Locoregional recurrence after breast cancer surgery: a systematic review by receptor phenotype

Breast Cancer Res Treat (2012) 133:831 841 DOI 10.1007/s10549-011-1891-6 REVIEW Locoregional recurrence after breast cancer surgery: a systematic review by receptor phenotype Aoife J. Lowery Malcolm R. Kell Ronan W. Glynn Michael J. Kerin Karl J. Sweeney Received: 23 August 2011 / Accepted: 18 November 2011 / Published online: 7 December 2011 Ó Springer Science+Business Media, LLC. 2011 Abstract Molecular subtyping confirms that breast cancer comprises at least four genetically distinct entities based on the expression of specific genes including estrogen receptor (ER), progesterone receptor (PR), and HER2/ neu receptor. The quantitative influence of subtype on ipsilateral locoregional recurrence (LRR) is unknown. The aim of this study was to systematically appraise the influence of breast cancer subtype on LRR following breast conserving therapy (BCT) and mastectomy. A comprehensive search for studies examining outcomes after BCT and/or mastectomy according to breast cancer subtype was performed using Medline and cross-referencing available data. Reviews of each study were conducted and data extracted to perform meta-analysis. Primary outcome was LRR related to breast cancer subtype. A total of 12,592 breast cancer patients who underwent either BCT (n = 7,174) or mastectomy (n = 5,418) were identified from 15 studies. Patients with luminal subtype tumors (ER/ PR?ve) had a lower risk of LRR than both triple-negative (RR 0.38; 95% CI 0.23 0.61); and HER2/neu-overexpressing (RR 0.34; 95% CI 0.26 0.45) tumors following Electronic supplementary material The online version of this article (doi:10.1007/s10549-011-1891-6) contains supplementary material, which is available to authorized users. A. J. Lowery R. W. Glynn M. J. Kerin K. J. Sweeney (&) Surgery, School of Medicine, National University of Ireland, Galway, Ireland e-mail: karl.sweeney@nuigalway.ie M. R. Kell Department of Surgery and Eccles Breast Screening Unit, Mater Misericordiae University Hospital, Dublin, Ireland K. J. Sweeney BreastCheck, Western Unit, Galway, Ireland BCT. Luminal tumors were also less likely to develop LRR than HER2/neu-overexpressing (OR 0.69; 95% CI 0.54 0.89) or triple-negative tumors (OR 0.61; 95% CI 0.46 0.79) after mastectomy. HER2/neu-overexpressing tumors have increased risk of LRR compared to triplenegative tumors (RR 1.44; 95% CI 1.06 1.95) following BCT but there was no difference in LRR between HER2/ neu-overexpressing and triple-negative tumors following mastectomy (RR 0.91; 95% CI 0.68 1.22). Luminal tumors exhibit the lowest rates of LRR. Patients with triple-negative and HER2/neu-overexpressing breast tumors are at increased risk of developing LRR following BCT or mastectomy. Breast cancer subtype should be taken into account when considering local control and identifies those at increased risk of LRR, who may benefit from more aggressive local treatment. Keywords Breast cancer subtype Receptor phenotype Locoregional recurrence Breast conserving therapy Introduction Developments in breast cancer therapeutics have reflected the growing understanding of cancer biology. Gene expression profiling of breast cancer has confirmed that it is not a single entity but a group of biologically distinct diseases. This may explain the difficulty in predicting disease progression, but also presents an opportunity for improved prognostic tools to guide individualized therapy. Based on the expression of a 496-gene intrinsic genesubset [1, 2] breast cancers can be categorized into: Luminal-like subtypes (Luminal) which predominantly express estrogen receptor (ER) and progesterone receptor (PR); HER2/neu-like subtypes (HER2/neu-overexpressing)

