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Impact of Postmastectomy Radiotherapy on Locoregional Control and Disease-Free Survival in Patients with Breast Cancer Treated with Neoadjuvant Chemotherapy

Impact of Postmastectomy Radiotherapy on Locoregional Control and Disease-Free Survival in... Hindawi Journal of Oncology Volume 2021, Article ID 6632635, 11 pages https://doi.org/10.1155/2021/6632635 Research Article ImpactofPostmastectomyRadiotherapyonLocoregionalControl and Disease-Free Survival in Patients with Breast Cancer Treated with Neoadjuvant Chemotherapy 1 1 1 1 1 1 Yanyu Zhang , Yaotian Zhang, Zhuang Liu, Zilan Qin, Yubing Li , Jiaming Zhao, 1 2 1 1 1 1 Xinchi Ma, Qiankun Yang , Ning Han, Xue Zeng, Hong Guo, and Na Zhang Department of Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang Liaoning 110042, China Department of Bone and Soft Tissue Tumour Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, China Correspondence should be addressed to Na Zhang; zhangna@cancerhosp-ln-cmu.com Received 15 October 2020; Revised 8 December 2020; Accepted 15 December 2020; Published 25 January 2021 Academic Editor: Pierfrancesco Franco Copyright © 2021 Yanyu Zhang et al. ,is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. ,e impact of postmastectomy radiotherapy (PMRT) in patients receiving neoadjuvant chemotherapy (NAC) is unclear. ,e purpose of this study is to identify the patients who may benefit from PMRT. Methods. We retrospectively analysed patients with clinical stage II-III breast cancer who underwent NAC and modified radical mastectomy at our centre from 2007 to 2015. We investigated the relationship amongst locoregional recurrence rate (LRR), disease-free survival (DFS), and clinical pathological characters. Results. A total of 554 patients were analysed in this study. ,e median follow-up time was 65 months. Amongst the patients, 58 (10.5%) had locoregional recurrence, 138 (24.9%) had distant metastasis, and 72 (13.0%) patients died. ,e 5-year cumulative incidence of LRR and DFS was 9.2% and 74.2%, respectively. A total of 399 (72%) patients received PMRTand 155 (28%) did not. ,e 5-year LRR of the patients with PMRT (7.3% vs. 14.1%, P � 0.01) decreased significantly. We found that PMRT was an independent prognostic factor of LRR and DFS. Patients with the persistent involvement of 1–3 lymph nodes (ypN1) and more than 4 positive lymph nodes (ypN2-3) had a better outcome after PMRT than those without. However, the LRR and DFS of patients with negative lymph nodes at the time of surgery (ypN0) and who received PMRT showed no significant benefits. Amongst all patients with the three molecular subtypes of breast cancer, patients with triple-negative breast cancer had the highest pathological complete response rate but the worst prognosis (P � 0.001). Conclusion. Results showed that PMRT significantly reduced the LRR of patients with clinical stage II-III breast cancer after receiving NAC and mas- tectomy. YpN0 patients derived no local control or survival benefit after receiving PMRT, whereas those with ypN1 and ypN2-3 could obviously benefit from PMRT. survival (OS) [4, 5]. However, clear data regarding the role of 1. Introduction adjuvant radiotherapy in the context of NAC remain lacking Neoadjuvant chemotherapy (NAC) is currently widely used [4, 6–9]. in patients with locally advanced breast cancer to transform A number of retrospective studies have shown that nonoperable cases into operable ones, thus improving breast PMRT can reduce the LRR of patients with NAC [10–13], preservation rates and reflecting the sensitivity of tumour but due to the change in tumour characters after NAC, the cells to systemic therapy [1–3]. A large number of studies optimal indication for PMRT for the management of pa- have shown that postmastectomy radiotherapy (PMRT) can tients treated with NAC remains controversial. An analysis significantly reduce the locoregional recurrence rate (LRR) of experiments on the two prospective neoadjuvants B-18 of patients with stage II-III breast cancer and increase overall and B-27 by the National Surgical Adjuvant Breast and 2 Journal of Oncology duration of 1 year. Radiotherapy included conventional Bowel Project (NSABP) in the United States suggested that tumour response and pathological lymph node status are external radiation, two-dimensional radiation, three-di- mensional conformal radiation therapy or intensity-mod- independent prognostic factors of LRR [14]. ,is study mainly aimed to explore the independent ulated radiation therapy. ,e clinician formulated a plan and prognostic factors affecting the LRR and disease-free sur- guided the treatment in accordance with the clinical path- vival (DFS) of patients with clinical stage II-III breast cancer ological characteristics of the tumour. undergoing NAC and mastectomy and to identify with increased accuracy the patients that should receive PMRT 1.3. Statistical Analysis. Collected patient information was following NAC. subjected to statistical analysis by using SPSS 25.0 software and GraphPad Prism8. Descriptive statistics was used to 1.1. Patients and Methods. ,is study retrospectively ana- describe each variable. ,e Kaplan–Meier method was used lysed the patients with clinical stage II-III breast cancer at to describe the LRR and DFS survival curves. ,e log-rank our centre from 2007 to 2015. ,e patients who received test was used to compare the survival curves. P< 0.05 in- NAC and modified radical mastectomy (MRM) after fine- dicated that the difference was statistically significant. ,e needle aspiration biopsy and had breast cancer diagnosis and Cox risk proportional model was applied to evaluate the complete treatment data were analysed. Patients with in- effect of variables that were related to LRR and DFS, and the flammatory breast cancer, male breast cancer, simultaneous independent prognostic factors of LRR and DFS were bilateral breast cancer, or a history of other malignant tu- clarified. Hazard ratios (HR) and 95% confidence intervals mours were excluded. Patients with the metastasis of (CI) were given. A two-sided P value of 0.05 was used as the supraclavicular/internal breast lymph nodes or distant alpha error for the consideration of statistical significance. metastases before NAC were also excluded. Breast tumour size and axillary lymph node status were 2. Results evaluated via physical examination and imaging examina- 2.1. Baseline Characteristics of *is Cohort. A total of 554 tion and staged on the basis of the seventh edition of the American Joint Committee on Cancer TNM staging clas- patients were analysed in this study. ,e median follow-up time was 65 months from diagnosis. ,e clinical and sification. Hormone receptor status was determined on the basis of reference pathology before treatment. Estrogen pathological characteristics of the patients are introduced in detail in Table 1. ,e median age at diagnosis was 51 years receptor (ER) and progesterone receptor (PR) positivity was (range: 22–78 years). Amongst the patients, 394 (71.1%) and defined as positive immunohistochemical staining in≥1% of 160 (28.9%) were in clinical stages II and III, respectively. A tumour cells. Human epidermal growth factor receptor total of 75% of the patients received anthracycline and (HER-2) positivity was defined as the immunohistochemical detection of 3+ or 2+ with amplification via fluorescent in paclitaxel chemotherapy regimens, and 7% of the patients received platinum-containing chemotherapy regimens. situ hybridization. Triple-negative breast cancer (TNBC) was defined as negative for ER, PR, and