Presented in part at the 33rd San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX.
There is limited information about the risk factors for ipsilateral breast tumor recurrence (IBTR) after patients undergo breast-conserving surgery plus radiotherapy (breast-conserving treatment [BCT]) subsequent to neoadjuvant chemotherapy (NAC). The objective of the current study was to analyze these risk factors.
The authors collected data from 375 patients who underwent BCT and received NAC and analyzed the risk of IBTR associated with undergoing BCT after NAC. The usefulness of the MD Anderson Prognostic Index (MDAPI) for IBTR also was validated using the current data set.
The median follow-up was 47.8 months, and the 4-year IBTR-free survival rate was 95.6%. Multivariate analysis demonstrated that estrogen receptor (ER) status and multifocality of the residual tumor were associated significantly with IBTR-free survival. In addition, patients who had ER-positive and human epidermal growth factor 2 (HER2)-negative tumors did not develop IBTR during the observation period. Although prognostic stratification according to MDAPI was relatively good for the prediction of IBTR in the study patients, the IBTR rate in the high-risk group was not very high and was lower than that in the intermediate-risk group. Multivariate analyses demonstrated that IBTR was an independent predictive factor for overall survival.
Breast-conserving surgery and radiotherapy (breast-conserving treatment [BCT]) is now accepted as a locoregional treatment alternative to mastectomy for women with early stage breast cancer.1, 2 For patients with larger tumors, neoadjuvant chemotherapy (NAC) is administered increasingly with the expectation of BCT. A major benefit of NAC is that it increases the proportion of patients who can undergo BCT.3-5 However, several authors have reported high local recurrence rates among patients who underwent BCT after NAC.3, 5, 6
It has long been believed that local recurrence has little effect on overall survival. In 2005, however, the Early Breast Cancer Trialists' Collaborative Group reported results from a meta-analysis of data from randomized controlled trials of breast-conserving surgery with or without breast radiotherapy.7 That analysis demonstrated that the use of radiation therapy decreased not only the rates of local recurrence but also the 15-year risk of dying, which generated a reappraisal of the importance of local control. Therefore, we believed it would be useful to accurately evaluate the risks of local recurrences.
The risk factors for developing ipsilateral breast tumor recurrence (IBTR) for patients who undergo BCT are well known. These include tumor size, lymph node status, histologic subtype, surgical margin status, and lymphovascular invasion and are used routinely in decisions regarding the locoregional management of breast cancer. However, few data are available concerning the risk factors of IBTR for patients who undergo BCT after receiving NAC.8-13
With regard to IBTR after NAC, in 2001, Rouzier et al reported their experience at Institute Curie.8 In their study, multivariate analysis demonstrated that the probability of local control was decreased by the following independent factors: age <40 years, excision margin <2 mm, S-phase fraction >4%, and clinical tumor size >2 cm at the time of surgery.
Chen et al identified clinicopathologic factors that would predict local recurrence after NAC followed by BCT and developed a prognostic index: the MD Anderson Prognostic Index (MDAPI).9, 14 Those authors reported that the MDAPI enabled the identification of patients who had a high risk of developing IBTR and locoregional recurrences when they underwent breast-conserving surgery after receiving NAC. The MDAPI was cited in published guidelines as a tool for the selection of patients with a high probability of developing local recurrence.15, 16 However, few reports have presented a validation study of the MDAPI, especially multi-institutional studies.17
It is now widely recognized that patients with IBTR have a worse prognosis than those without IBTR,18-21 but limited information is available about the prognosis for patients who undergo IBTR after receiving NAC. For the current study, we investigated the risk factors for IBTR after NAC and validated the MDAPI using data from a multi-institutional series. We also evaluated the impact of IBTR after NAC on overall survival.