832 Breast Cancer Res Treat (2012) 133:831 841 which overexpress the HER2/neu receptor but are negative for ER and PR expression; and Basal-like subtypes (triple negative, TN) which predominantly do not express ER, PR, or HER2/neu receptors. Comprehensive characterization of molecular subtypes requires whole genome profiling which is not routinely performed in the clinical setting. For this reason, the expression of the ER, PR, and HER2/neu receptors, which are routinely performed clinically to guide adjuvant therapy decisions, is frequently used as a practical, surrogate marker of breast cancer subtype. Expression of these receptors is measured by immunohistochemistry (IHC) that allows for subtyping in most laboratories. These tumor subtypes differ in their response to systemic treatment and their clinical outcome [3 5]. Although significant advances have been made in directed systemic therapy, a substantial survival benefit is derived from adequate locoregional control [6]. 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 [7, 8]. Locoregional relapses are unfortunately common in breast cancer and prognosis has been correlated with conventional clinicopathological parameters including tumor size, grade, and lymph node involvement [9]. With regard to the biology of breast cancer, however, the traditional prognostic factors provide limited information [10]. Molecular taxonomy of breast cancer may improve prediction of locoregional recurrence (LRR) and has the potential to hugely inform decision-making regarding local control strategies for breast cancer. This systematic review aims to determine and quantify the effect of breast cancer subtype on the risk of developing LRR after BCT or mastectomy. Methods Electronic searches were performed of Medline and EM- BASE using the following search algorithms: 1. Breast cancer AND ( breast conserving surgery OR breast conservation OR wide local excision OR WLE OR lumpectomy OR quadrantectomy ) AND ( recurrence OR outcome ) and 2. Breast cancer AND ( mastectomy OR modified radical mastectomy ) AND ( recurrence OR outcome ). English was set as a language restriction. The search was also restricted to publications from 2001 onward; when the molecular subtypes of breast cancer were first defined. Two authors (A.J.L. and R.W.G.) independently examined the title and abstract of citations and the full texts of potentially eligible studies. Prospective and retrospective series were examined on patients with operable breast cancer treated with BCT or mastectomy with curative intent. No prospective randomized data were identified relating breast cancer subtype to LRR following BCT or mastectomy. Only reports on patients in whom breast cancer subtype could be defined on the basis of ER, PR, and HER2/neu receptor status were included. All studies in which standardized adjuvant therapy was administered were considered eligible regardless of the exact chemotherapeutic regiments or radiotherapy protocols. When results for the same group of patients were reported more than once, only the report with the largest number of events was included to avoid duplication of information. Studies where the surgical procedure was not stated were excluded; likewise, studies where data relating to breast cancer subtype could not be accurately extracted were excluded (Fig. 1). Potentially relevant studies identified and full text obtained for review (N=64) Potentially appropriate studies to be included in the review (N=57) Potentially appropriate studies to be included in the review (N=20) Studies included in the analysis (N=15) Excluded Reason: No differentiation between patients who underwent BCT and Mastectomy (N=7) Excluded Reason: Combined ER, PR and HER2/neu receptor status not available in relation to LRR (N=37) Excluded Reason: Duplicated database (N=3) Reason: Only Triple Negative patients included (N=2) Fig. 1 Eligible studies; quality of reporting of meta-analyses (QUO- ROM) statement flow diagram

