Pathologic Response Rates for Breast Cancer Stages as a Predictor of Outcomes in Patients Receiving Neoadjuvant Chemotherapy Followed by Breast-Conserving Surgery

PURPOSE: To determine easy-to-use predictors of overall survival (OS), locoregional recurrence (LRR), and distant metastasis (DM) in patients with breast invasive ductal carcinoma (IDC) receiving neoadjuvant chemotherapy (NACT) followed by breast-conserving surgery (BCS), we obtained pathologic response rates (PRRs) for combined primary and nodal diseases (American Joint Committee on Cancer [AJCC] stages) from clinical and pathologic reports, and we used these as predictors. PATIENTS AND METHODS: We enrolled patients with IDC who had received NACT followed by BCS. Cox regression analysis was used to calculate hazard ratios (HRs) and condence intervals (CIs) for the patients’ PRRs; other independent predictors were controlled for or stratied in the analysis. RESULTS: We analyzed 1047 patients with IDC (611, 260, and 176 patients in clinical stages IIB, IIIA, and IIIB-C, respectively) receiving NACT and BCS. After multivariate Cox regression analyses, the adjusted HRs (aHRs; 95% CI) in patients with pathologic complete response (ypT0N0) were 0.26 (0.13–0.56), 0.36 (0.15–0.85), and 0.15 (0.08–0.31) for all-cause mortality, LRR, and DM, respectively. The aHRs (95% CI) in patients with downstaging of AJCC stages were 0.55 (0.35–0.89), 0.91 (0.62–0.96), and 0.63 (0.43– 0.91) for all-cause mortality, LRR, and DM, respectively. The aHRs (95% CI) in patients with upstaging of AJCC stages were 1.77 (1.06–2.24), 1.08 (1.03–1.82), and 1.19 (1.07–2.01) for all-cause mortality, LRR, and DM, respectively. CONCLUSION: The impacts useful and DM in patients with breast IDC receiving NACT followed by BCS. Condensed Abstract: No study has comprehensively analyzed the impact of pathologic response rates (PRRs) for disease stages on overall survival (OS), locoregional recurrence (LRR), or distant metastasis (DM) in patients with breast invasive ductal carcinoma (IDC) receiving neoadjuvant chemotherapy (NACT) and breast-conserving surgery (BCS). This large cohort study was used to estimate the impact of changes in American Joint Committee on Cancer stages on OS, LRR, and DM in patients with IDC receiving NACT and BCS. Our data indicate that PRRs, determined using staging records, provide a


Introduction
Neoadjuvant chemotherapy (NACT) is associated with high rates of clinical response and a greater likelihood that cosmetically acceptable surgery can be performed. [1,2] For example, patients who are not candidates for breast-conserving surgery (BCS) may become eligible after NACT; those with limited nodepositive diseases (cN1) may be appropriate candidates for more limited axillary surgery after NACT. [2,3] However, NACT alone has not been shown to improve disease-free survival (DFS) or overall survival (OS) compared with the same treatment administered after surgery. [1] Among patients treated with NACT, the achievement of a pathologic complete response (pCR) to surgery is prognostically signi cant. [4][5][6][7] Pathologic assessment of the breast and axillary nodes is performed to determine the presence and extent of residual invasive disease after NACT completion. The achievement of pCR in the breast and axilla (ypT0 & ypN0) correlates with improved survival. [6,8] Through the pooled analysis of the Collaborative Trials in Neoadjuvant Breast Cancer with mature follow-up data, we aimed to characterize the relationship between pCR and long-term outcomes. [9] Achieving a pCR in both the breast and the axilla was associated with improved event-free survival (EFS) and OS compared with a pCR (ypT0 & ypN0) in the breast alone (ypT0). [9] However, studies have associated a pCR with superior OS in patients with breast cancer receiving NACT followed by either total mastectomy (TM) or BCS, [4][5][6][7][9][10][11][12] but su cient data do not support the association between pCR and survival bene ts in patients receiving NACT followed by BCS. In addition, pathologic response after NACT includes not only pCR but also partial response, disease stability, and disease progression. [10] No study has shown the predictive ability of pathologic response in patients with breast cancer receiving NACT followed with mastectomy, particularly with respect to BCS.
