- Email: [email protected]
The Prognostic Effect of Changes in Tumor Stage and Nodal Status After Neoadjuvant Chemotherapy in Each Primary Breast Cancer Subtype
Accepted Manuscript The prognostic impact of changes in tumor stage and nodal status after neoadjuvant chemotherapy in each primary breast cancer subtype Naoki Hayashi, M.D., Ph.D., Yuko Takahashi, M.D., Naoko Matsuda, M.D., Hiroko Tsunoda, M.D., Atsushi Yoshida, M.D., Ph.D., Koyu Suzuki, M.D., Ph.D., Seigo Nakamura, M.D., Ph.D., Hideko Yamauchi, M.D. PII:
S1526-8209(17)30319-1
DOI:
10.1016/j.clbc.2017.09.013
Reference:
CLBC 688
To appear in:
Clinical Breast Cancer
Received Date: 25 May 2017 Accepted Date: 22 September 2017
Please cite this article as: Hayashi N, Takahashi Y, Matsuda N, Tsunoda H, Yoshida A, Suzuki K, Nakamura S, Yamauchi H, The prognostic impact of changes in tumor stage and nodal status after neoadjuvant chemotherapy in each primary breast cancer subtype, Clinical Breast Cancer (2017), doi: 10.1016/j.clbc.2017.09.013. 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.
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An Original article The prognostic impact of changes in tumor stage and nodal status after
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neoadjuvant chemotherapy in each primary breast cancer subtype
*Naoki Hayashi, M.D., Ph.D.1, *Yuko Takahashi, M.D.1, Naoko Matsuda, M.D.1,
Hiroko Tsunoda, M.D. 2, Atsushi Yoshida, M.D., Ph.D.1, Koyu Suzuki, M.D., Ph.D.3,
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Seigo Nakamura, M.D., Ph.D. 1, 4, and, Hideko Yamauchi, M.D. 1
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* Naoki Hayashi and Yuko Takahashi were equally contributed as first authors.
Affiliations:
Departments of 1Breast surgical oncology, 2Radiology, and 3Pathology, St. Luke’s
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International Hospital, Tokyo, Japan. 4Department of Breast surgical oncology, Showa
Funding:
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University, School of medicine, Tokyo, Japan.
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This work was supported in part by St. Luke life science research grant 2014. Running head: tumor stage and nodal status after NAC
Corresponding author: Naoki Hayashi, M.D., Ph.D. Department of Breast surgical oncology, St. Luke’s International Hospital 9-1 Akashi-cho, Chuo-ku, Tokyo 104-8560, Japan Tel: 81-3-3541-5151 Fax: 81-3-3544-0649
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E-mail: [email protected] Number of 248 Words / 1407 Characters in abstract
Conflict of interest statement:
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The authors have no conflicts of interest to declare.
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Number of 1884 Words / 10157 Characters in manuscript
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Micro abstract
Changes in tumor stage and nodal status might have different prognostic impact in patients with each subtypes of breast cancer. Tumor downstaging and loss of node
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positivity after neoadjuvant chemotherapy improved prognosis regardless of non-pCR in patients with HR+/HER2-/high nuclear grade or HR-/HER2- tumors. In contrast, in
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patients with HER2+ tumors, only achievement of pCR was prognostic factor.
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Abstract Background: While the prognostic value of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) depend on the intrinsic subtype of breast cancer, it
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is not clear whether chemosensitivity itself, shown by a decreasing tumor burden after NAC, contributes to improved prognosis in primary breast cancer patients, especially in patients with non-pCR. The aim of this study was to assess the prognostic impact of
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changes in tumor stage or nodal status after NAC in each primary breast cancer
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subtype.
Methods: We assessed 719 consecutive patients with primary breast cancer who underwent surgical resection after NAC between 2001 and 2010. The patients were divided into 5 subtypes according to their hormone receptor (HR) status, epidermal growth factor receptor-2 (HER2) status, and nuclear grade (NG: 1/2, low and 3, high).
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Results: In patients with HR+/HER2-/NG-low tumors, regardless of change in tumor size, the loss of node positivity after NAC significantly improved disease-free survival
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(DFS). In patients with HR+/HER2-/NG-high tumors, achievement of both of tumor downstaging and the loss of node positivity improved their DFS. In patients with
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HR-/HER2- tumors tumor downstaging and the loss of node positivity significantly improved DFS, despite a non-pCR. In contrast, in patients with HER2+ tumors, changes in tumor stage or nodal status were not associated with prognosis unless pCR was achieved.
Conclusion: Our results revealed that changes in tumor stage and nodal status after NAC might be prognostic markers in patients with HR+/HER2-/NG-high tumors or HR-/HER2- tumors, even if there are residual tumors in the breast.
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Key words Breast cancer, neoadjuvant chemotherapy, hormone receptor, epidermal growth factor
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receptor-2, pathologic complete response, nuclear grade
Introduction
Neoadjuvant chemotherapy (NAC) is a standard treatment for primary breast cancer
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patients, since its prognostic impact was revealed to be the same as that of adjuvant
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chemotherapy [1, 2]. The advantage of NAC is a reduction in tumor size and an increase in the rate of breast-conserving surgery. It is also beneficial for allowing assessment of the response of the primary tumor and lymph nodes to systemic treatment. A pathologic complete response (pCR) is an important prognostic factor in primary breast cancer patients [1, 3]. Several previous studies have shown that patients
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who achieved pCR after NAC had a significantly better prognosis than those who did not [3-5]. Recently, it has been shown that the effect of NAC and the prognostic value
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of pCR depend on the intrinsic subtype of breast cancer [6, 7]. pCR after NAC improves the survival of patients with epidermal growth factor receptor-2
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(HER2)-positive and triple-negative (TN) breast cancers, but that of those with hormone receptor (HR)-positive/HER2-negative breast cancer [1, 8-10]. However, regardless of residual tumors, it is not clear whether chemosensitivity, shown by a decrease in the tumor burden after NAC, contributes to an improvement in the prognosis of patients with primary breast cancer. Thus, the aim of this study was to assess the prognostic impact of changes in tumor stage or nodal status after NAC in each primary breast cancer subtype.