HER-2. Pathological A total of 472 (85.1%) patients achieved complete re- sponse (CR) or partial response (PR) after NAC, and 38 complete response (pCR) was defined as the absence of residual invasive tumours in primary and axillary lesions. (6.9%) reached pCR after surgery. ,e numbers of patients who had negative lymph nodes at the time of surgery LRR was the first endpoint, and DFS was the second (ypN0), persistent involvement of 1–3 lymph nodes (ypN1), endpoint. LRR was defined as recurrent disease in the chest and more than 4 positive lymph nodes (ypN2-3) were 177 wall and/or the ipsilateral internal mammary, axillary, or (32.0%), 192 (34.6%), and 185 (33.4%), respectively. A total supraclavicular nodes. DFS was defined as the absence of of 453 (81.6%) patients received adjuvant chemotherapy locoregional recurrence and distant metastasis (including after surgery, and 284 (83.2%) of of hormone receptor the metastasis of the contralateral breast, bone, liver, lung, brain, or other organs) or death from any cause and was positive (HR+) patients received endocrine therapy. A total of 399 (72%) of 554 patients received PMRT to the chest wall diagnosed by pathological or imaging examinations, in- cluding computed tomography, ultrasound, magnetic res- and/or the regional lymph nodes. No statistical difference in age, menstrual status, histological grade, pathological type, onance imaging (MRI), and bone scans. hormone receptor status, and HER-2 status was observed between the PMRT group and the non-PMRT group. Pa- 1.2. Treatment. All patients received NAC. Every two cycles tients who received PMRT had significantly more advanced of chemotherapy, the size of the tumour was evaluated tumour and nodal stages before and after NAC than those through ultrasound examination, and efficacy evaluation who did not receive PMRT. ,e rates of clinical stage II and was performed in accordance with the response evaluation stage III in both groups were 65.9% vs. 84.5% (P≤ 0.001) and criteria for solid tumours (RECIST 1.1). NAC plus targeted 34.09% vs. 15.48% (P≤ 0.001). In the non-PMRT group, therapy was feasible for HER-2 positive (HER-2+) patients. 60.7% patients were ypN0, whereas ypN0 patients accounted All patients underwent MRM for breast cancer. ,e patients for only 20.8% of the PMRT group. received adjuvant chemotherapy, radiotherapy, or endocrine therapy after NAC in accordance with the clinical patho- logical characteristics of the tumour. HER-2+ patients 2.2. Local Recurrence Pattern and Independent Prognostic continued to use trastuzumab after surgery for a total Factors of LRR and DFS. A total of 58 (10.5%) patients Journal of Oncology 3 Table 1: Clinical pathological characteristics of all patients (N � 554). All RT No RT Variable P value N � 554 % N � 399 % N � 155 % Age (years) 0.980 <50 239 43.1 172 43.10 67 43.20 ≥50 315 56.9 227 56.90 88 56.80 Menopausal status 0.609 Perimenopausal 255 46.0 184 46.11 71 45.81 Postmenopausal 265 47.8 193 48.37 72 46.45 Not known 34 6.1 22 5.51 12 7.74 Side of primary tumour 0.812 Left 294 53.1 213 53.38 81 52.26 Right 260 46.9 186 46.62 74 47.74 Tumour size, cm ≤0.001 <4 384 69.3 258 64.67 126 81.29 ≥1 170 30.7 141 35.33 29 18.71 Tumour grade 0.445 G1-G2 274 49.5 194 48.62 80 51.61 G3 54 9.8 41 20.28 13 8.39 Not known 226 40.8 164 41.10 62 40 Histological type 0.449 Ductal 485 87.6 345 86.47 140 90.32 Tubular 30 5.4 24 6.02 6 3.87 Others 39 7.0 30 7.52 9 5.81 ER status 0.618 ER+ 336 60.6 245 61.40 91 58.70 ER− 217 39.2 154 38.60 63 40.60 PR status 0.216 PR+ 264 47.7 197 49.40 67 43.23 PR− 289 52.2 202 50.60 87 56.13 HER-2 status 0.447 HER-2 positive 114 20.6 85 21.30 29 18.71 HER-2 negative 378 68.2 268 67.20 110 80.00 Not recorded 62 11.2 46 11.50 16 10.30 TBC 0.020 Yes 98 17.7 61 15.30 37 23.90 No 394 71.1 292 73.20 102 65.80 Clinical T stage ≤0.001 T1-T2 438 79.1 297 74.44 141 90.97 T3-T4 116 20.9 102 25.57 14 9.03 Clinical N stage ≤0.001 N0 130 23.5 69 17.30 61 39.35 N1 339 61.2 260 65.16 79 50.97 N2 85 15.3 70 17.54 15 9.68 Clinical TNM stage ≤0.001 II 394 71.1 263 65.91 131 84.52 III 160 28.9 136 34.09 24 15.48 Clinical tumour response 0.415 CR + PR 472 85.2 343 85.96 129 83.23 SD + PD 82 14.8 56 14.04 26 16.77 Pathological response ≤0.001 pCR 38 6.9 15 3.76 23 14.84 No pCR 516 94.1 384 96.24 132 85.16 LVI 0.315 Yes 62 11.2 48 12.03 14 9.03 No 492 88.8 351 87.97 141 90.97 Pathological T stage ≤0.001 T0/tis 55 9.9 29 7.27 26 16.77 T1 279 50.4 199 49.87 80 51.61 T2–T4 220 39.7 171 42.86 49 31.61 Pathological N stage ≤0.001 N0 177 31.0 83 20.80 94 60.65 4 Journal of Oncology Table 1: Continued. All RT No RT Variable P value N � 554 % N � 399 % N � 155 % N1 192 34.7 152 38.10 40 25.81 N2-3 185 33.3 164 41.10 21 13.55 Pathological stage ≤0.001 0 38 6.9 15 3.76 23 14.84 I 94 16.0 44 11.03 50 32.26 II 228 41.2 168 42.11 60 38.71 III 194 35.0 172 43.11 22 14.19 PMRT, postmastectomy radiation therapy; ER, estrogen receptor; PR, progesterone receptor; HER-2, human epidermal growth factor receptor; TNBC, triple- negative breast cancer; pCR, pathological complete response; CR, complete response; PR, partial response; SD, stable disease; PD, progress disease; LVI, lymphatic vascular infiltration; HR, hazard ratio. experienced local recurrence, including 28 (5.1%) patients with ipsilateral chest wall recurrence, 7 (1.3%) patients with axillary nodal recurrence, 14 (2.5 %) patients with ipsilateral supraclavicular recurrence, and 9 (1.6%) with simultaneous 5-year LRR: 7.3% vs. 14.1% recurrence at two or more positions. Logrank p value = 0.01 A total of 34 (8.2%) patients in the PMRT group and 24 (15.5%) in the non-PMRT group had locoregional recur- rence. ,e 5-year LRR of the PMRT group was significantly lower than that of the non-PMRT group (7.3% vs. 14.1%, P � 0.01) as shown in Figure 1. Univariate analysis showed that the factors associated with LRR included (Table 2) clinical tumour size, histological grade, clinical stage, LVI, 0 20406080 100 PR, ypN stage, TNBC, tumour chemotherapy response, and Time (months) PMRT. Incorporating these factors into the Cox risk pro- portional model revealed that patients with cT ≥4 cm, PR PMRT negativity, ypN 1, and ypN 2–3 and without PMRT had poor Non-PMRT LRR (Figure 2). ,e LRR of patients without PMRT was 4.47 Figure 1: Kaplan–Meier plot for the cumulative incidence of times that of patients with PMRT (CI 1.97–10.14, P≤ 0.01), locoregional recurrence. whereas the LRR of ypN2-3 patients was 4.68 times that of ypN0 patients. A total of 138 (25.0%) patients in the whole group had (P � 0.62, Figure 4(a)). 