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Original Study






IMPACT OF LOCO-REGIONAL UNDER-TREATMENT IN ELDERLY PATIENTS WITH EARLY BREAST CANCER (Protocol YAMEKA-09SDLT); 
Multi-centric Retrospective Cohort Study
		



Can Atalay1, Sertac Ata Guler2, Derya Selamoglu3, Vahit Ozmen4, Erol Aksaz5, Turgay Simsek6, N. Zafer Canturk6, Ulvi Meral7, Semih Gorgulu7, Evrim Kallem8, Serdar Ozbas8, L. Semiha Sen2, Bahadir M. Gulluoglu21Department of General Surgery, Ankara Oncology Hospital, Ankara, Turkey2Breast and Endocrine Surgery Unit, Department of General Surgery, Marmara University School of Medicine, 0stanbul, Turkey3General Surgery Unit, Florance Nightingale Metropolitan Hospital, 0stanbul, Turkey4Breast Surgery Unit, Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey5MAMER Breast Center, Bursa, Turkey6Breast and Endocrine Surgery Unit, Department of General Surgery, Kocaeli University School of Medicine, Kocaeli, Turkey7Department of General Surgery, Gulhane Military Medical Academy, Ankara, Turkey8Department of General Surgery, Adnan Menderes University School of Medicine, Aydin, Turkey

























ABSTRACT
Elderly breast cancer patients are generally excluded from clinical trials and non-standard treatments are administered more in this group of patients. Aim of the study is to assess the impact of non-standard loco-regional treatment on survival in elderly patients with clinically early stage breast cancer. Patients over 70 years of age operated for a unilateral, early stage breast cancer between 1998 and 2009 were retrospectively included in the study. Patient and tumor characteristics were recorded. Adjuvant treatments, last date of follow-up and recurrences and/or death were recorded. Treatments without radiotherapy after breast conserving therapy, without sentinel lymph node biopsy or axillary dissection, without axillary dissection or axillary radiotherapy in case of a positive sentinel lymph node and without radiotherapy in the presence of e"4 positive lymph nodes were regarded as loco-regional under-treatment. Disease-free, breast cancer-specific and overall survival of patients who received standard and non-standart loco-regional treatments were compared. 384 patients with a median age of 74 were included in the study. Median tumor size was 25 mm. Non-standard loco-regional treatment was applied in 90 (23.4%) patients.  Most commonly omitted was axillary treatment. Patients with 3 or more associated diseases significantly received less standard loco-regional treatment. Median follow-up period was 35 months and, during follow-up, 10.4% of patients had recurrence whereas 13% of patients died. Although disease-free survival were similar in both groups, overall and breast cancer-specific survivals were significantly less in those who received non-standart loco-regional treatment. As number of associated diseases reaches three or more, there was a strong tendency to administer less standard loco-regional treatment. Most commonly, patients did not undergo axillary staging or treatment. Although loco-regional under-treatment resulted poorer overall and breast cancer-specific survival, disease free survival was not different in those elderly early stage breast cancer patients who received adequate treatment. 

Keywords: elderly, breast cancer, under-treatment, loco-regional treatment, survival


Running title: Under-treatment of elderly breast cancer patients













INTRODUCTION

Breast cancer is the most common malignancy diagnosed among women and increased age is an important risk factor for its development [1]. As life expectancy increases in population, clinicians are dealing with patients at an advanced age either at the time of diagnosis or among long-term survivors [2]. Despite these facts, elderly breast cancer patients are not adequately represented in clinical trials in which effective treatment methods are determined [3]. In addition, non-standard loco-regional and systemic treatments are used more in this group of patients due to the presence of associated diseases. Most frequently omitted loco-regional treatments are axillary surgery and radiotherapy [RT] in case of breast conserving surgery [BCS]. On the other hand, chemotherapy [CT] is generally not administered as systemic treatment to elderly patients [4,5]. 
Although breast cancer might be diagnosed at an advanced stage, both clinical and pathological data are consistent with less aggressive disease in this elderly age group [6,7]. Supporters of non-standard treatments depend on these favourable assumptions.  Hormone responsive nature of breast cancer in elderly leads to the application of hormone treatment [HT] instead of CT or even adequate surgery [8-13]. In addition, concerns about quality of life of elderly breast cancer patients result in decreased use of RT or axillary dissection [14]. However, evidence showed that less aggressive treatment in breast cancer definitely increases the risk of recurrence and disease specific mortality [15-18]. Aim of this retrospective multi-centric cohort study is to assess the impact of non-standard loco-regional treatment on survival in elderly patients with early breast cancer. However, retrospective design and potential for selection bias are the limitations of this study. 