In the past, the residual cancer burden (RCB) score has provided a means for assessing the extent of residual invasive disease in the tumor bed and the extent of residual nodal involvement after NACT. [10] However, RCB is not widely used as a predictor for survival in current clinical practice because no consensus for reading RCB exists among pathologists. Thus, we used the clinical and pathological American Joint Committee on Cancer (AJCC) tumor, node, and metastasis system after NACT to obtain simple pathologic response rates (PRRs) as predictors for patients with breast cancer receiving NACT followed by BCS. For patients with breast cancer receiving NACT, according to their PRRs and the applicability of poor prognostic factors, BCS might be used as a more aggressive adjuvant, or consolidative chemotherapy might subsequently be necessary.

Patients And Methods
In this study, we established a cohort of patients with breast invasive ductal carcinoma (IDC) by using data from the Taiwan Cancer Registry database (TCRD). We enrolled patients with breast IDC diagnoses between January 1, 2007, and December 31, 2015. The follow-up duration was from the index date to December 31, 2016. The Cancer Registry database of the Collaboration Center of Health Information Application contains detailed cancer-related information of patients, including clinical stages, treatment modalities, pathologic data, irradiation doses, hormone receptor (HoR) status, human epidermal growth factor receptor 2 (HER2) status, and chemotherapy regimens used. [13][14][15][16][17][18][19][20][21] In the study, we included women with breast IDC receiving NACT followed by BCS. Our protocols were reviewed and approved by the Institutional Review Board of Taipei Medical University. The diagnoses of the enrolled patients were con rmed through their pathologic data, and patients who received a new diagnosis of breast IDC were con rmed to have no other types of cancer. Patients with a diagnosis of breast IDC who had received NACT followed by BCS, who were aged ≥ 20 years, and whose AJCC clinical cancer stages were IIB to IIIC were included. Moreover, initial AJCC clinical staging and pathologic staging were recorded in the TCRD.
The breast cancer stages were assessed according to the AJCC, seventh edition. Patients with metastasis, missing sex data, age < 20 years, receipt of nonstandard adjuvant whole breast radiotherapy (where standard RT means RT to treat the entire breast with 1.8-to 2-Gy daily fractions for 4.5 to 5 weeks, signifying a total dose of 45 to 50 Gy), unclear differentiation of tumor grade, unclear pathologic response, missing HoR status, missing HER2 status, or unclear staging were excluded. Furthermore, we excluded patients with unclear NACT regimens, receipt of fewer than four NACT cycles, ill-de ned nodal surgery, and missing hospital types [22] (academic center or community hospitals) in our cohort. PRRs were classi ed into upstages (clinical stage upgrade to advanced pathologic stage), equal stages (clinical stage equal to pathologic stage), downstages (clinical stage down to relatively early pathologic stages), and pCRs (absence of residual invasive cancer). HoR positivity was de ned as ≥ 1% of tumor cells demonstrating positive nuclear staining through immunohistochemistry, [23] and HER2 positive was de ned as an immunohistochemistry score 3 + or uorescence in situ hybridization ratio ≥ 2. [22,24] Finally, we enrolled patients with breast IDC receiving NACT followed by BCS and categorized them into clinical AJCC stage groups. The index date was the date of breast cancer diagnosis. Comorbidities were scored using the Charlson comorbidity index (CCI). [25,26] Only comorbidities observed 6 months before the index date were considered; comorbidities that were included were identi ed according to the main International Classi cation of Diseases, Ninth Revision, Clinical Modi cation (ICD-9-CM) diagnosis codes for the rst admission or the main diagnosis codes associated with more than two visits to the outpatient department.
After adjustment for confounders, the Cox proportional method was used to model the time from the index date to all-cause mortality, LRR, and DM among patients who had received NACT followed by BCS.
In the multivariate analysis, hazard ratios (HRs) were adjusted for the AJCC stage PRRs, initial clinical stage, age, diagnosis year, CCI score, differentiation, NACT regimen, nodal surgery, adjuvant RT, HoR status, HER2 status, and academic hospital status. Strati ed analyses for the various initial clinical stages were performed to evaluate the predictors of all-cause death; furthermore, in the multivariate analysis, we used the PRRs of AJCC stage, initial clinical stage, age, diagnosis year, CCI score, differentiation, NACT regimen, nodal surgery, adjuvant RT, HoR status, HER2 status, and academic hospital. Multivariate analysis with strati cation according to the PRRs for T stages or N stages was conducted to evaluate the impact on all-cause death, LRR, DM, and DFS of NACT followed by BCS. All analyses were performed using SAS (version 9.3; SAS, Cary, NC, USA). A two-tailed value of P < 0.05 was considered statistically signi cant.

