Number of negative lymph nodes as a prognostic factor for ypn0-n1 breast cancer patients undergoing neoadjuvant chemotherapy

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1 DOI.7/s ORIGINAL ARTICLE Number of negative lymph nodes as a prognostic factor for ypn-n breast cancer patients undergoing neoadjuvant chemotherapy Fei Xin,2,3 & Yue Yu,2,3 & Zheng-Jun Yang,2,3 & Li-Kun Hou,2,3 & Jie-Fei Mao,2,3 & Li Xia,2,3 & Xin Wang,2,3 & Xu-Chen Cao,2,3 Received: September 25 /Accepted: 3 December 25 # International Society of Oncology and BioMarkers (ISOBM) 26 Abstract Some of node-positive patients could have a pathologically complete response in terms of lymph nodes. For these patients, the number of negative lymph nodes (NLNs) may be higher than that in the same-stage patients who initially received mastectomy. After neoadjuvant chemotherapy (NAC), the following treatment especially the postmastectomy radiotherapy (PMRT) is controversial for ypn (with one to three positive lymph nodes after NAC) patients. A total of 289 patients who received NAC from 26 to 29 were included in the investigation. The prognostic value of the number of NLNs on these patients was analyzed. Besides, we analyzed if the number of NLNs would give some indications on PMRT in ypn patients. The follow-up of all the patients began the first chemotherapy on 5 March 25. The 5-year disease-free survival (DFS) and overall survival (OS) rates were determined as 67.2 and 8. %, respectively. The number of NLNs was associated with primary stage (p <.), pathological tumor size (p <.5), pathological nodal stage (p <.), and pathological stage after NAC (p <.). The univariate and multivariate analyses revealed that the number of NLNs is an independent prognostic factor in both DFS and OS. In ypn-n stage, patients with >3 Fei Xin, Yue Yu and Zheng-Jun Yang contributed equally to this work. * Xu-Chen Cao caoxuchen@tmu.edu.cn 2 3 The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin 36, China Key Laboratory of Cancer Prevention and Therapy, Tianjin 36, China Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin 36, China NLNs had better DFS (p <.) and OS (p <.) than the patients with 3 NLNs. Although the fact patients in ypn2-n3 stage with >3 NLNs had better DFS and OS than the others, there were no significant statistical difference. In the subgroup analysis, PMRT improved the OS (p <.5) and DFS (p <.5) of ypn patients with 3 NLNs. The number of NLNs is a prognostic indicator in ypn-n patients. Patients in ypn stage with less number of NLNs will benefit from PMRT. Keywords Neoadjuvant chemotherapy. Negative lymph nodes. Postmastectomy chemotherapy. ypn-n Introduction As one of the systemic treatments, neoadjuvant chemotherapy (NAC) was firstly utilized on patients with local advanced breast cancer to improve their operative resection rate. In recent years, NAC is becoming a frequently used option on operable breast cancer patients because of its efficacy in improving the prognosis of patients to achieve pathologic complete response (pcr) as well as the possibility of breast conservation [ 4]. Patients who achieved pcr means that there is no more residual disease in breast or lymph nodes. Lymph node is always an important prognostic factor in breast cancer, as it can guide local-regional and systemic treatments and facilitates staging. For positive-node breast cancer patients who received NAC, some of them could have pcr in terms of lymph nodes [5]. Therefore, these patients may have more negative lymph nodes (NLNs) than in the same-stage patients who initially underwent axillary lymph nodes dissection (ALND). The number of NLNs is the total number of lymph nodes removed by axillary dissection minus the number of positive lymph node number. Kuru B found that total number

2 of nodes removed, NLNs, and ratio of positive nodes to total nodes removed would predict prognostic in node-positive breast cancer patients [6]. A study based on SEER Program which analyzed 37,58 breast cancer patients found that in node-positive patients, the 5-year survival increased in patients with more NLNs [7]. Besides that, for patients undergoing NAC, there may be more occult residuals in the lymph nodes. Therefore, more number of NLNs removed may reduce the risk of local relapse to improve the prognostic. On the basis of these, we thought the number of NLNs may have prognostic value in the patients who undergoing NAC. After the NAC and surgery, the following treatments include postmastectomy radiotherapy (PMRT) and endocrine therapy. However, which part of ypn patients should undergo PMRT is controversial. Oncologists initially