PATIENTS and METHODS

Design:
Study was designed as a multicentric retrospective cohort study. Variables were retrieved from prospectively kept database. 

Patients (Inclusion & Exclusion Criteria):
Patients 70 years of age or over who were surgically treated for unilateral early stage (stage I-II) breast cancer between 1998 and 2009 were planned to be included in the study. Those who received only primary or any systemic neo-adjuvant treatment and those with clinically advanced (loco-regional or metastatic) disease or involved surgical margins were excluded from the study. Patients with no regular follow-up and missing variables were excluded. Those who were followed by physical examination and mammography at least once a year were included. Patients who turned out to be ductal carcinoma in situ [DCIS] after definitive histo-pathologic assessment were also excluded from the analysis. However, those found to be stage III after definitive pathology were included for statistical analysis. Only those with synchronous distant disease were excluded. 

Outcomes:
Patients were divided into two groups according to mode of loco-regional treatment they received; standard or non-standard treated groups. Patients in both groups were compared in terms of disease-free [DFS], overall [OS] and breast cancer specific survival [BCSS]. Independent factors for survival curves were also assessed. Patients with 3 or more associated diseases were compared to those with less whether there is a difference in receiving non-standard loco-regional treatment.    

Variables:
Clinical characteristics of patients such as age, associated diseases and type of surgery were recorded from their hospital records. In addition, histo-pathologic features of their tumors such as size [T stage], axillary involvement [N stage], grade, pathologic stage, and lympho-vascular invasion [LVI], ER, PR and HER2 status were noted. Adjuvant treatments, last date of follow-up and, if any, recurrences and/or death were recorded. 

Patients were grouped according to tumor size as ( 2 cm, 2-5 cm, and ( 5 cm. Axillary lymph node involvement was grouped as N1 (1-3 +), N2 (4-9 +), and N3 (> 9 +). Tumor grade was classified as I, II, and III. ER and PR status were grouped as positive and negative in which at least 1% immune-histo-chemistry [IHC] staining was regarded as positive (hormone sensitive). Tumor is regarded hormone receptor [HR] positive if at least ER or PR was found to be positive, whereas it is regarded negative if both ER and PR were found to be negative. HER2 status of patients were graded either according to their IHC staining if it reveals 0, +1 or +3 or FISH / SISH / CISH result as positive or negative. IHC staining of 0 and +1 was regarded as negative, +3 as positive. Those with +2 staining were graded according to their FISH / SISH or CISH result. Patients were classified for their pathological stages according to AJCC 2002. Apart from measuring absolute number of associated diseases, patients were grouped as those with less than 3 and those with 3 or more diseases.  

Definition of Inadequate / Non-standard Loco-regional Treatment: 
Any circumstances described below were regarded as non-standard loco-regional treatment:
Not receiving whole breast RT after BCS, 
Not undergoing any axillary treatment such as sentinel lymph node [SLN] biopsy or axillary dissection or receiving axillary RT,
Not undergoing axillary resection or receiving RT in case of metastatic SLN,
Not receiving three fields RT in case of e"4 metastatic axillary lymph node presence. 

Follow-up / End-points:
In addition to thorough physical examination, liver function tests, chest radiography, abdominal ultrasonography [USG] and bone scintigraphy were performed according to patient�s complaints/findings. Mammography and, if necessary, breast USG imaging were done annually. All recurrences within ipsilateral breast and axilla were regarded as loco-regional event. Metastatic involvement of distant organs was recorded as distant event. When death occurs due to breast cancer, it is regarded as disease (breast cancer)-specific. Time to loco-regional recurrence, distant metastasis and death were measured from the day of initial surgery to last follow-up or occurrence of the relevant end-point event. 