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Patients and Methods Patients We identified 719 consecutive patients with primary breast cancer who underwent
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surgical resection after NAC between January 2001 and December 2010 in our institute’s breast cancer database. Patients with estrogen receptor (ER)- and/or
progesterone receptor (PR)-positive tumors received adjuvant endocrine treatment.
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Adjuvant radiotherapy was applied to patients who underwent breast-conserving
surgery and those who underwent mastectomy with equal and larger than cT3, or cN2
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and cN3 disease. The clinical stage was defined using radiological findings of ultrasound, MRI, and CT scans. Clinical node positivity was confirmed using fine needle aspiration cytology if lymph node metastasis was suspected; this was based on ultrasound findings showing reduced fatty deposition, and demonstrating lateral
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cortical hypertrophy [11].
We excluded patients who underwent sentinel lymph node biopsy before NAC, as well as those with metastatic disease or other prior malignancies, inflammatory breast
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cancer, and a history of treatment for breast cancer. This study waived the need for written informed consent because of the retrospective nature. All specimens were
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collected following the protocol approved by the institutional review board.
Pathological assessment Invasive breast cancer was histologically confirmed in all patients using needle biopsy before NAC. ER/PR status was assessed using immunohistochemistry (IHC). ER/PR status was considered as positive if the Allred staining score was ≥3 for the receptor. HER2 status was determined using IHC and/or fluorescent in situ hybridization (FISH)
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assays. HER2 positivity was defined as a receptor overexpression staining score of 3+ on IHC, or as gene amplification using FISH with a CEP-17 ratio >2.0. We divided patients into the following 5 subtypes based on HR (ER and/or PR) status, HER2 status,
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and NG (1/2, low; 3, high). The subtypes were HR+/HER2-/NG-low tumors,
HR+/HER2-/NG-high tumors, HR-/HER2- tumors, HR+/HER2+ tumors, and
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HR-/HER2+ tumors. pCR was defined as no residual invasive tumor and ypN0.
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Staging analysis
Individual patient data regarding clinical characteristics, histopathological findings at surgery, and follow-up were extracted from the pooled databases of our institution. Based on changes in T stage, downstaging (DS) was defined as a decreased T stage and non-DS was defined as the same or an increased T stage after NAC, based on Union
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for International Cancer Control criteria [12]. In terms of changes in nodal status, the clinical nodal status before chemotherapy and the pathological nodal status after NAC
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were considered.
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Statistical analysis
We compared the patients with respect to disease-free survival (DFS) and overall survival (OS) based on changes in tumor stage and nodal status after NAC. DFS and OS were calculated from the date of diagnosis to local or distant recurrence, death, or last follow-up, and plotted as Kaplan-Meier curves. Log-rank P-values were calculated for the changes in tumor stage and nodal status after NAC. Hazard ratios (HRs), 95% confidence intervals (CIs), and corresponding P-values were calculated using Cox
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regression analysis. SPSS 17.0 (SPSS, Chicago, IL) was used to perform all analyses. P-values less than 0.05 were considered statistically significant.
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Results Patient characteristics
The median age of patients at diagnosis was 49 years (range, 24 to 75 years). Four
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hundred ninety-three patients had HR-positive tumors (69%) and 166 patients had
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HER2-positive tumors (23%) (Table 1). One hundred two (14%) patients achieved a pCR; 8 of these patients (2%) had HR+/HER2-/NG-low tumors, 5 (8%) had HR+/HER2-/NG-high tumors, 32 (24%) had HR-/HER2- tumors, 20 (26%) had HR+/HER2+ tumors, and 37 (41%) had HR-/HER2+ tumors.
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Prognostic impact of pCR in each subtype
With a median follow-up period of 78 months, patients with HR-/HER2- tumors who
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achieved pCR had longer DFS and OS than those who did not (P = 0.001, and 0.001 respectively). Furthermore, patients with HR-/HER2+ tumors who achieved a pCR had
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longer DFS and OS than those who did not (p=0.047, and p=0.025 respectively). However, in patients with HR+ tumors, there was no difference in DFS and OS between the pCR and non-pCR groups.