4 (4.8%) and 6 (6.3%) of the patients in distant metastasis (including 10 patients with contralateral the PMRT and non-PMRT groups experienced locoregional breast metastasis). DFS did not obviously differ between the recurrence, respectively. DFS did not differ between the two PMRT group and non-PMRT group (74% vs. 74.8%, groups (P � 0.88) (Figure 4(b)). P � 0.99). Univariate analysis revealed that the factors af- However, in the ypN1 and ypN2-3 cohorts, the 5-year fecting DFS included (Table 2) cT, pathological type, clinical LRR rates were significantly decreased in the patients with stage, cN, lymph-vascular infiltration (LVI), PR, HER-2, PMRT (ypN1: P≤ 0.001, ypN2-3: P≤ 0.001) (Figures 4(c) ypN, and TNBC. Considering that some studies have shown and 4(e)). Moreover, the DFS of these patients improved that PMRT can affect the DFS of patients, PMRT and the (ypN1: P � 0.02; ypN2-3: P≤ 0.001) (Figures 4(d) and 4(f)). related factors of the above univariate analysis were included in the multivariate analysis simultaneously. ,e independent prognostic factors of DFS were cT, PR, LVI, TNBC, HER-2, 2.4. Molecular Subtypes. Survival curves showed significant ypN, and PMRT (Figure 3). differences in LRR and DFS amongst the three subtypes (HR+ and HER-2−, HER-2+, and TNBC) (Figure 5). ,e 5- 2.3. ypN0, ypN1, and ypN2-3. ,e number of positive lymph year LRR of patients with TNBC was significantly higher nodes is an important variable that affects LRR and DFS. ,e than that of HR+ and HER-2− patients (15.3% vs. 5.6%, 5-year LRR of ypN0 patients was significantly lower than P � 0.006) (Figure 5(a)), whereas the 5-year DFS of TNBC that of ypN + patients (5.3% vs. 11.1%, P � 0.01). LRR and HER-2+ patients were worse than those of HR+ and gradually increased following the increase in the number of HER-2− patients (81.3% vs. 66.3%, P � 0.001; 81.3% vs. positive lymph nodes. ,e 5-year LRRs of the ypN0, ypN1, 68.8%, P � 0.011) (Figure 5(b)). No significant difference and ypN2-3 cohorts were 5.3%, 7.8%, and 14.7%, was observed in the LRR and DFS between the PMRT group respectively. and the non-PMRT group in the three subtypes. However, the survival curve of TNBC patients indicated that PMRT For patients with ypN0, the 5-year LRR was not significantly different between the PMRT group and non-PMRT group was beneficial (P � 0.065) (Figure 6). Locoregional recurrence rate Journal of Oncology 5 Table 2: Results of univariate analysis for locoregional recurrence and disease-free survival. LRR DFS Variable HR (95% CI) P value HR (95% CI) P value Age (years) 0.965 0.173 <50 1 (ref) 1 (ref) ≥50 0.988 (0.589–1.659) 1.243 (0.909–1.698) Tumour size, cm 0.01 ≤0.001 <4 1 (ref) 1 (ref) ≥r 2.355 (1.404–3.952) 1.758 (1.286–2.403) Tumour grade 0.015 0.488 G1-G2 1 (ref) 1 (ref) G3 2.377 (1.182–4.778) 1.203 (0.713–2.031) Histological type 0.806 0.035 Ductal 1 (ref) 1 (ref) Tubular 1.097 (0.0396–3.039) 1.132 (0.613–2.089) Others 0.692 (0.216–2.217) 0.302 (0.112–0.814) LVI 0.093 ≤0.001 Yes 1 (ref) 1 (ref) No 0.557 (0.282–1.103) 0.486 (0.327–0.723) Clinical N stage 0.461 0.007 N0 1 (ref) 1 (ref) N1 1.401 (0.733–2.676) 1.979 (1.292–3.031) N2 0.97 (0.382–2.465) 1.624 (0.937–2.812) Clinical TNM stage 0.044 0.002 Stage II 1 (ref) 1 (ref) Stage III 1.718 (1.015–2.907) 1.651 (1.205–2.260) ER status 0.405 0.901 ER+ 1 (ref) 1 (ref) ER− 1.249 (0.743–2.101) 1.020 (0.746–1.395) PR status 0.002 0.033 PR+ 1 (ref) 1 (ref) PR− 2.428 (1.379–4.276) 1.400 (1.027–1.909) HER-2 status 0.483 0.094 HER-2 positive 1 (ref) 1 (ref) HER-2 negative 0.797 (0.424–1.500) 0.726 (0.499–1.056) TNBC 0.017 0.006 TNBC 1 (ref) 1 (ref) No TNBC 0.485 (0.268–0.878) 0.592 (0.405–0.863) Clinical tumour response 0.012 0.273 CR + PR 1 (ref) 1 (ref) SD + PD 2.126 (1.180–3.831) 1.255 (0.836–1.886) Pathological response 0.162 0.010 pCR 1 (ref) 1 (ref) No pCR 4.099 (0.567–29.615) 6.262 (1.553–25.256) Pathological N stage ≤0.001 ≤0.001 N0 1 (ref) 1 (ref) N1 1.712 (0.79–3.711) 1.753 (1.085–2.832) N2 2.547 (1.166–5.565) 3.554 (2.231–5.662) N3 5.644 (2.472–12.882) 7.249 (4.371–12.022) PMRT 0.013 0.993 RT 1 (ref) 1 (ref) No RT 1.935 (1.147–3.266) 0.999 (0.708–1.407) Anti-HER-2 therapy 0.629 0.983 Yes 1 (ref) 1 (ref) 0.751 (0.235–2.401) 1.007 (0.546–1.856) Adjuvant chemotherapy 0.184 0.524 Yes 1 (ref) 1 (ref) No 1.238 (0.903–1.695) 1.083 (0.847–1.384) Endocrinotherapy 0.218 0.121 Yes 1 (ref) 1 (ref) No 1.119 (0.935–1.339) 1.093 (0.977–1.223) LRR, locoregional recurrence rates; DFS, disease-free survival; HR, hazard ratio; CI, confidence interval; ER, estrogen receptor; PR, progesterone receptor; HER-2, human epidermal growth factor receptor; TNBC, triple-negative breast cancer; pCR, pathological complete response; CR, complete response; PR, partial response; SD, stable disease; PD, progress disease. 6 Journal of Oncology All patients No. of patients (%) HR (95% CI) p value tumor size <4 cm 384 (69.31) 1 (Reference) ≥4 cm 170 (30.69) 3.37 (1.62 − 6.98) ≤0.001 Tumor grade G1 – G2 274 (49.46) 1 (Reference) G3 54 (9.75) 1.74 (0.78 − 3.87) 0.180 LVI Yes 62 (11.19) 1 (Reference) No 492 (88.81) 0.55 (0.21 − 1.42) 0.220 Clinical TNM stage stage II 62 (11.19) 1 (Reference) stage III 492 (88.81) 1.02 (0.47 − 2.20) 0.960 PR status PR+ 62 (11.19) 1 (Reference) PR− 492 (88.81) 3.782 (1.55 − 9.23) <0.001 TNBC TNBC 98 (17.70) 1 (Reference) NO TNBC 394 (71.10) 0.57 (0.24 − 1.40) 0.220 Clinical tumor response CR + PR 98 (17.70) 1 (Reference) SD + PD 394 (71.10) 0.11 (0.45 − 2.74) 0.820 Pathological N stage N0 177 (31.95) 1 (Reference) N1 192 (34.66) 2.99 (1.06 − 8.42) 0.040 N2 − 3 185 (33.39) 4.679 (1.50 − 14.59) 0.010 PMRT RT 399 (72.02) 1 (Reference) No RT 155 (27.98) 4.47 (1.97 − 10.14) ≤0.001 0 1 2 3 4 4.5 4.75 5 LRR Figure 2: Results of the multivariate Cox regression analysis of LRR. LRR: locoregional recurrence; PMRT: postmastectomy radiation therapy; TNBC: triple-negative breast cancer; LVI: lymphatic vascular infiltration; PR: progesterone receptor; TNBC: triple-negative breast cancer; pCR: pathological complete response; CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; HR: hazard ratio; CI: confidence interval. A clear relationship was observed between tumour re- pCR patients. McGuire believed that patients with stage I-II sponse and subtypes. ,e pCR rates of HR+, HER-2+, and pCR do not need radiotherapy. However, even for patients TNBC patients were 3.6%, 9.6%, and 14.3%, respectively. with stage III breast cancer who achieved pCR after NAC, TBC and HER + patients were more likely to achieve pCR PMRTcan still reduce LRR by 26% and significantly improve than HR + patients after receiving NAC (Table 3: HER-2+: OS [14]. A retrospective study obtained a similar conclusion OR � 4.40, 95% CI: 1.89–10.27, P � 0.001; TNBC: OR � 2.82, that PMRT can still reduce the LRR of patients with clinical III-IV disease and pCR in 10 years (3% vs. 33%; 95% CI: 1.16–6.84, P � 0.02). P � 0.006) but does not benefit patients with clinical stage I-II disease [10]. 3. Discussion In our study, 83.23% of 554 patients exhibited tumour shrinkage of more than 30% after NAC, 9.9% of patients NAC has been recently widely used in patients with clinical experienced the complete disappearance of primary breast stage II or III breast cancer. Although NAC has improved tumours, and 6.8% of patients achieved pCR because only the surgical outcomes for many patients with breast cancer, 18% of patients underwent full-course NAC. ,erefore, the the risk of relapse remains high especially for patients with proportion of postoperative pCR patients in our study was locally advanced breast cancer. However, the indication for lower than that in other studies. PMRT in patients treated with NAC remains controversial ,e number of positive lymph nodes is an important given the lack of prospective evidence. prognostic indicator [18, 19]. Some studies thought that the Multiple studies have shown that pCR is an important initial lymph node status before NAC and postoperative prognostic indicator for survival [15–17]. NSABP B-18/27 lymph node status should be referenced to consider whether analysis confirmed that, amongst patients with clinical stage the patient should accept PMRT [20, 21]. However, some I-II disease, pCR patients had better DFS and OS than non- Journal of Oncology 7 All patients No. of patients (%) HR (95% CI) p value tumor size <4 cm 384 (69.31) 1 (Reference) ≥4 cm 170 (30.69) 1.486 (1.02 − 2.17) 0.040 Histological type Ductal 485 (87.55) 1 (Reference) Tubular 30 (5.42) 1.35 (0.61 − 2.98) 0.460 Other 39 (7.04) 0.49 (0.18 − 1.33) 0.160 LVI Yes 62 (11.19) 1 (Reference) No 492 (88.81) 0.61 (0.39 − 0.95) 0.030 Clinical N stage N0 130 (23.47) 1 (Reference) N+ 424 (76.53) 1.14 (0.65 − 1.98) 0.660 Clinical TNM stage stage II 62 (11.19) 1 (Reference) stage III 492 (88.81) 0.88 (0.59 − 1.31) 0.520 PR status PR+ 62 (11.19) 1 (Reference) PR− 492 (88.81) 1.45 (0.90 − 2.33) 0.120 HER2 status HER2 positive 114 (23.17) 1 (Reference) HER2 negative 378 (76.83) 0.60 (0.36 − 0.97) 0.038 TNBC TNBC 98 (17.70) 1 (Reference) NO TNBC 394 (71.10) 0.40 (0.23 − 0.70) 0.001 Pathological response pCR 38 (6.86) 1 (Reference) no pCR 516 (94.14) 3.75 (0.87 − 16.21) 0.760 Pathological N stage N0 177 (31.95) 1 (Reference) N1 192 (34.66) 1.74 (0.97 − 3.10) 0.060 N2−3 185 (33.39) 5.44 (2.94 − 10.05) ≤0.001 PMRT RT 399 (72.02) 1 (Reference) No RT 155 (27.98) 2.16 (1.42 − 3.31) ≤0.001 01234 4.54.755 DFS Figure 3: Results of the multivariate Cox regression analysis of DFS. DFS: disease-free survival; PMRT: postmastectomy radiation therapy; TNBC: triple-negative breast cancer; LVI: lymphatic vascular infiltration; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epidermal growth factor receptor; TNBC: triple-negative breast cancer; pCR: pathological complete response; HR: hazard ratio; CI: confidence interval. experts disagree with this view and believe that patients with After receiving PMRT, the OS of patients in each layer of ypN (ypN0, ypN1, and ypN2-3) improved [20]. N0 can be exempted from radiotherapy [10, 22]. A 2016 National Cancer Database study involving 10 283 patients Another study showed that the risk of regional recur- with clinical T1-3N1M0 breast cancer (ypN2-3) identified rence, distant metastasis, and death did not increase in 56 PMRTas an independent prognostic factor of improving OS. (41.8%) out of 134 ypN0 patients without PMRT compared 8 Journal of Oncology ypN0 ypN0 100 100 80 80 60 60 40 40 p = 0.62 p = 0.88 20 20 0 0 0 20406080 100 0 20406080 100 Time (months) Time (months) PMRT PMRT Non-PMRT Non-PMRT (a) (b) ypN1 ypN1 p ≤ 0.001 p = 0.02 0 20406080 100 40 020 60 80 100 Time (months) Time (months) PMRT PMRT Non-PMRT Non-PMRT (c) (d) ypN2-3 ypN2-3 100 100 80 80 60 60 40 40 p ≤ 0.001 p ≤ 0.001 20 20 0 0 0 20406080 100 020 60 80 100 Time (months) Time (months) PMRT PMRT Non-PMRT Non-PMRT (e) (f) Figure 4: Locoregional recurrence and disease-free survival of patients with breast cancer with or without PMRT in the (a) LRR of ypN0, (b) DFS of ypN0, (c) LRR of ypN1, (d) DFS of ypN1, (e) LRR of ypN2-3, and (f) DFS of ypN2-3. Locoregional recurrence rates Locoregional recurrence rates Locoregional recurrence rates Disease-free survival Disease-free survival Disease-free survival Journal of Oncology 9 100 100 HR+, HER2– vs HR+/–, HER2+: p = 0.153 HR+/–, HER2+ vs TBC: p = 0.328 80 80 HR+, HER2– vs TBC: p = 0.006 60 60 40 40 HR+, HER2– vs HR+/–, HER2+: p = 0.011 HR+/–, HER2+ vs TBC: p = 0.488 HR+, HER2– vs TBC: p = 0.001 20 20 0 0 0 20406080 100 0 20406080 100 Time (months) Time (months) HR+, HER2– HR+, HER2– HR+/–, HER2+ HR+/–, HER2+ TBC TBC (a) (b) Figure 5: (a) Locoregional recurrence of three molecular subtypes. (b) Disease-free survival of the three molecular subtypes. TNBC p = 0.065 0 20 40 60 80 100 Time (months) PMRT Non-PMRT Figure 6: Locoregional recurrence of TNBC patients with or without PMRT. patients after NAC in accordance with molecular subtypes. Table 3: Relationship between pCR rates and molecular subtypes. A total of 189 patients were included in this analysis, and the Molecular pCR rates (%) OR (95% CI) P effects of PMRT on locoregional control, DFS, and OS were HR+HER-2− 3.60 1 (ref) — evaluated. However, PMRT provides no additional survival HR+/HR−, HER-2+ 9.60 2.82 (1.16–6.84) 0.02 benefits for any molecular subtype [25]. TBC 14.30 4.40 (1.89–10.27) 0.001 A number of retrospective studies have shown that TNBC: triple-negative breast cancer; HR: hormone receptor; HER-2 human sentinel lymph node biopsy (SLNB) after NAC can prevent epidermal growth factor receptor; TNBC: triple-negative breast cancer; patients with negative axillary lymph nodes from under- pCR: pathological complete response; HR: hazard ratio; CI: confidence going unnecessary axillary lymph node dissection (ALND) interval. [26–28]. However, the false negative of SNLB can lead to incorrect lymph node staging and affect the formulation of comprehensive treatment plans after surgery. ,erefore, the with that of 78 (58.2%) patients who received PMRT [18]. patients analysed in this study all underwent ALND. Shim and Kantor et al. similarly concluded that PMRT may Whether SNLB can replace ALND still needs to be further be unnecessary in patients with ypN0 regardless of clinical verified in the prospective study Alliance A011202. stage [23, 24]. A study explored the benefit of PMRT in ypN0 Locoregional recurrence rates Locoregional recurrence rates Disease-free survival 10 Journal of Oncology Patients with lymph node positivity after surgery are Acknowledgments strongly recommended for PMRT [29, 30]. However, experts ,is study was funded by the Science and Technology Plan have not reached a consensus on whether ypN0 patients Project of Shenyang (19–112-4–083), Science and Tech- require PMRT and still expect confirmation from the pro- nology Plan Project of Liaoning Province of China spective randomised controlled trial RTOG1304/NSABP (20180540129 and 20180530095), Key Laboratory of Tumor B51. Radiosensitization and Normal Tissue Radioprotection ,is study has numerous deficiencies given the limita- Project of Liaoning Province (No. 2018225102), and the tions of retrospective research. ,e baseline characteristics Personnel Training Project of Liaoning Cancer Hospital and of the patients in the two groups were different. Nearly 90% Institute of China (201703). Medical-Industrial Interdisci- of the patients’ lymph node status before neoadjuvant plinary Research Fund (LD202005). therapy was based on clinical examination or ultrasound, mammography, or MRI. Moreover, only 10% patients un- derwent lymph node fine-needle aspiration biopsy. ,us, a References certain error existed in the judgment of preoperative lymph node status. Standard MRM involves the removal of the [1] T. Ikeda, H. Jinno, A. Matsui, S. Masamura, and M. Kitajima, affected breast and parallel ALND with the number of lymph “,e role of neoadjuvant chemotherapy for breast cancer treatment,” Breast Cancer, vol. 9, no. 1, pp. 8–14, 2002. nodes removed ≥10. In our study, we included 15 patients [2] G. Vugts, A. J. G. Maaskant-Braat, G. A. P. Nieuwenhuijzen, who underwent ALND but had only 5–9 lymph node dis- R. M. H. Roumen, E. J. T. Luiten, and A. C. Voogd, “Patterns sections. ,e patients received different treatments during of care in the administration of neo-adjuvant chemotherapy different periods with the change in NAC regimen, che- for breast cancer: a population-based study,” *e Breast motherapy cycle, and radiotherapy technology. 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Willis et al., “Quality of life after postmastectomy radiotherapy in patients with intermediate- In this retrospective study, we found that patients with risk breast cancer (SUPREMO): 2-year follow-up results of a clinical stage II-III breast cancer receiving NAC exhibited randomised controlled trial,” Lancet Oncology, vol. 19, no. 11, reduced LRR after PMRT and those with ypN1 and ypN2-3 pp. 1516–1529, 2018. showed significantly reduced LRR and improved DFS after [6] M. Overgaard, P. S. Hansen, J. Overgaard et al., “Postoperative receiving PMRT. Patients with pCR and ypN0 did not radiotherapy in high-risk premenopausal women with breast present increased LRR and DFS after exemption from cancer who receive adjuvant chemotherapy,” New England PMRT. Prospective trials are expected to verify whether Journal of Medicine, vol. 337, no. 14, pp. 949–955, 1997. radiotherapy can be omitted for these patients. [7] M. Clarke, R. Collins, S. 