Statistical Analysis:
Patients in standard and non-standard loco-regional treatment groups were compared. Survival estimates were determined using Kaplan-Meier method. For their impact on DFS, OS and BCCS, univariate analysis of prognostic factors such as pathological stage and mode of loco-regional treatment was performed with log-rank test. For multivariate analysis, Cox stepwise regression method was used to determine independent factors affecting DFS, OS and BCCS. Frequencies of different variables in two patient groups were compared with Pearson�s chi-square or Fisher�s exact tests, wherever appropriate. Mean values are given with standard error. Statistical analyses were performed with SPSS 15.0 statistical software package (SPSS Inc., Chicago, IL). All of the tests applied were two-way and level of significance (p) was accepted as significant when it is <0.05.

RESULTS
	
Three hundred eighty four patients with a median age of 74 (range, 70-96) were included in the study during January 1998 - June 2009. Seven tertiary medical centers included their patients to the study. Median number of patients enrolled from centers was 45 (range 6 - 116). 

	Demographic / Histopathologic / Treatment Features of the Cohort	
	Demographic and histo-pathologic characteristics of patients are shown in Table 1. Median tumor size was 25 mm (range, 5-100 mm). Most patients had T2 (n=221; 57.6%) and grade II (n=211; 54.9%) tumors. Patients frequently had hormone receptor positive tumors (n=291; 75.8%), whereas only 48 patients (12.5%) had tumors with HER2 over-expression. Modified radical mastectomy [MRM] was done at most (n=246; 64.1%) patients. SLN biopsy was a part of their surgical treatment in 76 patients (19.8%) and most of these procedures (n=51; 67.1%) revealed no axillary metastases.  287 (74.7%) patients had at least one associated disease, whereas 25 patients (6.5%) had e"3 diseases other than breast cancer. HT was administered to 301 patients (78.4%) whereas CT was only given to 134 patients (34.9%).
	
	Non-standard Loco-regional Treatment
	In this cohort, non-standard loco-regional treatment was applied in 90 (23.4%) patients, whereas 294 patients received standard treatment. Most commonly omitted loco-regional treatment was axillary treatment. Any type of axillary treatment (surgical dissection or RT) or, at least, SLN biopsy was not done in 47 (12.2%) patients. Whole breast RT was not administered in 24 (6.2%) patients in whom BCS is performed. Three fields RT was not given to 17 (4.4%) patients who had e"4 metastatic axillary lymph nodes and, out of 25 patients, completion axillary dissection was not done in 2 (0.8%) patients in whom their SLN was found to be metastatic. 
	It was found that patients with 3 or more associated diseases (n=25; 6.5%) significantly received less standard loco-regional treatment when compared to those with less than 3 diseases (n=262; 68.2%; p=0.025). 
	Comparison of clinical, hist0-pathology and treatment related parameters between two groups are given at Table 2. Chemotherapy was significantly found to be administered more commonly to patients treated with a standard loco-regional treatment (p< 0.0001).

	Survival
	Median follow-up time was 35 months (range, 5-159). During follow-up 40 patients (10.4%) had recurrence, whereas 50 patients (13.0%) died (Table 2). Mean DFS, OS and BCSS durations were found to be 134.8�3.8, 121.5�4.9 and 146.4�2.7 months, respectively, for overall cohort. 5-year DFS, OS and BCSS rates of the cohort were 88.2%, 87.4% and 92.8%, whereas 10�year DFS, OS and BCSS rates were 77.6%, 62.9% and 89.1%, respectively. 
	Mean DFS, OS and BCSS durations were 119.9�7.1, 109.5�7.5 and 128.2�6.2 months for non-standard loco-regional treatment group, whereas mean DFS, OS and BCSS durations were 137.3�4.2, 125.2�5.4 and 149.3�2.8 months for standard treatment group.
	Recurrence and death rates in both groups are given at Table 3. 
	Although both 5-year and 10-year DFS rates were higher in standard group (90.3% and 79.3%, respectively) when compared to non-standard group (81.4% and 74.0%, respectively), differences did not reach statistical significance (p=0.12). 
	On the other hand, 5-year (76.6% in non-standard group and 91.0% in standard group) and 10-year OS (63.5% in non-standard group and 64.4% in standard group) rates were higher in standard group (p=0.007). 
	Similarly, both 5-year and 10-year BCSS rates were significantly higher in standard group (94.9% and 91.6%, respectively) when compared to non-standard group (85.9% and 81.8%, respectively; p= 0.036; Table 4). Graphs of Kaplan-Meier analysis for DFS, OS and BCSS are shown in Fig. 1, 2, and 3, respectively. 
	
