Background
Breast cancer is the most common cancer in women worldwide, and 1.68 million cases are newly diagnosed annually [
1]. It is the second most common cancer in females in South Korea, where 15,942 women were newly diagnosed in 2011 [
2]. About 44 % of the newly diagnosed breast cancer patients are initially stage II or III, and neoadjuvant chemotherapy (NAC) or primary systemic therapy has become the standard treatment for this population [
3,
4]. Response to NAC is known to be useful in prognostic and predictive aspects. Pathologic complete response (pCR) is the most useful surrogate marker for overall survival in the NAC setting [
5‐
7]. However, despite its clinical usefulness, pCR alone has limitations in evaluating residual disease after NAC. Recent pooled analysis of neoadjuvant clinical trials revealed that pCR is not a surrogate end-point marker for survival in the overall population because response to NAC is heterogeneous among breast cancer subgroups [
8]. Several methods have been devised to evaluate the response to NAC, one of which is the American Joint Committee on Cancer (AJCC) response criteria for NAC [
9]. Keam et al. [
10] validated AJCC response criteria for NAC in 398 patients who received 3 cycles of doxorubicin plus docetaxel, and found these criteria to be useful in evaluating the response to NAC as well as predicting survival after short-course NAC.
Since the middle of the last decade the importance of pCR achievement has been emphasized, and to obtain higher rates of pCR extended cycles of neoadjuvant chemotherapy have been introduced [
11,
12]. Six to eight cycles of NAC has recently become the standard treatment in clinical practice. In this study, we evaluated the clinical impact of AJCC response criteria in patients undergoing six or more cycles of NAC. In addition, we evaluated the clinical usefulness and prognostic value of the AJCC criteria in four different breast cancer subgroups [
13].
Discussion
Response to the neoadjuvant chemotherapy in stage II or stage III breast cancer has a prognostic impact on RFS and overall survival [
33‐
35]. pCR is the current standard criterion for evaluation of the response after NAC [
5‐
7]. Addition of preoperative taxanes to doxorubicin and cyclophosphamide (AC) increased the proportion of patients with pCR compared with preoperative AC alone (26 % vs. 13 %, respectively;
P < 0.001) [
11,
36]. Following publication of the results of NSABP B-27 together with B-18 and several other studies, extended NAC to obtain a higher pCR rate became the standard treatment in clinical practice [
11,
12,
36,
37]. Despite its clinical usefulness, pCR has some limitations as a prognostic and predictive marker, and several groups proposed new methods for grouping post-NAC patients to evaluate the response to NAC [
35,
38,
39], one of which is the AJCC response criteria for NAC. A previous study by Keam et al. [
10] showed that the AJCC response criteria for NAC correlate well with radiologic response criteria and have a prognostic value for both RFS and overall survival in patients with three cycles of concurrent doxorubicin plus docetaxel neoadjuvant chemotherapy. CR, PR, and NR rates were 9.8, 59.3, and 30.7 %, 5-year RFS 89.6, 74.1, and 62.6 % (
P = 0.002), and 5-year overall survival 97.4, 88.6, and 78.3 % (
P = 0.012), respectively [
10]. In the current study, we demonstrated that the AJCC response criteria represent a useful prognostic factor for RFS in patients undergoing 6 or more cycles of NAC. The rates of CR and PR are significantly higher (12 and 67.2 %, respectively) than those from 3 cycles of NAC in the previous study [
10]. Because the follow-up duration is short, the prognostic impact of AJCC response with extended NAC on the overall survival has not yet been obtained.
Previous studies reported different rates of pCR after NAC between breast cancer subgroups, and suggested the clinical usefulness of pCR as a surrogate marker of survival is different in each breast cancer subtype [
13]. According to von Minckwitz et al., pCR is a suitable surrogate end point for patients with LB/HER2-negative, HER2-positive (non-luminal), and triple-negative disease but not for those with LB/HER2-positive or LA tumors [
13]. LA is a slowly proliferating tumor type, whose response to NAC is not as good as that in highly proliferating tumor types. Given these heterogeneous responses to NAC, a recent meta-analysis revealed that pCR alone is not sufficient as a surrogate end point for event-free survival and overall survival in the general breast cancer population [
8]. In fact, no patients achieved pCR in the LA group in our current study. Furthermore, in contrast to previous studies, pCR was not associated with RFS in any of our subgroups. This might result from a short follow-up period and a lack of sufficient events (relapse) for obtaining statistical power. By contrast, our analyses of the four breast cancer subtypes demonstrated that AJCC response after NAC was a significant prognostic marker for RFS in all four breast cancer subgroups, even in LA patients.
There was no significant difference in RFS between pCR and non-pCR groups (P = 0.110, log-rank test). The AJCC response in CR and PR patients showed a similar prognosis, but PR and NR groups showed a significant difference in RFS probability. We also compared the RFS of CR + PR groups with that of the NR group using AJCC response criteria. The RFS of CR + PR patients was significantly longer than that in the NR group (median RFS not reached vs. 29 months, P < 0.001, log-rank test). The RFS probability difference between the CR and PR groups was not significantly different, although the HR of PR patients was higher, at 2.067 (95 % CI 0.485–8.803, P = 0.326). This might result from the small sample size and, thus, insufficient events (sample size 145 and 24 events at the data cut-off). The AJCC response criteria may thus represent a simple and easily applicable tool to evaluate residual disease and a new surrogate end point in neoadjuvant trials. Further follow-up is needed to confirm the prognostic impact of the AJCC response criteria and pCR in each breast cancer subgroup.