obtain indications from the patients who first received mastectomy and then adjuvant radiotherapy []. PMRT is a regular treatment forpatientswithfourormorepositivelymphnodes,butis strongly recommended for N patients at high risk. The National Comprehensive Cancer Network (Version.24) [8] states that PMRT should be based on the worst tumor characteristics of these patients during their pre- or posttreatment stages. However, acquiring the exact number of positive lymph nodes of patients before they could receive NAC is difficult. Moreover, the number of negative lymph nodes of these patients may be higher than that of patients who initially underwent surgery. Accordingly, we analyzed whether the number of NLNs could give us some indications of PMRT for ypn patients. The primary aim of the retrospective study is to investigate the prognostic value of the number of negative lymph node in breast cancer patients after NAC, and the second aim is to analyze whether the number of NLNs could give us some indications about PMRT in ypn patients. Materials and methods Patients The records of breast cancer patients who were treated at Tianjin Medical University Cancer Institute and Hospital from January 26 to December 29 were retrospectively analyzed. The participants of this study were selected based on the following criteria: () females with pathologically confirmed unilateral invasive breast cancer; (2) patients who received mastectomy and ALND after at least one cycle of chemotherapy and whose number of removed axillary lymph nodes was ; and (3) patients who had complete immunohistochemistry results, including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2). The exclusion criteria were patients who had breast cancer before or other sites cancers. Two hundred eighty-nine patients were included in this study, 4 patients were excluded. The type of NAC included T and (or) E regimens (paclitaxel, epirubicin, or cyclophosphamide, epirubicin, 5fluorouracil) and others (paclitaxel, platinum, and capecitabine combined). This study was approved by the Ethics Committees at the Tianjin Medical University Cancer Institute and Hospital. The clinicopathological characteristics of the patients were retrospectively obtained from their medical records and were evaluated as prognostic factors. These characteristics included the patient s age, menopausal status, physical examination, ultrasound of breast before chemotherapy and mastectomy, primary clinical stage (according to AJCC 7th), chemotherapy regimens, cycles of chemotherapy before mastectomy, ypt stage, ypn stage, pathological stage after NAC (according to AJCC 7th), Ki-67 level, pathological type, radiotherapy site, radiation dose, and recurrence incident. The risk of recurrences were primary evaluated such as patient s age,menopausal status, luminal categories, primary clinical stage, ypt stage, ypn stage, Ki-67 level, and so on. More than % of the immunostained malignant cells were ER and PR positive. Her2 positive was indicated by a 3+ or 2+ score upon immunohistochemical evaluation and confirmed using a fluorescence in situ hybridization test for Her2. Ki-67 values were acquired as the percentage of positively marking malignant cells by immunohistochemical stain. Therefore, we classified breast cancer subtypes as follows: () luminal A (ER+ and/ or PR+, Her2, and Ki-67 4 %); (2) luminal B (ER+ and/ or PR+, Her2+; or ER+ and/ or PR+, Ki-67 > 4 %); (3) Erb-B2 overexpression (ER,PR, and Her2+); (4) Basal-like (ER, PR, and Her2 ). Recurrence incident was defined as ipsilateral breast cancer or chest wall recurrence, as well as isolated axillary, supraclavicular, or internal mammary axillary node recurrence or distant metastasis. Follow-up The follow-up for all patients began from the date of chemotherapy treatments. Overall survival (OS) was defined as a means of measuring the first cycle of chemotherapy to the last follow-up of cancer-related death. Disease-free survival (DFS) was defined as a duration of time between the date of the first cycle of chemotherapy and the first regional recurrence or distant metastasis, or the last follow-up. When the patients completed all treatments, they were followed up by our outpatient department every 6 months for the first 3 years, after which follow-up was conducted annually. Physical examination, ultrasound, and chest X-ray were performed to observe the regional recurrence or distant metastasis among patients during the follow-up. The last follow-up was conducted on 5 March 25. The endpoints of the study were DFS and OS, which obtained from the medical records of patients or by telephone interview.