Prognostic impact of changes in tumor stage and nodal status after NAC Because a pCR had a prognostic impact in patients with HR-/HER2- and HR-/HER2+ tumors, but not in HR+ tumors, we excluded patients with HR-/HER2- and HR-/HER2+ tumors with a pCR from further analysis; we assessed the significance of 7
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changes in tumor size and nodal status for patients with residual tumors who had a worse prognosis. In patients with HR+/HER2-/NG-low tumors (n = 353), there was no significant difference between DS and non-DS with respect to both DFS and OS (P =
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0.14, and 0.89, respectively). In terms of changes in nodal status, a change from
clinical node-positive (cN+) to pathological node-negative after NAC (ypN0) resulted in a significantly longer DFS than those remained pathologically node-positive (ypN+)
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(P = 0.004). A similar trend was found with respect to OS (P = 0.055) (Supplementary
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Fig 1, d). In patients with HR+/HER2-/NG-high tumors (n = 64), patients with DS had significantly longer DFS than those with non-DS; however, it was not associated with an improvement in OS (P = 0.015, and 0.123, respectively) (Supplementary Fig 2, a and b). The loss of node-positivity from cN+ to ypN0 resulted in a significantly longer DFS than those remained ypN+, and there was a similar trend with respect to OS (P =
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0.006, and 0.077, respectively) (Supplementary Fig 2, c and d). In patients with HR-/HER2- tumors with a non-pCR (n = 136), patients with DS had a significantly
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better prognosis than those non-DS with respect to both DFS and OS (P = 0.003, and 0.001, respectively). The loss of node positivity was associated with a significantly
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better DFS than those remained ypN+ after NAC; however, it was not associated with an improvement in OS (P = 0.045, and 0.163, respectively) (Supplementary Fig 3). However, in patients with HR+/HER2+ tumors (n = 76) and HR-/HER2+ tumors (n = 90) with non-pCR, changes in both tumor stage and nodal status after NAC did not improve their prognosis (Supplementary Fig 4 and 5). Finally, we assessed the prognostic impact of the combination of changes in tumor stage and nodal stage in each of the 5 subtypes (Fig 1). In patients with HR+/HER2-/NG-low tumors, regardless of non-DS, the loss of node positivity 8
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significantly improved DFS (Fig 1, a). In patients with HR+/HER2-/NG-high tumors, achievement of both DS and loss of node positivity improved their DFS (P = 0.021, cN0 to ypN0/DS vs. cNany to ypN+/non-DS; and P = 0.028, cN+ to ypN+/non-DS vs.
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cNany to ypN+/non-DS, respectively) (Fig 1, b). In patients with HR-/HER2- tumors with a non-pCR, DS in addition to the loss of node positivity significantly improved
DFS, regardless of the non-pCR (Fig 1, c). In contrast, in patients with HER2+ tumors,
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changes in tumor stage or nodal status were not associated with prognosis (Fig 1, d and
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e).
Discussion
Because a pCR has been confirmed as a prognostic marker in primary breast cancer patients with HR-/HER2+ tumors and HR-/HER2- tumors, the treatment strategy aims
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to achieve pCR with NAC to improve the prognosis [1, 13, 14]. However, in patients with HR+/HER2- tumors, it has been reported that a pCR is not a prognostic marker
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[1]. In this study, we demonstrated that changes in tumor stage and nodal status after NAC were associated with prognosis in patients with HR+/HER2-/NG-high tumors,
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regardless of the presence of a residual tumor. Furthermore, we showed that the extent of the impact on prognosis depends on the intrinsic subtype of breast cancer. Loss of node positivity after NAC has been reported in approximately 40% of cases [2, 15]. Previous studies have shown that the pathologic nodal status after NAC is a better prognostic marker than a pCR [16-19]. The prognostic importance of involved lymph nodes after NAC has already been shown by previous studies [19, 20]. From our results, patients with HR+/HER2- disease and loss of node positivity had significantly better DFS than those with pathologically node-positive disease. In addition, in luminal 9
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B-like tumors with a high NG, changes in tumor stage were significantly associated with a better prognosis; however, this was not the case in patients with luminal A-like tumors with a low NG. We also showed that, for patients with HR+/HER2- tumors, the
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loss of node positivity after NAC may be a prognostic marker. Notably, for patients with HR-/HER2- tumors, changes in tumor stage and nodal status after NAC were
significantly associated with prognosis, even if they did not achieve a pCR. In general,
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patients with HR+ tumors with either pCR or non-pCR had a better prognosis than
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those with HR- tumors. However, even for patients with luminal–B like tumors who need systemic chemotherapy to prolong their survival, there is no clear prognostic marker. Therefore, our results indicated that, especially for HR+/HER2- and NG-high tumors, so-called luminal B-like tumors, and HR-/HER2- tumors, NAC aiming DS
tumors.
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might contribute to improved survival in patients with node positivity and large
For patients with HER2+ tumors, regardless of HR-positivity, only a pCR has a
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prognostic impact. Therefore, patients with HER2+ subtype disease need to achieve pCR to improve their prognosis. Fortunately, novel HER2-targeting agents, such as
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pertuzumab, lapatinib, and trastuzumab emtansine (T-DM1), increase the pCR rate in patients with HER2+ tumors [21, 22]. Additional novel treatments to support current standard treatments should be used for patients with no change in tumor stage and node positivity with a poor prognosis. There are some limitations in our study; patient data were retrospectively collected, and the accurate number of clinical node metastases was hard to assess in radiological findings. However, we could show the importance of node positivity itself as a prognostic marker without considering the number in our study. 10
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Conclusions Our results revealed that changes in tumor stage and nodal status after NAC might be
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prognostic markers in patients with HR+/HER2-/NG-high tumors or HR-/HER2-
tumors, even if there are residual tumors in the breast. NAC may be beneficial for
patients with HR+/HER2-/NG-high tumors and node-positive and/or large tumors.
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Prospective studies are needed to assess the role of additional adjuvant treatment for
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such patients with these poor prognostic factors after NAC.
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Clinical Practice Points: In current clinical practice, the prognostic impact of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) depends on the intrinsic subtype of
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breast cancer. However, it is not clear the prognostic impact of changes in tumor stage or nodal status after NAC in each primary breast cancer subtype, especially in patients with non-pCR. In our study, results revealed that changes in tumor stage and nodal
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status after NAC might be prognostic markers in patients with HR+/HER2-/NG-high
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tumors or HR-/HER2- tumors, even if there are residual tumors in the breast. In patients with hormone receptor (HR)+/ epidermal growth factor receptor-2 (HER2)-/ nuclear grade (NG)-low (1 or 2) tumors, regardless of change in tumor size, the loss of node positivity after NAC was prognostic factor. In patients with HR+/HER2-/NG-high (3) tumors, achievement of both of tumor downstaging and the
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loss of node positivity improved their DFS. In patients with HR-/HER2- tumors tumor downstaging and the loss of node positivity significantly improved prognosis, despite a
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non-pCR. In contrast, in patients with HER2+ tumors, changes in tumor stage or nodal status were not associated with prognosis unless pCR was achieved. NAC may be
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beneficial because the response to treatment can show their prognosis in each breast cancer subtype regardless of no achievement of pCR. Prospective studies are needed to assess the role of additional adjuvant treatment for such patients with these poor prognostic factors after NAC.