We further analyzed the LA patients. In our hospital’s NAC cohort, we were able to obtain the clinicopathologic and survival data of all the LA patients, regardless of the number of NAC cycles (<6 or ≥6 cycles). For the LA patients, pCR was achieved in neither group. The AJCC response rate (CR + PR portion) was higher in the extended-NAC group than in the short-course NAC group (70.5 % vs. 56.3 %), although statistically not significant (
P = 0.302). This trend is consistent with the previous report by Moon et al. [
40], which showed that continuous tumor shrinkage occurred in their ER-positive tumor group during extended NAC, while tumor shrinkage mainly occurred in the early period of NAC in the ER-negative group. By Cox regression of prognostic factors on RFS in the LA subgroup, premenopausal patients showed a significantly lower risk of relapse than the postmenopausal patients (HR 0.092, 95 % CI 0.009–0.906,
P = 0.041; Table
4). This benefit might result from the additional secondary ovarian function suppression effect of chemotherapeutic agents in premenopausal patients. All things considered, in younger LA patients in premenopausal status an extended-NAC strategy might be more beneficial.
From the hazard rate of RFS of the patients according to AJCC responses (Fig.
2), we discerned several clinical implications. In the NR group 27, 41, and 52 % of the patients relapsed during first 1, 2, and 3 years after diagnosis, respectively. For these patients, thorough physical examination and work-up for locoregional and/or distant metastases should be performed even during adjuvant therapies. From these data, we may suggest the necessity of further adjuvant chemotherapy even after the use of both an anthracycline- and taxane-containing NAC regimen and the selection of high-risk patients who require adjuvant chemotherapy. Ongoing adjuvant clinical trials (JBCRG04 (CREATE-X), NCT01864746 (PENELOPE-B)) are targeting high-risk patients with residual diseases after neoadjuvant chemotherapy. The recent results of the CREATE-X trial revealed that treatment with adjuvant capecitabine increased disease-free survival for patients with HER2-negative breast cancer who had residual disease after neoadjuvant chemotherapy [
41]. The data also showed a tendency toward improving overall survival, albeit statistically insignificant, which might derive from the short follow-up period.
Our study has some limitations. First, because of the retrospective design of the study, the probability existed of selecting patients with a good response to NAC (whose cancer did not progress during NAC) while excluding patients with early progression or non-response. The investigation of those who received a short course of NAC (<6 cycles, total n = 66) provided some clues. They encompassed both groups who were initially scheduled to receive a short course of chemotherapy and who progressed during NAC. Although it was difficult to distinguish the two groups by retrospective medical record review, there was only one patient with definite clinical disease progression during NAC who received mastectomy after three cycles of NAC. According to the radiologic response criteria, there was no difference in the portion of patients with progressive disease (4.5 % vs. 4.4 %, <6 cycles vs. ≥6 cycles of NAC). Therefore, the selection bias is expected to be minimal in this study. Second, the follow-up duration in this study is short, so the prognostic impact of the AJCC response criteria on overall survival for a long course of NAC could not be demonstrated. Third, the sample sizes of the each breast cancer subgroup are rather small, so the prognostic impact of the AJCC response criteria in each breast cancer subtype should be investigated in a larger population in subsequent studies.
Despite these limitations, this is the first report to demonstrate the clinical usefulness of AJCC response criteria in patients undergoing six or more cycles of NAC with neoadjuvant chemotherapy regimens used in clinical practice. Furthermore, our analyses demonstrated that the AJCC response criteria represented a significant prognostic marker for RFS in all four breast cancer subgroups, including the LA subgroup in which pCR has a limited role. The AJCC response criteria serve as a simple and easily reproducible tool for response evaluation in breast cancer patients in the NAC setting in comparison with the classically used Residual Cancer Burden measurement method or Miller-Payne grading system [
35,
38]. The AJCC response criteria could help overcome the limitations of pCR, as they may be valid in all breast cancer subgroups and be helpful in selecting those high-risk patients who need further adjuvant treatment. In addition, we performed a pre- and post-NAC paired imaging study (breast MRI or chest CT with breast ultrasonography) for accurate clinical staging, examination of radiologic response, and evaluation of AJCC response. Further follow-up is needed to establish the potential prognostic role of the AJCC response criteria and other clinicopathologic markers of overall survival in the NAC setting of six to eight cycles.
Abbreviations
AJCC, American Joint Committee on Cancer; CI, confidence interval; CR, complete response; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; IHC, immunohistochemistry; LA, luminal A; LB, luminal B; NAC, neoadjuvant chemotherapy; NR, no response; pCR, pathologic CR; PR, partial response; PR, progesterone receptor; RFS, relapse-free survival; TNBC, triple-negative breast cancer