3 Statistical analysis All statistical analyses were performed with SPSS Version 8. for Windows (Chicago, USA). The receiver operating characteristic (ROC) curve was calculated to evaluate the cut-off point of NLNs for DFS and OS. The patients were divided into two groups based on the cutoff point of NLNs. Pearson s χ 2 test was used to examine the correlations of NLNs with clinicopathological parameters. Kaplan Meier method and long-rank test were performed to explore the associations of NLNs with DFS and OS. Cox proportional hazards model was applied to multivariate analysis. All tests were two sided, and the p value of <.5 was considered statistically significant. Results Identification of optimal cutoff points of NLNs After excluding 4 patients, 275 patients were included in this study. The median number of the total removed lymph nodes was 22, ranging from 3 to 78. The median number of NLNs was 6, ranging from to 6. The results showed that 3 was the optimal cutoff point of NLNs (area under ROC curve =.7, p <.)(Fig. ). Therefore, the optimal cutoff value of 3 was validated as a prognostic factor. Based on this, patients were divided in two groups: groups (patients with to 3 NLNs, n =4)and2(patientswith3to6 NLNs, n =7). Clinicopathological features The median age at diagnosis was 5 years (range, 23 to 72 years), 5 cases (54.5 %) were in premenopausal, and 25 cases (45.5 %) were in postmenopausal. According to Sensitivity.2.2 -Specificity p. Fig. Receiver operating characteristics curve of the optimum cutoff point for the NLNs the body max index (BMI), 43 cases (52 %) were normal, cases (36.7 %) were overweight, and 3 cases (.3 %) were obese. The pre-nac clinical stages were stages I and II in 32 cases (48 %) and stage III in 43 cases (52 %). The characteristics of these patients are summarized in Table. The patients were further classified into two groups, namely, clinical complete response (ccr) and non-ccr, based on their responses to NAC before surgery. Patients belonged to the ccr group when no tumor was found in their ultrasound results; otherwise, the patient belonged to the non-ccr group. As shown in Table, the number of NLNs was associated with primary stage (p <.), pathological tumor size (p <.5), pathological nodal stage (p <.), and pathological stage after NAC (p <.), but was not related to age (p = 4), menopausal status (p =.93), body mass index (BMI) (p =.28), chemotherapy regimens (p =.36), response to chemotherapy (p =.9), chemotherapy cycles before surgery (p = 82), histological type (p =.28), Ki-67 levels (p = 92), and breast subtype (p =.744). Moreover, we identified the different biological difference among ypn- N3 patients. It turned out that different ypn stages were related with Ki-67 levels (p <.5), breast cancer subtype (p <.5), ypt stages (p <.), response to chemotherapy (p <.), and stages before and after chemotherapy (both p <.) (Table 2).ComparingwithNLNs,ypNstage seemed to be more related with biological characteristics of patients. Treatment and response The percentage of patients treated with T and (or) E regimens and others was 93.8 and 6.2 %, respectively. The cycles before mastectomy ranged from to 6. One hundred eleven patients (4 %) received or 2 cycles of chemotherapy before surgery, 29 (46.9 %) patients received 3 or 4 cycles, and 35 (2.7 %) patients received 5 or 6 cycles. After chemotherapy, 5 patients (8.5 %) achieved ccr and 224 patients (8.5 %) did not. According to pathological results, patients in ypt-t stage, ypt2, and ypt3-t4 were 95 (34.5 %), 35 (49. %), and 45 (6.4 %), respectively; patients in ypn-n, ypn2, and ypn3 were 45 (52.7 %), 58 (2. %), and 72 (26.2 %), respectively. One hundred thirty-nine patients (5.5 %) were in stages II and 36 (49.5 %) patients were in stage III. Patients in luminal A, luminal B, Erb-B2 overexpression, and basal-like subtype were 4 (4.5 %), 7 (42.5 %), 4 (4.9 %), and 77 (28 %), respectively. After mastectomy and axillary surgery, a total of 87 patients (68 %) received PMRT, and the target volume included the ipsilateral chest wall and supraclavicular lymph node areas. The radiation dose was 46 5 Gy/23 25 times. All patients with positive hormone receptors received endocrine therapy. The pre- and postmenopausal patients received tamoxifen (TAM) and TAM or an aromatase inhibitor, respectively.