MATERIALS AND METHODS
In total, 375 consecutive breast cancer patients with newly diagnosed, noninflammatory tumors measuring ≥2 cm who had no metastases and who underwent breast-conserving surgery after NAC between 1995 and 2009 were included in this analysis from 8 institutions in Japan. This retrospective study was approved by each institutional review board.
Inclusion criteria were: 1) patients with solitary tumor measuring ≥2 cm; 2) patients who received at least 3 courses of NAC; 3) patients who underwent breast-conserving surgery, axillary surgery (sentinel lymph node biopsy only was allowed if these lymph nodes had no metastases), and radiotherapy to the affected breast. Exclusion criteria were: 1) patients who underwent mastectomy; 2) patients with synchronous (defined as occurring within 3 months) bilateral breast cancer; 3) patients who underwent/received prior breast surgery, hormone therapy, chemotherapy, or radiation therapy; 4) patients who received trastuzumab before breast surgery, or 5) patients who underwent excisional biopsy. The eligibility for BCT after NAC depended on the physician's decision at each institution as well as patient preference.
All patients received adjuvant external-beam radiation therapy to the affected breast. The median radiation dose to the breast was 50 grays (Gy) (range, 40-51 Gy). The tumor bed was boosted with external radiotherapy in 112 patients (29.9%; median dose, 10 Gy; range, 9-20 Gy). In addition, radiation to the supraclavicular fossa was received by 13 patients (3.5%).
Questionnaire forms were sent to the members of this study in October 2009 to collect clinicopathologic patient data. The questionnaire requested the following data: age at diagnosis, date of birth, age at definitive surgery, date of definitive surgery, initial tumor size on palpation, clinical lymph node status, type of NAC regimen, number of NAC courses, clinical tumor size at surgery, pathologic lymph node status, residual invasive tumor size, residual tumor multifocality, chemotherapeutic effect, histologic margin status, lymphovascular invasion, histologic grade, estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status before and after NAC, postoperative endocrine therapy, postoperative chemotherapy, postoperative trastuzumab, dose of postoperative irradiation, boost radiation, IBTR and its date of detection, death, and date of death or last visit. The initial clinical stage and pathologic stage of disease in all patients were revised and based on the seventh edition of the American Joint Committee on Cancer staging criteria.22 Histologic type and grade were defined according to the World Health Organization classification system.23 Information on ER or HER2 status obtained from surgical specimens was used for analyses. However, when there was insufficient material to evaluate ER or HER2 status in the surgical specimens, ER or HER2 status was based instead on core-needle samples obtained before NAC. A pathologic complete response (pCR) was defined as no involvement of invasive or noninvasive cancer in the breast tumor.
IBTR was defined as all events that occurred in the remaining breast after BCT. IBTRs were counted as events regardless of whether they occurred at the initial sites of failure or concurrent with or after distant metastasis. IBTR-free survival and overall survival were calculated using the Kaplan-Meier method. Log-rank tests or chi-square tests were used to evaluate differences in IBTR-free survival and overall survival among various patient subgroups. Multivariate analyses for IBTR-free survival and overall survival were performed using a Cox proportional hazards model.
We also evaluated the usefulness of the MDAPI14 in our patient cohort. In the MDAPI, 4 clinicopathologic factors were selected to predict IBTR in patients who received NAC followed by BCT. These factors were initial clinical lymph node status (N0-N1 vs N2-N3), pathologic tumor size (≤2 cm of invasive disease vs >2 cm), pattern of tumor morphology after pathologic analysis (solitary vs multifocal residual disease), and lymphovascular space invasion in the tumor specimen (present vs absent). The MDAPI was derived by assigning a score of 0 (favorable) or 1 (unfavorable) based on the presence or absence of each of these factors. The MDAPI score (0, 1, 2, 3, or 4) for each patient was determined by totaling the scores of these 4 individual variables. Finally, the scores were grouped into 3 subsets: a low-risk group (MDAPI score, 0 or 1), an intermediate-risk group (MDAPI score, 2), and a high-risk group (MDAPI score, 3 or 4).