Factors Related to Survival
	In both univariate and multivariate analysis, both pathologic tumor stage and mode of loco-regional treatment were found to be independent factors affecting OS and BCSS. Patients with earlier tumor stage and who were treated in standard fashion had significantly longer OS and BCSS. 
	On the other hand, in univariate analysis, only pathological tumor stage was found to be the significant factor for DFS, whereas impact of mode of loco-regional treatment was insignificant. Pathologic tumor stage was found as the independent prognostic factor for DFS in multivariate analysis, as well. Significantly less recurrence was observed in patients with earlier pathologic tumor stage. Results are depicted in Table 5.

DISCUSSION

In this cohort although only 7% of them had three or more associated diseases, nearly one forth of elderly breast cancer patients received loco-regional under-treatment. Most commonly omitted treatment was axillary staging or clearance. Results of this multi-centric retrospective cohort study indicate that elderly early-stage breast cancer patients receiving standard loco-regional treatments have prolonged OS and BCSS compared to those patients receiving non-standard treatments. However, DFS of patients was not affected by mode of loco-regional treatment. Significant factor that affected all three survival (DFS, OS and BCSS) curves was pathologic tumor stage. Patients with more than three associated diseases significantly received less standard loco-regional treatment when compared to those with less or no disease. It was found that as the number of associated diseases increased, probability of applying non-standard treatment increased. Therefore co-morbidity seemed to affect the decision on mode of loco-regional treatment. 
In this study, multi-centric design allowed us to expand sample size of the study. Contributing centers were selected among tertiary institutions which have reliable and complete database regarding their breast cancer cases and follow-up. All data are retrieved from prospectively kept databases, which further increased reliability of data. Moreover, homogenous sampling of the study, which is including only early stage breast cancer patients, made comparisons much more relevant. In addition, we defined the non-standard loco-regional treatment by including all possibilities with clear definition and grouped all patients accordingly. On the other hand, retrospective design of the study and potential for selection bias were among the limitations of this study. Along with these, since HT and/or CT would also have an impact on both loco-regional and overall disease control, we did not include the adequacy of systemic treatment in our analysis. 
Evidences for tailoring the treatment of elderly breast cancer patients is largely extrapolated from trials, which included younger patients. Therefore, relevant recommendations is lacking for elderly. When compared to younger patients, elderly breast cancer patients generally have tumors with more favorable biological characteristics such as higher expression of hormone receptors, lower rates of tumor cell proliferation, lower expression of HER2, higher frequency of diploidy and lower rates of p53 positivity [6,7]. These findings frequently make physicians to omit particular components of gold standard treatments for breast cancer in this age group. 
	Elderly patients usually present with associated diseases other than breast cancer and these may also have an important impact on treatment decisions. Probability of administering non-standard treatment increases as number of associated diseases increases. This attitude in clinical practice is supported by a previous report in which a 20-fold increase in mortality was found in breast cancer patients with three or more associated diseases [19]. Also in the current study, patients with three or more associated diseases were significantly found to be treated loco-regionally more in a non-standard fashion. 
	Inadequate loco-regional treatment is expected to result poorer DFS with more local and regional recurrences. Hence loco-regional failure would further lead to worse outcome in both OS and BCSS. However, in this study, we found that DFS was not different in patients who underwent loco-regional under-treatment from those who received adequate treatment. But OS and BCSS were found to be poorer in those who received inadequate loco-regional treatment. Multivariate analysis also revealed that mode of loco-regional treatment is a significant predictor for both OS and BCSS but not for DFS. In clinical practice, mastectomy, as loco-regional treatment, is offered more often to elderly patients due to difficulties in administering RT to those with less social support and more associated diseases [20]. MRM was found to be the most preferred method of surgical treatment in our current study, as well. However, elderly patients prefer BCS as much as their younger counterparts when such an option is given. Moreover, quality-of-life in elderly patients was found to be better in those who underwent BCS when compared to those who had mastectomy [21]. However, previous studies revealed that RT is not frequently applied after BCS in elderly patients. Omitting RT after BCS was found to result an increase in mortality two-fold when compared to mastectomy [20]. A meta-analysis which assessed the impact of RT after BCS revealed that absolute risk reduction on loco-regional recurrence in patients 70 years or older was less than it was observed in patients who are younger than 50 in which RT decreased rate of loco-regional recurrence rate from 13% to 3% in elderly [22]. Previous studies reveled that although actual in-breast recurrence rates were higher in patients who did not receive RT after BCS, OS was not different from those who received RT [23]. However in this study of Tinterri et al., T1 tumors constituted the majority (85%) of the cohort. Furthermore, another study which showed that there is no survival difference between patients who received RT and not following BCS only recruited patients whose tumors are less than 2 cm and hormone sensitive [24]. In contrast to these studies we found that loco-regional under-treatment resulted poorer OS and BCSS whereas no difference in DFS. However, in our current cohort, only 6% of patients who had BCS did not receive whole breast RT, which is considerably low when compared to similar studies. Therefore OS and BCSS differences between study groups in our study might be attributable to factors other than not receiving adequate loco-regional treatment.  