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Acknowledgements: The authors thank all the staff from the departments of Breast Surgical Oncology, Radiology and Pathology, St. Luke’s International Hospital, for their help in collecting
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the clinical data.
A part of this study has been presented at San Antonio Breast Cancer Symposium 2013
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in Texas, and Annual meeting Japanese Breast Cancer Society 2016 in Tokyo.
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Figure legends Figure 1: The prognostic impact of change in tumor stage and nodal status on disease-free
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survival (DFS); (a) in HR+/HER2-/NG-low tumors, (b) in HR+/HER2-/NG-high
tumors, (c) in HR-/HER2- tumors, (d) in HR+/HER2+ tumors, and (e) in HR-/HER2+ tumors
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Abbreviation: cN, clinical nodal status; ypN, pathological node status after
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neoadjuvant chemothrapy; DS, down stage; HR, hormone receptor; HER2, Human Epidermal growth factor Receptor-2
Supplementary Figure 1:
The prognostic impact of change in tumor stage and nodal status in patients with
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HR+HER2-/NG-low tumor, (a) on Disease-free survival (DFS) and (b) overall survival (OS) in patients according to change in tumor stage; (c) DFS and (d) OS in patients
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according to change in nodal stage. Supplementary Figure 2:
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The prognostic impact of change in tumor stage and nodal status in patients with status for HR+/HER2-/NG-high tumor, (a) on Disease-free survival (DFS) and (b) overall survival (OS) in patients according to change in tumor stage; (c) DFS and (d) OS in patients according to change in nodal stage. Supplementary Figure 3: The prognostic impact of change in tumor stage and nodal status in patients with
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HR-/HER2- tumor, (a) on Disease-free survival (DFS) and (b) overall survival (OS) in patients according to change in tumor stage; (c) DFS and (d) OS in patients according
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to change in nodal stage. Supplementary Figure 4:
The prognostic impact of change in tumor stage and nodal status in patients with
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HR+/HER2+ tumor, (a) on Disease-free survival (DFS) and (b) overall survival (OS)
according to change in nodal stage.
Supplementary Figure 5:
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in patients according to change in tumor stage; (c) DFS and (d) OS in patients
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The prognostic impact of change in tumor stage and nodal status in patients with HR-/HER2+ tumor, (a) on Disease-free survival (DFS) and (b) overall survival (OS) in patients according to change in tumor stage; (c) DFS and (d) OS in patients according
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to change in nodal stage.
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All patients
HR+/HER2-/NG-low
HR+/HER2-/NG-high
HR+/HER2+
%
N
%
N
%
N
%
719
100
353
49
64
9
76
11
<35
48
7
20
6
6
9
35-39
75
10
40
11
7
40-49
255
36
155
44
28
50-59
225
31
94
27
13
60-
116
16
44
12
10
NG1
303
42
247
NG2
196
27
106
NG3
214
30
0
All patients
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Age, years
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N
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Table 1 Patient characteristics HR-/HER2+
HR-/HER2-
N
%
N
%
90
12
136
19
7
2
2
15
11
11
4
5
12
13
12
9
44
21
28
16
18
35
26
20
35
46
41
46
42
31
16
11
14
19
21
32
23
EP
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5
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Nuclear Grade 70
0
0
19
25
15
17
22
16
30
0
0
29
38
30
33
31
23
0
64
100
27
36
41
46
82
60
21
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6
<1
0
0
0
0
1
1
cTis
3
<1
3
<1
0
0
0
0
cT1
88
12
44
13
3
5
10
13
cT2
515
72
253
72
50
78
53
cT3
79
11
38
11
7
11
12
cT4
34
5
15
43
4
6
cN0
313
44
146
41
26
cN1
352
49
184
52
cN2
19
3
7
2
cN3
30
4
16
15
10
ypT0/Tis
111
1
1
0
0
0
17
19
14
10
62
69
97
71
16
6
7
16
12
1
1
5
6
9
6
41
33
43
40
44
68
50
32
50
37
49
43
48
61
45
6
3
4
4
4
1
<1
70
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4
SC
0
nodal status
pathological tumor stage
4
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clinical Tumor stage
4
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NA
5
2
3
3
4
3
3
6
5
3
5
8
23
30
39
43
34
25
22
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31
92
26
26
41
29
38
ypT2
242
34
154
44
23
36
16
21
ypT3
85
12
61
17
5
8
7
9
ypT4
55
8
36
10
5
8
1
1
36
47
35
16
18
33
24
3
3
9
7
0
0
13
10
375
52
121
34
33
52
50
66
73
81
98
72
ypN1
225
31
150
42
19
30
21
28
14
16
21
15
ypN2
89
12
59
17
9
14
4
5
3
3
14
10
ypN3
30
4
23
7
3
5
1
1
0
0
3
2
pCR
102
14
8
2
8
20
26
37
41
32
24
non-pCR
617
86
345
226
31
0
ER/PgR status negative
5
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ypN0
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32
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226
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ypT1
98
59
92
56
74
53
59
104
76
0
0
0
0
0
90
100
136
100
23
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493
69
353
100
64
100
76
100
negative
553
77
353
100
64
100
0
0
positive
166
23
0
0
0
0
76
100
0
0
0
0
0
136
100
90
100
0
0
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HER2 status
0
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S1526-8209(17)30319-1
DOI:
10.1016/j.clbc.2017.09.013
Reference:
CLBC 688
To appear in:
Clinical Breast Cancer
Received Date: 25 May 2017 Accepted Date: 22 September 2017
Please cite this article as: Hayashi N, Takahashi Y, Matsuda N, Tsunoda H, Yoshida A, Suzuki K, Nakamura S, Yamauchi H, The prognostic impact of changes in tumor stage and nodal status after neoadjuvant chemotherapy in each primary breast cancer subtype, Clinical Breast Cancer (2017), doi: 10.1016/j.clbc.2017.09.013. 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.
