Limited Supraclavicular Radiation Field in Breast Cancer With ≥ 10 Positive Axillary Lymph Nodes

Accepted Manuscript The Limited Supraclavicular Radiation Field in Breast Cancer with ≥ 10 Positive Axillary Lymph Nodes Jeong Il Yu, MD, Won Park, MD, Doo Ho Choi, MD, Seung Jae Huh, MD, Seok Jin Nam, MD, Seok Won Kim, MD, Jeong Eon Lee, MD, Won Ho Kil, MD, Young-Hyuck Im, MD, Jin Seok Ahn, MD, Yeon Hee Park, MD, Eun Yun Cho, MD PII:

S1526-8209(15)00281-5

DOI:

10.1016/j.clbc.2015.11.008

Reference:

CLBC 439

To appear in:

Clinical Breast Cancer

Received Date: 25 August 2015 Revised Date:

25 November 2015

Accepted Date: 25 November 2015

Please cite this article as: Yu JI, Park W, Choi DH, Huh SJ, Nam SJ, Kim SW, Lee JE, Kil WH, Im YH, Ahn JS, Park YH, Cho EY, The Limited Supraclavicular Radiation Field in Breast Cancer with ≥ 10 Positive Axillary Lymph Nodes, Clinical Breast Cancer (2016), doi: 10.1016/j.clbc.2015.11.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Category: clinical

The Limited Supraclavicular Radiation Field in Breast Cancer with ≥ 10 Positive

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Axillary Lymph Nodes

Jeong Il Yu, MD,1 Won Park, MD,1 Doo Ho Choi, MD,1 Seung Jae Huh, MD,1 Seok Jin Nam, MD,2 Seok Won Kim, MD,2 Jeong Eon Lee, MD,2 Won Ho Kil, MD,2 Young-Hyuck

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Im, MD,3 Jin Seok Ahn, MD, 3 Yeon Hee Park, MD,3 Eun Yun Cho, MD4

Department of 1Radiation Oncology, 2Surgery, 3Medicine, and 4Pathology, Samsung

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Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Corresponding author: Won Park, M.D., Ph.D.,

Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University

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School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul 135-710, Korea

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Tel.: +82-2-3410-2616, Fax: +82-2-3410-2619, E-mail:[email protected]

Running title: Limited supraclavicular RT in breast cancer

Conflict of Interest Statement: The authors have no conflicts of interest to disclose.

ACCEPTED MANUSCRIPT Clinical Practice Points

There is no clearly defined supraclavicular radiotherapy (SCRT) field in breast cancer patients who showed higher tumor burden, like ≥10 positive axillary lymph node metastasis. We evaluated

axillary or supraclavicular recurrence in those patients who received the current standard

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systemic management and limited field SCRT, and lymph node ratio was a significant prognostic factor of axillary or supraclavicular recurrence. It will provide valuable information

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about optimal SCRT field.

ACCEPTED MANUSCRIPT Microabstract We evaluated axillary or supraclavicular recurrence (ASR) in breast cancer with ≥10 positive axillary lymph node metastasis received the current standard systemic management and limited

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field supraclavicular radiotherapy (SCRT). The only significant prognostic factor of ASR was lymph node ratio, therefore modification of the SCRT field including full axilla should

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be considered in these patients.

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Abstract

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Purpose: This study was conducted to evaluate patterns of recurrence and factors related to axillary or supraclavicular recurrence (ASR), and to suggest probable indications of supraclavicular radiotherapy (SCRT) field modification in breast cancer patients with ≥10

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axillary lymph node (LN) metastases who received the current standard systemic management and limited field SCRT.

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Materials and Methods: We performed a retrospective study in breast cancer patients with 10 or more axillary LN metastases who received standard surgery with postoperative RT including limited SCRT (level III and supraclavicular area) and taxane-based adjuvant chemotherapy (except neoadjuvant chemotherapy) from January 2000 to June 2012. ASR

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was defined as recurrence to levels I to III of the axillary or supraclavicular areas. Results: The present study included 301 breast cancer patients with ≥10 axillary LN metastases. The median follow-up period was 59.1 months (range, 7.4 to 167.9 months).

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Overall, 32 (10.6%) cases of locoregional recurrence were observed and 27 (9.0%) patients exhibited ASR. Additionally, 16 (5.3%) patients showed recurrences in levels I or II of the

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axillary area, which are not included in the SCRT field. ASR-free survival was significantly related to the lymph node ratio (LNR) in both univariate and multivariate analysis. Conclusions: ASR was the most prevalent locoregional recurrence pattern in breast cancer patients with ≥10 axillary LN metastases, and LNR was a significant prognostic factor for ASR. Modification of the SCRT field including full axilla should be considered in patients with a higher LNR.