	Axillary surgery also plays an important role in staging and loco-regional control of breast cancer. Axillary management can either be performed as axillary dissection or SLN biopsy. However, axillary treatment is the most commonly omitted form of treatment in elderly breast cancer patients. Axillary staging is not done at all in approximately 10% of the elderly patients [25]. Hillner et al. found that as patient�s age increased by 10 years, probability of not performing an axillary dissection increased by 2.5 fold [26]. Requirements for general anesthesia and longer hospitalization as well as possible complications related to shoulder and arm movements are the main reasons underlying this decision [14]. In our current study, axillary treatment was still the most commonly omitted form of surgical treatment where 47 (12% of all cohort) patients did not receive any type of axillary intervention at all. In addition, two patients (0.8%) who underwent SLN biopsy and had metastasis in their SLN did not receive either level I-II axillary dissection or axillary RT. Supporting this conservative approach, it was previously reported that in early stage breast cancer, as age of the patient increases, rate of axillary metastases decreases, most probably due to better biological characteristics of the tumor [27]. Newlin et al., studied patients older than 70 years of age with T1 tumors who were treated with axillary dissection and reported no significant difference in DFS between lymph node positive and negative patients [27]. Other than this, very few prospective randomized studies compared different management options, especially regarding axillary surgery, in this age group. Such studies suggested that, for tumors less than 2 cm, any axillary treatment may be avoided, especially in patients with severe co-morbid diseases [28,29]. In a randomized study, after 6.6 years of median follow-up, DFS and OS were similar in patients with a median age of 74 who were treated with or without axillary dissection and 5-years of tamoxifen [TMX]. Local recurrence rate was only 3% in those treated without axillary dissection [28]. Similarly, in another study, after 60 months of median follow-up BCSS and OS rates were similar in patients with clinically T1N0 tumors who were randomized to axillary treatment or none in which all patients received TMX. Local recurrence rate was 1.8% in no axillary dissection group [29]. With contrast to these studies, 63% of our current cohort had tumors more than 2 cm, which indicates that our cohort had tendency for a higher risk of recurrence and poorer survival. Again, although their risk is higher, less standart loco-regional treatment did not result poorer DFS. Therefore, it seems that adequate loco-regional treatment, including axillary treatment and whole breast RT, may not be required to diminish local and regional recurrence rate even at those elderly patients who have high risk as it was shown at our current study where pathological tumor stage remained to be the only significant predictor for DFS.    
It is known that both HT and CT have impact on systemic disease control as well as  loco-regional control of breast cancer. It is well known that HT is preferred systemic treatment over CT in elderly breast cancer patients since overall approximately 80% of the tumors are hormone responsive [30]. Also, in our current cohort, patients were found to receive HT with high rate (78.4%), irrespective of their hormone responsiveness and co-morbidity. On the other hand, although CT was administered to a larger number of patients (34.9%) in contrast to previous studies, OS and BCSS were significantly poorer in patients who received non-standard loco-regional treatment. However, we found that those patients who had 3 or more associated diseases were less likely to receive CT when compared to those with less or no co-morbidity. This finding might explain the difference of OS and BCSS rates between study groups where those who already received standard loco-regional treatment would also have received adequate CT and, on the contrary, those who received non-standard loco-regional treatment due to co-morbidity would also have been undertreated in means of CT whether or not they have any type of recurrence. Same limited approach regarding systemic treatment would have been applied to those who received non-standard loco-regional treatment. However, we failed to include adequacy of systemic treatment in multivariate analysis for survival outcomes due to lack of detailed related data. Moreover, life expectancy is expected to be shorter in those with more associated diseases which might further explain shorter OS in those who received non-standard loco-regional treatment. Therefore it is most probable to conclude that adequate systemic treatment and life expectancy may have main impacts on both OS and BCSS rather than mode of loco-regional treatment alone in elderly since loco-regional under-treatment was found to have insignificant impact on DFS. On the other hand, pathologic tumor stage remained to be the independent predictor for OS, BCSS and as well as DFS as it is expected.
As conclusion; nearly one forth of elderly breast cancer patients at our study cohort received loco-regional under-treatment. As number of associated diseases reaches three or more, there was a strong tendency to administer less standard loco-regional treatment. Most commonly, patients did not undergo axillary staging or treatment by means of surgical dissection or RT to axilla. Although loco-regional under-treatment resulted poorer OS and BCSS, DFS including adequacy of local tumor control was not deteriorated by less standart treatment. 	Since there are controversial findings in previous studies, results of further randomized studies with adequate power, in which elderly patients are exclusively recruited, should be awaited to develop breast cancer treatment guidelines in this growing population. Unfortunately, scope of prospective studies, which are underway in elderly patient group, are for those with minimum risk [31]. Therefore, evidence for elderly breast cancer patients whose risks are above average still remain to be determined.