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An Original article The prognostic impact of changes in tumor stage and nodal status after
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neoadjuvant chemotherapy in each primary breast cancer subtype
*Naoki Hayashi, M.D., Ph.D.1, *Yuko Takahashi, M.D.1, Naoko Matsuda, M.D.1,
Hiroko Tsunoda, M.D. 2, Atsushi Yoshida, M.D., Ph.D.1, Koyu Suzuki, M.D., Ph.D.3,
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Seigo Nakamura, M.D., Ph.D. 1, 4, and, Hideko Yamauchi, M.D. 1
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* Naoki Hayashi and Yuko Takahashi were equally contributed as first authors.
Affiliations:
Departments of 1Breast surgical oncology, 2Radiology, and 3Pathology, St. Luke’s
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International Hospital, Tokyo, Japan. 4Department of Breast surgical oncology, Showa
Funding:
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University, School of medicine, Tokyo, Japan.
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This work was supported in part by St. Luke life science research grant 2014. Running head: tumor stage and nodal status after NAC
Corresponding author: Naoki Hayashi, M.D., Ph.D. Department of Breast surgical oncology, St. Luke’s International Hospital 9-1 Akashi-cho, Chuo-ku, Tokyo 104-8560, Japan Tel: 81-3-3541-5151 Fax: 81-3-3544-0649
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E-mail: [email protected] Number of 248 Words / 1407 Characters in abstract
Conflict of interest statement:
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The authors have no conflicts of interest to declare.
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Number of 1884 Words / 10157 Characters in manuscript
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Micro abstract
Changes in tumor stage and nodal status might have different prognostic impact in patients with each subtypes of breast cancer. Tumor downstaging and loss of node
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positivity after neoadjuvant chemotherapy improved prognosis regardless of non-pCR in patients with HR+/HER2-/high nuclear grade or HR-/HER2- tumors. In contrast, in
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patients with HER2+ tumors, only achievement of pCR was prognostic factor.
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Abstract Background: While the prognostic value of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) depend on the intrinsic subtype of breast cancer, it
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is not clear whether chemosensitivity itself, shown by a decreasing tumor burden after NAC, contributes to improved prognosis in primary breast cancer patients, especially in patients with non-pCR. The aim of this study was to assess the prognostic impact of
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changes in tumor stage or nodal status after NAC in each primary breast cancer
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subtype.
Methods: We assessed 719 consecutive patients with primary breast cancer who underwent surgical resection after NAC between 2001 and 2010. The patients were divided into 5 subtypes according to their hormone receptor (HR) status, epidermal growth factor receptor-2 (HER2) status, and nuclear grade (NG: 1/2, low and 3, high).
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Results: In patients with HR+/HER2-/NG-low tumors, regardless of change in tumor size, the loss of node positivity after NAC significantly improved disease-free survival
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(DFS). In patients with HR+/HER2-/NG-high tumors, achievement of both of tumor downstaging and the loss of node positivity improved their DFS. In patients with
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HR-/HER2- tumors tumor downstaging and the loss of node positivity significantly improved DFS, despite a non-pCR. In contrast, in patients with HER2+ tumors, changes in tumor stage or nodal status were not associated with prognosis unless pCR was achieved.
Conclusion: Our results revealed that changes in tumor stage and nodal status after NAC might be prognostic markers in patients with HR+/HER2-/NG-high tumors or HR-/HER2- tumors, even if there are residual tumors in the breast.
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Key words Breast cancer, neoadjuvant chemotherapy, hormone receptor, epidermal growth factor
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receptor-2, pathologic complete response, nuclear grade
Introduction
Neoadjuvant chemotherapy (NAC) is a standard treatment for primary breast cancer
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patients, since its prognostic impact was revealed to be the same as that of adjuvant
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chemotherapy [1, 2]. The advantage of NAC is a reduction in tumor size and an increase in the rate of breast-conserving surgery. It is also beneficial for allowing assessment of the response of the primary tumor and lymph nodes to systemic treatment. A pathologic complete response (pCR) is an important prognostic factor in primary breast cancer patients [1, 3]. Several previous studies have shown that patients
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who achieved pCR after NAC had a significantly better prognosis than those who did not [3-5]. Recently, it has been shown that the effect of NAC and the prognostic value
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of pCR depend on the intrinsic subtype of breast cancer [6, 7]. pCR after NAC improves the survival of patients with epidermal growth factor receptor-2
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(HER2)-positive and triple-negative (TN) breast cancers, but that of those with hormone receptor (HR)-positive/HER2-negative breast cancer [1, 8-10]. However, regardless of residual tumors, it is not clear whether chemosensitivity, shown by a decrease in the tumor burden after NAC, contributes to an improvement in the prognosis of patients with primary breast cancer. Thus, the aim of this study was to assess the prognostic impact of changes in tumor stage or nodal status after NAC in each primary breast cancer subtype.
