NACT is the systemic treatment of breast cancer prior to definitive 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, 27–29] Typically, neoadjuvant treatment is administered in the form of chemotherapy such as anthracycline-based chemotherapy, taxane-based chemotherapy, or both as basic regimens.[30–32] 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.[4–7, 9–12] 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,[4–7, 9–12] but no further data are available on the associations of other pathologic responses, based on AJCC stages (downstages, upstages, or equal stages), with survival outcomes for OS, LRR, or DM. Therefore, the use of AJCC stage PRRs (equal stages, upstages, downstages, and pCR) as predictors in patients with breast IDC receiving NACT followed by BCS provides a valuable tool. The respective outcomes might indicate further adjuvant treatments. Our study is the first to demonstrate the real value of PRRs in patients with breast IDC receiving NACT followed by BCS. According to our findings (Table 2–3), in the future, physicians might consider subsequent alternative treatments such as further TM instead of BCS or adjuvant RT in patients with high LRR risk. In patients for whom PRRs indicate high DM risk, adjuvant or consolidative chemotherapy with innovative regimens might be considered for decreasing the risk of DM. Thus, the use of PRRs for patients with breast IDC receiving NACT followed by BCS, which acts as a simple predictive tool, is potentially valuable for identifying further treatment choices for patients with high LRR or DM risk. As such, aggressive treatments might be omitted in patients with low DM and LRR risk.
Multivariable analysis demonstrated the AJCC stage PRRs to be significant predictors for OS, LRR, and DM in patients with breast IDC receiving NACT followed by BCS (Table 2). Our study is the first study to show that AJCC stage PRRs are strong predictors in patients receiving NACT followed by BCS. In our study, we evaluated the predictive ability of PRRs not only for OS and EFS[4–7, 9–12] 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 beneficial 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 benefits for patients with breast IDC receiving NACT followed by BCS. The value of adjuvant RT after NACT followed by BCS has never been quantified, and clinical trials may be unable to resolve this. Our study showed that adjuvant RT is a significantly 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 first study to show the survival benefits of adjuvant RT for patients with breast IDC receiving NACT followed by BCS. HoR positivity was also a significant 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 findings 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 specifically in patients with breast IDC receiving NACT followed by BCS. In our study, anthracycline- or taxane-based NACT regimens were not significant 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 significant predictors of OS, LRR, and DM in patients with breast IDC receiving NACT followed by BCS. Therefore, clinical states are stratified 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 stratified 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 findings 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 significantly 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 nonsignificant for LRR. The findings 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 significant predictors for LRR). In Supplemental Fig. 2, N-stage pCR (ypN0) is seen to be a significant predictor of OS, LRR, DM, and DFS. N-stage pCR indicated superior OS in patients with breast cancer receiving NACT, as in the results of other research.[39] The downstaging of N stages was not significant for OS, LRR, DM, or DFS, demonstrating that the downstaging of N stages was not a significant 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 significant 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.
The strength of our research was that it constituted the first and largest cohort study in which the impacts of AJCC stage, T-stage, and N-stage PRRs on OS, LRR, and DM have been evaluated in patients with breast IDC receiving NACT followed by BCS. The NACT regimens used to treat patients were relatively homogenous in our study. No studies have used stratification of all predictors, including clinical stage, to evaluate in detail the impact of PRRs on treatment outcomes in patients with breast cancer receiving NACT followed by BCS. In our study, the poor prognostic factors of OS in breast cancer patients receiving NACT followed by BCS were no use of adjuvant RT, pre-NACT disease status in advanced clinical stages IIIA to IIIC, HoR negativity, and HER2 positivity (Table 2). Our simple tool, which used available AJCC clinical and pathologic staging records to obtain PRRs, differs from other research approaches wherein RCB was calculated as a continuous index combining pathologic measurements by trained pathologists.[33] Our PRRs were straightforward to use on the basis of staging records; were powerful for predicting OS, LRR, and DM in patients with breast IDC receiving NACT followed by BCS, regardless of clinical stages; and can be used to guide adjuvant treatment recommendations. In the future, the ability to identify the optimal NACT regimens for increasing pCRs or downstaging and for preventing the possibility of upstaging in patients with breast cancer receiving NACT will be valuable for precision medicine.[40, 41] For AJCC upstaging in patients with breast IDC receiving NACT, adjuvant chemotherapy or subsequent TM is greatly preferable to BCS because of the high risk of all-cause death, LRR, and DM (Table 2–3).
This study has some limitations. First, because all patients with breast IDC were enrolled from an Asian population, their ethnic susceptibility compared with non-Asian populations remains unclear. Hence, our results should be cautiously extrapolated to non-Asian populations. However, no evidence exists to demonstrate the differences between Asian and non-Asian populations in PRRs for patients with breast cancer receiving NACT followed by BCS. Second, the diagnoses for all comorbid conditions were based on ICD-9-CM codes. Nevertheless, the Taiwan Cancer Registry Administration randomly reviews charts and interviews patients to verify the accuracy of the diagnoses, and hospitals with outlier chargers or practices may be audited, and consequently, heavily penalized if malpractice or discrepancies are identified. Third, to prevent the formation of several subgroups, various regimens of NACT were not categorized separately during the analyses. Thus, the effects of specific neoadjuvant treatments remain unclear. Nevertheless, four cycles of NACT for each enrolled patient with breast IDC achieved consistent responses. Accordingly, to obtain crucial information on population specificity and disease occurrence, a large-scale randomized trial comparing carefully selected patients undergoing suitable treatments is essential. Finally, the TCRD contains no information regarding dietary habits, socioeconomic status, or body mass index, all of which may be risk factors for mortality. However, considering the magnitude and statistical significance of the effects observed in this study, these limitations are unlikely to have affected the conclusions.