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Table 1. Demographic and histo-pathologic characteristics of overall cohort

Age
Associated diseases
None
1
2
e" 3
Type of surgery
Modified radical mastectomy
Lumpectomy + AD
Lumpectomy + SLNB
Lumpectomy
Simple mastectomy
Simple mastectomy + SLNB
SLNB
Negative
1 (+)
2 (+)
3 (+)
Pathologic stage (AJCC)
I
IIA
IIB
IIIA
IIIB
IIIC
Tumor size (T)
T1
T2
T3
Tumor grade
I
II
III
Unknown
HR
Negative
Positive
Unkown
HER2
Negative
Positive
Unknown
Lymphovascular invasion
Absent
Present
Unknown
Chemotherapy
Absent
Present
Hormonotherapy
Absent
Present
    Tamoxifen
    AI
    Tamoxifen + AIN
Median 74

97
146
116
25

246
41
40
34
14
9

51
22
2
1

99
140
73
33
12
27

140
221
23

69
211
80
24

84
291
9

173
48
163

269
112
3

250
134

83
301
200
96
5%
Range 70 � 96 

25.3
38.0
30.2
6.5

64.1
10.7
10.4
8.9
3.6
2.3

67.1
29.0
2.6
1.3

25.8
36.5
19.0
8.6
3.1
7.0

36.5
57.6
5.9

18.0
54.9
20.8
6.3

21.9
75.8
2.3

45.1
12.5
42.4

70.1
29.2
0.7

65.1
34.9

21.6
78.4
52.1
25.0
1.3HR: hormone receptor, SLNB: sentinel lymph node biopsy, AD: axillary dissection, AJCC;: American Joint Committee on Cancer 2002, AI: aromatase inhibitor