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Patients and Methods Patients We identified 719 consecutive patients with primary breast cancer who underwent
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surgical resection after NAC between January 2001 and December 2010 in our institute’s breast cancer database. Patients with estrogen receptor (ER)- and/or
progesterone receptor (PR)-positive tumors received adjuvant endocrine treatment.
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Adjuvant radiotherapy was applied to patients who underwent breast-conserving
surgery and those who underwent mastectomy with equal and larger than cT3, or cN2
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and cN3 disease. The clinical stage was defined using radiological findings of ultrasound, MRI, and CT scans. Clinical node positivity was confirmed using fine needle aspiration cytology if lymph node metastasis was suspected; this was based on ultrasound findings showing reduced fatty deposition, and demonstrating lateral
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cortical hypertrophy [11].
We excluded patients who underwent sentinel lymph node biopsy before NAC, as well as those with metastatic disease or other prior malignancies, inflammatory breast
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cancer, and a history of treatment for breast cancer. This study waived the need for written informed consent because of the retrospective nature. All specimens were
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collected following the protocol approved by the institutional review board.
Pathological assessment Invasive breast cancer was histologically confirmed in all patients using needle biopsy before NAC. ER/PR status was assessed using immunohistochemistry (IHC). ER/PR status was considered as positive if the Allred staining score was ≥3 for the receptor. HER2 status was determined using IHC and/or fluorescent in situ hybridization (FISH)
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assays. HER2 positivity was defined as a receptor overexpression staining score of 3+ on IHC, or as gene amplification using FISH with a CEP-17 ratio >2.0. We divided patients into the following 5 subtypes based on HR (ER and/or PR) status, HER2 status,
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and NG (1/2, low; 3, high). The subtypes were HR+/HER2-/NG-low tumors,
HR+/HER2-/NG-high tumors, HR-/HER2- tumors, HR+/HER2+ tumors, and
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HR-/HER2+ tumors. pCR was defined as no residual invasive tumor and ypN0.
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Staging analysis
Individual patient data regarding clinical characteristics, histopathological findings at surgery, and follow-up were extracted from the pooled databases of our institution. Based on changes in T stage, downstaging (DS) was defined as a decreased T stage and non-DS was defined as the same or an increased T stage after NAC, based on Union
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for International Cancer Control criteria [12]. In terms of changes in nodal status, the clinical nodal status before chemotherapy and the pathological nodal status after NAC
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were considered.
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Statistical analysis
We compared the patients with respect to disease-free survival (DFS) and overall survival (OS) based on changes in tumor stage and nodal status after NAC. DFS and OS were calculated from the date of diagnosis to local or distant recurrence, death, or last follow-up, and plotted as Kaplan-Meier curves. Log-rank P-values were calculated for the changes in tumor stage and nodal status after NAC. Hazard ratios (HRs), 95% confidence intervals (CIs), and corresponding P-values were calculated using Cox
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regression analysis. SPSS 17.0 (SPSS, Chicago, IL) was used to perform all analyses. P-values less than 0.05 were considered statistically significant.
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Results Patient characteristics
The median age of patients at diagnosis was 49 years (range, 24 to 75 years). Four
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hundred ninety-three patients had HR-positive tumors (69%) and 166 patients had
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HER2-positive tumors (23%) (Table 1). One hundred two (14%) patients achieved a pCR; 8 of these patients (2%) had HR+/HER2-/NG-low tumors, 5 (8%) had HR+/HER2-/NG-high tumors, 32 (24%) had HR-/HER2- tumors, 20 (26%) had HR+/HER2+ tumors, and 37 (41%) had HR-/HER2+ tumors.
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Prognostic impact of pCR in each subtype
With a median follow-up period of 78 months, patients with HR-/HER2- tumors who
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achieved pCR had longer DFS and OS than those who did not (P = 0.001, and 0.001 respectively). Furthermore, patients with HR-/HER2+ tumors who achieved a pCR had
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longer DFS and OS than those who did not (p=0.047, and p=0.025 respectively). However, in patients with HR+ tumors, there was no difference in DFS and OS between the pCR and non-pCR groups.
Prognostic impact of changes in tumor stage and nodal status after NAC Because a pCR had a prognostic impact in patients with HR-/HER2- and HR-/HER2+ tumors, but not in HR+ tumors, we excluded patients with HR-/HER2- and HR-/HER2+ tumors with a pCR from further analysis; we assessed the significance of 7
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changes in tumor size and nodal status for patients with residual tumors who had a worse prognosis. In patients with HR+/HER2-/NG-low tumors (n = 353), there was no significant difference between DS and non-DS with respect to both DFS and OS (P =
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0.14, and 0.89, respectively). In terms of changes in nodal status, a change from
clinical node-positive (cN+) to pathological node-negative after NAC (ypN0) resulted in a significantly longer DFS than those remained pathologically node-positive (ypN+)
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(P = 0.004). A similar trend was found with respect to OS (P = 0.055) (Supplementary
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Fig 1, d). In patients with HR+/HER2-/NG-high tumors (n = 64), patients with DS had significantly longer DFS than those with non-DS; however, it was not associated with an improvement in OS (P = 0.015, and 0.123, respectively) (Supplementary Fig 2, a and b). The loss of node-positivity from cN+ to ypN0 resulted in a significantly longer DFS than those remained ypN+, and there was a similar trend with respect to OS (P =
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0.006, and 0.077, respectively) (Supplementary Fig 2, c and d). In patients with HR-/HER2- tumors with a non-pCR (n = 136), patients with DS had a significantly
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better prognosis than those non-DS with respect to both DFS and OS (P = 0.003, and 0.001, respectively). The loss of node positivity was associated with a significantly
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better DFS than those remained ypN+ after NAC; however, it was not associated with an improvement in OS (P = 0.045, and 0.163, respectively) (Supplementary Fig 3). However, in patients with HR+/HER2+ tumors (n = 76) and HR-/HER2+ tumors (n = 90) with non-pCR, changes in both tumor stage and nodal status after NAC did not improve their prognosis (Supplementary Fig 4 and 5). Finally, we assessed the prognostic impact of the combination of changes in tumor stage and nodal stage in each of the 5 subtypes (Fig 1). In patients with HR+/HER2-/NG-low tumors, regardless of non-DS, the loss of node positivity 8
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significantly improved DFS (Fig 1, a). In patients with HR+/HER2-/NG-high tumors, achievement of both DS and loss of node positivity improved their DFS (P = 0.021, cN0 to ypN0/DS vs. cNany to ypN+/non-DS; and P = 0.028, cN+ to ypN+/non-DS vs.
