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Omitting radiation therapy in women with triple-negative breast cancer leads to worse breast cancer-specific survival
The Breast 32 (2017) 18e25
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Original article
Omitting radiation therapy in women with triple-negative breast cancer leads to worse breast cancer-specific survival I. Kindts a, b, *, P. Buelens a, b, A. Laenen c, E. Van Limbergen a, b, H. Janssen a, b, H. Wildiers a, d, C. Weltens a, b a
KU Leuven e University of Leuven, Department of Oncology, B-3000, Leuven, Belgium University Hospitals Leuven, Department of Radiation Oncology, Herestraat 49, B-3000, Leuven, Belgium Leuven Biostatistics and Statistical Bioinformatics Centre (L-Biostat), KU Leuven University, Kapucijnenvoer 35, B-3000, Leuven, Belgium d University Hospitals Leuven, Department of General Medical Oncology, Herestraat 49, B-3000, Leuven, Belgium b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 October 2016 Received in revised form 8 December 2016 Accepted 13 December 2016
Purpose: To examine locoregional recurrence (LRR) and breast cancer-specific survival (BCSS) after breast-conserving therapy (BCT) or mastectomy (ME) with or without radiation therapy (RT) in triplenegative breast cancer (TNBC). Material & Methods: We identified non-metastatic TNBC cases from a single institution database. BCT, ME with RT (ME þ RT) and ME only were compared with respect to LRR and BCSS. Cox regression models were used to analyze the association between prognostic factors and outcome. Results: 439 patients fulfilled the inclusion criteria. Median follow-up was 10.2 years (interquartile range 7.9; 12.4 years). Patients in the BCT (n ¼ 239), ME þ RT (n ¼ 116) and ME only (n ¼ 84) group differed with respect to age, pT, pN, lymphovascular invasion, lymph node dissection and chemotherapy administration. Ten-year LRR rates were seven percent, three percent and eight percent for the BCT, ME þ RT and ME only group, respectively. pN was associated with LRR. In multivariable analysis LRR were significantly lower in the ME þ RT group compared to the BCT and the ME only group (p 0.037 and 0.020, respectively). Ten year BCSS was 87%, 84% and 75% for the BCT, ME þ RT and ME only group, respectively. pT, pN, lymph node dissection, lymphovascular invasion and the administration of chemotherapy were associated with BCSS. In multivariable analysis BCSS was significantly lower in the ME only group compared to the BCT group and the ME þ RT group (p 0.047 and 0.003, respectively). Conclusion: TNBC patients treated with ME without adjuvant RT showed significant lower BCSS compared to patients treated with BCT or ME þ RT and significant more LRR compared to ME þ RT when corrected for known clinicopathological prognostic factors. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Triple-negative breast cancer Radiation therapy Breast-conserving therapy Mastectomy Indication
1. Introduction Breast cancer is a heterogeneous disease encompassing distinct molecular profiles associated with different clinical outcomes. Based on gene expression profiling a molecular classification system has been proposed characterizing five subtypes: luminal A or B,
* Corresponding author. E-mail addresses: [email protected] (I. Kindts), pieterjan.buelens@ uzleuven.be (P. Buelens), [email protected] (A. Laenen), erik. [email protected] (E. Van Limbergen), [email protected] (H. Janssen), [email protected] (H. Wildiers), caroline.weltens@uzleuven. be (C. Weltens). http://dx.doi.org/10.1016/j.breast.2016.12.007 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
Human Epidermal growth factor Receptor 2 (HER2)-positive, normal and basal-like [1,2]. The basal-like subtype is characterized by the molecular absence or minimal expression of receptors for estrogen (ER), progesterone (PR), and HER2 in addition to high expression of c-Kit, myoepithelial cytokeratins 5, 6 and 17, and HER1. In clinical routine, these molecular subtypes are approximated using immunohistochemistry (IHC) for ER, PR and HER2. The basal-like subtype is then represented by the lacking of these three markers and entitled Triple Negative Breast Cancer (TNBC) even though there is 25e30% discordance [3]. TNBC comprises 15e20% of breast cancers and has worse outcomes compared to other breast cancer subtypes [4,5]. Studies exploring the importance of molecular subtyping
I. Kindts et al. / The Breast 32 (2017) 18e25
suggested that the luminal-A subtype has the lowest risk for locoregional recurrence, while HER2 positive and triple negative subtypes are associated with a substantially higher risks [6,7]. Even though the prognostic and predictive value of breast cancer subtypes are widely recognized and used in the elaboration of systemic treatment, their value for locoregional management needs further clarification [4,5]. There are two main pathways for locoregional therapy. Firstly, there is breast conserving therapy (BCT), including breast conserving surgery (BCS) followed by radiation therapy (RT); and secondly there is mastectomy (ME) with or without adjuvant RT; both with axillary nodal assessment and treatment. Level-I evidence has shown equivalence of these two strategies in terms of survival without taking molecular subtypes into account [8,9]. The poor prognosis of TNBC could suggest the need for an aggressive locoregional approach such as more radical surgery or the addition of radiation therapy. A randomized controlled multi-center trial from Wang et al. included 681 women with stage I-II TNBC treated with mastectomy and chemotherapy of whom 366 patients received radiation therapy. Five-year overall survival significantly improved in the RT group [10]. Limited data also suggest a better locoregional control for TNBC when treated with BCT compared to ME without adjuvant RT [11e13]. With this paper, we want to clarify the following remaining question further: is there a difference in locoregional recurrence (LRR) and breast cancer-specific survival (BCSS) in TNBC patients treated with BCT, ME plus adjuvant RT and ME only?
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involved cyclophosphamide, methotrexate, 5-fluorouracil, epirubicin and taxanes. Based on the locoregional treatment, patients were divided into three groups: BCT, ME with adjuvant local, regional or locoregional RT (ME þ RT) and ME only. This study was approved by the Clinical Trial Center and the Ethics Committee of our institution. 2.2. Endpoints LRR was defined as local and or regional (axillar, parasternal or supraclavicular region) recurrence. BCSS was defined as death from breast cancer. Death from other causes, or death from unknown cause was not included, and patients were censored when these events occurred. Patients were also censored at the last date of follow-up. Clinicopathological risk factors (age, grade, pT, pN, lymphovascular invasion, perineural invasion, surgical margins, extensive ductal carcinoma in situ, histology, details on surgery, radiation therapy and chemotherapy) for LRR and BCSS were available in the database. LRR and BCSS were compared for the BCT, ME þ RT and ME only group. Subgroup analysis involved patients with an invasive ductal adenocarcinoma not otherwise specified (IDA_NOS) to create a more pathologically homogenous subgroup, this means excluding for example cystic, apocrine and medullary-like tumors [16]. A second subgroup analysis involved all patients who would not receive RT after ME according to the current guidelines: pT1-2N0 tumors with negative surgical margins [17].
2. Material & methods 2.3. Statistical analysis 2.1. Patient selection and data collection A large prospectively collected database, set up in January 2000 and now containing prospectively obtained data of more than 12.200 patients files was used for selection. The database includes data of all patients diagnosed with breast cancer and having at least one of the following treatments, i.e. surgery and/or RT and/or systemic therapy, at University Hospitals Leuven, Belgium. The patient cohort used for this analysis included patients diagnosed with a non-metastasized invasive TNBC between January the first, 2000 and December 31, 2009. TNBC was defined as tumors with negative IHC for the ER (
Summary statistics were presented as medians and range for continuous variables and as frequencies and percentages for categorical variables. Summary statistics on time-to-event outcome variables were based on the cumulative incidence function considering death without event as competing event. Summary statistics for followup time were based on the Kaplan-Meier estimate of potential follow-up [18]. Group differences were tested by a Chi-square test for categorical variables or one-way ANOVA for continuous variables. Cox regression models were used to analyze the association between prognostic factors and outcome. A non-linear trend for age was tested. Results were presented as hazard ratios with 95% confidence intervals. Outcome variables were defined as the time between diagnosis and the time of event. Patients without the respective event were censored at time of death or last follow-up. Analyzing the association between treatment approach and outcome, correction was performed by including possible confounders as covariates in the multivariable model. Variables corrected for were these clinicopathological factors that were associated with outcome and for which there were differences between treatment approaches. All tests were two-sided, a five % significance level was assumed for all tests. Analyses have been performed using SAS software (version 9.4 for Windows). 3. Results 3.1. Patients, tumor and treatment characteristics Clinicopathological factors of 439 TNBC patients were assessed. 239 patients were included in the BCT group, 116 in the ME þ RT group, 84 in the ME only group. Median follow-up time for the 439 patients was 10.2 years (interquartile range 7.9; 12.4 years, range 0.36; 15.6 years).