Breast Cancer Res Treat (2012) 133:831 841 833 The following information regarding each eligible series was recorded: authors, country of origin, journal, year of publication, follow-up time, and number of patients who underwent BCT or mastectomy. Tumor histopathological data (tumor size, grade, and nodal status) was extracted where possible. Data pertaining to adjuvant systemic therapy (chemotherapy and hormonal therapy) and adjuvant radiotherapy were extracted where possible. Tumor subtypes were defined according to the expression of ER, PR, and HER2/neu receptor on IHC as Luminal (ER?/ PR?/HER2/neu?/-), TN (ER-/PR-/HER2/neu-) and HER2/neu-overexpressing (ER-/PR-/HER2/neu?). The primary outcome was LRR defined as recurrence in the ipsilateral breast or chest wall or ipsilateral draining lymph nodes. The relative risk (RR) of LRR in each study was estimated, with its variance and 95% confidence interval (CI). In studies that did not provide explicit accounting of the numbers of events for each arm this was calculated from percentages at study end point for LRR or from other information available in the publication. Heterogeneity between the RRs for the LRR between different studies was assessed by use of the v 2 -based Q statistic. Data were then combined across studies by the use of general variance methods with random effects models. To assess the effect of breast cancer subtype on LRR rates, data were pooled and outcomes given by type of local therapy. Comparison of outcome between BCT and mastectomy was limited to data derived only from studies directly compared the LRR following BCT and mastectomy. Analyses were conducted using StatsDirect version 2.5.6 (StatsDirect Ltd, Cheshire, UK) and SPSS version 12.0 (SPSS, Inc, Chicago, IL). A P value \0.05 was considered statistically significant. All statistical tests were two tailed. Results Sixty-four potentially eligible studies were identified that reported LRR in relation to ER, PR, and HER2/neu receptor status in breast cancer patients following BCT or mastectomy. Forty-nine studies were excluded from the analysis following intensive review of the full text (Fig. 1), resulting in 15 suitable studies included in this review (Table 1) [11 25]. These 15 studies presented data for 12,592 patients who underwent either BCT (n = 7,176) or mastectomy (n = 5,416) for breast cancer. The median patient age was 51 years (median age range was 49 61 years). All patients received radiotherapy following BCT and 44% of patients received post-mastectomy chest wall radiotherapy. Patients with hormone receptor positive tumors received hormone therapy as per standard clinical guidelines and cytotoxic chemotherapy was administered to 48% of patients (n = 6,151). Administration of systemic trastuzumab was reported for 140 patients, which represented \6% of patients with tumors that overexpressed HER2/neu. Table 1 Details of eligible studies Authors Country of origin Year Study duration Median follow-up time (months) Median age (years) Number of patients analyzed BCT (n) Mastectomy (n) Luminal (n) Her2? (n) TN (n) Arvold et al. USA 2011 1997 2006 85 * 1,434 1,434 0 1,208 55 171 Siponen et al. Finland 2011 2001 2005 57 58 1,281 1,281 0 1,178 23 80 Mersin et al. Turkey 2011 2004 2008 44 49 1,101 0 1,101 913 82 106 Meyers et al. USA 2011 1997 2005 55 48 149 49 100 80 20 49 Wong et al. Singapore 2011 1989 2007 72 49 413 413 0 323 34 56 Wang et al. China 2010 2000 2004 47 49 835 0 835 595 99 141 Voduc et al. Canada 2010 1986 1992 144 59 2,985 1,271 1,714 2,202 227 556 Straver et al. Netherlands 2010 2000 2007 35 45 251 126 125 138 56 57 Gabos et al. Canada 2010 1998 2003 58 * 602 233 369 442 88 72 Millar et al. Australia 2009 * 84 61 482 482 0 417 13 52 Solin et al. USA 2009 1990 2003 47 55 519 519 0 370 59 90 Kyndi et al. Denmark 2008 1982 1990 204 * 996 0 996 724 120 152 Freedman et al. USA 2008 1990 2006 44 54 753 753 0 600 55 98 Ihemelandu et al. USA 2008 1998 2005 * * 309 131 178 207 34 68 Haffty et al. USA 2006 1980 2003 95 * 482 482 0 365 * 117 BCT breast conserving therapy, Luminal Luminal A and B subtype, HER2? HER2/neu-overexpressing, TN triple negative, % all percentages are of number of patients analyzed within the study, * data not reported or not extractable from publication

