence rates between the TN group and non-TN group in patients receiving BCT [28,30e34,41e51]. The overall ILRR rate in this cohort was 5.7% (595/10,485), and the TN subtype increased the risk of ILRR as compared to the non-TN subtype (11.1% vs. 4.8%, RR 1.88, 95% CI 1.58e2.22, P < 0.00001), with significant heterogeneity observed

* ** ** * * * ** ** * * * ** * **

* * * * * * * * * * * * * * * * *

* * * * * * *

Total score

8 9 7 6 7 7 6 7 8 7 6 7 8 7 8 7 7 7 9 7 7

(I2 ¼ 68%, P < 0.0001) (Fig. 3(A)). The overall DM rate in this cohort was 7.7% (366/4765), and likewise the TN subtype increased the risk of DM more significantly than the non-TN subtype (14.6% vs. 6.5%, RR 2.12, 95% CI 1.72e2.62, P < 0.00001), with favorable homogeneity (I2 ¼ 9%, P ¼ 0.36) (Fig. 3(B)). According to the significant heterogeneity calculated in both fixed and random effects models, further subgroup analysis stratified by molecular phenotype was applied. As expected, patients with luminal subtype provided the most favorable prognosis, with the overall ILRR and DM rates of only 4.0% and 4.6%. Conversely, HER-2 subtype exhibited the highest rates of ILRR (15.5%) and DM (12.6%). Patients with TN subtype were more likely to develop ILRR than those with luminal subtype (11.0% vs. 4.0%, RR 2.16, 95% CI 1.78e2.63, P < 0.00001) (Fig. 4(A)), but less likely to develop ILRR than those with HER-2 subtype (11.0% vs. 15.5%, RR 0.69, 95% CI 0.53e0.91, P ¼ 0.008) (Fig. 4(B)). Meanwhile, the TN subtype also increased the risk of DM more significantly than the luminal subtype (11.9% vs. 4.6%, RR 2.45, 95% CI 1.80e3.32, P < 0.00001) (Fig. 4(C)). However, there was no difference in DM rate between TN and HER-2 group (11.9% vs. 12.6%, RR 0.83, 95% CI 0.54e1.28, P ¼ 0.41) (Fig. 4(D)). Discussions In the last two decades, based on several randomized-controlled trials, BCT has been proved to have the equivalent long-term outcomes with mastectomy, and has become the standard treatment option for women with early stage breast cancer [22,23,53e59]. Especially, a recent meta-analysis showed that the overall survival in 3, 5, 10, 15 and 20 years were not statistically significantly different between group BCT and group mastectomy. However, in the subgroup analysis, 20-year locoregional recurrence (LRR) rate was statistically significantly higher in group BCT than group mastectomy for women with tumors 2 cm or smaller [24]. The most common reasons for LRR are thought to be poor patient selection,

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Figure 2. Relative risks of ILRR and DM associated with BCT compared with mastectomy in patients with TNBC In comparison with mastectomy, BCT decreased the risks of both ILRR (A) and DM (B) more significantly in patients with TNBC.

inadequate surgery or radiotherapy, or biologically aggressive disease [22,23]. Given TNBC’s aggressive features [8], there is a concern that perhaps a more aggressive surgical approach (i.e., mastectomy) should be considered. To evaluate the effectiveness of BCT in controlling locoregional recurrences for TNBC, several investigations have been taken to compare the recurrence rates between BCT group and mastectomy group in patients with TNBC [26e30,39e41]. Parker et al. [26] addressed neither locoregional recurrence rate nor isolated distant recurrence rate was significantly different between the BCT and mastectomy groups. On the other hand, several studies corroborated that the BCT could decreased both ILRR and DM in patients with TNBC [29,40]. In contrast, Ihemelandu et al. [30] reported that mastectomy would benefit patients with TNBC in preventing ILRR and DM rather than BCT. In our meta-analysis, the cumulative rate of ILRR in patients receiving BCT was 16.9%, which was statistically less than 21.9% in mastectomy group (RR 0.75, 95% CI 0.65e0.87, P < 0.0001). Likewise, the patients receiving BCT were less likely to develop DM than the patients receiving mastectomy (23.6% vs. 34.4%, RR 0.68, 95% CI 0.60e0.76, P < 0.00001) as well. Furthermore, two studies adjusting for early stage breast cancers were identified, including 962 patients with stage IeII TNBC [27,39]. The subgroup analysis showed that the ILRR rate of patients undergoing mastectomy was 2.5-fold as much as that of patients undergoing BCT, with favorable homogeneity observed (I2 ¼ 0%, P ¼ 0.57). Similarly, the DM rate in mastectomy group was twice as much as that in BCT group. Hence it follows that the breast conserving surgery plus radiotherapy could benefit patients with TNBC in decreasing both ILRR and DM, compared to the mastectomy, especially for the patients with early