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Patients in the ME þ RT group presented with higher pT and pN tumor stages and more lymphovascular invasion compared to the other two groups. Patients in the ME only group were older and received less adjuvant chemotherapy compared to the other two groups. Patients in the BCT group underwent more sentinel lymph node and less axillary lymph node dissection (Table 1). In the BCT group 236 patients (99%) received a boost after WBI. Of the 116 patients in the ME þ RT group, 88 (76%) received RT to the chest wall with or without the nodal areas and 28 (24%) patients received only nodal irradiation. In the BCT and ME þ RT group, 211 patients (59%) received RT to the median subclavian and parasternal regions and 16 patients (five %) received RT to the axillary regions. 342 patients were classified as IDA_NOS with comparable patient, tumor and treatment characteristics as the whole population (Appendix 1). Besides IDA_NOS, histological subtypes comprised adenoid cystic, apocrine, medullary (-like), metaplastic, adeno-squamous, colloid, neuro-endocrine
differentiation and tubular. 3.2. Locoregional recurrence FIve-year LRR-free rates were 94%, 97% and 92% for the BCT, ME þ RT and ME only group, respectively. Ten-year LRR-free rates were 93%, 97% and 92% for the BCT, ME þ RT and ME only group, respectively. 3.2.1. Risk factors for LRR Patients with a higher pathological nodal stage were at higher risk for LRR (HR 1.81, p 0.001). There was a trend towards more LRR in tumors with lymphovascular invasion (Table 2). 3.2.2. LRR by group LRR was compared for the three groups in multivariable analysis with correction of pN stage (Table 3). Patients in the BCT and the ME only group showed a significant higher risk for LRR compared to the ME þ RT group (HR 3.29, p 0.037 and HR 4.45, p 0.020 respectively).
Table 1 Patient, tumor and treatment characteristics.
Age Median Range Tumor grade 1 2 3 Pathological tumor stage 1 2 3 4 in situ Pathological nodal stage 0 1 2 3 Lymphovascular invasion Present Absent Perineural invasion Present Absent Surgical margins invasive Free Involved Surgical margins in situ Free Involved Extensive DCIS (ductal carcinoma in situ) Yes No Adjuvant chemotherapy Yes No Sentinel Lymph Node Excision Yes No Axillary Lymph Node Dissection Yes No
BCT (n ¼ 239)*
ME þ RT (n ¼ 116)*
ME only (n ¼ 84)*
Number (percentage)
Number (percentage)
Number (percentage)
53.0 26.0; 90.0
53.0 27.0; 88.0
57.0 24.0; 88.0
7/238 (2.94%) 21/238 (8.82%) 210/238 (88.24%)
0/116 (0.00%) 12/116 (10.34%) 104/116 (89.66%)
2/83 (2.41%) 9/83 (10.84%) 72/83 (86.75%)
144/239 (60.25%) 93/239 (38.93%) 1/239 (0.42%) 1/239 (0.42%) 0/239 (0.00%)
20/116 (17.24%) 70/116 (60.34%) 25/116 (21.55%) 1/116 (0.86%) 0/116 (0.00%)
36/84 (42.86%) 41/84 (48.81%) 5/84 (5.95%) 1/84 (1.19%) 1/84 (1.19%)
177/236 (75.00%) 46/236 (19.49%) 10/236 (4.24%) 3/236 (1.27%)
46/116 (39.66%) 50/116 (43.10%) 14/116 (12.07%) 6/116 (5.17%)
61/81 (75.31%) 13/81 (16.05%) 5/81 (6.17%) 2/81 (2.47%)
26/154 (16.88%) 128/154 (83.12%)
42/98 (42.86%) 56/98 (57.14%)
14/58 (24.14%) 44/58 (75.86%)
6/128 (4.69%) 122/128 (95.31%)
2/74 (2.70%) 72/74 (97.30%)
1/47 (2.13%) 46/47 (97.87%)
227/236 (96.19%) 9/236 (3.81%)
111/115 (96.52%) 4/115 (3.48%)
78/82 (95.12%) 4/82 (4.88%)
127/130 (97.69%) 3/130 (2.31%)
68/70 (97.14%) 2/70 (2.86%)
50/50 (100.00%) 0/50 (0.00%)
65/179 (36.31%) 114/179 (63.69%)
37/93 (39.78%) 56/93 (60.22%)
28/70 (40.00%) 42/70 (60.00%)
185/239 (77.41%) 54/239 (22.59%)
90/116 (77.59%) 26/116 (22.41%)
43/84 (51.19%) 41/84 (48.81%)
101/237 (42.62%) 136/237 (57.38%)
11/116 (9.48%) 105/116 (90.52%)
13/82 (15.85%) 69/82 (84.15%)
164/237 (69.20%) 73/237 (30.80%)
111/116 (95.69%) 5/116 (4.31%)
73/82 (89.02%) 9/82 (10.98%)
P-value
0.019
0.443
<0.001
<0.001
<0.001
0.638
0.875
0.510
0.794
<0.001
<0.001
<0.001
*BCT ¼ breast-conserving therapy, ME ¼ mastectomy, RT ¼ radiation therapy.
I. Kindts et al. / The Breast 32 (2017) 18e25
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Table 2 Risk factors for locoregional recurrence (LRR) and breast cancer-specific mortality (BCSS) in univariable analysis.
Age (þ1 year) Tumor grade (þ1) Tumor stage (pT) (þ1) Nodal stage (pN) (þ1) Lymphovascular invasion (Yes vs No) Perineural invasion (Yes vs No) Surgical margins invasive (Involved vs Free) Surgical margins in situ (Involved vs Free) Extensive DCIS (ductal carcinoma in situ) (Yes vs No) Adjuvant Chemotherapy (Yes vs No) Sentinel Lymph Node Excision (Yes vs No) Axillary Lymph Node Dissection (Yes vs No)
LRR *HR (95% CI)
P-value
BCSS* HR (95% CI)
P-value
0.99 0.67 0.99 1.81 2.15 2.26 0.76 2.79 0.66 1.07 0.93 1.39
0.231 0.255 0.977 0.001 0.065 0.433 0.790 0.320 0.357 0.866 0.850 0.499
1.00 1.19 1.59 1.82 1.72 2.94 1.03 1.97 0.99 0.58 0.44 2.81
0.756 0.602 0.006 <0.0001 0.053 0.075 0.955 0.347 0.983 0.024 0.011 0.016
(0.96; (0.34; (0.57; (1.26; (0.95; (0.29; (0.10; (0.37; (0.27; (0.48; (0.43; (0.54;
1.01) 1.33) 1.73) 2.59) 4.83) 17.30) 5.59) 21.05) 1.60) 2.38) 2.00) 3.61)
(0.98; (0.62; (1.14; (1.41; (0.99; (0.90; (0.33; (0.50; (0.59; (0.36; (0.23; (1.22;
1.01) 2.26) 2.23) 2.35) 2.96) 9.60) 3.29) 8.12) 1.67) 0.93) 0.83) 6.49)
*LRR ¼ locoregional recurrence, BCSS ¼ breast cancer-specific survival.