Table 2.  Comparison of clinical, histo-pathology and treatment related parameters between study groups.
				Non-standard LRT Group	Standard LRT Group		p
Tumor size
T1					37 (41.1%)			104 (35.4%)
T2					47 (52.2%)			171 (58.2%)
T3					6 (6.7%)			19 (6.4%)		0.47
Tumor grade				
I					10 (11.6%)			59 (21.5%)
II					57 (66.3%)			154 (56.2%)
III					19 (22.1%)			61 (22.3%)		0.1
Hormone receptor
Positive				68 (78.2%)			223 (77.4%)
Negative				19 (21.8%)			65 (22.6%)		1.0
HER2
Positive				5 (10.9%)			43 (24.6)
Negative				41 (89.1%)			132 (75.4%)		0.06
Lymphovascular invasion
Present				33 (37.5%)			79 (27.0%)
Absent				55 (62.5%)			214 (73.0%)		0.06
Chemotherapy
Present				17 (18.9%)			117 (39.8)
Absent				73 (81.1%)			177 (60.2%)	        < 0.0001
Hormonotherapy
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$d�a$gd�}�kd$$IfT�F��F�����#���0�������������������������4�
Fa��T	���2�R�w�����֖ۖ��(�@�c����������$�M�N�k�l�m���������������������������������d�gd�}gd�}dhgd�}'�(�@���������������H�L�M�N�j�v�����������������
��=������������-�0�F�G�������������������Ŵ���x�����a��Ŵ�,h�}5�CJOJQJaJmH	nHo(sH	tH*h�L�h�}6�CJOJQJ]�aJmH
sH
$h�L�h�}CJOJQJaJmH
sH
$h�}6�CJOJQJ]�aJmH	sH	!h�}>*CJOJQJaJmH	sH	!h�}5�CJOJQJaJmH	sH	U'h�+h�}6�CJOJQJaJmH	sH	h�}h�}CJOJQJaJmH	sH	&Present				65 (72.2%)			235 (80.0%)
Absent				25 (27.8%) 			59 (20.0%)		0.19

LRT; loco-regional treatment


Table 3.  Comparison of recurrence and death incidences between study groups.
					Non-standard LRT Group	Standard LRT Group	
		              			n=90				n=294 	
Loco-regional recurrence			3 (3.3%)			5 (1.7%)
Distant metastases				10 (11.1%)			22 (7.5%)

Breast cancer-related death			9 (10%)				13 (4.4%)
Death from other causes			10 (11.1%)			18 (6.1%)

LRT; loco-regional treatment














Table 4. Survival comparison between study groups.
		Non-standard LRT Group	Standard LRT Group		p
		              n=90				n=294 	
5-year DFS		81.4%				90.3%	
10-year DFS		74.0%				79.3%			0.12			
5-year OS		76.6%				91.0%		
10 year-OS		63.5%				64.4%			0.007

5-year BCSS		85.9%				94.9%		
10-year BCSS		81.8%				91.6%			0.036


LRT; loco-regional treatment, DFS; disease free survival, OS; overall survival, BCSS; breast cancer-specific survival. Table 5. Prognostic factors affecting disease-free, overall and breast cancer-specific survival.
VariableDFS (p)OS (p)BCSS (p)Pathologic tumor stage0.046* / 0.02**0.02* / 0.003**0.o1* / 0.027**Mode of loco-regional treatment 
(non-standard vs. standard)0.12* / 0.1**0.005* / 0.007**0.044* / 0.036*** log-rank; ** Cox-regression; DFS: disease-free survival; OS: overall survival; BCSS: breast cancer-specific survival 










Figure 1. Kaplan-Meier estimates of disease-free survival in both study groups. 







Figure 2. Kaplan-Meier estimates of overall survival in both study groups. 

Figure 3. Kaplan-Meier estimates of breast cancer-specific survival in both study groups.
















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