Based on the data from our multivariate analyses, we built a new prognostic index. In this index, scores for ER status (0, ER positive; 1, ER negative) and residual tumor morphology (0, none or solitary; 1, multifocal) were added, and total scores of 0/1 and 2 were used to classify patients into a low IBTR risk group and a high IBTR risk group, respectively.
All statistical tests and P values were 2-sided, and P values < .05 were considered significant. All statistical analyses were performed with StatView 5.0 software (SAS Institute, Cary, NC).
In total, 375 patients were registered in this analysis. Patient and pathologic characteristics are provided in Tables 1 and 2, respectively. The median age at diagnosis was 48 years (range, 18-76 years). The median clinical tumor size at diagnosis was 40 mm (range, 20-130 mm). For NAC, 89 patients received an anthracycline-containing regimen, 31 patients received a taxane-containing regimen, and 255 patients received both anthracycline-containing and taxane-containing regimens. The median number of NAC courses actually administered was 4 (range, 3-8 NAC courses). There were no significant differences between participating institutions with regard to distribution of the characteristics listed in Tables 1 and 2 (data not shown).
Table 1. Patient Characteristics (n = 375)
No. of Patients
Age at diagnosis, y
Clinical tumor classification
Clinical lymph node status
Neoadjuvant chemotherapy regimen
Anthracycline and taxane
Postoperative hormone therapy
Table 2. Pathologic Characteristics (n = 375)
No. of Patients
Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; pCR, pathologic complete response.
Residual clinical tumor size, cm
Pathologic tumor size, cm
Solitary or none
Margin width, mm
Pathologic lymph node status
The median follow-up after definitive surgery was 47.8 months (range, 4-137 months). The 4-year overall survival rate was 91.8%, and the IBTR-free survival rate was 95.6% (Fig. 1a,b). There were no significant differences between participating institutions with regard to the overall survival rate or the IBTR-free survival rate (data not shown). Various clinical and pathologic factors associated with IBTR-free survival are presented in Table 3. ER status, residual multifocal lesions, and pathologic lymph node status were associated significantly with IBTR-free survival in log-rank tests. In addition, none of the patients with ER-positive and HER2-negative tumors developed IBTR during the study period, and the frequency of IBTR for this subgroup was significantly less than that for patients in the categories with other ER and HER2 status (P = .0121; chi-square test). Furthermore, none of 55 patients who achieved a pCR developed IBTR during the study period, and 13 of 274 patients who failed to achieve a pCR developed IBTR. The 4-year IBTR-free survival rate for the patients who achieved a pCR (100%) was better than that for the patients who did not achieve a pCR (95.7%), although the difference was not statistically significant (P = .0993; chi-square test). Multivariate analyses using ER status, multifocal lesions at surgery, and pathologic lymph node status demonstrated that ER status and multifocal lesions at surgery were independent predictive factors of IBTR-free survival (Table 4).
Table 3. Four-Year Ipsilateral Breast Tumor Recurrence-Free Survival Rates According to Various Clinicopathologic Factors
Table 4. Multivariate Analyses of Predictors for Ipsilateral Breast Tumor Recurrence
Abbreviations: CI, confidence interval; ER, estrogen receptor; HR, hazard ratio.
Tumor morphology (none or solitary vs multiple)
Pathologic lymph node status (N0 vs N1-N3)
ER status (positive vs negative)
We also calculated the MDAPI in our patient cohort and then grouped the patients into low-risk, intermediate-risk, and high-risk groups. Of 375 patients, all 4 clinicopathologic factors on the MDAPI were available for 252 patients. Of these, 171 patients (67.9%) were classified into the low-risk category, 52 patients (20.6%) were classified into the intermediate-risk category, and 29 patients (11.5%) were classified into the high-risk category. It is noteworthy that no patient had an MDAPI score of 4. Among the 3 groups, the IBTR-free survival rate differed significantly (P = .0092; log-rank test). However, patients in the intermediate-risk group had paradoxically worse IBTR-free survival than those in the high-risk group (4-year IBTR-free survival rate: low-risk category, 98.1%; intermediate-risk category, 87.1; high-risk category, 93%). Furthermore, the IBTR-free survival rate differed significantly between the low-risk group versus the intermediate-risk and high-risk groups. The 4-year IBTR-free survival rate was 98.1% in the low-risk group and 89.3% in the intermediate-risk and high-risk groups (P = .0087; log-rank test).