Table 3 Multivariable analysis for locoregional recurrence (LRR) and breast cancer-specific survival (BCSS). All patients
ME only vs BCT*
LRR** HR (95% CI) 1.35 (0.56; 3.25) p-value 0.499 BCSS** HR (95% CI) 1.84 (1.00; 3.36) p-value 0.047 T1-2N0 Negative section margins LRR** HR (95% CI) 1.14 (0.31; 4.24) p-value 0.841 BCSS** HR (95% CI) 2.02 (0.84; 4.87) p-value 0.118
BCT vs ME þ RT*
ME only vs ME þ RT *
3.29 (1.08; 10.06) 0.037
4.45 (1.26; 15.69) 0.020
1.56 (0.81; 3.02) 0.184
2.88 (1.43; 5.80) 0.003
N/A*** N/A***
N/A*** N/A***
2.25 (0.46; 10.99) 0.318
4.53 (0.98; 20.92) 0.053
* BCT ¼ breast-conserving therapy, ME ¼ mastectomy, RT ¼ radiation therapy.* LRR ¼ locoregional recurrence, BCSS ¼ breast cancer-specific survival*** Not available due to no LLR in the ME þ RT group.
Results showed no evidence of a difference between ME only and BCT. IDA_NOS patients treated with ME only had significantly more LRR compared to the ME þ RT group (HR 5.42, p 0.016) (Appendix 2). LRR-free curves for the three groups as estimated from the multivariable model are presented in Fig. 1. 3.3. Breast cancer-specific survival Sixty-nine patients died because of breast cancer. Five-year BCSS rates were 90%, 86% and 80% for the BCT, ME þ RT and ME only group, respectively. Ten-year BCSS rates were 87%, 84% and 75% for the BCT, ME þ RT and ME only group, respectively. 3.3.1. Risk factors for BC-specific mortality BC-specific mortality increased with higher pT and pN stages (HR 1.59, p 0.006 and HR 1.82, p < 0.0001, respectively). Patients with an axillary lymph node dissection (HR 2.81, p 0.016) and with lymphovascular invasion (HR 1.72, p 0.053) had lower BCSS.
Fig. 1. LRR-free curves for the three groups as estimated from the multivariable model (with correction for pN). The figure presents the estimated curves for patients with pN0. BCT ¼ breast-conserving therapy, ME ¼ mastectomy, RT ¼ radiation therapy.
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Fig. 2. BCSS curves for the three groups as estimated from the multivariable model (with correction for pT, pN, lymphovascular invasion, lymph node dissection and adjuvant chemotherapy). The figure presents the estimated curves for patients with pT2, pN0, no lymphovascular invasion, with adjuvant chemotherapy, without sentinel and with axillary lymph node dissection. BCT ¼ breast-conserving therapy, ME ¼ mastectomy, RT ¼ radiation therapy.
Adjuvant chemotherapy administration was a protective factor for BC-specific mortality (HR 0.58, p 0.024) (Table 2). 3.3.2. BCSS by group Multivariable analysis was conducted to assess differences between the three groups with correction for pT, pN, lymphovascular invasion, lymph node dissection and adjuvant chemotherapy (Table 3). Patients in the ME only group had significant lower BCSS compared to the BCT and the ME þ RT group (HR 1.84, p 0.047 and HR 2.88, p 0.003, respectively). No significant differences were observed for the comparison of BCT versus ME þ RT. BCSS curves for the three groups as estimated from the multivariable model are presented in Fig. 2. In the IDA_NOS subgroup, results were comparable with higher HR (Appendix 2). 3.4. T1-2N0 negative section margins subgroup Two hundred fifty-nine patients had pT1-2N0 tumors with negative surgical margins. Nine out of 167 patients (5.4%) in the BCT group developed LRR, none out of 36 patients in the ME þ RT group and three out of 56 (5.4%) in the ME only group. No significant differences were observed between the three groups for LRR (p 0.381) (Table 3). Thirteen out of 167 patients (7.8%) from the BCT group died because of breast cancer, two out of 36 (5.6%) from the ME þ RT group and 12 out of 56 (21.4%) from the ME only group. There was a trend towards lower BCSS in the ME only group compared to the ME þ RT group (HR 4.53, p 0.053) (Table 3). 4. Discussion Breast cancer subtypes are taken into account in the patienttailored elaboration of systemic therapy. The breast cancer
subtypes are however not counted for the decision-making of locoregional treatment. TNBC, defined as the absence of ER, PR and HER2 expression, is associated with worse outcomes compared to the other subtypes [4e7]. Because of the poorer outcome, an intensified locoregional approach could be suggested. Therefore two strategies can be proposed: either adjuvant radiation therapy or more radical surgery. First, concerning radiation therapy, it remains unclear if and to what extent TNBC is biologically radioresistant or radiosensitive. Pre-clinical studies suggest the TNBC subtype to be more radioresistant due to for example ERp29 expression (increases promotor hypo-methylation of a DNA repair gene), overexpression of HER1 (an epidermal growth factor receptor) or overexpression of mir-27 (a direct target of mir-27a, DC-27 increases radioresistance of TNBC cells) [19e21]. Additionally, clinical data support the radioresistance in the meta-analysis from the Early Breast Cancer Trialists' Collaborative Group and the Danish 82b/c trials reporting less benefit from RT in ER-negative tumors [7,22e24]. On the other hand, in vitro studies also show the radiosensitivity of TNBC. For example, radioresistance could be reduced in vitro by impairing the BRCA1/2 expression, a germline mutation present in 11e16% of TNBC [25]. The mutation leads to a defect in the BRCA1 pathway which makes tumors inherently more radiosentitive by the inability to repair treatment-induced damage (defects in the DNA homologous recombination) and would potentially provide a benefit in tumor-cell killing [26,27]. Also clinical data have been reported supporting the radiosensitivity of TNBC. Overall survival rates in the MA.20 trial randomizing breast cancer patients to undergo regional nodal irradiation or not approached statistical significance only in the subgroup with ER-negative disease in favor of irradiation (81% vs 74%, HR 0.69, 95% CI 0.47e1.00, p 0.05) [28].