Results
The nal cohort eligible for further analysis consisted of 1047 patients (611, 260, and 176 patients in clinical stages IIB, IIIA, and IIIB-IIIC, respectively). The patient characteristics are summarized in Table 1. Initial clinical stages were found to exert no statistically signi cant effects in terms of CCI score, tumor differentiation, diagnosis year, use of adjuvant RT, HoR status, HER2 receptor status, or academic hospital status ( Table 1). The disease was in the advanced stages IIIB to IIIC for more of a greater number of elderly patients in the cohort. More patients receiving NACT were diagnosed between 2011 and 2015 than between 2007 and 2010. More patients with breast IDC in the advanced stages IIIA to IIIC received taxanebased NACT regimens and axillary lymph node dissection (ALND). In addition, patients with breast cancer in the more advanced clinical stages IIIA to IIIC exhibited more AJCC-stage, T-stage, and N-stage pCRs or downstaging. Risks for all-cause death, LRR, and DM were signi cantly higher in advanced clinical stages, such as stage IIIA to IIIC, compared with in stage IIB (Table 1).  (Table 2). Moreover, multivariate analysis revealed that AJCC clinical stages IIIA to IIIC, post-NACT upstaging of AJCC stages, no use of adjuvant RT treatment, HoR negativity, and HER2 positivity were independently poor prognostic factors for DM after multivariate analysis. factors of all-cause death for stages IIB to IIIC. HER2 positivity was an independent poor prognostic factor of all-cause death among clinical stages IIIA to IIIC (Table 3).   Fig. 2). The upstaging of N stages was a signi cantly poor prognostic factor for all-cause death, DM, and DFS but was not a signi cant predictor for LRR.

Discussion
NACT is the systemic treatment of breast cancer prior to de nitive surgical therapy such as TM or BCS with ALND or SLNB. [2-7, 9, 10] Although all systemic therapy for nonmetastatic invasive breast cancer is intended to reduce the risk of DM, the purpose of administering chemotherapy prior to surgery is to downstage tumors and provide information regarding treatment response. [3,11,[27][28][29] Typically, neoadjuvant treatment is administered in the form of chemotherapy such as anthracycline-based chemotherapy, taxane-based chemotherapy, or both as basic regimens. [30][31][32] No data or research have indicated an association between pathologic response and survival outcomes such as all-cause death, LRR, and DM in patients with breast IDC receiving NACT followed by BCS. Most studies have shown that pCR in patients with breast cancer receiving NACT indicates superior survival outcomes compared with those non-pCR patients with breast cancer receiving NACT followed by either TM or BCS. [4][5][6][7][9][10][11][12] However, no other pathologic responses, such as partial pathologic response or progressive change of pathologic response, function as predictors for survival outcomes in patients with breast cancer receiving NACT followed by BCS. Studies have shown associations between pCR and EFS or OS, [4][5][6][7][9][10][11][12] [4][5][6][7][9][10][11][12] but also for LRR and DM in patients with breast IDC receiving NACT followed by BCS. Although studies have found the RCB to predict survival after NACT, [10,33] the complicated measurement system for the RCB, requiring consensus among particular pathologists, is not popularly used globally. Moreover, although the RCB is used as a predictor for DM or OS, it is not used for LRR, regardless of subsequent surgical procedures, such as TM, BCS, ALND, or SLNB, assessed in other research. [10,33] In Table 2, the upstaging of AJCC stages after NACT is seen to be associated with high risk of all-cause death, LRR, and DM. Therefore, in the future, patients with breast IDC receiving NACT upstaging of AJCC stages might be considered for subsequent aggressive treatments such as TM, adjuvant RT, or innovative consolidative chemotherapy regimens.