Keywords: breast neoplasm; recurrence; regional; radiotherapy

ACCEPTED MANUSCRIPT Introduction

The effect of radiotherapy (RT) on breast cancer in pathologic T3-4 and/or lymph node (LN) metastasis has been repeatedly confirmed in the Danish Breast Cancer Cooperative

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Group (DBCG) 82 b and c studies,1,2 and the British Colombia trial.3 These studies

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that RT not only reduces loco-regional recurrence (LRR) but also overall distant metastasis (DM).4,5 The benefit of RT is more clearly defined in patients with axillary LN

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metastasis receiving adjuvant systemic therapy to eradicate locoregional disease.6 Based on these results, postoperative RT including the supraclavicular area with systemic

or more LN metastases are present.

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therapy is the standard of care in breast cancer with LN metastasis, especially when four

Although there is little doubt about the efficacy of adjuvant RT, several controversies still remain concerning optimal application. The necessity for full coverage of the axilla

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and internal mammary area in adjuvant RT after optimal axillary LN dissection is one of the most important unresolved issues.7 Despite the lack of a clearly defined adjuvant RT

applications.7,8

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field, the wide field, including the whole axillary area, is generally used in clinical

Lymphedema is one of the most serious complications caused by RT of the full axillary

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area.9 Furthermore, it has been reported that axillary recurrence did not develop in patients with 10 or more positive nodes, regardless of full coverage of the axilla.10 Therefore, a determination of risk-specific supraclavicular RT (SCRT) field is needed to maintain the effects of adjuvant RT without increasing the risk of lymphedema. After standard axillary LN dissection, our institution used limited SCRT field, including axillary level III and the supraclavicular area and excluding axillary levels I and II. Clinical outcomes of the limited SCRT field could categorize patients into two groups:

ACCEPTED MANUSCRIPT low risk group and high risk group needed to expanding SCRT to cover full axilla. Especially, it might be more important in patients showed higher tumor burden, like patients had 10 or more positive axillary LN metastasis.

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This study was designed to evaluate patterns and prognostic factors related to the recurrence of breast cancer to the axillary or supraclavicular areas and to suggest indications of SCRT field modification in breast cancer patients with 10 or more axillary

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LN metastases who received the current standard of systemic treatment.

ACCEPTED MANUSCRIPT Materials and Methods

Patients This retroactive study was conducted using patients from the Samsung Medical Center

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from January 2000 to June 2012 with confirmed diagnosis of invasive breast cancer with 10 or more axillary LN metastases. Additional inclusion criteria were as follows: curative resection performed, taxane-based chemotherapy and postoperative RT including SCRT used,

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and immunohistochemistry (IHC) of HER-2 examination performed. Exclusion criteria were as follows: male, neoadjuvant chemotherapy, distant metastasis detected before surgery,

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recurrence detected within six months after surgery, and internal mammary LN or supraclavicular LN metastasis detected. The Samsung Medical Center Institutional Review Board approved this study and the need for informed consent was waived. The study enrolled a total of 301 patients satisfying the inclusion and exclusion criteria.

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The baseline characteristics of enrolled patients are illustrated in Table 1. The median followup time for all patients was 59.1 months (range, 7.4 to 167.9 months) and the median patient

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age was 48 years (range, 28 to 76 years).

Surgical treatment and pathologic results

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Total mastectomy was performed in 201 patients (66.8%). All patients received axillary LN dissection, usually confined to levels I and II of the axillary area. The median number of dissected axillary LNs was 26 (range, 10 to 61), and 10 to 55 LNs were diagnosed as metastatic tumors. The highest axillary LN levels of detected metastatic tumors were level I in 42 patients (14.0%), level II in 202 patients (67.1%), and infraclavicular LN in 57 patients (18.9%). Most patients (196 of 248), unless their status was not reported (53), exhibited

ACCEPTED MANUSCRIPT extracapsular extension of the LN. Lymphovascular invasion was detected in 254 patients (84.4%).