I. Kindts et al. / The Breast 32 (2017) 18e25
In the present study, we wanted to further clarify the impact of the extent of locoregional therapy on LRR and BCSS in TNBC. Four hundred thirty-nine TNBC patients, treated at a single institution, were included in the analyses: 239 underwent BCT, 116 ME þ RT and 84 ME only. Cox multivariable regression models were used to analyze the association between prognostic factors and outcome. LRR were significantly higher in the BCT and the ME only group compared to the ME þ RT group (HR 3.29, 95% CI 1.08e10.06, p 0.037 and HR 4.45, 95% CI 1.26e15.69, p 0.020, respectively). BCSS however was significantly lower in the ME only group compared to the BCT group (HR 1.84, 95% CI 1.00e3.36, p 0.047) and the ME þ RT group (HR 2.88, 95% CI 1.43e5.80, p 0.003). Our data support the strategy of incorporating radiation therapy in the locoregional treatment of TNBC patients. Second, our data refute the need for a more aggressive surgical approach in TNBC by means of ME. Concerning survival, patients treated with ME only presented with worse BCSS compared to BCT when corrected for known clinicopathological prognostic factors. If however radiation therapy was added to ME, BCT and ME resulted in similar survival. Concerning the endpoint of LRR, patients treated with ME þ RT had significantly better locoregional control compared to those treated with BCT. These findings are in line with the results from the 20 year follow-up study of the EORTC 10801 trial randomizing patients between BCT and ME in stage I-II breast cancer. ME resulted in better local control, but did not affect overall survival [9]. In contrary two recent population-based studies on breast cancer patients in the Netherlands evaluated 10-year survival after BCT compared with ME. In women with early breast cancer and in those with T2N2 stage, treatment with BCT showed improved 10year overall survival compared with ME after adjusting for confounding variables. In women with T1N2 stage breast cancer however, no significant difference was seen. For relative survival, a significant benefit was seen for patients treated with BCT and T1N0 or T2N2 stage or in the cohort treated in 2003. The authors concluded that BCT is at least equivalent to ME with respect to overall survival [29,30]. Also, for TNBC patients, a meta-analysis by Wang et al. reported significantly lower LRR and distant metastasis rates in the BCT compared to the ME group, of whom 21% received adjuvant radiation therapy (16.9% versus 21.9%, relative risk (RR) 0.75, 95% CI 0.65e0.87 and 23.6% versus 34.4%, RR 0.68, 95% CI 0.60e0.76, respectively) [12]. ME only was an independent predictor of LRR compared to BCT in a retrospective series at the University of Alberta in 768 TNBC patients (HR 3.44, 95% CI 2.04e5.80, p < 0.001) [11]. In their subgroup analysis of 468 patients with T1-2N0 TNBC, five-year LRR-free survival was 96% in the BCT group and 90% in the ME group (p 0.027) [11]. More recent data suggest no difference in the T1-2N0 stages, but worse results with ME only in T2-3N2-3 stages [13,31]. In our series, subgroup analysis of T1-2N0 TNBC patients with negative surgical margins did not show any difference between ME and BCT for LRR. However, since no LRR occurred in the ME þ RT group, no hard conclusions can be drawn. Another meta-analysis by Lowery et al. has analyzed LRR by receptor phenotype in early stage breast cancer: no difference was observed in LRR between BCT and ME, of whom 44% received adjuvant radiation therapy [32]. According to international guidelines, post ME RT is advised in case of T3-4 or Nþ tumors or in case of positive surgical section margins [17]. In our series, adding RT to ME significantly decreased LRR and increased BCSS. Subgroup analysis of T1-2N0 patients with
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negative surgical margins statistically just reached significance in favor of adding RT for BCSS. Our series support the results from the only prospective study addressing the need of post ME RT in stage III TNBC cases. Thereby 681 stage I-II TNBC patients were randomized to undergo RT or not after ME and adjuvant chemotherapy. Recurrence-free survival and overall survival were significantly higher in the arm with post ME RT (88.3% vs 74.6% and 90.4% vs 78.7% at five years) [10]. Comparable results were obtained in retrospective series, for example the study from Abdulkarim et al. and from the Danish Breast Cancer Cooperative Group [11,23,33,34]. Based on a subgroup analysis of the 82 b and c trials, a significantly lower rate of LRR was reported by adding RT to ME in TNBC patients (HR 0.33, 95% CI 0.14e0.78, p 0.001) [23]. A general remark however, as suggested by Poortmans et al. is that it is strongly advised to use “any recurrence” as endpoint in future studies instead of “locoregional recurrence”. They postulate that once distant metastases are found, in general no further efforts are undertaken to detect locoregional recurrences [35]. The retrospective study from Steward et al. on the contrary found no improved survival when RT was added to ME in stage I-III TNBC patients [36]. Our findings intensify the hypothesis that patients with TNBC benefit from radiation therapy. However, TNBC comprises a very heterogeneous entity and treating all TNBC according to the same protocol might be an oversimplification. To create a more homogeneous subgroup from a pathology point of view, we have conducted the analyses on only IDA_NOS TNBC subtypes; BCSS results did not differ significantly. Future translational research is needed regarding the different underlying tumorigenic pathways in TNBC. Data are sparsly emerging; Wushou et al. oberserved that two gene signatures specifically identified a radiosensitive population that had improved outcome with differences between “radiosensitive” and “radioresistant” TNBC patients [37]. The strengths of our study include the comprehensive prospectively registered single institution database with patient characteristics, treatment and patients status at regular follow-up with accurate information on LRR and BCSS. In consequence, our study represents one of the largest analyses of the impact of different curative treatment options for TNBC with long-term follow-up. On the other hand, we acknowledge the limitations of a retrospective series with inherent biases in patient and treatment selection. The numbers of events are relatively low resulting in limited statistical power. In addition, we acknowledge that due to the retrospective nature of the study, we might not have been able to correct for all potential confounding variables. Hence, the results of our study should be interpreted carefully and firm conclusions should not be drawn. In conclusion, the results of our study support the hypothesis that treatment of TNBC with ME without adjuvant RT results in significant lower BCSS compared to treatment with BCT or ME þ RT.
Conflict of interest There is no conflict of interest.
Funding source This research did not receive any specific grand from funding agencies in the public, commercial, or not-for-profit sectors.
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Appendix 1. Patient, tumor and treatment characteristics of 389 patients with IDA_NOS patients (invasive ductal carcinoma_not otherwise specified)
Age Median Range Tumor grade 1 2 3 Pathological tumor stage 1 2 3 4 Pathological nodal stage 0 1 2 3 Lymphovascular invasion Present Absent Perineural invasion Present Absent Surgical margins invasive Free Involved Surgical margins in situ Free Involved Extensive DCIS (ductal carcinoma in situ) Yes No Adjuvant chemotherapy Yes No Sentinel Lymph Node Excision Yes No Axillary Lymph Node Dissection Yes No
BCT (n ¼ 190)* Number (percentage)
ME þ RT (n ¼ 88)* Number (percentage)
ME only (n ¼ 64)* Number (percentage)
53.0 26.0; 90.0
51.0 29.0; 81.0
55.5 24.0; 87.0
3/190 (1.58%) 17/190 (8.95%) 170/190 (89.47%)
0/88 (0.00%) 6/88 (6.82%) 82/88 (93.18%)
1/64 (1.56%) 5/64 (7.81%) 58/64 (90.63%)
117/190 (61.58%) 71/190 (37.37%) 1/190 (0.53%) 1/190 (0.53%)
17/88 (19.32%) 54/88 (61.36%) 17/88 (19.32%) 0/88 (0.00%)
32/64 (50.00%) 29/64 (45.31%) 3/64 (4.69%) 0/64 (0.00%)
141/188 (75.00%) 37/188 (19.68%) 7/188 (3.72%) 3/188 (1.60%)
34/88 (38.64%) 39/88 (44.32%) 9/88 (10.23%) 6/88 (6.82%)
49/61 (80.33%) 9/61 (14.75%) 3/61 (4.92%) 0/61 (0.00%)
21/121 (17.36%) 100/121 (82.64%)
33/73 (45.21%) 40/73 (54.79%)
10/45 (22.22%) 35/45 (77.78%)
2/100 (2.00%) 98/100 (98.00%)
1/52 (1.920%) 51/52 (98.08%)
1/35 (2.86%) 34/35 (97.14%)
182/188 (96.81%) 6/188 (3.19%)
83/87 (95.40%) 4/87 (4.60%)
61/63 (96.83%) 2/63 (3.17%)
106/109 (97.25%) 3/109 (2.75%)
54/55 (98.18%) 1/54 (1.82%)
42/42 (100.00%) 0/42 (0.00%)
54/142 (38.03%) 88/142 (61.97%)
45/71 (63.38%) 26/71 (36.62%)
24/55 (43.64%) 31/55 (56.36%)
153/190 (80.53%) 37/190 (19.47%)
72/88 (81.82%) 16/88 (18.18%)
36/64 (56.25%) 28/64 (43.75%)
86/188 (45.74%) 102/188 (54.26%)
10/88 (11.36%) 78/88 (88.64%)
11/62 (17.74%) 51/62 (82.26%)
127/188 (67.55%) 61/188 (32.45%)
83/88 (94.32%) 5/88 (5.68%)
54/62 (87.10%) 8/62 (12.90%)
Pvalue 0.153
0.768
<0.001
<0.001
<0.001
0.948
0.829
0.510
0.698
<0.001
<0.001
<0.001
*BCT ¼ breast-conserving therapy, ME ¼ mastectomy, RT ¼ radiation therapy.
References
Appendix 2. Results of multivariable analysis between 3 subgroups in IDA_NOS (invasive ductal carcinoma_not otherwise specified) patients
LRR** HR (95% CI) p-value BCSS** HR (95% CI) p-value
ME only vs BCT*
BCT vs ME þ RT*
ME only vs ME þ RT*
2.48 (0.90; 6.84) 0.080
2.19 (0.66; 7.26) 0.200
5.42 (1.37; 21.49) 0.016
2.55 (1.27; 5.10) 0.008
1.49 (0.67; 3.30) 0.324
3.80 (1.64; 8.81) 0.002
*BCT ¼ breast-conserving therapy, ME ¼ mastectomy, RT ¼ radiation therapy.* LRR ¼ locoregional recurrence, BCSS ¼ breast cancer-specific survival.