Because of the poor adaptability of the MDAPI to our patients, we constructed a new IBTR prognostic index using data on ER status and tumor morphology. The vast majority of patients were categorized to the low-risk group (267 patients), and only 33 patients were categorized into the high-risk group. The 4-year IBTR-free survival rate was 96.5% in the low-risk group and 87.4% in the high-risk group (P = .0028; log-rank test) (Fig. 2).
Univariate analyses that included various clinical and pathologic factors were performed to identify which factors were predictive of overall survival. Pathologic lymph node status (N0 vs others), histologic grade (grade 1 or 2 vs grade 3), pathologic tumor size (T0 or T1 vs others), ER status (positive vs negative), and IBTR (absent vs present) were associated significantly with overall survival. Multivariate analyses that included these 5 factors identified IBTR as an independent predictive factor for overall survival (hazard ratio, 2.732; 95% confidence interval, 1.076-6.944; P = .0344) (Table 5).
Table 5. Univariate and Multivariate Analyses of Predictors for Overall Survival
Abbreviations: CI, confidence interval; ER, estrogen receptor; HR, hazard ratio; IBTR, ipsilateral breast tumor recurrence.
Pathologic lymph node status (N0 vs N1-N3)
Pathologic tumor size (T0 or T1 vs others)
Histologic grade (1 or 2 vs 3)
ER status (positive vs negative)
IBTR (absent vs present)
To our knowledge, the current study is the largest to date investigating the risk factors for IBTR in patients with breast cancer who undergo BCT after receiving NAC. Several authors have reported factors that predict IBTR after NAC.8-13 Among these, the MDAPI9, 14 is well known and is cited by published guidelines.15, 16 The MDAPI includes 4 factors (initial clinical lymph node status, pathologic tumor size, pattern of tumor morphology after pathologic analysis, and lymphovascular space invasion). In our study, among these factors, only tumor multifocality was identified as an independent predictive factor of IBTR after NAC. In other published reports, the most frequently identified factors were classic morphologic factors, such as tumor size,8, 9, 12 lymph node status,9 stage,10, 12, 13 or margin status.8, 10, 11 These factors also are recognized as risk factors for IBTR without NAC. Among these factors, margin status was not associated with IBTR-free survival in our study. Margin status tended to be a significant predictive factor in studies in which patients had a greater frequency of positive margin (range, 7%-12.3%)8, 10, 11 than other reports (range, 0%-4%).9, 12, 13 The frequency of positive margins in our study was relatively high (10.5%), but margin status was not significant. The reason for this finding remains unknown. Our results regarding margin status may have differed from previous reports partially because of difference in the definition of positive margins. In our study, clinical lymph node status was not associated with IBTR-free survival, but pathologic lymph node status was correlated significantly with IBTR-free survival. The reason of this discrepancy may be the high frequency of inconsistency between clinical and pathologic lymph node status.