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cNany to ypN+/non-DS, respectively) (Fig 1, b). In patients with HR-/HER2- tumors with a non-pCR, DS in addition to the loss of node positivity significantly improved
DFS, regardless of the non-pCR (Fig 1, c). In contrast, in patients with HER2+ tumors,
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changes in tumor stage or nodal status were not associated with prognosis (Fig 1, d and
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e).
Discussion
Because a pCR has been confirmed as a prognostic marker in primary breast cancer patients with HR-/HER2+ tumors and HR-/HER2- tumors, the treatment strategy aims
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to achieve pCR with NAC to improve the prognosis [1, 13, 14]. However, in patients with HR+/HER2- tumors, it has been reported that a pCR is not a prognostic marker
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[1]. In this study, we demonstrated that changes in tumor stage and nodal status after NAC were associated with prognosis in patients with HR+/HER2-/NG-high tumors,
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regardless of the presence of a residual tumor. Furthermore, we showed that the extent of the impact on prognosis depends on the intrinsic subtype of breast cancer. Loss of node positivity after NAC has been reported in approximately 40% of cases [2, 15]. Previous studies have shown that the pathologic nodal status after NAC is a better prognostic marker than a pCR [16-19]. The prognostic importance of involved lymph nodes after NAC has already been shown by previous studies [19, 20]. From our results, patients with HR+/HER2- disease and loss of node positivity had significantly better DFS than those with pathologically node-positive disease. In addition, in luminal 9
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B-like tumors with a high NG, changes in tumor stage were significantly associated with a better prognosis; however, this was not the case in patients with luminal A-like tumors with a low NG. We also showed that, for patients with HR+/HER2- tumors, the
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loss of node positivity after NAC may be a prognostic marker. Notably, for patients with HR-/HER2- tumors, changes in tumor stage and nodal status after NAC were
significantly associated with prognosis, even if they did not achieve a pCR. In general,
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patients with HR+ tumors with either pCR or non-pCR had a better prognosis than
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those with HR- tumors. However, even for patients with luminal–B like tumors who need systemic chemotherapy to prolong their survival, there is no clear prognostic marker. Therefore, our results indicated that, especially for HR+/HER2- and NG-high tumors, so-called luminal B-like tumors, and HR-/HER2- tumors, NAC aiming DS
tumors.
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might contribute to improved survival in patients with node positivity and large
For patients with HER2+ tumors, regardless of HR-positivity, only a pCR has a
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prognostic impact. Therefore, patients with HER2+ subtype disease need to achieve pCR to improve their prognosis. Fortunately, novel HER2-targeting agents, such as
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pertuzumab, lapatinib, and trastuzumab emtansine (T-DM1), increase the pCR rate in patients with HER2+ tumors [21, 22]. Additional novel treatments to support current standard treatments should be used for patients with no change in tumor stage and node positivity with a poor prognosis. There are some limitations in our study; patient data were retrospectively collected, and the accurate number of clinical node metastases was hard to assess in radiological findings. However, we could show the importance of node positivity itself as a prognostic marker without considering the number in our study. 10
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Conclusions Our results revealed that changes in tumor stage and nodal status after NAC might be
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prognostic markers in patients with HR+/HER2-/NG-high tumors or HR-/HER2-
tumors, even if there are residual tumors in the breast. NAC may be beneficial for
patients with HR+/HER2-/NG-high tumors and node-positive and/or large tumors.
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Prospective studies are needed to assess the role of additional adjuvant treatment for
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such patients with these poor prognostic factors after NAC.
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Clinical Practice Points: In current clinical practice, the prognostic impact of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) depends on the intrinsic subtype of
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breast cancer. However, it is not clear the prognostic impact of changes in tumor stage or nodal status after NAC in each primary breast cancer subtype, especially in patients with non-pCR. In our study, results revealed that changes in tumor stage and nodal
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status after NAC might be prognostic markers in patients with HR+/HER2-/NG-high
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tumors or HR-/HER2- tumors, even if there are residual tumors in the breast. In patients with hormone receptor (HR)+/ epidermal growth factor receptor-2 (HER2)-/ nuclear grade (NG)-low (1 or 2) tumors, regardless of change in tumor size, the loss of node positivity after NAC was prognostic factor. In patients with HR+/HER2-/NG-high (3) tumors, achievement of both of tumor downstaging and the
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loss of node positivity improved their DFS. In patients with HR-/HER2- tumors tumor downstaging and the loss of node positivity significantly improved prognosis, despite a
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non-pCR. In contrast, in patients with HER2+ tumors, changes in tumor stage or nodal status were not associated with prognosis unless pCR was achieved. NAC may be
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beneficial because the response to treatment can show their prognosis in each breast cancer subtype regardless of no achievement of pCR. Prospective studies are needed to assess the role of additional adjuvant treatment for such patients with these poor prognostic factors after NAC.