4 Table Clinicopathological features with the number of NLNs Variables Number 3 NLNs 3 6 NLNs p value Age (years) (6.7 %) 8 (6.5 %) 28 (.2 %) >4 229 (83.3 %) 86 (3.3 %) 43 (52 %) Menopausal status.93 Premenopausal 5 (54.5 %) 5 (8.2 %) (36.3 %) Postmenopausal 25 (45.5 %) 54 (9.7 %) 7 (25.8 %) BMI.28 Normal 43 (52 %) 62 (22.5 %) 8 (29.5 %) Overweight (36.7 %) 3 (.3 %) 7 (25.4 %) Obesity 3 (.3 %) (4 %) 2 (7.3 %) Stages before NAC <. Stage I-II 32 (48 %) 29 (.5 %) 3 (37.5 %) Stage III 43 (52 %) 75 (27.3 %) 68 (24.7 %) Response to chemotherapy.9 ccr 5 (8.6 %) 4 (5. %) 37 (3.5 %) Non-cCR 224 (8.4 %) 9 (32.7 %) 34 (48.7 %) Chemotherapy regimens.22 Include T and (or) E regimens 258 (93.8 %) 6 (58.2 %) 98 (35.6 %) Others 7 (6.2 %) 8 (2.9 %) 9 (3.3 %) The chemotherapy cycles before surgery 82 or 2 cycles (4 %) 42 (5.3 %) 69 (25. %) 3 or 4 cycles 29 (46.9 %) 5 (8.2 %) 79 (28.7 %) 5 or 6 cycles 35 (2.7 %) 5 (5.5 %) 2 (7.2 %) Histological type.328 IDC 25 (9.9 %) 95 (34.5 %) 55 (56.4 %) Others 25 (9. %) 2 (4.4 %) 3 (4.7 %) Ki-67 levels 92 4 % 57 (2.7 %) 22 (8 %) 35 (2.7 %) >4 % 28 (79.3 %) 82 (29.8 %) 36 (49.5 %) Breast cancer subtype.744 Luminal A 4 (4.5 %) 3 (4.7 %) 27 (9.8 %) Luminal B 7 (42.5 %) 47 (7. %) 7 (25.4 %) Erb-B2 overexpression 4 (4.9 %) 7 (6.2 %) 24 (8.7 %) Basal-like 77 (28 %) 27 (9.8 %) 5 (8.2 %) Pathological tumor size <.5 ypt-t 95 (34.5 %) 3 (.9 %) 65 (23.6 %) ypt2 35 (49. %) 48 (7.5 %) 87 (3.6 %) ypt3-t4 45 (6.4 %) 26 (9.5 %) 9 (6.9 %) Pathological nodal stage <. ypn-n 45 (52.7 %) 23 (8.4 %) 22 (44.3 %) ypn2 58 (2. %) 24 (8.7 %) 34 (2.4 %) ypn3 72 (26.2 %) 6 (2.8 %) 2 (4.4 %) Pathological stage after NAC <. Stage II 39 (5.5 %) 9 (6.9 %) 2 (43.6 %) Stage III 36 (49.5 %) 85 (3.9 %) 5 (8.6 %) NLNs negative lymph nodes, BMI body max index, NAC neoadjuvant chemotherapy, ccr clinical complete response, non-ccr non-clinical complete response, T paclitaxel or docetaxel, E anthracylines, IDC invasive ductal cancer

5 Survival and disease progression The median follow-up duration was 56.6 months (range,.3 to 7.5 months), during which time 27 patients (78.9 %) were still alive, 98 (35.6 %) experienced locoregional recurrence or distant metastases, and 58 (2. %) died of breast cancer. The 5-year DFS and OS were 67.2 and 8. %, respectively. Table 2 Clinicopathological features with the different ypn patients Variables Number ypn-n ypn2 ypn3 p value Age (years) (6.7 %) 23 (8.4 %) 4 (5. %) 9 (3.2 %) >4 229 (83.3 %) 22 (44.4 %) 44 (6 %) 63 (22.9 %) Menopausal status.79 Premenopausal 5 (54.5 %) 8 (29.5 %) 37 (3.5 %) 32 (.5 %) Postmenopausal 25 (45.5 %) 64 (23.3 %) 2 (7.6 %) 4 (4.6 %) BMI.66 Normal 43 (52 %) 7 (25.8 %) 39 (4.2 %) 33 (2 %) Overweight (36.7 %) 56 (2 %) 7 (6.2 %) 28 (. %) Obesity 3 (.3 %) 8 (6.5 %) 2 (.7 %) (4 %) Stages before NAC <. Stage I II 32 (48 %) 89 (32.4 %) 23 (8.4 %) 2 (7.2 %) Stage III 43 (52 %) 56 (2 %) 35 (2.7 %) 52 (8.9 %) Response to chemotherapy <. ccr 5 (8.5 %) 39 (4.2 %) 4 (.5 %) 8 (2.8 %) Non-cCR 224 (8.5 %) 6 (38.5 %) 54 (9.6 %) 64 (23.4 %) Chemotherapy regimens.33 T and (or) E regimens 258 (93.8 %) 39 (5.5 %) 53 (9.3 %) 66 (24 %) Others 7 (6.2 %) 6 (2.2 %) 