834 Breast Cancer Res Treat (2012) 133:831 841 The median follow-up period was 57 months (median follow-up range was 35 204 months). The overall LRR rate was 7.9% (n = 996). The LRR rate following BCT was 7.12% (n = 511), and 8.95% (n = 485) following mastectomy (P = 0.0002, Fisher s exact test). According to the phenotype expression of biological breast cancer subtype, based on ER, PR, and HER2/neu receptor expression, 77.5% of the patients had Luminal subtype breast cancers (n = 9,762), 7.5% had HER2/neuoverexpressing tumors (n = 965), and 15% had TN tumors (n = 1,865). Patients with a non-tn breast cancer (Luminal or HER2/neu-overexpressing) were less likely to develop LRR than those with a TN tumor after either BCT (RR 0.49; 95% CI 0.33 0.73), or mastectomy (RR 0.66; CI 0.53 0.83) (Fig. 2). Among patients who underwent BCT, those with Luminal tumors were less likely to develop LRR than those with HER2/neu-overexpressing (RR 0.34; 95% CI 0.26 0.45) or TN tumors (RR 0.38; 95% CI 0.23 0.61); patients with HER2/neu-overexpressing tumors had a higher risk of LRR than those with TN tumors (RR 1.44; 95% CI 1.06 1.95) (Fig. 3). Among patients who underwent mastectomy, those with Luminal tumors were less likely to develop LRR than HER2/neu-overexpressing (RR 0.69; 95% CI 0.54 0.89) or TN (RR 0.61; 95% CI 0.46 0.79) tumors; there was no difference in LRR between HER2/neu-overexpressing and TN tumors (RR 0.91; 95% CI 0.68 1.22) (Fig. 4). In nine studies [11 13, 15, 17, 19, 22, 23, 25] the Luminal subtype could be divided into Luminal (ER?/ PR?/HER2/neu-) and Luminal (ER?/PR?/HER2/neu?) Fig. 2 LRR in patients with triple negative (TN) versus non- TN tumors. In each panel, each study is shown by the point estimate of the relative risk (RR; square proportional to the weight of each study) and 95% CI for the RR (extending lines); the combined RR and 95% CI by random effects calculations are shown by diamonds. a Non- TN versus TN tumors in patients who underwent BCT (n = 7,174, P = 0.0005; test for heterogeneity, Q = 31.2, df = 11, I 2 = 64.8%). b Non- TN versus TN tumors in patients who underwent mastectomy (n = 5,418, P = 0.0003; test for heterogeneity, I 2 = 10.2%)

Breast Cancer Res Treat (2012) 133:831 841 835 Fig. 3 LRR according to tumor subtype following BCT. Each study is shown by the point estimate of the relative risk (RR; square proportional to the weight of each study) and 95% CI for the RR (extending lines); the combined RR and 95% CI by random effects calculations are shown by diamonds. The arrow indicates that 95% CI extends beyond the depicted range. a Luminal versus HER2/ neu-overexpressing tumors (n = 5,338, P \ 0.0001; test for heterogeneity, Q = 6.38, df = 8, I 2 = 0%) (*excluded as there were no LRR in either group). b Luminal versus TN tumors (n = 5,906, P = 0.0001; test for heterogeneity, Q = 23.77, df = 9, I 2 = 62%). c HER2/ neu-overexpressing versus TN tumors (n = 1,218, P = 0.02; test for heterogeneity, Q = 7.97, df = 9, I 2 = 0%) subtypes and the risk of LRR according to these breast cancer subtypes was analyzed. This subgroup analysis included 9,306 patients; 4,013 who were treated with BCT and 5,293 who underwent mastectomy. There was no significant difference in the risk of LRR following BCT in patients with Luminal (ER?/PR?/ HER2/neu-) compared to Luminal (ER?/PR?/HER2/ neu?) breast tumors (RR 0.8; 95% CI 0.49 1.32). Patients with both Luminal (ER?/PR?/HER2/neu-) and Luminal (ER?/PR?/HER2/neu?) tumors were less likely to develop LRR than HER2/neu-overexpressing tumors (RR 0.3; 95% CI 0.18 0.46, and RR 0.35; 95% CI 0.21 0.58, respectively) or TN tumors (RR 0.33; 95% CI 0.18 0.61, and RR 0.49; 95% CI 0.26 0.91, respectively) (Fig. 5). Among patients who underwent mastectomy, those with Luminal (ER?/PR?/HER2/neu-) tumors were less likely to develop LRR than any of the other subtypes: Luminal (ER?/PR?/HER2/neu?) (RR 0.59; 95% CI 0.46 0.78), HER2/neu-overexpressing (RR 0.58; 95% CI 0.39 0.85), or TN tumors (RR 0.51; 95% CI 0.36 0.73) (Fig. 6). There was no significant difference in LRR between Luminal (ER?/PR?/HER2/neu?) and HER2/neu-overexpressing (RR -0.009; 95% CI -0.04 0.023) or TN tumors (RR 0.91; 95% CI 0.68 1.21) following mastectomy. Five of the studies included comparable data on patients who underwent BCT (n = 1,810) and those who underwent mastectomy (n = 2,486) [11, 15, 16, 20, 22]. There was a lower LRR following mastectomy compared to BCT