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Systemic chemotherapy During the study period, four cycles of doxorubuicin and cyclophosphamide (AC) followed by four cycles of docetaxel (T) were recommended to patients after surgery based on

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institutional protocol. In 279 (92.7%) patients, the four cycles of AC followed by four cycles of T was used as adjuvant chemotherapy. Through 2005, RT was administered between the

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AC and T to maximize locoregional control. However, in 2006, RT was delayed until after chemotherapy was completed. Among 279 patients who received AC-T, 86 patients received RT between AC and T chemotherapy, and 193 patients received RT after completion of AC and T. Six cycles of TAC (docetaxel, cyclophosphamide and Adriamycin) or TC (docetaxel

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and cyclophosphamide) were used in the remaining 22 patients (7.3%).

IHC profiles, molecular subtypes and endocrine or targeted therapy

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Positive estrogen receptor (ER), progesterone receptor (PR), and HER-2 status was seen in 220 (73.1%), 215 (71.4%), and 78 (25.9%) patients, respectively. Endocrine therapy was used

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in all 225 (74.8%) patients who were hormone receptor positive, and trastuzumab was used in 57 of the 78 HER-2 positive patients (73.1%). The patients were classified into four subtypes based on their ER/PR/HER-2 status and the Ki-67 index was combined in the process if the status was checked. The Ki-67 index was examined by Ki-67 antibody (DAKO, clone MIB-1, dilution 1:300), and counted using a computerized image analysis system (I-SOLUTION DT, Vancouver, BC, Canada). Ki-67 positivity was defined as ≥ 14%. One hundred patients were classified as luminal A (33.2%), 119 as luminal B (39.5%), 35 as HER-2 enriched (11.6%), and 47 as triple negative (15.6%).

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Radiation therapy Adjuvant RT with a 2-dimensional technique to the chest wall, breast, and supraclavicular

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area was conducted in all patients. A single iso-center technique was used to match the breast, chest wall, and SCRT fields. Four or six megavolt photon tangential fields were used for breast and chest wall RT at a median dose of 50.4 Gy (range, 50.0 to 50.4 Gy) at

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1.8 to 2.0 Gy per fraction by 4- or 6-megavolt photon beams. For SCRT, the gantry was rotated 10 to 15 degrees to avoid exposure to the spinal cord. Borders of the SCRT field

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were set superiorly at the thyrocricoid groove and medially at the anatomical midline. The lateral border was determined by a vertical line at the level of the coracoid process, and the inferior boarder was matched to the tangential beast or chest wall field just below the clavicular head. After whole breast RT, electron boost was routinely applied to the tumor

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bed with 9.0 to 10.5 Gy per three fractions according to the patient’s surgical margin status. Internal mammary RT was not routinely used in patients without evidence of metastasis in that area, but 20 (6.6%) patients received elective internal mammary nodal

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RT. For internal mammary RT, partial wide tangential field or anterior electron field matched to standard tangential field were used, and target was defined as first to third

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intercostal space area.

Statistical analysis

If the tumor reappeared in the ipsilateral breast, chest wall, axilla, internal mammary, infraclavicular or supraclavicular areas, the case was defined as locoregional recurrence. Axillary/supraclavicular LN recurrence (ASR) was defined as recurrence to levels I to III of the axillary LN or supraclavicular LN. Biopsy or excision was always performed in

ACCEPTED MANUSCRIPT cases in which isolated LRR was suspected. It was regarded as simultaneous recurrence if the recurrence was detected at multiple sites in a month. A template case (phantom patient without neck adenopathy) of adjuvant RT was chosen to display schematic ASR sites and

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the area of recurrence was delineated via fusion of all epicenters of recurrences, then connected and smoothed.

LRR-free survival (LRRFS) and ASR-free survival (ASRFS) were measured from the

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date of surgery to the date at which LRR or ASR was detected, or to the date of last follow-up if no recurrence occurred. If patients showed other site recurrence or died

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without LRR or ASR, they were regarded as censored at the time of diagnosis or death. The Kaplan-Meier product limit method was used to estimate survival. The log-rank test was used to compare survival differences between curves, and the Cox proportional hazards model was used for multivariate survival analysis of variables having probable

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statistical significance (p<0.1),. The Cox proportional hazards model was tested using the Schoenfeld residuals method. All statistical analyses were performed using PASW 21.0 software for Windows (IBM, Armonk, NY, USA), and p<0.05 was considered statistically

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significant.

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Results Patterns of first site recurrence During the follow-up period, 99 patients (32.9%) experienced recurrence of any form.

median of 25.9 months (range, 7.2 to 148.2).