5 (.8 %) 6 (2.2 %) The chemotherapy cycles before surgery.576 or 2 cycles (4 %) 57 (2.7 %) 2 (7.7 %) 33 (2 %) 3 or 4 cycles 29 (46.9 %) 69 (25. %) 27 (9.8 %) 33 (2 %) 5 or 6 cycles 35 (2.7 %) 9 (6.9 %) (3.6 %) 6 (2.2 %) Histological type.58 IDC 25 (9.9 %) 37 (49.8 %) 52 (8.9 %) 6 (22.2 %) Others 25 (9. %) 8 (2.9 %) 6 (2.2 %) (4 %) Ki-67 levels <.5 4 % 57 (2.7 %) 4 (4.9 %) 7 (2.5 %) 9 (3.3 %) >4 % 28 (79.3 %) 4 (37.8 %) 5 (8.5 %) 63 (22.8 %) Breast cancer subtype <.5 Luminal A 4 (4.5 %) 27 (9.8 %) 9 (3.3 %) 4 (.4 %) Luminal B 7 (42.5 %) 49 (7.8 %) 28 (.2 %) 4 (4.5 %) Erb-B2 overexpression 4 (4.9 %) 2 (7.3 %) (3.6 %) (4 %) Basal-like 77 (28 %) 49 (7.8 %) (4 %) 7 (6.2 %) Pathological tumor size <. ypt-t 95 (34.5 %) 66 (24 %) 7 (6.2 %) 2 (4.3 %) ypt2 35 (49. %) 67 (24.4 %) 27 (9.8 %) 4 (4.9 %) ypt3-t4 45 (6.4 %) 2 (4.4 %) 4 (5. %) 9 (6.9 %) Pathological stage after NAC <. Stage II 39 (5.5 %) 36 (49.5 %) 2 (.7 %) (.3 %) Stage III 36 (49.5 %) 9 (3.3 %) 56 (2 %) 7 (25.8 %)

6 Univariate and multivariate analyses As shown in Table 3, univariate analysis of patients undergoing NAC showed that primary stage, breast cancer subtype, pathological tumor size, pathological nodal stage, pathological stage after NAC, and the number of NLNs were prognostic factors that affected both OS and DFS (all, p<.5), whereas age could only affect the DFS rate of patients (p<.5) (Table 3). Multivariate cox analysis showed that the number of NLNs was a significant independent prognostic factor of OS ([HR] = 54, CI , p<.5) and DFS ([HR] = 4, CI 45 2, p<.5) (Table 4). In addition, age, primary stage, BCS, and the number of pathological positive nodes were detected as independent prognostic factors (all, p<.5) (Table 4). The prognostic value of the number of NLNs in patients undergoing NAC Kaplan Meier analysis revealed that ypn-n patients with >3 NLNs had better prognosis than those with 3 NLNs, the 5-year DFS was 85.6 and 65.2 % (Fig. 2a; p<.), and the 5-year OS was 94.4 and 66.7 % (Fig. 2b; p<.). Although there was no significant prognosis in ypn2 and ypn3 patients, patients with >3 NLNs in both stages were still had better prognosis. In ypn2 stage, the 5-year DFS and OS in patients with >3 and 3 NLNs were 67.6 and 4.7 % (Fig. 2c; p =.22) and 82.4 and 7 % (Fig. 2d; p =.3); in ypn3 stage, the 5-year DFS and OS in patients with >3 and 3 NLNs were 66.7 and 36.6 % (Fig. 2e; p =4)and 75 and 58.3 % (Fig. 2f; p =.26). Prognostic value of the number of NLNs in ypn patients undergoing PMRT We further examined the effect of PMRT on prognosis of ypn patients with 3 NLNs or >3 NLNs. PMRT improved the recurrence with the 5-year DFS was 9.6 and 5 %, respectively (p <.5; Fig. 3a). Meanwhile, the 5-year OS of ypn patients who received and did not receive PMRT was 9.6 and 62.5 %, respectively (p <.5; Fig. 3b). In patients with >3 NLNs, PMRT did not improve the recurrence and overall survival, the 5-year DFS was 86. and 85 % (p =.73; Fig. 3c), and the 5-year OS was 95.3 and 93.3 % (p = 9; Fig. 3d), respectively. Together, the results indicated that PMRT improved the OS and DFS of ypn patients with 3 NLNs undergoing NAC. Discussion