836 Breast Cancer Res Treat (2012) 133:831 841 Fig. 4 LRR according to tumor subtype following mastectomy. Each study is shown by the point estimate of the relative risk (RR; square proportional to the weight of each study) and 95% CI for the RR (extending lines); the combined RR and 95% CI by random effects calculations are shown by diamonds. The arrow indicates that 95% CI extends beyond the depicted range. a Luminal versus HER2/neuoverexpressing tumors (n = 4,571, P = 0.0038; test for heterogeneity, Q = 6.9, df = 7, I 2 = 0%). b Luminal versus TN tumors (n = 4,848, P = 0.0003; test for heterogeneity, Q = 9.09, df = 7, I 2 = 23%). c HER2/ neu-overexpressing versus TN tumors (n = 1,417, P = 0.538; test for heterogeneity, Q = 3.14, df = 7, I 2 = 0%) for Luminal and HER2/neu-overexpressing tumors (RR 0.74; 95% CI 0.58 0.94 and RR 0.32; 95% CI 0.18 0.56, respectively) but no difference in LRR was observed between BCT and mastectomy for TN tumors (OR 0.83; 95% CI 0.37 1.85). Discussion Patients who develop LRR have a substantially worse overall survival [26 28]; however, few studies have assessed the impact of breast cancer subtype or receptor phenotype on locoregional breast cancer recurrence. Trials of partial breast irradiation, narrower resection margins, and avoidance of completion axillary clearance have been accepted and their principles applied without consideration of breast cancer subtype [28 30]. This current analysis of 12,592 breast cancer patients represents a systematic review of the published data which confirms that breast cancer subtype has an impact on LRR in patients treated with BCT or mastectomy. In this analysis, the breast cancer subtypes are constructed based on the expression of ER, PR, and the HER2/ neu receptor to resemble the intrinsic subtypes found to be prognostic of survival in gene expression studies [1, 2] with ER?/PR?/HER2/neu- and ER?/PR?/HER2/

Breast Cancer Res Treat (2012) 133:831 841 837 Fig. 5 LRR according to tumor subtype following BCT (subgroup analysis). Each study is shown by the point estimate of the odds ratio (RR; square proportional to the weight of each study) and 95% CI for the RR (extending lines); the combined RR and 95% CI by random effects calculations are shown by diamonds. The arrow indicates that 95% CI extends beyond the depicted range. a Luminal (ER?/PR?/HER2/ neu-) versus Luminal (ER?/ PR?/HER2/neu?) tumors (n = 3,176, P = 0.38; test for heterogeneity, Q = 5.12, df = 5, I 2 = 2.4%). b Luminal (ER?/PR?/HER2/neu-) versus HER2/neuoverexpressing tumors (n = 3,042, P \ 0.0001; test for heterogeneity Q = 6.5, df = 5, P = 0.23, I 2 = 23.9%). c Luminal (ER?/PR?/HER2/ neu-) versus TN tumors (n = 3,425, P = 0.0004; test for heterogeneity Q = 19.5, df = 6, I 2 = 69.4%). d Luminal (ER?/PR?/HER2/neu?) versus HER2/neuoverexpressing tumors (n = 588, P \ 0.0001; test for heterogeneity Q = 3.07, df = 5, I 2 = 0%). e Luminal (ER?/PR?/HER2/neu?) versus TN tumors (n = 971, P = 0.02; test for heterogeneity Q = 7.34, df = 6, I 2 = 0%) neu? subtypes resembling the Luminal subtypes, and the ER-/PR-/HER2/neu- and ER-/PR-/HER2/neu? resembling the Basal (triple negative, TN) and HER2/neuoverexpressing subtypes, respectively. It has been shown that IHC determined ER, PR, and HER2/neu status largely describe the subgroups when genetic profiling data is unavailable [31], and guidelines have been issued by the American Society of Clinical Oncology (ASCO) to ensure standardized and accurate testing for these markers [32, 33]. The TN status in particular is generally accepted based on negative assays of all three receptors. There is such a degree of overlap between TN breast cancers defined by IHC and basal-like breast cancers defined by gene expression profiling that these two entities are frequently considered to be clinically synonymous [34, 35], while it has been suggested that there may be some degree of overlap between the Luminal and HER2/neu-overexpressing subtypes based on IHC of receptor status alone [31].