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Jones et al., “,e impact of postmastectomy and regional nodal radiation after neoadjuvant chemotherapy for clinically lymph node-positive breast cancer: a national cancer database (NCDB) analysis,” Annals of Oncology, vol. 27, no. 5, pp. 818–827, 2016. [21] B. G. Haffty, L. M. McCall, K. V. Ballman, T. A. Buchholz, K. K. Hunt, and J. C. Boughey, “Impact of radiation on locoregional control in women with node-positive breast cancer treated with neoadjuvant chemotherapy and axillary lymph node dissection: results from ACOSOG Z1071 clinical trial,” International Journal of Radiation Oncology∗Biology∗Physics, vol. 105, no. 1, pp. 174–182, 2019. [22] S. E. McGuire, A. M. Gonzalez-Angulo, E. H. Huang et al., “Postmastectomy radiation improves the outcome of patients with locally advanced breast cancer who achieve a pathologic complete response to neoadjuvant chemotherapy,” Interna- tional Journal of Radiation Oncology∗Biology∗Physics, vol. 68, no. 4, pp. 1004–1009, 2007. [23] S. J. Shim, W. Park, S. J. Huh et al., “,e role of postmas- tectomy radiation therapy after neoadjuvant chemotherapy in clinical stage II-III breast cancer patients with pN0: a mul- ticenter, retrospective study (KROG 12-05),” International Journal of Radiation Oncology∗Biology∗Physics, vol. 88, no. 1, pp. 65–72, 2014. [24] O. Kantor, C. Pesce, P. Singh et al., “Post-mastectomy radi- ation therapy and overall survival after neoadjuvant http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Oncology Hindawi Publishing Corporation

Impact of Postmastectomy Radiotherapy on Locoregional Control and Disease-Free Survival in Patients with Breast Cancer Treated with Neoadjuvant Chemotherapy

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Copyright © 2021 Yanyu Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Journal of Oncology Volume 2021, Article ID 6632635, 11 pages https://doi.org/10.1155/2021/6632635 Research Article ImpactofPostmastectomyRadiotherapyonLocoregionalControl and Disease-Free Survival in Patients with Breast Cancer Treated with Neoadjuvant Chemotherapy 1 1 1 1 1 1 Yanyu Zhang , Yaotian Zhang, Zhuang Liu, Zilan Qin, Yubing Li , Jiaming Zhao, 1 2 1 1 1 1 Xinchi Ma, Qiankun Yang , Ning Han, Xue Zeng, Hong Guo, and Na Zhang Department of Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang Liaoning 110042, China Department of Bone and Soft Tissue Tumour Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, China Correspondence should be addressed to Na Zhang; zhangna@cancerhosp-ln-cmu.com Received 15 October 2020; Revised 8 December 2020; Accepted 15 December 2020; Published 25 January 2021 Academic Editor: Pierfrancesco Franco Copyright © 2021 Yanyu Zhang et al. ,is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. ,e impact of postmastectomy radiotherapy (PMRT) in patients receiving neoadjuvant chemotherapy (NAC) is unclear. ,e purpose of this study is to identify the patients who may benefit from PMRT. Methods. We retrospectively analysed patients with clinical stage II-III breast cancer who underwent NAC and modified radical mastectomy at our centre from 2007 to 2015. We investigated the relationship amongst locoregional recurrence rate (LRR), disease-free survival (DFS), and clinical pathological characters. Results. A total of 554 patients were analysed in this study. ,e median follow-up time was 65 months. Amongst the patients, 58 (10.5%) had locoregional recurrence, 138 (24.9%) had distant metastasis, and 72 (13.0%) patients died. ,e 5-year cumulative incidence of LRR and DFS was 9.2% and 74.2%, respectively. A total of 399 (72%) patients received PMRTand 155 (28%) did not. ,e 5-year LRR of the patients with PMRT (7.3% vs. 14.1%, P � 0.01) decreased significantly. We found that PMRT was an independent prognostic factor of LRR and DFS. Patients with the persistent involvement of 1–3 lymph nodes (ypN1) and more than 4 positive lymph nodes (ypN2-3) had a better outcome after PMRT than those without. However, the LRR and DFS of patients with negative lymph nodes at the time of surgery (ypN0) and who received PMRT showed no significant benefits. Amongst all patients with the three molecular subtypes of breast cancer, patients with triple-negative breast cancer had the highest pathological complete response rate but the worst prognosis (P � 0.001). Conclusion. Results showed that PMRT significantly reduced the LRR of patients with clinical stage II-III breast cancer after receiving NAC and mas- tectomy. YpN0 patients derived no local control or survival benefit after receiving PMRT, whereas those with ypN1 and ypN2-3 could obviously benefit from PMRT. survival (OS) [4, 5]. However, clear data regarding the role of 1. Introduction adjuvant radiotherapy in the context of NAC remain lacking Neoadjuvant chemotherapy (NAC) is currently widely used [4, 6–9]. in patients with locally advanced breast cancer to transform A number of retrospective studies have shown that nonoperable cases into operable ones, thus improving breast PMRT can reduce the LRR of patients with NAC [10–13], preservation rates and reflecting the sensitivity of tumour but due to the change in tumour characters after NAC, the cells to systemic therapy [1–3]. A large number of studies optimal indication for PMRT for the management of pa- have shown that postmastectomy radiotherapy (PMRT) can tients treated with NAC remains controversial. An analysis significantly reduce the locoregional recurrence rate (LRR) of experiments on the two prospective neoadjuvants B-18 of patients with stage II-III breast cancer and increase overall and B-27 by the National Surgical Adjuvant Breast and 2 Journal of Oncology duration of 1 year. Radiotherapy included conventional Bowel Project (NSABP) in the United States suggested that tumour response and pathological lymph node status are external radiation, two-dimensional radiation, three-di- mensional conformal radiation therapy or intensity-mod- independent prognostic factors of LRR [14]. ,is study mainly aimed to explore the independent ulated radiation therapy. ,e clinician formulated a plan and prognostic factors affecting the LRR and disease-free sur- guided the treatment in accordance with the clinical path- vival (DFS) of patients with clinical stage II-III breast cancer ological characteristics of the tumour. undergoing NAC and mastectomy and to identify with increased accuracy the patients that should receive PMRT 1.3. Statistical Analysis. Collected patient information was following NAC. subjected to statistical analysis by using SPSS 25.0 software and GraphPad Prism8. Descriptive statistics was used to 1.1. Patients and Methods. ,is study retrospectively ana- describe each variable. ,e Kaplan–Meier method was used lysed the patients with clinical stage II-III breast cancer at to describe the LRR and DFS survival curves. ,e log-rank our centre from 2007 to 2015. ,e patients who received test was used to compare the survival curves. P< 0.05 in- NAC and modified radical mastectomy (MRM) after fine- dicated that the difference was statistically significant. ,e needle aspiration biopsy and had breast cancer diagnosis and Cox risk proportional model was applied to evaluate the complete treatment data were analysed. Patients with in- effect of variables that were related to LRR and DFS, and the flammatory breast cancer, male breast cancer, simultaneous independent prognostic factors