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Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Omitting radiation therapy in women with triple-negative breast cancer leads to worse breast cancer-specific survival I. Kindts a, b, *, P. Buelens a, b, A. Laenen c, E. Van Limbergen a, b, H. Janssen a, b, H. Wildiers a, d, C. Weltens a, b a
KU Leuven e University of Leuven, Department of Oncology, B-3000, Leuven, Belgium University Hospitals Leuven, Department of Radiation Oncology, Herestraat 49, B-3000, Leuven, Belgium Leuven Biostatistics and Statistical Bioinformatics Centre (L-Biostat), KU Leuven University, Kapucijnenvoer 35, B-3000, Leuven, Belgium d University Hospitals Leuven, Department of General Medical Oncology, Herestraat 49, B-3000, Leuven, Belgium b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 October 2016 Received in revised form 8 December 2016 Accepted 13 December 2016
Purpose: To examine locoregional recurrence (LRR) and breast cancer-specific survival (BCSS) after breast-conserving therapy (BCT) or mastectomy (ME) with or without radiation therapy (RT) in triplenegative breast cancer (TNBC). Material & Methods: We identified non-metastatic TNBC cases from a single institution database. BCT, ME with RT (ME þ RT) and ME only were compared with respect to LRR and BCSS. Cox regression models were used to analyze the association between prognostic factors and outcome. Results: 439 patients fulfilled the inclusion criteria. Median follow-up was 10.2 years (interquartile range 7.9; 12.4 years). Patients in the BCT (n ¼ 239), ME þ RT (n ¼ 116) and ME only (n ¼ 84) group differed with respect to age, pT, pN, lymphovascular invasion, lymph node dissection and chemotherapy administration. Ten-year LRR rates were seven percent, three percent and eight percent for the BCT, ME þ RT and ME only group, respectively. pN was associated with LRR. In multivariable analysis LRR were significantly lower in the ME þ RT group compared to the BCT and the ME only group (p 0.037 and 0.020, respectively). Ten year BCSS was 87%, 84% and 75% for the BCT, ME þ RT and ME only group, respectively. pT, pN, lymph node dissection, lymphovascular invasion and the administration of chemotherapy were associated with BCSS. In multivariable analysis BCSS was significantly lower in the ME only group compared to the BCT group and the ME þ RT group (p 0.047 and 0.003, respectively). Conclusion: TNBC patients treated with ME without adjuvant RT showed significant lower BCSS compared to patients treated with BCT or ME þ RT and significant more LRR compared to ME þ RT when corrected for known clinicopathological prognostic factors. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Triple-negative breast cancer Radiation therapy Breast-conserving therapy Mastectomy Indication
1. Introduction Breast cancer is a heterogeneous disease encompassing distinct molecular profiles associated with different clinical outcomes. Based on gene expression profiling a molecular classification system has been proposed characterizing five subtypes: luminal A or B,
* Corresponding author. E-mail addresses: [email protected] (I. Kindts), pieterjan.buelens@ uzleuven.be (P. Buelens), [email protected] (A. Laenen), erik. [email protected] (E. Van Limbergen), [email protected] (H. Janssen), [email protected] (H. Wildiers), caroline.weltens@uzleuven. be (C. Weltens). http://dx.doi.org/10.1016/j.breast.2016.12.007 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
Human Epidermal growth factor Receptor 2 (HER2)-positive, normal and basal-like [1,2]. The basal-like subtype is characterized by the molecular absence or minimal expression of receptors for estrogen (ER), progesterone (PR), and HER2 in addition to high expression of c-Kit, myoepithelial cytokeratins 5, 6 and 17, and HER1. In clinical routine, these molecular subtypes are approximated using immunohistochemistry (IHC) for ER, PR and HER2. The basal-like subtype is then represented by the lacking of these three markers and entitled Triple Negative Breast Cancer (TNBC) even though there is 25e30% discordance [3]. TNBC comprises 15e20% of breast cancers and has worse outcomes compared to other breast cancer subtypes [4,5]. Studies exploring the importance of molecular subtyping
I. Kindts et al. / The Breast 32 (2017) 18e25
suggested that the luminal-A subtype has the lowest risk for locoregional recurrence, while HER2 positive and triple negative subtypes are associated with a substantially higher risks [6,7]. Even though the prognostic and predictive value of breast cancer subtypes are widely recognized and used in the elaboration of systemic treatment, their value for locoregional management needs further clarification [4,5]. There are two main pathways for locoregional therapy. Firstly, there is breast conserving therapy (BCT), including breast conserving surgery (BCS) followed by radiation therapy (RT); and secondly there is mastectomy (ME) with or without adjuvant RT; both with axillary nodal assessment and treatment. Level-I evidence has shown equivalence of these two strategies in terms of survival without taking molecular subtypes into account [8,9]. The poor prognosis of TNBC could suggest the need for an aggressive locoregional approach such as more radical surgery or the addition of radiation therapy. A randomized controlled multi-center trial from Wang et al. included 681 women with stage I-II TNBC treated with mastectomy and chemotherapy of whom 366 patients received radiation therapy. Five-year overall survival significantly improved in the RT group [10]. Limited data also suggest a better locoregional control for TNBC when treated with BCT compared to ME without adjuvant RT [11e13]. With this paper, we want to clarify the following remaining question further: is there a difference in locoregional recurrence (LRR) and breast cancer-specific survival (BCSS) in TNBC patients treated with BCT, ME plus adjuvant RT and ME only?
19
involved cyclophosphamide, methotrexate, 5-fluorouracil, epirubicin and taxanes. Based on the locoregional treatment, patients were divided into three groups: BCT, ME with adjuvant local, regional or locoregional RT (ME þ RT) and ME only. This study was approved by the Clinical Trial Center and the Ethics Committee of our institution. 2.2. Endpoints LRR was defined as local and or regional (axillar, parasternal or supraclavicular region) recurrence. BCSS was defined as death from breast cancer. Death from other causes, or death from unknown cause was not included, and patients were censored when these events occurred. Patients were also censored at the last date of follow-up. Clinicopathological risk factors (age, grade, pT, pN, lymphovascular invasion, perineural invasion, surgical margins, extensive ductal carcinoma in situ, histology, details on surgery, radiation therapy and chemotherapy) for LRR and BCSS were available in the database. LRR and BCSS were compared for the BCT, ME þ RT and ME only group. Subgroup analysis involved patients with an invasive ductal adenocarcinoma not otherwise specified (IDA_NOS) to create a more pathologically homogenous subgroup, this means excluding for example cystic, apocrine and medullary-like tumors [16]. A second subgroup analysis involved all patients who would not receive RT after ME according to the current guidelines: pT1-2N0 tumors with negative surgical margins [17].
2. Material & methods 2.3. Statistical analysis 2.1. Patient selection and data collection A large prospectively collected database, set up in January 2000 and now containing prospectively obtained data of more than 12.200 patients files was used for selection. The database includes data of all patients diagnosed with breast cancer and having at least one of the following treatments, i.e. surgery and/or RT and/or systemic therapy, at University Hospitals Leuven, Belgium. The patient cohort used for this analysis included patients diagnosed with a non-metastasized invasive TNBC between January the first, 2000 and December 31, 2009. TNBC was defined as tumors with negative IHC for the ER (
Summary statistics were presented as medians and range for continuous variables and as frequencies and percentages for categorical variables. Summary statistics on time-to-event outcome variables were based on the cumulative incidence function considering death without event as competing event. Summary statistics for followup time were based on the Kaplan-Meier estimate of potential follow-up [18]. Group differences were tested by a Chi-square test for categorical variables or one-way ANOVA for continuous variables. Cox regression models were used to analyze the association between prognostic factors and outcome. A non-linear trend for age was tested. Results were presented as hazard ratios with 95% confidence intervals. Outcome variables were defined as the time between diagnosis and the time of event. Patients without the respective event were censored at time of death or last follow-up. Analyzing the association between treatment approach and outcome, correction was performed by including possible confounders as covariates in the multivariable model. Variables corrected for were these clinicopathological factors that were associated with outcome and for which there were differences between treatment approaches. All tests were two-sided, a five % significance level was assumed for all tests. Analyses have been performed using SAS software (version 9.4 for Windows). 3. Results 3.1. Patients, tumor and treatment characteristics Clinicopathological factors of 439 TNBC patients were assessed. 239 patients were included in the BCT group, 116 in the ME þ RT group, 84 in the ME only group. Median follow-up time for the 439 patients was 10.2 years (interquartile range 7.9; 12.4 years, range 0.36; 15.6 years).