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The most frequent failure pattern was DM, which was found in 68 patients (22.6%) at a

Overall, LRR developed in 32 patients (10.6%). Isolated LRR was seen in 16 of the 32

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(5.3%) and the other 16 LRR patients also exhibited DM. The median time to surgery and detection of LRR was 24.1 months (range, 7.7 to 92.8 months). Among the 32 patients

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with LRR, the axillary and supraclavicular area was the most frequent site of recurrence, observed in 27 patients (9.0%). Isolated axilla and infraclavicular/supraclavicular LN recurrence without DM was seen in four (1.3%) and six (2.0%) patients, respectively. Isolated internal mammary LN recurrence was detected in two (0.6%) patients, and

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internal mammary LN recurrence combined with other types of recurrence was seen in four (1.3%) patients. Local recurrence alone was seen in two (0.6%) patients, and local

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recurrence combined with other types of recurrence was observed in four (1.3%) patients.

Patterns of LRR according to the RT field

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Our institutional SCRT field and LRR site are displayed in Fig 1A. The location of LRR was also represented as a schematic location in a digitally reconstructed image of a planned CT on a phantom patient. Among 27 patients with ASR, 18 cases (66.7%) developed within the limited SCRT field, and recurrence in axillary levels I or II was also detected in seven of these patients. The lateral part of the axillary area, which was not included in the limited SCRT field, also showed frequent recurrences. Among the 27 cases of ASR, 16 recurrences (59.3%) developed at the axillary I/II level of the lateral margin of the SCRT field with or without

ACCEPTED MANUSCRIPT other regional areas. Of these 16 patients, only one patient showed a LNR of less than 50%, and seven patients showed a LNR of more than 80%. Additionally, in some cases of ASR, some parts of the SCRT field received less than 90%

accessible (Fig 1B).

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Prognostic factors and outcomes of LRRFS and ASRFS

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of prescribed dose only, even though the real dosimetry of each ASR patient was not

The Kaplan-Meier curves of LRRFS and ASRFS are displayed in Fig. 2A. At five and

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10 years, the LRRFS rates were 87.8% and 80.4%, respectively, and the ASRFS rates were 90.4% and 82.8%, respectively. The results of univariate and multivariate analysis of ASRFS are displayed in Table 2.

Upon univariate analysis, a younger age (≤ 40 years) was associated with significantly

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lower ASRFS (p=0.046). ASRFS was affected by the lymph node ratio (LNR, p=0.005). Clinical N stage, type of surgery, a high number of metastatic LNs (15 or more), high tumor grade (Grade III), and molecular subtype were not prognostic factors of ASRFS. In

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the multivariate analysis, LNR was the only significant prognostic factor of ASRFS (50 to 80%; p=0.04, HR 3.84, 95% CI 1.06 – 13.89, ≥ 80%; p=0.001, HR 5.93, 95% CI 1.48 –

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23.79) (Fig. 2B). The ASRFS rate at 5 years was 82.4% with a high LNR (≥ 80 %), 91.0% with an intermediate LNR (50% to 80%), and 96.4% with a low LNR (≤ 50 %). In LRRFS analysis, LNR was the only significant prognostic factor, though the differences in survival were much smaller than those of ASRFS (p=0.03). Younger age and triple negative status conferred a tendency for poor survival, but the p-value was not significant.

ACCEPTED MANUSCRIPT Discussion In the present study, performed on breast cancer patients with 10 or more positive axillary LNs receiving current standard systemic management with limited SCRT field,

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ASR was the most important failure pattern in LRR and ASRFS was closely related to LNR.

The efficacy of postoperative RT including the supraclavicular area in breast cancer with LN metastasis has been repeatedly confirmed in many large, randomized, controlled

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studies and meta-analyses1-3,6 as it has been shown to reduce DM as well as LRR.5

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However, several controversies remain regarding adjuvant RT, including the optimal RT target in SCRT after full axillary LN dissection.

Currently, generally accepted post-surgery RT in cases of breast cancer with axillary node metastasis includes the whole breast or chest wall and supraclavicular area with or without the internal mammary area.7,8 However, there is a wide spectrum of tumor burden

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and clinical outcomes from micrometastasis to 10 or more metastasis of LN.11,12 Considering the clear difference in prognosis, risk-specific customized RT is needed to

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enhance clinical outcomes.