of LRR and DFS were bilateral breast cancer, or a history of other malignant tu- clarified. Hazard ratios (HR) and 95% confidence intervals mours were excluded. Patients with the metastasis of (CI) were given. A two-sided P value of 0.05 was used as the supraclavicular/internal breast lymph nodes or distant alpha error for the consideration of statistical significance. metastases before NAC were also excluded. Breast tumour size and axillary lymph node status were 2. Results evaluated via physical examination and imaging examina- 2.1. Baseline Characteristics of *is Cohort. A total of 554 tion and staged on the basis of the seventh edition of the American Joint Committee on Cancer TNM staging clas- patients were analysed in this study. ,e median follow-up time was 65 months from diagnosis. ,e clinical and sification. Hormone receptor status was determined on the basis of reference pathology before treatment. Estrogen pathological characteristics of the patients are introduced in detail in Table 1. ,e median age at diagnosis was 51 years receptor (ER) and progesterone receptor (PR) positivity was (range: 22–78 years). Amongst the patients, 394 (71.1%) and defined as positive immunohistochemical staining in≥1% of 160 (28.9%) were in clinical stages II and III, respectively. A tumour cells. Human epidermal growth factor receptor total of 75% of the patients received anthracycline and (HER-2) positivity was defined as the immunohistochemical detection of 3+ or 2+ with amplification via fluorescent in paclitaxel chemotherapy regimens, and 7% of the patients received platinum-containing chemotherapy regimens. situ hybridization. Triple-negative breast cancer (TNBC) was defined as negative for ER, PR, and HER-2. Pathological A total of 472 (85.1%) patients achieved complete re- sponse (CR) or partial response (PR) after NAC, and 38 complete response (pCR) was defined as the absence of residual invasive tumours in primary and axillary lesions. (6.9%) reached pCR after surgery. ,e numbers of patients who had negative lymph nodes at the time of surgery LRR was the first endpoint, and DFS was the second (ypN0), persistent involvement of 1–3 lymph nodes (ypN1), endpoint. LRR was defined as recurrent disease in the chest and more than 4 positive lymph nodes (ypN2-3) were 177 wall and/or the ipsilateral internal mammary, axillary, or (32.0%), 192 (34.6%), and 185 (33.4%), respectively. A total supraclavicular nodes. DFS was defined as the absence of of 453 (81.6%) patients received adjuvant chemotherapy locoregional recurrence and distant metastasis (including after surgery, and 284 (83.2%) of of hormone receptor the metastasis of the contralateral breast, bone, liver, lung, brain, or other organs) or death from any cause and was positive (HR+) patients received endocrine therapy. A total of 399 (72%) of 554 patients received PMRT to the chest wall diagnosed by pathological or imaging examinations, in- cluding computed tomography, ultrasound, magnetic res- and/or the regional lymph nodes. No statistical difference in age, menstrual status, histological grade, pathological type, onance imaging (MRI), and bone scans. hormone receptor status, and HER-2 status was observed between the PMRT group and the non-PMRT group. Pa- 1.2. Treatment. All patients received NAC. Every two cycles tients who received PMRT had significantly more advanced of chemotherapy, the size of the tumour was evaluated tumour and nodal stages before and after NAC than those through ultrasound examination, and efficacy evaluation who did not receive PMRT. ,e rates of clinical stage II and was performed in accordance with the response evaluation stage III in both groups were 65.9% vs. 84.5% (P≤ 0.001) and criteria for solid tumours (RECIST 1.1). NAC plus targeted 34.09% vs. 15.48% (P≤ 0.001). In the non-PMRT group, therapy was feasible for HER-2 positive (HER-2+) patients. 60.7% patients were ypN0, whereas ypN0 patients accounted All patients underwent MRM for breast cancer. ,e patients for only 20.8% of the PMRT group. received adjuvant chemotherapy, radiotherapy, or endocrine therapy after NAC in accordance with the clinical patho- logical characteristics of the tumour. HER-2+ patients 2.2. Local Recurrence Pattern and Independent Prognostic continued to use trastuzumab after surgery for a total Factors of LRR and DFS. A total of 58 (10.5%) patients Journal of Oncology 3 Table 1: Clinical pathological characteristics of all patients (N � 554). All RT No RT Variable P value N � 554 % N � 399 % N � 155 % Age (years) 0.980 <50 239 43.1 172 43.10 67 43.20 ≥50 315 56.9 227 56.90 88 56.80 Menopausal status 0.609 Perimenopausal 255 46.0 184 46.11 71 45.81 Postmenopausal 265 47.8 193 48.37 72 46.45 Not known 34 6.1 22 5.51 12 7.74 Side of primary tumour 0.812 Left 294 53.1 213 53.38 81 52.26 Right 260 46.9 186 46.62 74 47.74 Tumour size, cm ≤0.001 <4 384 69.3 258 64.67 126 81.29 ≥1 170 30.7 141 35.33 29 18.71 Tumour grade 0.445 G1-G2 274 49.5 194 48.62 80 51.61 G3 54 9.8 41 20.28 13 8.39 Not known 226 40.8 164 41.10 62 40 Histological type 0.449 Ductal 485 87.6 345 86.47 140 90.32 Tubular 30 5.4 24 6.02 6 3.87 Others 39 7.0 30 7.52 9 5.81 ER status 0.618 ER+ 336 60.6 245 61.40 91 58.70 ER− 217 39.2 154 38.60 63 40.60 PR status 0.216 PR+ 264 47.7 197 49.40 67 43.23 PR− 289 52.2 202 50.60 87 56.13 HER-2 status 0.447 HER-2 positive 114 20.6 85 21.30 29 18.71 HER-2 negative 378 68.2 268 67.20 110 80.00 Not recorded 62 11.2 46 11.50 16 10.30 TBC 0.020 Yes 98 17.7 61 15.30 37 23.90 No 394 71.1 292 73.20 102 65.80 Clinical T stage ≤0.001 T1-T2 438 79.1 297 74.44 141 90.97 T3-T4 116 20.9 102 25.57 14 9.03 Clinical N stage ≤0.001 N0 130 23.5 69 17.30 61 39.35 N1 339 61.2 260 65.16 79 50.97 N2 85 15.3 70 17.54 15 9.68 Clinical TNM stage ≤0.001 II 394 71.1 263 65.91 131 84.52 III 160 28.9 136 34.09 24 15.48 Clinical tumour response 0.415 CR + PR 472 85.2 343 85.96 129 83.23 SD + PD 82 14.8 56 14.04 26 16.77 Pathological response ≤0.001 pCR 38 6.9 15 3.76 23 14.84 No pCR 516 94.1 384 96.24 132 85.16 LVI 0.315 Yes 62 11.2 48 12.03 14 9.03 No 492 88.8 351 87.97 141 90.97 Pathological T stage ≤0.001 T0/tis 55 9.9 29 7.27 26 16.77 T1 279 50.4 199 49.87 80 51.61 T2–T4 220 39.7 171 42.86 49 31.61 Pathological N stage ≤0.001 N0 177 31.0 83 20.80 94 60.65 4 Journal of Oncology Table 1: Continued. All RT No RT Variable P value N � 554 % N � 399 % N � 155 % N1 192 34.7 152 38.10 40 25.81 N2-3 185 33.3 164 41.10 21 13.55 Pathological stage ≤0.001 0 38 6.9 15 3.76 23 14.84 I 94 16.0 44 11.03 50 32.26 II 228 41.2 168 42.11 60 38.71 III 194 35.0 172 43.11 22 14.19 PMRT, postmastectomy radiation therapy; ER, estrogen receptor; PR, progesterone receptor; HER-2, human epidermal growth factor receptor; TNBC, triple- negative breast cancer; pCR, pathological complete response; CR, complete response; PR, partial response; SD, stable disease; PD, progress disease; LVI, lymphatic vascular infiltration; HR, hazard ratio. experienced local recurrence, including 28 (5.1%) patients with ipsilateral chest wall recurrence, 7 (1.3%) patients with axillary nodal recurrence, 14 (2.5 %) patients with ipsilateral supraclavicular recurrence, and 9 (1.6%) with simultaneous 5-year LRR: 7.3% vs. 14.1% recurrence at two or more positions. Logrank p value = 0.01 A total of 34 (8.2%) patients in the PMRT group and 24 (15.5%) in the non-PMRT group had locoregional recur- rence. ,e 5-year LRR of the PMRT group was significantly lower than that of the non-PMRT group (7.3% vs. 14.1%, P � 0.01) as shown in Figure 1. Univariate analysis showed that the factors associated with LRR included (Table 2) clinical tumour size, histological grade, clinical stage, LVI, 0 20406080 100 PR, ypN stage, TNBC, tumour chemotherapy response, and Time (months) PMRT. Incorporating these factors into the Cox risk pro- portional model revealed that patients with cT ≥4 cm, PR PMRT negativity, ypN 1, and ypN 2–3 and without PMRT had poor Non-PMRT LRR (Figure 2). ,e LRR of patients without PMRT was 4.47 Figure 1: Kaplan–Meier plot for the cumulative incidence of times that of patients with PMRT (CI 1.97–10.14, P≤ 0.01), locoregional recurrence. whereas the LRR of ypN2-3 patients was 4.68 times that of ypN0 patients. A total of 138 (25.0%) patients in the whole group had (P � 0.62, Figure 4(a)). 