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Patients in the ME þ RT group presented with higher pT and pN tumor stages and more lymphovascular invasion compared to the other two groups. Patients in the ME only group were older and received less adjuvant chemotherapy compared to the other two groups. Patients in the BCT group underwent more sentinel lymph node and less axillary lymph node dissection (Table 1). In the BCT group 236 patients (99%) received a boost after WBI. Of the 116 patients in the ME þ RT group, 88 (76%) received RT to the chest wall with or without the nodal areas and 28 (24%) patients received only nodal irradiation. In the BCT and ME þ RT group, 211 patients (59%) received RT to the median subclavian and parasternal regions and 16 patients (five %) received RT to the axillary regions. 342 patients were classified as IDA_NOS with comparable patient, tumor and treatment characteristics as the whole population (Appendix 1). Besides IDA_NOS, histological subtypes comprised adenoid cystic, apocrine, medullary (-like), metaplastic, adeno-squamous, colloid, neuro-endocrine
differentiation and tubular. 3.2. Locoregional recurrence FIve-year LRR-free rates were 94%, 97% and 92% for the BCT, ME þ RT and ME only group, respectively. Ten-year LRR-free rates were 93%, 97% and 92% for the BCT, ME þ RT and ME only group, respectively. 3.2.1. Risk factors for LRR Patients with a higher pathological nodal stage were at higher risk for LRR (HR 1.81, p 0.001). There was a trend towards more LRR in tumors with lymphovascular invasion (Table 2). 3.2.2. LRR by group LRR was compared for the three groups in multivariable analysis with correction of pN stage (Table 3). Patients in the BCT and the ME only group showed a significant higher risk for LRR compared to the ME þ RT group (HR 3.29, p 0.037 and HR 4.45, p 0.020 respectively).
Table 1 Patient, tumor and treatment characteristics.
Age Median Range Tumor grade 1 2 3 Pathological tumor stage 1 2 3 4 in situ Pathological nodal stage 0 1 2 3 Lymphovascular invasion Present Absent Perineural invasion Present Absent Surgical margins invasive Free Involved Surgical margins in situ Free Involved Extensive DCIS (ductal carcinoma in situ) Yes No Adjuvant chemotherapy Yes No Sentinel Lymph Node Excision Yes No Axillary Lymph Node Dissection Yes No
BCT (n ¼ 239)*
ME þ RT (n ¼ 116)*
ME only (n ¼ 84)*
Number (percentage)
Number (percentage)
Number (percentage)
53.0 26.0; 90.0
53.0 27.0; 88.0
57.0 24.0; 88.0
7/238 (2.94%) 21/238 (8.82%) 210/238 (88.24%)
0/116 (0.00%) 12/116 (10.34%) 104/116 (89.66%)
2/83 (2.41%) 9/83 (10.84%) 72/83 (86.75%)
144/239 (60.25%) 93/239 (38.93%) 1/239 (0.42%) 1/239 (0.42%) 0/239 (0.00%)
20/116 (17.24%) 70/116 (60.34%) 25/116 (21.55%) 1/116 (0.86%) 0/116 (0.00%)
36/84 (42.86%) 41/84 (48.81%) 5/84 (5.95%) 1/84 (1.19%) 1/84 (1.19%)
177/236 (75.00%) 46/236 (19.49%) 10/236 (4.24%) 3/236 (1.27%)
46/116 (39.66%) 50/116 (43.10%) 14/116 (12.07%) 6/116 (5.17%)
61/81 (75.31%) 13/81 (16.05%) 5/81 (6.17%) 2/81 (2.47%)
26/154 (16.88%) 128/154 (83.12%)
42/98 (42.86%) 56/98 (57.14%)
14/58 (24.14%) 44/58 (75.86%)
6/128 (4.69%) 122/128 (95.31%)
2/74 (2.70%) 72/74 (97.30%)
1/47 (2.13%) 46/47 (97.87%)
227/236 (96.19%) 9/236 (3.81%)
111/115 (96.52%) 4/115 (3.48%)
78/82 (95.12%) 4/82 (4.88%)
127/130 (97.69%) 3/130 (2.31%)
68/70 (97.14%) 2/70 (2.86%)
50/50 (100.00%) 0/50 (0.00%)
65/179 (36.31%) 114/179 (63.69%)
37/93 (39.78%) 56/93 (60.22%)
28/70 (40.00%) 42/70 (60.00%)
185/239 (77.41%) 54/239 (22.59%)
90/116 (77.59%) 26/116 (22.41%)
43/84 (51.19%) 41/84 (48.81%)
101/237 (42.62%) 136/237 (57.38%)
11/116 (9.48%) 105/116 (90.52%)
13/82 (15.85%) 69/82 (84.15%)
164/237 (69.20%) 73/237 (30.80%)
111/116 (95.69%) 5/116 (4.31%)
73/82 (89.02%) 9/82 (10.98%)
P-value
0.019
0.443
<0.001
<0.001
<0.001
0.638
0.875
0.510
0.794
<0.001
<0.001
<0.001
*BCT ¼ breast-conserving therapy, ME ¼ mastectomy, RT ¼ radiation therapy.
I. Kindts et al. / The Breast 32 (2017) 18e25
21
Table 2 Risk factors for locoregional recurrence (LRR) and breast cancer-specific mortality (BCSS) in univariable analysis.
Age (þ1 year) Tumor grade (þ1) Tumor stage (pT) (þ1) Nodal stage (pN) (þ1) Lymphovascular invasion (Yes vs No) Perineural invasion (Yes vs No) Surgical margins invasive (Involved vs Free) Surgical margins in situ (Involved vs Free) Extensive DCIS (ductal carcinoma in situ) (Yes vs No) Adjuvant Chemotherapy (Yes vs No) Sentinel Lymph Node Excision (Yes vs No) Axillary Lymph Node Dissection (Yes vs No)
LRR *HR (95% CI)
P-value
BCSS* HR (95% CI)
P-value
0.99 0.67 0.99 1.81 2.15 2.26 0.76 2.79 0.66 1.07 0.93 1.39
0.231 0.255 0.977 0.001 0.065 0.433 0.790 0.320 0.357 0.866 0.850 0.499
1.00 1.19 1.59 1.82 1.72 2.94 1.03 1.97 0.99 0.58 0.44 2.81
0.756 0.602 0.006 <0.0001 0.053 0.075 0.955 0.347 0.983 0.024 0.011 0.016
(0.96; (0.34; (0.57; (1.26; (0.95; (0.29; (0.10; (0.37; (0.27; (0.48; (0.43; (0.54;
1.01) 1.33) 1.73) 2.59) 4.83) 17.30) 5.59) 21.05) 1.60) 2.38) 2.00) 3.61)
(0.98; (0.62; (1.14; (1.41; (0.99; (0.90; (0.33; (0.50; (0.59; (0.36; (0.23; (1.22;
1.01) 2.26) 2.23) 2.35) 2.96) 9.60) 3.29) 8.12) 1.67) 0.93) 0.83) 6.49)
*LRR ¼ locoregional recurrence, BCSS ¼ breast cancer-specific survival.