In this study, we found that the number of NLNs as a prognostic value in ypn-n patients who received NAC. Moreover, the number of NLNs could predict the efficacy of PMRT in ypn patients. The number of NLNs is related with the total number of axillary lymph node dissection (ALND) and the positive lymph nodes. Nevertheless, sentinel lymph node biopsy (SLNB) has been commonly performed among clinically node-negative breast cancer patients; the false-negative rates of this technique after NAC may lead to a high risk of mortality. The SLNB of patients with positive nodes and who received NAC produced false-negative rates that ranged from.6 to 25 % [9 2]. Therefore, ALND is still considered a precise method for obtaining the value of the axillary lymph node status. As previously mentioned, the patients who received NAC may have higher number of NLNs. Therefore, the number of NLNs was analyzed in this retrospective study. The number of NLNs exploits the total number of lymph nodes dissected. However, this cannot rule out all the misclassification. For example, if the total removed number of lymph nodes is small, the patients may result in higher staging. Although the AJCC requires that a minimum of 6 axillary lymph nodes be removed and examined, other authorities recommend that at least lymph nodes be examined [3, 4]. To ensure patients in this study received appropriate axillary dissection and combined original data, patients who had a minimum of 3 dissected lymph nodes were included. The prognostic value of NLNs has been identified in esophageal, lung, colorectal, gastric, and cervical cancers [5 9]. Early studies mainly focused on pn breast cancer patients, and researchers posited that patients with less negative nodes have worse prognosis [2]. In a recent investigation which involved patients, the number of NLNs is an independent prognostic factor of DFS. They classified patients by quartile and the cutoff number was NLNs [2]. Wu et al. put that patients with four or more positive nodes, the cutoff point of NLNs was 2 by ROC curve, and NLN was determined an independent prognostic factor that could affect locoregional recurrence (LRR)-free survival [22]. The different cutoff numbers are mainly because of the different definition of cutoff methods. Similar to the study of Wu et al., we chose ROC curve to define the cutoff value. However, the cutoff values are higher. This difference probably contributes to NAC. Several other studies used ratio of positive lymph nodes (LNR) instead the number of NLNs [23, 24]. There are few studies about LNR in patients who underwent NAC. Sheng Chen et al. analyzed 569 stage II/III patients with breast cancer who underwent NAC and put that LNR might be a complementary or alternative method to traditional ypn staging. Similar to this study, San-Gang Wu et al. suggested that LNR and ypn to evaluate the prognosis of stage II/III breast cancer patients who underwent mastectomy after NAC [25]. It seems that the ratio of positive lymph nodes and number of NLNs