stage. The favorable outcome brought by BCT might be the contribution of the postoperative radiotherapy, which also contradicts the previous view that TNBC tumors exhibited high radio resistant [60]. Since BCT is the optimal local treatment for patients with TNBC based on the pooled data, the prognosis of triple-negative phenotype compared with other molecular phenotypes in conservatively managed patients were further investigated in our meta-analysis. Several studies have demonstrated that the locoregional recurrence rate after BCT was significantly greater for those patients with TNBC compared with other subtypes [31,51]. Whereas others have shown that no significant differences were found in the local control rates between TNBC and the other subtypes when BCT was carried out [32e34]. A few researchers even corroborated that TNBC is likely to develop an expanding growth pattern instead of extensive intraductal spread and is a better candidate for BCT than other breast cancer subtypes [61]. As expected, our meta-analysis showed that the patients with luminal subtypes provided the most favorable prognosis, with the overall ILRR and DM of only 4.0% and 4.6%, respectively. Conversely, HER-2 subtype exhibited the highest rates of ILRR (15.5%) and DM (12.6%). The TN subtype decreased the risk of ILRR more significantly than the HER-2 subtype. However, there was no difference in DM rate between TN and HER-2 group. The addition of radiation therapy is identified to significantly reduce the risk of local recurrence in prospective randomized trials with or without adjuvant systemic therapy [22,62]. Currently, postmastectomy radiotherapy is recommended for patients with N (þ) or T3N0 disease without specific consideration of biologic subtype

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Figure 3. Relative risks of ILRR and DM associated with TN subtype compared with non-TN subtype in patients receiving BCT. In comparison with non-TN subtype, the TN subtype increased the risks of both ILRR (A) and DM (B) more significantly in patients receiving BCT.

[19,63]. However the biologic response of TNBC tumors to RT has not been well documented. Compared with other biologic subtypes, TNBC tumors exhibit high proliferative potential and are presumed to be clinically radio resistant. Nevertheless, our data indicates that the women receiving BCT had less local relapse than those receiving mastectomy in TNBC, implying these triple-negative tumors might not be radiation resistant. This is consistent with the results from Danish BC studies that patients with TN tumors treated with modified radical mastectomy showed a significant increased risk of LRR independent of adjuvant post-mastectomy radiotherapy [60]. On the other hand, our data also showed that the triple-negative subtype was a hazardous factor for both ILRR and DM in conservatively managed patients, it may be prudent to consider the addition of a local cavity boost, the whole-breast radiation, the higher boost doses or the concomitant chemoradiotherapy for TNBC as Millar et al. [32] and Hattangadi-Gluth et al. [44] proposed.

Although the included observational studies were all welldesigned with high quality, selection bias was unavoidable given its retrospective design. For instance, treatment assignment was not random in most observational studies, and the definition of local recurrence varies vastly, which made ILRR as the unified primary endpoint. Another limitation, unavoidable, is the patients included in the meta-analysis were treated from 1980 to 2009, there have been dramatic changes in both local and systemic treatments over the past few decades, which may lead to methodology flaws. In conclusion, given the aggressive nature of TNBC, triplenegative subtype predicts a worse outcome than the luminal subtype for patients undergoing BCT. However, BCT still provides a better prognosis for TNBC in decreasing the risks of both local and distant recurrences, as compared to mastectomy. To refine the prognosis and optimize the treatment in patients with TNBC, the benefit of adjuvant radiotherapy should be further investigated in

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Figure 4. Subgroup analyses of ILRR and DM in patients receiving BCT. Patients with TN subtype were more likely to develop ILRR than those with luminal subtype (A), but less likely to develop ILRR than those with HER-2 subtype (B). Meanwhile, the TN subtype also increased the risk of DM more significantly than the luminal subtype (C). There was no difference in DM rate between TN and HER-2 group (D).

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