Table 3 Multivariable analysis for locoregional recurrence (LRR) and breast cancer-specific survival (BCSS). All patients
ME only vs BCT*
LRR** HR (95% CI) 1.35 (0.56; 3.25) p-value 0.499 BCSS** HR (95% CI) 1.84 (1.00; 3.36) p-value 0.047 T1-2N0 Negative section margins LRR** HR (95% CI) 1.14 (0.31; 4.24) p-value 0.841 BCSS** HR (95% CI) 2.02 (0.84; 4.87) p-value 0.118
BCT vs ME þ RT*
ME only vs ME þ RT *
3.29 (1.08; 10.06) 0.037
4.45 (1.26; 15.69) 0.020
1.56 (0.81; 3.02) 0.184
2.88 (1.43; 5.80) 0.003
N/A*** N/A***
N/A*** N/A***
2.25 (0.46; 10.99) 0.318
4.53 (0.98; 20.92) 0.053
* BCT ¼ breast-conserving therapy, ME ¼ mastectomy, RT ¼ radiation therapy.* LRR ¼ locoregional recurrence, BCSS ¼ breast cancer-specific survival*** Not available due to no LLR in the ME þ RT group.
Results showed no evidence of a difference between ME only and BCT. IDA_NOS patients treated with ME only had significantly more LRR compared to the ME þ RT group (HR 5.42, p 0.016) (Appendix 2). LRR-free curves for the three groups as estimated from the multivariable model are presented in Fig. 1. 3.3. Breast cancer-specific survival Sixty-nine patients died because of breast cancer. Five-year BCSS rates were 90%, 86% and 80% for the BCT, ME þ RT and ME only group, respectively. Ten-year BCSS rates were 87%, 84% and 75% for the BCT, ME þ RT and ME only group, respectively. 3.3.1. Risk factors for BC-specific mortality BC-specific mortality increased with higher pT and pN stages (HR 1.59, p 0.006 and HR 1.82, p < 0.0001, respectively). Patients with an axillary lymph node dissection (HR 2.81, p 0.016) and with lymphovascular invasion (HR 1.72, p 0.053) had lower BCSS.
Fig. 1. LRR-free curves for the three groups as estimated from the multivariable model (with correction for pN). The figure presents the estimated curves for patients with pN0. BCT ¼ breast-conserving therapy, ME ¼ mastectomy, RT ¼ radiation therapy.
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Fig. 2. BCSS curves for the three groups as estimated from the multivariable model (with correction for pT, pN, lymphovascular invasion, lymph node dissection and adjuvant chemotherapy). The figure presents the estimated curves for patients with pT2, pN0, no lymphovascular invasion, with adjuvant chemotherapy, without sentinel and with axillary lymph node dissection. BCT ¼ breast-conserving therapy, ME ¼ mastectomy, RT ¼ radiation therapy.
Adjuvant chemotherapy administration was a protective factor for BC-specific mortality (HR 0.58, p 0.024) (Table 2). 3.3.2. BCSS by group Multivariable analysis was conducted to assess differences between the three groups with correction for pT, pN, lymphovascular invasion, lymph node dissection and adjuvant chemotherapy (Table 3). Patients in the ME only group had significant lower BCSS compared to the BCT and the ME þ RT group (HR 1.84, p 0.047 and HR 2.88, p 0.003, respectively). No significant differences were observed for the comparison of BCT versus ME þ RT. BCSS curves for the three groups as estimated from the multivariable model are presented in Fig. 2. In the IDA_NOS subgroup, results were comparable with higher HR (Appendix 2). 3.4. T1-2N0 negative section margins subgroup Two hundred fifty-nine patients had pT1-2N0 tumors with negative surgical margins. Nine out of 167 patients (5.4%) in the BCT group developed LRR, none out of 36 patients in the ME þ RT group and three out of 56 (5.4%) in the ME only group. No significant differences were observed between the three groups for LRR (p 0.381) (Table 3). Thirteen out of 167 patients (7.8%) from the BCT group died because of breast cancer, two out of 36 (5.6%) from the ME þ RT group and 12 out of 56 (21.4%) from the ME only group. There was a trend towards lower BCSS in the ME only group compared to the ME þ RT group (HR 4.53, p 0.053) (Table 3). 4. Discussion Breast cancer subtypes are taken into account in the patienttailored elaboration of systemic therapy. The breast cancer
subtypes are however not counted for the decision-making of locoregional treatment. TNBC, defined as the absence of ER, PR and HER2 expression, is associated with worse outcomes compared to the other subtypes [4e7]. Because of the poorer outcome, an intensified locoregional approach could be suggested. Therefore two strategies can be proposed: either adjuvant radiation therapy or more radical surgery. First, concerning radiation therapy, it remains unclear if and to what extent TNBC is biologically radioresistant or radiosensitive. Pre-clinical studies suggest the TNBC subtype to be more radioresistant due to for example ERp29 expression (increases promotor hypo-methylation of a DNA repair gene), overexpression of HER1 (an epidermal growth factor receptor) or overexpression of mir-27 (a direct target of mir-27a, DC-27 increases radioresistance of TNBC cells) [19e21]. Additionally, clinical data support the radioresistance in the meta-analysis from the Early Breast Cancer Trialists' Collaborative Group and the Danish 82b/c trials reporting less benefit from RT in ER-negative tumors [7,22e24]. On the other hand, in vitro studies also show the radiosensitivity of TNBC. For example, radioresistance could be reduced in vitro by impairing the BRCA1/2 expression, a germline mutation present in 11e16% of TNBC [25]. The mutation leads to a defect in the BRCA1 pathway which makes tumors inherently more radiosentitive by the inability to repair treatment-induced damage (defects in the DNA homologous recombination) and would potentially provide a benefit in tumor-cell killing [26,27]. Also clinical data have been reported supporting the radiosensitivity of TNBC. Overall survival rates in the MA.20 trial randomizing breast cancer patients to undergo regional nodal irradiation or not approached statistical significance only in the subgroup with ER-negative disease in favor of irradiation (81% vs 74%, HR 0.69, 95% CI 0.47e1.00, p 0.05) [28].