4 (4.8%) and 6 (6.3%) of the patients in distant metastasis (including 10 patients with contralateral the PMRT and non-PMRT groups experienced locoregional breast metastasis). DFS did not obviously differ between the recurrence, respectively. DFS did not differ between the two PMRT group and non-PMRT group (74% vs. 74.8%, groups (P � 0.88) (Figure 4(b)). P � 0.99). Univariate analysis revealed that the factors af- However, in the ypN1 and ypN2-3 cohorts, the 5-year fecting DFS included (Table 2) cT, pathological type, clinical LRR rates were significantly decreased in the patients with stage, cN, lymph-vascular infiltration (LVI), PR, HER-2, PMRT (ypN1: P≤ 0.001, ypN2-3: P≤ 0.001) (Figures 4(c) ypN, and TNBC. Considering that some studies have shown and 4(e)). Moreover, the DFS of these patients improved that PMRT can affect the DFS of patients, PMRT and the (ypN1: P � 0.02; ypN2-3: P≤ 0.001) (Figures 4(d) and 4(f)). related factors of the above univariate analysis were included in the multivariate analysis simultaneously. ,e independent prognostic factors of DFS were cT, PR, LVI, TNBC, HER-2, 2.4. Molecular Subtypes. Survival curves showed significant ypN, and PMRT (Figure 3). differences in LRR and DFS amongst the three subtypes (HR+ and HER-2−, HER-2+, and TNBC) (Figure 5). ,e 5- 2.3. ypN0, ypN1, and ypN2-3. ,e number of positive lymph year LRR of patients with TNBC was significantly higher nodes is an important variable that affects LRR and DFS. ,e than that of HR+ and HER-2− patients (15.3% vs. 5.6%, 5-year LRR of ypN0 patients was significantly lower than P � 0.006) (Figure 5(a)), whereas the 5-year DFS of TNBC that of ypN + patients (5.3% vs. 11.1%, P � 0.01). LRR and HER-2+ patients were worse than those of HR+ and gradually increased following the increase in the number of HER-2− patients (81.3% vs. 66.3%, P � 0.001; 81.3% vs. positive lymph nodes. ,e 5-year LRRs of the ypN0, ypN1, 68.8%, P � 0.011) (Figure 5(b)). No significant difference and ypN2-3 cohorts were 5.3%, 7.8%, and 14.7%, was observed in the LRR and DFS between the PMRT group respectively. and the non-PMRT group in the three subtypes. However, the survival curve of TNBC patients indicated that PMRT For patients with ypN0, the 5-year LRR was not significantly different between the PMRT group and non-PMRT group was beneficial (P � 0.065) (Figure 6). Locoregional recurrence rate Journal of Oncology 5 Table 2: Results of univariate analysis for locoregional recurrence and disease-free survival. LRR DFS Variable HR (95% CI) P value HR (95% CI) P value Age (years) 0.965 0.173 <50 1 (ref) 1 (ref) ≥50 0.988 (0.589–1.659) 1.243 (0.909–1.698) Tumour size, cm 0.01 ≤0.001 <4 1 (ref) 1 (ref) ≥r 2.355 (1.404–3.952) 1.758 (1.286–2.403) Tumour grade 0.015 0.488 G1-G2 1 (ref) 1 (ref) G3 2.377 (1.182–4.778) 1.203 (0.713–2.031) Histological type 0.806 0.035 Ductal 1 (ref) 1 (ref) Tubular 1.097 (0.0396–3.039) 1.132 (0.613–2.089) Others 0.692 (0.216–2.217) 0.302 (0.112–0.814) LVI 0.093 ≤0.001 Yes 1 (ref) 1 (ref) No 0.557 (0.282–1.103) 0.486 (0.327–0.723) Clinical N stage 0.461 0.007 N0 1 (ref) 1 (ref) N1 1.401 (0.733–2.676) 1.979 (1.292–3.031) N2 0.97 (0.382–2.465) 1.624 (0.937–2.812) Clinical TNM stage 0.044 0.002 Stage II 1 (ref) 1 (ref) Stage III 1.718 (1.015–2.907) 1.651 (1.205–2.260) ER status 0.405 0.901 ER+ 1 (ref) 1 (ref) ER− 1.249 (0.743–2.101) 1.020 (0.746–1.395) PR status 0.002 0.033 PR+ 1 (ref) 1 (ref) PR− 2.428 (1.379–4.276) 1.400 (1.027–1.909) HER-2 status 0.483 0.094 HER-2 positive 1 (ref) 1 (ref) HER-2 negative 0.797 (0.424–1.500) 0.726 (0.499–1.056) TNBC 0.017 0.006 TNBC 1 (ref) 1 (ref) No TNBC 0.485 (0.268–0.878) 0.592 (0.405–0.863) Clinical tumour response 0.012 0.273 CR + PR 1 (ref) 1 (ref) SD + PD 2.126 (1.180–3.831) 1.255 (0.836–1.886) Pathological response 0.162 0.010 pCR 1 (ref) 1 (ref) No pCR 4.099 (0.567–29.615) 6.262 (1.553–25.256) Pathological N stage ≤0.001 ≤0.001 N0 1 (ref) 1 (ref) N1 1.712 (0.79–3.711) 1.753 (1.085–2.832) N2 2.547 (1.166–5.565) 3.554 (2.231–5.662) N3 5.644 (2.472–12.882) 7.249 (4.371–12.022) PMRT 0.013 0.993 RT 1 (ref) 1 (ref) No RT 1.935 (1.147–3.266) 0.999 (0.708–1.407) Anti-HER-2 therapy 0.629 0.983 Yes 1 (ref) 1 (ref) 0.751 (0.235–2.401) 1.007 (0.546–1.856) Adjuvant chemotherapy 0.184 0.524 Yes 1 (ref) 1 (ref) No 1.238 (0.903–1.695) 1.083 (0.847–1.384) Endocrinotherapy 0.218 0.121 Yes 1 (ref) 1 (ref) No 1.119 (0.935–1.339) 1.093 (0.977–1.223) LRR, locoregional recurrence rates; DFS, disease-free survival; HR, hazard ratio; CI, confidence interval; ER, estrogen receptor; PR, progesterone receptor; HER-2, human epidermal growth factor receptor; TNBC, triple-negative breast cancer; pCR, pathological complete response; CR, complete response; PR, partial response; SD, stable disease; PD, progress disease. 6 Journal of Oncology All patients No. of patients (%) HR (95% CI) p value tumor size <4 cm 384 (69.31) 1 (Reference) ≥4 cm 170 (30.69) 3.37 (1.62 − 6.98) ≤0.001 Tumor grade G1 – G2 274 (49.46) 1 (Reference) G3 54 (9.75) 1.74 (0.78 − 3.87) 0.180 LVI Yes 62 (11.19) 1 (Reference) No 492 (88.81) 0.55 (0.21 − 1.42) 0.220 Clinical TNM stage stage II 62 (11.19) 1 (Reference) stage III 492 (88.81) 1.02 (0.47 − 2.20) 0.960 PR status PR+ 62 (11.19) 1 (Reference) PR− 492 (88.81) 3.782 (1.55 − 9.23) <0.001 TNBC TNBC 98 (17.70) 1 (Reference) NO TNBC 394 (71.10) 0.57 (0.24 − 1.40) 0.220 Clinical tumor response CR + PR 98 (17.70) 1 (Reference) SD + PD 394 (71.10) 0.11 (0.45 − 2.74) 0.820 Pathological N stage N0 177 (31.95) 1 (Reference) N1 192 (34.66) 2.99 (1.06 − 8.42) 0.040 N2 − 3 185 (33.39) 4.679 (1.50 − 14.59) 0.010 PMRT RT 399 (72.02) 1 (Reference) No RT 155 (27.98) 4.47 (1.97 − 10.14) ≤0.001 0 1 2 3 4 4.5 4.75 5 LRR Figure 2: Results of the multivariate Cox regression analysis of LRR. LRR: locoregional recurrence; PMRT: postmastectomy radiation therapy; TNBC: triple-negative breast cancer; LVI: lymphatic vascular infiltration; PR: progesterone receptor; TNBC: triple-negative breast cancer; pCR: pathological complete response; CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; HR: hazard ratio; CI: confidence interval. A clear relationship was observed between tumour re- pCR patients. McGuire believed that patients with stage I-II sponse and subtypes. ,e pCR rates of HR+, HER-2+, and pCR do not need radiotherapy. However, even for patients TNBC patients were 3.6%, 9.6%, and 14.3%, respectively. with stage III breast cancer who achieved pCR after NAC, TBC and HER + patients were more likely to achieve pCR PMRTcan still reduce LRR by 26% and significantly improve than HR + patients after receiving NAC (Table 3: HER-2+: OS [14]. A retrospective study obtained a similar conclusion OR � 4.40, 95% CI: 1.89–10.27, P � 0.001; TNBC: OR � 2.82, that PMRT can still reduce the LRR of patients with clinical III-IV disease and pCR in 10 years (3% vs. 33%; 95% CI: 1.16–6.84, P � 0.02). P � 0.006) but does not benefit patients with clinical stage I-II disease [10]. 