7 Table 3 Univariate analysis of prognostic factors Characteristic OS DFS HR 95% CI p value HR 95% CI p value Age (years) 4 > <.5 Menopausal status Premenopausal Postmenopausal BMI Normal Overweight Obesity Primary stage Stage I II Stage III < <. Response to chemotherapy ccr Non-cCR Chemotherapy regimens CEF TE/TEC Others The chemotherapy cycles before surgery or 2 cycles 3 or 4 cycles or 6 cycles Histological type IDC Others Ki-67 levels 4 % >4 % Breast cancer subtype Luminal A Luminal B Erb-B2 overexpression < <.5 Basal-like Pathological tumor size ypt-t ypt < <. ypt3-t < <. Pathological nodal stage ypn-n ypn < <. ypn < <. PMRT No Yes Number of NLNs 3 NLNs 4 6 NLNs < <.

8 Table 4 Multivariate analysis of prognostic factors OS DFS Characteristics HR 95% CI p value HR 95% CI p value Age <.5 Primary stage < <.5 Breast cancer subtype < <.5 Pathological tumor size Pathological nodal stage <.5 Number of NLNs < <.5 both highlight the sufficient dissection of axillary lymph nodes. However, ratio of positive lymph nodes fails to classify ypn patients. Meanwhile, few studies have investigated the prognostic value of NLNs in breast cancer patients treated with NAC. Therefore, we analyzed the prognostic of the number of NLNs. In our study, the different numbers of NLNs were related with stage before and after chemotherapy. All above, these Fig. 2 Impact of the NLNs on the DFS (a) and OS (b) ofdifferent ypn stages patients with NAC A Disease-free survival (%).2 NLNs 3 NLNs > 3 P C Disease-free survival (%) ypn2 ypn-n.2 NLNs 3 NLNs > 3 P = B ypn-n NLNs 3.2 NLNs > 3 P Overall survival (%) D ypn2.2 NLNs 3 NLNs > 3 P = Overall survival (%) E Disease-free survival (%) ypn3.2 NLNs 3 NLNs > 3 P = F Overall survival (%) ypn3.2 NLNs 3 P =.26 NLNs >

9 Fig. 3 Impact of the PMRT on the DFS and OS of ypn patients. a, b Impact of the PMRT on the DFS (a) and OS (b) ofypn patients with NLN number 3. c, d Impact of the PMRTon the DFS (c) andos(d) of ypn patients with NLN number >3 A Disease-free survival (%).2 Without PMRT With PMRT P C Disease-free survival (%) ypn NLNs 3 ypn NLNs > 3.2 Without PMRT P =.73 With PMRT B Overall survival (%).2 Without PMRT With PMRT P D Overall survival (%) ypn NLNs 3 ypn NLNs > 3.2 Without PMRT P = 9 With PMRT pointed that NLNs may be a prognostic factor in patients underwent NAC. In the univariate and multivariate analysis, NLNs had been proved as an independent prognostic factor. The following analysis turn out that NLNs is a prognostic factor for ypn-n patients (Fig. 2a, b, bothp <.) but not for ypn2-n3 patients. However, compared with ypn2-n3 patients with 3 NLNs, patients with >3 NLNs still has better prognosis. This finding can be explained that the positive number of lymph nodes plays more importantly in latestage patients. In the early stage, NLNs can be an appropriate prognostic factor. This finding could be supported by three conditions. First, in the early stage, the more number of NLNs means that the less possibility of latent cancer cell in lymph nodes. Second, in the ypn-n stage, if few nodes could not be clearly reviewed via ALND, the number of NLNs may play a more important role in prognosis. Third, a high number of NLNs implies that the primary tumor is