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Acknowledgements: The authors thank all the staff from the departments of Breast Surgical Oncology, Radiology and Pathology, St. Luke’s International Hospital, for their help in collecting
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the clinical data.
A part of this study has been presented at San Antonio Breast Cancer Symposium 2013
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in Texas, and Annual meeting Japanese Breast Cancer Society 2016 in Tokyo.
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Figure legends Figure 1: The prognostic impact of change in tumor stage and nodal status on disease-free
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survival (DFS); (a) in HR+/HER2-/NG-low tumors, (b) in HR+/HER2-/NG-high
tumors, (c) in HR-/HER2- tumors, (d) in HR+/HER2+ tumors, and (e) in HR-/HER2+ tumors
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Abbreviation: cN, clinical nodal status; ypN, pathological node status after
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neoadjuvant chemothrapy; DS, down stage; HR, hormone receptor; HER2, Human Epidermal growth factor Receptor-2
Supplementary Figure 1:
The prognostic impact of change in tumor stage and nodal status in patients with
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HR+HER2-/NG-low tumor, (a) on Disease-free survival (DFS) and (b) overall survival (OS) in patients according to change in tumor stage; (c) DFS and (d) OS in patients
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according to change in nodal stage. Supplementary Figure 2:
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The prognostic impact of change in tumor stage and nodal status in patients with status for HR+/HER2-/NG-high tumor, (a) on Disease-free survival (DFS) and (b) overall survival (OS) in patients according to change in tumor stage; (c) DFS and (d) OS in patients according to change in nodal stage. Supplementary Figure 3: The prognostic impact of change in tumor stage and nodal status in patients with
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HR-/HER2- tumor, (a) on Disease-free survival (DFS) and (b) overall survival (OS) in patients according to change in tumor stage; (c) DFS and (d) OS in patients according
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to change in nodal stage. Supplementary Figure 4:
The prognostic impact of change in tumor stage and nodal status in patients with
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HR+/HER2+ tumor, (a) on Disease-free survival (DFS) and (b) overall survival (OS)
according to change in nodal stage.
Supplementary Figure 5:
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in patients according to change in tumor stage; (c) DFS and (d) OS in patients
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The prognostic impact of change in tumor stage and nodal status in patients with HR-/HER2+ tumor, (a) on Disease-free survival (DFS) and (b) overall survival (OS) in patients according to change in tumor stage; (c) DFS and (d) OS in patients according
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to change in nodal stage.
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All patients
HR+/HER2-/NG-low
HR+/HER2-/NG-high
HR+/HER2+
%
N
%
N
%
N
%
719
100
353
49
64
9
76
11
<35
48
7
20
6
6
9
35-39
75
10
40
11
7
40-49
255
36
155
44
28
50-59
225
31
94
27
13
60-
116
16
44
12
10
NG1
303
42
247
NG2
196
27
106
NG3
214
30
0
All patients
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Age, years
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N
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Table 1 Patient characteristics HR-/HER2+
HR-/HER2-
N
%
N
%
90
12
136
19
7
2
2
15
11
11
4
5
12
13
12
9
44
21
28
16
18
35
26
20
35
46
41
46
42
31
16
11
14
19
21
32
23
EP
TE D
5
AC C
Nuclear Grade 70
0
0
19
25
15
17
22
16
30
0
0
29
38
30
33
31
23
0
64
100
27
36
41
46
82
60
21
ACCEPTED MANUSCRIPT
6
<1
0
0
0
0
1
1
cTis
3
<1
3
<1
0
0
0
0
cT1
88
12
44
13
3
5
10
13
cT2
515
72
253
72
50
78
53
cT3
79
11
38
11
7
11
12
cT4
34
5
15
43
4
6
cN0
313
44
146
41
26
cN1
352
49
184
52
cN2
19
3
7
2
cN3
30
4
16
15
10
ypT0/Tis
111
1
1
0
0
0
17
19
14
10
62
69
97
71
16
6
7
16
12
1
1
5
6
9
6
41
33
43
40
44
68
50
32
50
37
49
43
48
61
45
6
3
4
4
4
1
<1
70
M AN U
TE D
AC C
4
SC
0
nodal status
pathological tumor stage
4
EP
clinical Tumor stage
4
RI PT
NA
5
2
3
3
4
3
3
6
5
3
5
8
23
30
39
43
34
25
22
ACCEPTED MANUSCRIPT
31
92
26
26
41
29
38
ypT2
242
34
154
44
23
36
16
21
ypT3
85
12
61
17
5
8
7
9
ypT4
55
8
36
10
5
8
1
1
36
47
35
16
18
33
24
3
3
9
7
0
0
13
10
375
52
121
34
33
52
50
66
73
81
98
72
ypN1
225
31
150
42
19
30
21
28
14
16
21
15
ypN2
89
12
59
17
9
14
4
5
3
3
14
10
ypN3
30
4
23
7
3
5
1
1
0
0
3
2
pCR
102
14
8
2
8
20
26
37
41
32
24
non-pCR
617
86
345
226
31
0
ER/PgR status negative
5
AC C
Reeponse
TE D
ypN0
EP
M AN U
pathological nodal status
32
RI PT
226
SC
ypT1
98
59
92
56
74
53
59
104
76
0
0
0
0
0
90
100
136
100
23
ACCEPTED MANUSCRIPT
493
69
353
100
64
100
76
100
negative
553
77
353
100
64
100
0
0
positive
166
23
0
0
0
0
76
100
0
0
0
0
0
136
100
90
100
0
0
AC C
EP
TE D
M AN U
SC
HER2 status
0
RI PT
positive
24
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
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