838 Breast Cancer Res Treat (2012) 133:831 841 Fig. 6 LRR according to tumor subtype following mastectomy (subgroup analysis). Each study is shown by the point estimate of the odds ratio (RR; square proportional to the weight of each study) and 95% CI for the RR (extending lines); the combined RR and 95% CI by random effects calculations are shown by diamonds. The arrow indicates that 95% CI extends beyond the depicted range. a Luminal (ER?/PR?/HER2/ neu-) versus Luminal (ER?/ PR?/HER2/neu?) tumors (n = 3,934, P = 0.0001; test for heterogeneity, Q = 6.01, df = 6, I 2 = 0.3%). b Luminal (ER?/PR?/HER2/neu-) versus HER2/neuoverexpressing tumors (n = 3,717, P = 0.004; test for heterogeneity Q = 9.09, df = 6, P = 0.54, I 2 = 34%). c Luminal (ER?/PR?/HER2/ neu-) versus TN tumors (n = 3,984, P = 0.0003; test for heterogeneity Q = 10.9, df = 6, I 2 = 45%). d Luminal (ER?/PR?/HER2/neu?) versus HER2/neuoverexpressing tumors (n = 1,309, P = 0.56; test for heterogeneity Q = 3.7, df = 6, I 2 = 0%). e Luminal (ER?/ PR?/HER2/neu?) versus TN (n = 1,576, P = 0.526; test for heterogeneity Q = 5.87, df = 6, I 2 = 0%) A B C D Luminal (ER+/PR+/HER2-) vs Luminal (ER+/PR+/HER2+) tumors Luminal (ER+/PR+/HER2-) vs HER2/neu-overexpressing tumors Luminal (ER+/PR+/HER2-) vs TN tumors Kyndi et al 0.75 (0.51, 1.12) Luminal (ER+/PR+/HER2+) vs HER2/neu-overexpressing tumors RR (95% confidence interval) Kyndi et al 0.92 (0.56, 1.56) Wang et al 0.44 (0.26, 0.73) Ihemelandu et al 0.25 (0.06, 1.23) Voduc et al 0.64 (0.41, 1.01) Gabos et al 0.43 (0.16, 1.13) Meyer et al 0.90 (0.13, 6.71) Mersin et al 0.37 (0.10, 1.34) combined [random] 0.59 (0.46, 0.78) 0.01 0.1 0.2 0.5 1 2 5 10 Kyndi et al 0.84 (0.54, 1.34) Wang et al 0.49 (0.27, 0.91) Ihemelandu et al 1.51 (0.18, infinity) Voduc et al 0.68 (0.45, 1.06) Gabos et al 0.38 (0.13, 1.08) Meyer et al 0.75 (0.11, 5.59) Mersin et al 0.12 (0.03, 0.44) combined [random] 0.58 (0.39, 0.85) 0.01 0.1 0.2 0.5 1 2 5 10 Wang et al 0.53 (0.30, 0.94) Ihemelandu et al 0.39 (0.09, 1.63) Voduc et al 0.68 (0.50, 0.95) Gabos et al 0.22 (0.08, 0.59) Meyer et al 0.25 (0.06, 1.04) Mersin et al 0.16 (0.04, 0.58) combined [random] 0.51 (0.36, 0.73) 0.01 0.1 0.2 0.5 1 2 Kyndi et al -0.013 (-0.109, 0.089) Wang et al 0.015 (-0.078, 0.099) Ihemelandu et al 0.118 (-0.051, 0.347) Voduc et al 0.010 (-0.075, 0.099) Gabos et al -0.013 (-0.122, 0.076) Meyer et al -0.011 (-0.257, 0.208) Mersin et al -0.033 (-0.104, 0.005) combined [random] -0.009 (-0.041, 0.023) -0.40-0.15 0 0.10 0.35 E Luminal (ER+/PR+/HER2+) vs TN tumors Kyndi et al 0.82 (0.45, 1.46) Wang et al 1.22 (0.68, 2.17) Ihemelandu et al 1.53 (0.32, 6.95) Voduc et al 1.07 (0.65, 1.74) Gabos et al 0.50 (0.21, 1.24) Meyer et al 0.28 (0.04, 1.58) Mersin et al 0.43 (0.12, 1.55) combined [random] 0.91 (0.68, 1.21) 0.01 0.1 0.2 0.5 1 2 5 10 For this reason, the first analysis performed compared the TN group with the non-tn breast cancers. The LRR rate following BCT and mastectomy was significantly higher in TN tumors (13.5 and 12.9%, respectively) compared with non-tn tumors. This observation is in keeping with previous reports that the TN subtype of breast cancer is an aggressive form of tumor associated with increased metastatic potential and decreased overall survival [36, 37]. High post-mastectomy LRR in the TN group has implications for adjuvant radiotherapy. Post-mastectomy radiotherapy (PMRT) is one of the more controversial issues in adjuvant breast cancer therapy. The traditional indications for PMRT including tumor size[t3/5 cm and positive axillary lymph nodes [38] have been challenged and attempts made to identify patients with smaller size (T1 T2) tumors exhibiting other poor prognostic factors who may benefit from PMRT [39]. The MRC/EORTC SUPREMO trial is expanding the indications for PMRT and is likely to demonstrate additional subgroups of breast cancer patients