less invasive and less metastatic. Since the number of NLNs is an independent prognostic factor in ypn-n patients, we wondered that whether it could give us some indications for the following treatments. About more than half of patients were in ypn-n stage, and most of them underwent the PMRT. There are still a lot of controversies about whether ypn patients should undergo PMRT. Previous studies were all retrospective and focused on the pathological involvement of four or more lymph nodes, clinical stage, no use of tamoxifen, and pathological tumor size [26]. A prospective study NSABP B8 and B27 has gave us more credible indications about locoregional recurrence which could be predicted by age, clinical tumor characteristic before NAC, and pathological nodal status/breast tumor response after NAC to optimize the use of adjuvant radiotherapy [2, 27], whereas the trials focus on the LRR, not the PMRT itself. Besides the aforementioned risk factors, patients with one to three positive lymph nodes were strongly recommended with PMRT [28]. All these can be concluded that some part of ypn patients can benefit from PMRT. Unfortunately, we do not know the exactly part of patients will benefit from the PMRT to avoid unnecessary wastage. In this study, we investigated whether the number of NLNs could predict the efficacy of PMRT among ypn patients. In this subgroup study, PMRT improved the DFS (p <.5) and OS (p <.) of ypn patients with 3 NLNs (Fig. 3). Consequently, we deemed that the number of NLNs among ypn patients must also be evaluated, and combining NLNs could benefit a higher number of patients via PMRT. Similar to other studies, the current research has certain limitations that must be considered. First, this research is a single-center retrospective study. Hence, the majority of the population may not be represented. Second, patients received different cycles of chemotherapy before surgery. This heterogeneity may influence the treatment, although it seems that the chemotherapy cycles before surgery has no relationship with either NLNs or ypn stages. Third, the patients involved in the study were ranged from ypn to ypnn3, though more than

10 half of the patients were in ypn-n, it still need additional prospective studies to be performed to confirm our findings. Acknowledgments This study was supported by the National Natural Science Foundation of China (no , no , and no ) and the National Science and Technology Support Program (no. 25BAI2B5). Compliance with ethical standards This study was approved by the Ethics Committees at the Tianjin Medical University Cancer Institute and Hospital Conflicts of interest References None. Bernier J. Post-mastectomy radiotherapy after neodjuvant chemotherapy in breast cancer patients: a review. Crit Rev Oncol Hematol. 25;93: Colleoni M, Goldhirsch A. Neoadjuvant chemotherapy for breast cancer: any progress? Lancet Oncol. 24;5: Mamounas EP. Timing of determining axillary lymph node status when neoadjuvant chemotherapy is used. Curr Oncol Rep. 24;6: Kong XN, Moran MS, Zhang N, Haffty B, Yang QF. 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