Previous studies have shown that axillary recurrence is infrequent after optimal axillary

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LN dissection with or without adjuvant RT.10,13-19 In the present study, however, recurrences were relatively frequent in the upper axillary level I/II, which is known as inadequately covered by tangential RT fields.20-22 Interpectoral area which is not usually dissected, therefore, could be one of the reasons for high recurrence rate in the lateral margin area of the SCRT field.23,24 Furthermore, it was not covered intentionally in the SCRT field under our institutional policy. Among all patients, 16 (5.3%) experienced recurrence at the lateral margin of the SCRT field mainly targeted at the infra- and supraclavicular LN. According to our results, all levels of the axilla are at potential risk for

ACCEPTED MANUSCRIPT recurrence in breast cancer patients with 10 or more axillary LN metastases. Therefore, a wide SCRT field that covers the whole axillary area might be needed for reducing ASR. Cases of infra- and/or supraclavicular LN recurrence were also frequent in the present

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study, despite these areas being irradiated in the SCRT field. Using routine 2-dimensional SCRT field without target delineation might cause suboptimal dose delivery to these sites and it may be a reason of higher recurrence rates. Full coverage of the axilla and more

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accurate dose delivery to the SCRT field may be related to improved clinical outcomes when considering the patterns of recurrence in the present study. However, lymphedema, a

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common RT side effect that compromises quality of life, is of concern when modifying the SCRT field. SCRT is an important risk factor for lymphedema, and we expect that the incidence of lymphedema would increase by widening the RT field and increasing the dose delivered to the axillary and supraclavicular areas.22,25,26 Careful selection of patients

modifications.

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and further investigation of efficacy and toxicity are needed to adapt RT field

To select more optimal candidates for SCRT modification, the risk factors of ASR were

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analyzed and LNR was found to be the only significant factor for stratifying ASR by risk groups. Patients with a higher LNR (≥80%) showed less than 80% ASRFS. On the

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contrary, those with a lower LNR (≤50%) showed better ASRFS. Although these patients were categorized with the same pN3a, a different approach based on risk of recurrence may be needed. Patients with a higher LNR could benefit from modification of the SCRT field when considering the risk of ASRFS, although modification could increase the risk of lymphedema. On the contrary, limited SCRT field confined to the infra- and supraclavicular area could be optimal in patients with a LNR of ≤50%. Further, large multi-institutional studies are needed to confirm the results of the present study. This study has several limitations. First, it was a retrospective study at a single institution,

ACCEPTED MANUSCRIPT so selection bias was inevitable. Second, the follow-up period used may be insufficient for assessing the clinical outcomes of breast cancer, especially considering the long-term recurrence pattern of the disease. Third, the present study focused only on SCRT field and

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ASR. Effect on LRR according to the internal mammary RT which is a part of important adjuvant regional RT should be evaluated in the future studies. Another problem of the present study is the lack of 3-dimenstional dosimetry of axilla and supraclavicular area

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which demonstrates adequate coverage of these regions.27 Finally, all patients enrolled in the present study had received full axillary LN dissection. More careful determination of

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SCRT field for patients who received more conservative surgery including sentinel LN sampling without axillary LN dissection current standard in clinically N0 breast cancer should be needed.

Nevertheless, our study is the first to evaluate patterns of recurrence in pN3 breast cancer

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after full axillary LN dissection based on the SCRT field. Our findings suggest that modifying the SCRT field including axillary level I/II might be needed in in patients with

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higher LNR with 10 or more axillary LN metastases.

ACCEPTED MANUSCRIPT Conclusion In breast cancer patients with 10 or more axillary LN metastases treated with limited SCRT and taxane-based chemotherapy, we showed that ASR was an important pattern of

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LRR. Our results suggest that limited SCRT may not be appropriate in patients with higher LNR, because of significantly related ASR, therefore modification of the SCRT field including full axilla should be considered. On the contrary, limited SCRT could be

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an option in patients with lower LNR. However, large prospective studies are needed to

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validate the results.

ACCEPTED MANUSCRIPT Acknowledgements:

Conflicts of Interest Statement:

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There are no conflicts of interest relevant to this article.

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This research was supported by a Samsung Medical Center grant (GF01130081).

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Figure legends

Figure 1. Patterns of locoregional recurrence (LRR) according to the radiotherapy (RT)

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and the iso-dose curve of the SCRT field (B) is displayed.

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field. The relation between LRR sites and routine supraclavicular RT (SCRT) field (A),

Figure 2. Kaplan-Meier survival curves and prognostic factors. The curves of LRRFS

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and axillary/supraclavicular recurrence-free survival (ASRFS) are displayed in A. Lymph

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node ratio was the only significant prognostic factor (B).