Breast Cancer Res Treat (2012) 133:831 841 839 who will benefit from radiotherapy [40]. The increased LRR observed in TN breast cancers highlights these tumors as a subgroup that may benefit from PMRT. This hypothesis is supported by a recent report from Abdulkarim et al. [41] who analyzed LRR and survival according to initial surgical therapy in a cohort of TN breast cancers and found that the highest LRR rates were in those patients who underwent mastectomy without adjuvant radiotherapy. The authors highlighted the need for investigation and evidence regarding the indications and use of radiotherapy in TN breast cancers specifically. In this series, 44% of patients undergoing mastectomy received PMRT. The effect of PMRT on LRR, however, was only analyzed in two of the data sets [14, 18] and so could not be systematically reviewed. Interestingly both of these studies found that the benefit of PMRT was more pronounced in breast cancers characterized by good prognostic markers including ER positivity and PR positivity. Specifically, TN tumors exhibited a smaller reduction LRR following PMRT; it is postulated that this may be due to relative radioresistance of ER negative tumors [18], however, clinical data of receptor phenotype in patients randomly assigned to receive PRMT are lacking. TN breast cancers represent a challenge to many current principles in breast cancer management and it is clear that the role of adjuvant radiotherapy in breast cancers of distinct receptor phenotype requires additional study. In contrast, Luminal tumors had a lower LRR rate following BCT (5%) or mastectomy (7.7%) than both TN and HER2/neu-overexpressing breast cancers which is in keeping with reports that Luminal cancers have a more favorable prognosis than the other subtypes [2, 4]. Furthermore, patients with Luminal tumors benefit from adjuvant hormonal therapy, which is known to reduce LRR and mortality by 30% [42]. In these data sets, adjuvant hormonal therapy was administered according to standard protocols at the time of treatment, with treatment dates ranging from 1980 to 2007 indicating that even lower rates of relapse may be achievable with modern endocrine therapy regimens. Furthermore, the cutoff for determination of ER and PR positivity by IHC has recently been reduced to [1% of tumor cells staining positive [43]. The use of this criterion to determine hormone receptor positivity was reported in only one of the studies in this series [11] with other series reporting a higher cutoff of[10% of tumor cells staining positive. The Early Breast Cancer Trialists Collaborative Group have recently updated their meta-analysis of randomized trials of patients treated with tamoxifen; one of the striking findings in their analysis was that even patients who are weakly ER positive derive a substantial benefit from tamoxifen therapy [44]. It is possible that if the lower cutoff of 1% was used in these studies a proportion of patients who may have benefited from adjuvant hormonal therapy might have been identified and had improved outcomes if treated accordingly. The HER2/neu-overexpressing breast cancers had a particularly poor prognosis following BCT, with LRR rates of 15.7%, approaching that of patients treated with breast conserving surgery alone [6]. The importance of HER2/neu receptor status as a driver of prognosis is well recognized [45] and targeted therapy has been developed in the form of trastuzumab. The high rate of LRR in the HER2/neuoverexpressing subgroup of breast cancers in this analysis likely reflects the study periods of many of the data sets which were prior to the routine availability of trastuzumab (\6% of HER2/neu-overexpressing tumors were treated with trastuzumab). Due to the lack of adjuvant trastuzumab use in the patients in these data sets, there is insufficient data to suggest that