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In the present study, we wanted to further clarify the impact of the extent of locoregional therapy on LRR and BCSS in TNBC. Four hundred thirty-nine TNBC patients, treated at a single institution, were included in the analyses: 239 underwent BCT, 116 ME þ RT and 84 ME only. Cox multivariable regression models were used to analyze the association between prognostic factors and outcome. LRR were significantly higher in the BCT and the ME only group compared to the ME þ RT group (HR 3.29, 95% CI 1.08e10.06, p 0.037 and HR 4.45, 95% CI 1.26e15.69, p 0.020, respectively). BCSS however was significantly lower in the ME only group compared to the BCT group (HR 1.84, 95% CI 1.00e3.36, p 0.047) and the ME þ RT group (HR 2.88, 95% CI 1.43e5.80, p 0.003). Our data support the strategy of incorporating radiation therapy in the locoregional treatment of TNBC patients. Second, our data refute the need for a more aggressive surgical approach in TNBC by means of ME. Concerning survival, patients treated with ME only presented with worse BCSS compared to BCT when corrected for known clinicopathological prognostic factors. If however radiation therapy was added to ME, BCT and ME resulted in similar survival. Concerning the endpoint of LRR, patients treated with ME þ RT had significantly better locoregional control compared to those treated with BCT. These findings are in line with the results from the 20 year follow-up study of the EORTC 10801 trial randomizing patients between BCT and ME in stage I-II breast cancer. ME resulted in better local control, but did not affect overall survival [9]. In contrary two recent population-based studies on breast cancer patients in the Netherlands evaluated 10-year survival after BCT compared with ME. In women with early breast cancer and in those with T2N2 stage, treatment with BCT showed improved 10year overall survival compared with ME after adjusting for confounding variables. In women with T1N2 stage breast cancer however, no significant difference was seen. For relative survival, a significant benefit was seen for patients treated with BCT and T1N0 or T2N2 stage or in the cohort treated in 2003. The authors concluded that BCT is at least equivalent to ME with respect to overall survival [29,30]. Also, for TNBC patients, a meta-analysis by Wang et al. reported significantly lower LRR and distant metastasis rates in the BCT compared to the ME group, of whom 21% received adjuvant radiation therapy (16.9% versus 21.9%, relative risk (RR) 0.75, 95% CI 0.65e0.87 and 23.6% versus 34.4%, RR 0.68, 95% CI 0.60e0.76, respectively) [12]. ME only was an independent predictor of LRR compared to BCT in a retrospective series at the University of Alberta in 768 TNBC patients (HR 3.44, 95% CI 2.04e5.80, p < 0.001) [11]. In their subgroup analysis of 468 patients with T1-2N0 TNBC, five-year LRR-free survival was 96% in the BCT group and 90% in the ME group (p 0.027) [11]. More recent data suggest no difference in the T1-2N0 stages, but worse results with ME only in T2-3N2-3 stages [13,31]. In our series, subgroup analysis of T1-2N0 TNBC patients with negative surgical margins did not show any difference between ME and BCT for LRR. However, since no LRR occurred in the ME þ RT group, no hard conclusions can be drawn. Another meta-analysis by Lowery et al. has analyzed LRR by receptor phenotype in early stage breast cancer: no difference was observed in LRR between BCT and ME, of whom 44% received adjuvant radiation therapy [32]. According to international guidelines, post ME RT is advised in case of T3-4 or Nþ tumors or in case of positive surgical section margins [17]. In our series, adding RT to ME significantly decreased LRR and increased BCSS. Subgroup analysis of T1-2N0 patients with
23
negative surgical margins statistically just reached significance in favor of adding RT for BCSS. Our series support the results from the only prospective study addressing the need of post ME RT in stage III TNBC cases. Thereby 681 stage I-II TNBC patients were randomized to undergo RT or not after ME and adjuvant chemotherapy. Recurrence-free survival and overall survival were significantly higher in the arm with post ME RT (88.3% vs 74.6% and 90.4% vs 78.7% at five years) [10]. Comparable results were obtained in retrospective series, for example the study from Abdulkarim et al. and from the Danish Breast Cancer Cooperative Group [11,23,33,34]. Based on a subgroup analysis of the 82 b and c trials, a significantly lower rate of LRR was reported by adding RT to ME in TNBC patients (HR 0.33, 95% CI 0.14e0.78, p 0.001) [23]. A general remark however, as suggested by Poortmans et al. is that it is strongly advised to use “any recurrence” as endpoint in future studies instead of “locoregional recurrence”. They postulate that once distant metastases are found, in general no further efforts are undertaken to detect locoregional recurrences [35]. The retrospective study from Steward et al. on the contrary found no improved survival when RT was added to ME in stage I-III TNBC patients [36]. Our findings intensify the hypothesis that patients with TNBC benefit from radiation therapy. However, TNBC comprises a very heterogeneous entity and treating all TNBC according to the same protocol might be an oversimplification. To create a more homogeneous subgroup from a pathology point of view, we have conducted the analyses on only IDA_NOS TNBC subtypes; BCSS results did not differ significantly. Future translational research is needed regarding the different underlying tumorigenic pathways in TNBC. Data are sparsly emerging; Wushou et al. oberserved that two gene signatures specifically identified a radiosensitive population that had improved outcome with differences between “radiosensitive” and “radioresistant” TNBC patients [37]. The strengths of our study include the comprehensive prospectively registered single institution database with patient characteristics, treatment and patients status at regular follow-up with accurate information on LRR and BCSS. In consequence, our study represents one of the largest analyses of the impact of different curative treatment options for TNBC with long-term follow-up. On the other hand, we acknowledge the limitations of a retrospective series with inherent biases in patient and treatment selection. The numbers of events are relatively low resulting in limited statistical power. In addition, we acknowledge that due to the retrospective nature of the study, we might not have been able to correct for all potential confounding variables. Hence, the results of our study should be interpreted carefully and firm conclusions should not be drawn. In conclusion, the results of our study support the hypothesis that treatment of TNBC with ME without adjuvant RT results in significant lower BCSS compared to treatment with BCT or ME þ RT.
Conflict of interest There is no conflict of interest.
Funding source This research did not receive any specific grand from funding agencies in the public, commercial, or not-for-profit sectors.
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Appendix 1. Patient, tumor and treatment characteristics of 389 patients with IDA_NOS patients (invasive ductal carcinoma_not otherwise specified)
Age Median Range Tumor grade 1 2 3 Pathological tumor stage 1 2 3 4 Pathological nodal stage 0 1 2 3 Lymphovascular invasion Present Absent Perineural invasion Present Absent Surgical margins invasive Free Involved Surgical margins in situ Free Involved Extensive DCIS (ductal carcinoma in situ) Yes No Adjuvant chemotherapy Yes No Sentinel Lymph Node Excision Yes No Axillary Lymph Node Dissection Yes No
BCT (n ¼ 190)* Number (percentage)
ME þ RT (n ¼ 88)* Number (percentage)
ME only (n ¼ 64)* Number (percentage)
53.0 26.0; 90.0
51.0 29.0; 81.0
55.5 24.0; 87.0
3/190 (1.58%) 17/190 (8.95%) 170/190 (89.47%)
0/88 (0.00%) 6/88 (6.82%) 82/88 (93.18%)
1/64 (1.56%) 5/64 (7.81%) 58/64 (90.63%)
117/190 (61.58%) 71/190 (37.37%) 1/190 (0.53%) 1/190 (0.53%)
17/88 (19.32%) 54/88 (61.36%) 17/88 (19.32%) 0/88 (0.00%)
32/64 (50.00%) 29/64 (45.31%) 3/64 (4.69%) 0/64 (0.00%)
141/188 (75.00%) 37/188 (19.68%) 7/188 (3.72%) 3/188 (1.60%)
34/88 (38.64%) 39/88 (44.32%) 9/88 (10.23%) 6/88 (6.82%)
49/61 (80.33%) 9/61 (14.75%) 3/61 (4.92%) 0/61 (0.00%)
21/121 (17.36%) 100/121 (82.64%)
33/73 (45.21%) 40/73 (54.79%)
10/45 (22.22%) 35/45 (77.78%)
2/100 (2.00%) 98/100 (98.00%)
1/52 (1.920%) 51/52 (98.08%)
1/35 (2.86%) 34/35 (97.14%)
182/188 (96.81%) 6/188 (3.19%)
83/87 (95.40%) 4/87 (4.60%)
61/63 (96.83%) 2/63 (3.17%)
106/109 (97.25%) 3/109 (2.75%)
54/55 (98.18%) 1/54 (1.82%)
42/42 (100.00%) 0/42 (0.00%)
54/142 (38.03%) 88/142 (61.97%)
45/71 (63.38%) 26/71 (36.62%)
24/55 (43.64%) 31/55 (56.36%)
153/190 (80.53%) 37/190 (19.47%)
72/88 (81.82%) 16/88 (18.18%)
36/64 (56.25%) 28/64 (43.75%)
86/188 (45.74%) 102/188 (54.26%)
10/88 (11.36%) 78/88 (88.64%)
11/62 (17.74%) 51/62 (82.26%)
127/188 (67.55%) 61/188 (32.45%)
83/88 (94.32%) 5/88 (5.68%)
54/62 (87.10%) 8/62 (12.90%)
Pvalue 0.153
0.768
<0.001
<0.001
<0.001
0.948
0.829
0.510
0.698
<0.001
<0.001
<0.001
*BCT ¼ breast-conserving therapy, ME ¼ mastectomy, RT ¼ radiation therapy.
References
Appendix 2. Results of multivariable analysis between 3 subgroups in IDA_NOS (invasive ductal carcinoma_not otherwise specified) patients
LRR** HR (95% CI) p-value BCSS** HR (95% CI) p-value
ME only vs BCT*
BCT vs ME þ RT*
ME only vs ME þ RT*
2.48 (0.90; 6.84) 0.080
2.19 (0.66; 7.26) 0.200
5.42 (1.37; 21.49) 0.016
2.55 (1.27; 5.10) 0.008
1.49 (0.67; 3.30) 0.324
3.80 (1.64; 8.81) 0.002
*BCT ¼ breast-conserving therapy, ME ¼ mastectomy, RT ¼ radiation therapy.* LRR ¼ locoregional recurrence, BCSS ¼ breast cancer-specific survival.
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