3. Discussion In our study, 83.23% of 554 patients exhibited tumour shrinkage of more than 30% after NAC, 9.9% of patients NAC has been recently widely used in patients with clinical experienced the complete disappearance of primary breast stage II or III breast cancer. Although NAC has improved tumours, and 6.8% of patients achieved pCR because only the surgical outcomes for many patients with breast cancer, 18% of patients underwent full-course NAC. ,erefore, the the risk of relapse remains high especially for patients with proportion of postoperative pCR patients in our study was locally advanced breast cancer. However, the indication for lower than that in other studies. PMRT in patients treated with NAC remains controversial ,e number of positive lymph nodes is an important given the lack of prospective evidence. prognostic indicator [18, 19]. Some studies thought that the Multiple studies have shown that pCR is an important initial lymph node status before NAC and postoperative prognostic indicator for survival [15–17]. NSABP B-18/27 lymph node status should be referenced to consider whether analysis confirmed that, amongst patients with clinical stage the patient should accept PMRT [20, 21]. However, some I-II disease, pCR patients had better DFS and OS than non- Journal of Oncology 7 All patients No. of patients (%) HR (95% CI) p value tumor size <4 cm 384 (69.31) 1 (Reference) ≥4 cm 170 (30.69) 1.486 (1.02 − 2.17) 0.040 Histological type Ductal 485 (87.55) 1 (Reference) Tubular 30 (5.42) 1.35 (0.61 − 2.98) 0.460 Other 39 (7.04) 0.49 (0.18 − 1.33) 0.160 LVI Yes 62 (11.19) 1 (Reference) No 492 (88.81) 0.61 (0.39 − 0.95) 0.030 Clinical N stage N0 130 (23.47) 1 (Reference) N+ 424 (76.53) 1.14 (0.65 − 1.98) 0.660 Clinical TNM stage stage II 62 (11.19) 1 (Reference) stage III 492 (88.81) 0.88 (0.59 − 1.31) 0.520 PR status PR+ 62 (11.19) 1 (Reference) PR− 492 (88.81) 1.45 (0.90 − 2.33) 0.120 HER2 status HER2 positive 114 (23.17) 1 (Reference) HER2 negative 378 (76.83) 0.60 (0.36 − 0.97) 0.038 TNBC TNBC 98 (17.70) 1 (Reference) NO TNBC 394 (71.10) 0.40 (0.23 − 0.70) 0.001 Pathological response pCR 38 (6.86) 1 (Reference) no pCR 516 (94.14) 3.75 (0.87 − 16.21) 0.760 Pathological N stage N0 177 (31.95) 1 (Reference) N1 192 (34.66) 1.74 (0.97 − 3.10) 0.060 N2−3 185 (33.39) 5.44 (2.94 − 10.05) ≤0.001 PMRT RT 399 (72.02) 1 (Reference) No RT 155 (27.98) 2.16 (1.42 − 3.31) ≤0.001 01234 4.54.755 DFS Figure 3: Results of the multivariate Cox regression analysis of DFS. DFS: disease-free survival; PMRT: postmastectomy radiation therapy; TNBC: triple-negative breast cancer; LVI: lymphatic vascular infiltration; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epidermal growth factor receptor; TNBC: triple-negative breast cancer; pCR: pathological complete response; HR: hazard ratio; CI: confidence interval. experts disagree with this view and believe that patients with After receiving PMRT, the OS of patients in each layer of ypN (ypN0, ypN1, and ypN2-3) improved [20]. N0 can be exempted from radiotherapy [10, 22]. A 2016 National Cancer Database study involving 10 283 patients Another study showed that the risk of regional recur- with clinical T1-3N1M0 breast cancer (ypN2-3) identified rence, distant metastasis, and death did not increase in 56 PMRTas an independent prognostic factor of improving OS. (41.8%) out of 134 ypN0 patients without PMRT compared 8 Journal of Oncology ypN0 ypN0 100 100 80 80 60 60 40 40 p = 0.62 p = 0.88 20 20 0 0 0 20406080 100 0 20406080 100 Time (months) Time (months) PMRT PMRT Non-PMRT Non-PMRT (a) (b) ypN1 ypN1 p ≤ 0.001 p = 0.02 0 20406080 100 40 020 60 80 100 Time (months) Time (months) PMRT PMRT Non-PMRT Non-PMRT (c) (d) ypN2-3 ypN2-3 100 100 80 80 60 60 40 40 p ≤ 0.001 p ≤ 0.001 20 20 0 0 0 20406080 100 020 60 80 100 Time (months) Time (months) PMRT PMRT Non-PMRT Non-PMRT (e) (f) Figure 4: Locoregional recurrence and disease-free survival of patients with breast cancer with or without PMRT in the (a) LRR of ypN0, (b) DFS of ypN0, (c) LRR of ypN1, (d) DFS of ypN1, (e) LRR of ypN2-3, and (f) DFS of ypN2-3. Locoregional recurrence rates Locoregional recurrence rates Locoregional recurrence rates Disease-free survival Disease-free survival Disease-free survival Journal of Oncology 9 100 100 HR+, HER2– vs HR+/–, HER2+: p = 0.153 HR+/–, HER2+ vs TBC: p = 0.328 80 80 HR+, HER2– vs TBC: p = 0.006 60 60 40 40 HR+, HER2– vs HR+/–, HER2+: p = 0.011 HR+/–, HER2+ vs TBC: p = 0.488 HR+, HER2– vs TBC: p = 0.001 20 20 0 0 0 20406080 100 0 20406080 100 Time (months) Time (months) HR+, HER2– HR+, HER2– HR+/–, HER2+ HR+/–, HER2+ TBC TBC (a) (b) Figure 5: (a) Locoregional recurrence of three molecular subtypes. (b) Disease-free survival of the three molecular subtypes. TNBC p = 0.065 0 20 40 60 80 100 Time (months) PMRT Non-PMRT Figure 6: Locoregional recurrence of TNBC patients with or without PMRT. patients after NAC in accordance with molecular subtypes. Table 3: Relationship between pCR rates and molecular subtypes. A total of 189 patients were included in this analysis, and the Molecular pCR rates (%) OR (95% CI) P effects of PMRT on locoregional control, DFS, and OS were HR+HER-2− 3.60 1 (ref) — evaluated. However, PMRT provides no additional survival HR+/HR−, HER-2+ 9.60 2.82 (1.16–6.84) 0.02 benefits for any molecular subtype [25]. TBC 14.30 4.40 (1.89–10.27) 0.001 A number of retrospective studies have shown that TNBC: triple-negative breast cancer; HR: hormone receptor; HER-2 human sentinel lymph node biopsy (SLNB) after NAC can prevent epidermal growth factor receptor; TNBC: triple-negative breast cancer; patients with negative axillary lymph nodes from under- pCR: pathological complete response; HR: hazard ratio; CI: confidence going unnecessary axillary lymph node dissection (ALND) interval. [26–28]. However, the false negative of SNLB can lead to incorrect lymph node staging and affect the formulation of comprehensive treatment plans after surgery. ,erefore, the with that of 78 (58.2%) patients who received PMRT [18]. patients analysed in this study all underwent ALND. Shim and Kantor et al. similarly concluded that PMRT may Whether SNLB can replace ALND still needs to be further be unnecessary in patients with ypN0 regardless of clinical verified in the prospective study Alliance A011202. stage [23, 24]. A study explored the benefit of PMRT in ypN0 Locoregional recurrence rates Locoregional recurrence rates Disease-free survival 10 Journal of Oncology Patients with lymph node positivity after surgery are Acknowledgments strongly recommended for PMRT [29, 30]. However, experts ,is study was funded by the Science and Technology Plan have not reached a consensus on whether ypN0 patients Project of Shenyang (19–112-4–083), Science and Tech- require PMRT and still expect confirmation from the pro- nology Plan Project of Liaoning Province of China spective randomised controlled trial RTOG1304/NSABP (20180540129 and 20180530095), Key Laboratory of Tumor B51. Radiosensitization and Normal Tissue Radioprotection ,is study has numerous deficiencies given the limita- Project of Liaoning Province (No. 2018225102), and the tions of retrospective research. ,e baseline characteristics Personnel Training Project of Liaoning Cancer Hospital and of the patients in the two groups were different. Nearly 90% Institute of China (201703). Medical-Industrial Interdisci- of the patients’ lymph node status before neoadjuvant plinary Research Fund (LD202005). therapy was based on clinical examination or ultrasound, mammography, or MRI. 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