BCT is inappropriate for HER2/neuoverexpressing cancers. Both HER2/neu-overexpressing and TN tumors also had higher LRR rates following mastectomy, but the differences between the subtypes were less distinct and there were no significant differences in LRR between HER2/neuoverexpressing and TN tumors. This finding is interesting as it would be expected that in the absence of trastuzumab, HER2/neu-overexpressing tumors would have an increased LRR compared to TN tumors following mastectomy, as was observed in the BCS cohort. This finding may be partly explained by differences in administration and response to PMRT between these subgroups; data on PMRT was not extractable for all patients in the series, however, where it was extractable [11, 14, 16, 18] a higher proportion of HER2/neu-overexpressing tumors (48.8%) were treated with PMRT compared with TN tumors (39%). It has also been hypothesized that ER negative and TN tumors in particular exhibit a degree of radioresistance [18] which could be a contributory factor in the high LRR following mastectomy in this cohort of patients. A subgroup analysis performed on the data sets in which both BCT and mastectomy were compared according to breast cancer subtype demonstrated decreased LRR in both Luminal and HER2/neu-overexpressing tumors following mastectomy compared to BCT, but no significant difference for TN patients. The higher LRR rates in Luminal and HER2/neu-overexpressing tumors may be explained by the lack of concurrent adjuvant systemic therapies to decrease LRR and mortality [42, 46]. In particular, the lack of adjuvant trastuzumab is likely to contribute to the high recurrence rate in this Luminal cohort. Indeed the subgroup analysis of mastectomy patients revealed a significantly lower LRR rate of 7.5% in the Luminal (ER?/PR?/HER2/neu-) tumors compared to 9.4% in the Luminal (ER?/PR?/HER2/neu?) tumors, most of which had not been treated with trastuzumab despite overexpression of HER2/neu. Importantly, patients with TN tumors can be considered candidates for BCT as

840 Breast Cancer Res Treat (2012) 133:831 841 there does not appear to be any difference in local control based on surgical approach. There are limitations to this review that must be acknowledged. First, the data sets included in this analysis are all observational or retrospective series; the breast tumors were classified prior to standardization of immunohistochemical analysis of ER, PR, and HER2/neu receptor expression in breast cancer [32, 33]. It was not possible to compare the precise adjuvant therapies for different data sets as these data were not specified in all cases and in many of the data sets adjuvant therapy, particularly with regards to trastuzumab, cannot be compared to current practice. In addition, it was not possible to verify all the individual patient data from each study, including variables that may be important risk factors for LRR such as age and tumor histology. The analysis is based on available published results, and the use of updated individual patient data would possibly further enhance the accuracy of the analysis [47]. A further potential bias is the variation in duration of follow-up between studies that ranged from 35 to 204 months; this coupled with the fact that simple proportions were used to quantify the risk of LRR between patient cohorts, could introduce a potential source of error. Despite these limitations, this large series of 12,592 patients confirms that breast cancer biologic subtype is associated with differences in LRR in breast cancer patients treated with BCT or mastectomy. The data demonstrates that TN breast cancers behave less favorably than Luminal breast cancers and almost as poorly as HER2/neu over-expressing cancers in an era prior to the availability of trastuzumab. 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