ACCEPTED MANUSCRIPT Table 1. Patient characteristics Variables

No of patients (%)

Variables

No of patients (%)

T1 T2 T3 T4

85 (28.2) 167 (55.5) 44 (14.6) 5 (1.7)

Clinical N stage

N0 N1 N2 N3

46 (15.3) 186 (61.8) 54 (17.9) 15 (5.0)

Type of operation

Total mastectomy Partial mastectomy

201 (66.8) 100 (33.2)

Pathology

IDC Other

249 (82.7) 52 (17.3)

Pathologic T stage

T1 T2 T3 T4

51 (16.9) 180 (59.8) 68 (22.6) 2 (0.7)

Metastatic LN level

I II III

42 (14.0) 202 (67.1) 57 (18.9)

Histologic grade

1 2 3 unknown

26 (8.6) 128 (42.5) 144 (47.8) 3 (1.0)

Nuclear grade

1 2 3 unknown

15 (5.0) 135 (44.9) 150 (49.8) 1 (0.3)

Dissected ALN number

Median Range

26 10-61

Metastatic ALN number

Median Range

15 10-55

Lymphovascular invasion

No Yes unknown

45 (15.0) 254 (84.4) 2 (0.6)

Extracapsular extension

No Yes unknown

52 (17.3) 196 (65.1) 53 (17.6)

Estrogen receptor

Positive Negative

220 (73.1) 81 (26.9)

Progesterone receptor

Positive Negative

215 (71.4) 86 (28.6)

HER-2

Positive Negative

78 (25.9) 223 (74.1)

Trastuzumab

No Yes

244 (81.1) 57 (18.9)

Chemotherapy

AC - T TAC TC

279 (92.7) 11 (3.7) 11 (3.7)

Endocrine therapy

No Yes

76 (25.2) 225 (74.8)

TE D

M AN U

SC

RI PT

Clinical T stage

AC C

EP

IDC=invasive ductal carcinoma; ALN=axillary lymph node; HER-2=human epidermal growth factor receptor-2; AC=cyclophosphamide and adriamycin; T=docetaxel; TAC= docetaxel, cyclophosphamide and adriamycin; TC=docetaxel and cyclophosphamide

ACCEPTED MANUSCRIPT Table 2. Prognostic factors predicting axilla/supraclavicular recurrence-free survival (ASRFS). P value No of pts

5-yr ASRFS (%)

Univariate

≤ 40 > 40

67 234

82.9 92.6

0.046

Clinical N stage

N0 N1-3

46 255

97.6 88.9

0.25

Type of surgery

Partial mastectomy Total mastectomy

201 100

94.6 88.5

0.15

pT-stage

1-2 3-4

231 70

92.3 84.1

0.06

LVI

No Yes

45 254

94.4 89.6

ECE

No Yes

52 196

78.8 94.0

(+) LN number

< 15 ≥ 15

144 157

(+) LN level

I II III

42 202 57

LNR (%)

≤ 50 50 - 80 ≥ 80

82 146 73

Histologic grade

1-2 3

Nuclear grade

1-2 3

Molecular subtype

Luminal A Luminal B HER-2 Triple negative No Yes

97.6 87.3 96.2

0.49 – 2.50

0.09

M AN U 94.8 86.3

1.11

0.69

0.15

0.24

96.4 91.0 82.4

0.005

154 144

91.7 88.7

0.52

150 150

93.5 87.2

0.11

100 119 35 47 76 225

89.9 93.2 90.7 85.7 88.5 91.2

0.45

TE D

EP

AC C

Endocrine therapy

0.80

95 % CI

SC

Age (years)

Multivariate HR

RI PT

Variables

0.04 0.001

3.84 5.93

1.06 – 13.89 1.48 – 23.79

0.44

RFS=recurrence-free survival; HR=hazard ratio; CI=confidence interval; LVI=lymphovascular invasion; LN=lymph node; LNR=lymph node ratio; ECE=extracapsular extension; HER-2=human epidermal growth factor receptor-2

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT Highlights

We examine pattern of failure in patients with ≥10 positive axillary lymph node metastasis. Axillary or supraclavicular recurrence was observed in 9% of the patients.

RI PT

Lymph node ratio was a significant prognostic factor of axillary or supraclavicular recurrence.

AC C

EP

TE D

M AN U

SC

Modification of supraclavicular radiotherapy field could be needed in