Adjuvant RT is potentially valuable for patients with breast IDC receiving NACT followed by BCS (Tables 2-3). Adjuvant RT was shown to decrease the risk of all-cause death, LRR, and DM in these patients (Table 2). Physicians previously believed adjuvant RT to be bene cial for patients with breast IDC receiving BCS on the basis of old studies in which patients with breast cancer received BCS without NACT [34]; however, no data had suggested that it exhibits real bene ts for patients with breast IDC receiving NACT followed by BCS. The value of adjuvant RT after NACT followed by BCS has never been quanti ed, and clinical trials may be unable to resolve this. Our study showed that adjuvant RT is a signi cantly valuable treatment for the improvement of OS, LRR, or DM in patients with breast IDC receiving NACT followed by BCS, even in patients with AJCC stage pCR or downstaging (Table 2-3). This is the rst study to show the survival bene ts of adjuvant RT for patients with breast IDC receiving NACT followed by BCS. HoR positivity was also a signi cant predictor for OS, LRR, and DM in patients with breast IDC receiving NACT followed by BCS (Table 2). Our results, showing that HoR positivity is associated with superior survival outcomes in patients with breast cancer, corroborate those of other studies on various treatments. [35] Although HoR positivity was a good prognostic factor for OS, LRR, and DM in patients with breast cancer, [35] no data indicate HoR positivity to be a good prognostic factor in patients receiving NACT followed by BCS. Our study provides the best evidence that HoR positivity is a good prognostic factor for patients with breast IDC receiving NACT followed by BCS. In Table 2, HER2 positivity is seen to be a poor prognostic factor for LRR and DM in patients with breast IDC receiving NACT followed by BCS. Our ndings are compatible with those of other studies that have similarly concluded that HER2 positivity is a risk factor for LRR and DM, [36], [37] although not speci cally in patients with breast IDC receiving NACT followed by BCS. In our study, anthracycline-or taxane-based NACT regimens were not signi cant predictors of survival, as in the results of one meta-analysis that enrolled 1695 patients in nine trials. [38] As seen in Table 2, multivariable analysis revealed initial clinical AJCC stages to be signi cant predictors of OS, LRR, and DM in patients with breast IDC receiving NACT followed by BCS. Therefore, clinical states are strati ed in Table 3 to assess the value of PRRs as predictors in patients with breast IDC receiving NACT followed by BCS. As seen in Table 3, PRRs are strong predictors of OS, LRR, and DM in patients, even for strati ed analysis of initial clinical AJCC stages. Multivariable analysis revealed that adjuvant RT, HoR positivity, and HER2 negativity were good prognostic factors of survival outcomes at all clinical stages (Table 3). Our ndings indicate that PRRs are a simple and useful predictive tool, using clinical and pathologic AJCC stages from current pathologic practice for patients with breast IDC receiving NACT followed by BCS, regardless of their clinical stages. Adjuvant RT, HoR status, and HER2 status were also notable predictors for survival outcomes. For patients with breast IDC receiving NACT followed by BCS, adjuvant RT signi cantly decreased the risk of all-cause death, LRR, and DM, regardless of the initial clinical stage (Table 3).
As well as estimating the predictive ability of AJCC stage PRRs, we wished to estimate the predictive ability of T-stage PRRs (Supplemental Fig. 1) and N-stage PRRs (Supplemental Fig. 2). Multivariable analysis revealed that T-stage (ypT0) pCR and downstaging were good prognostic factors for OS, LRR, DM, and DFS but were nonsigni cant for LRR. The ndings show that T-stage PRRs were also good predictors for survival outcomes, although AJCC stage PRRs might be more useful for all OS, LRR, and DM outcomes than are T-stage PRRs (which are not signi cant predictors for LRR). In Supplemental [39] The downstaging of N stages was not signi cant for OS, LRR, DM, or DFS, demonstrating that the downstaging of N stages was not a signi cant predictor of survival outcomes, in accord with other research results. [39] In addition, the upstaging of N stages was a poor prognostic factor for OS, DM, and DFS but was not a signi cant predictor of LRR. Taken together, the T-stage and N-stage PRRs both predicted partial survival outcomes in patients with breast IDC receiving NACT followed by BCS.
Nevertheless, AJCC stage PRRs provided a more powerful predictive tool for all survival outcomes, including OS, LRR, and DM.

Conclusions
PRRs provide an easy-to-use predictive tool, and they are strong predictors for OS, LRR, and DM in patients with breast IDC receiving NACT followed with BCS, regardless of the respective clinical stages.