In our study population, the MDAPI accurately could predict IBTR-free survival only if we combined the intermediate-risk and high-risk groups. There have been few reports regarding validation of the MDAPI, except from The MD Anderson Cancer Center itself.17 We constructed a new prognostic index using data on ER status and tumor morphology. Our index separated patients into a low-risk group, which had an acceptable 4-year IBTR rate of 3.5%, and a high-risk group, which had an unacceptably high IBTR rate of 12.6%. However, the possibility could not be ruled out that the paradoxical findings among the women who had an intermediate MDAPI score resulted from the differences in several baseline characteristics between our cohort and those in other reports from the MD Anderson Cancer Center. For example, the frequency of positive lymphovascular invasion in our study (36.5%) was higher than that in the study from the MD Anderson Cancer Center (15%).9 Also, the frequency of clinical N2 or N3 lymph node status in our study (4.6%) was lower than that in the study from the MD Anderson Cancer Center (23.2%).9 These differences may have resulted in rendering lymphovascular invasion and clinical lymph node status nonsignificant as predictive factors for IBTR in our study along with the subsequent paradoxical findings mentioned above. Further validation studies of the MDAPI and our new prognostic index are needed.
Recently, there has been considerable evidence that gene expression profile-based24, 25 and immunohistochemistry-based26, 27 subtypes are associated significantly with distant metastases. More recently, several reports have demonstrated that the subtypes also predict the risk of local recurrence.28-31 In our study, none of the patients with ER-positive and HER2-negative tumors developed IBTR during follow-up. To our knowledge, there is no report regarding the significance of an immunohistochemistry-based subgroup with IBTR after NAC. Several groups have identified negative hormone receptor status as the strongest predictive factor for a pCR.32-34 Results from a Japanese multicenter phase 2 study34 indicated that patients with ER-positive and HER2-negative tumors had remarkably low pCR rates compared with other subgroups. Despite low pCR rates among patients with ER-positive and HER2-negative tumors, this subgroup has better disease-free and overall survival. This may be because these are slowly proliferating tumors that are more amenable to local treatment and because these patients also benefit from a much longer course of endocrine treatment.15 The results of the current study are comparable to these findings and demonstrate the safety of BCT after NAC for patients with ER-positive and HER2-negative tumors. Although this finding is very promising, caution is needed, because approximately 25% of the samples in our study provided no information about HER2 status. If all the missing data of HER2 are positive or negative, then the difference in IBTR rates between the ER-positive and HER2-negative subtype and other subtypes remains statistically significant (P = .0021 and P = .0155, respectively; chi-square test). Further studies are needed, including Ki-67 analyses.
In the current study, we demonstrated that IBTR after NAC was a strong predictor of overall survival. Several studies have suggested that the development of IBTR after BCT for patients with early-stage cancer predicts a poorer prognosis.18-21 However, there has been limited information about IBTR after NAC. Rouzier et al8 reported that patients who developed IBTR after NAC had significantly worse distant metastases-free survival. To our knowledge, there have not been any studies regarding the significance of IBTR after NAC on overall survival.
One of the limitations in our study is the lack of uniform eligibility criteria for BCT after NAC among the participating institutions. However, in our study, the 4-year IBTR rate of 4.4% in patients who underwent BCT after NAC was acceptably low. Several authors have reported high local recurrence rates in patients who underwent BCT after NAC.3, 5, 6 More recently, however, a systematic review demonstrated that the increased local recurrence rate associated with NAC is greatly reduced after excluding studies in which patients received radiotherapy alone after complete tumor regression.35 An annual IBTR rate of approximately 1% in this study seems to support the validity of each institution's eligibility criteria for BCT.
The second limitation is the relatively short follow-up (median, 47.8 months). The possibility could not be ruled out that our findings that patients with ER-positive tumors had better IBTR-free survival than those with ER-negative tumors merely reflected the different timing of IBTR among the intrinsic subtypes. It is now well known that triple-negative and HER2-positive disease is most likely to recur within the first 3 years, whereas ER-positive disease may recur many years later.
The third limitation is the high frequency of missing data, especially HER2 status (24.3%). This may have affected our results, both with respect to the original MDAPI score validation and ER/HER2.
In conclusion, ER status and multifocality of the residual tumor were identified as independent predictors of IBTR after NAC. The MDAPI was barely adaptable to our patients in terms of predicting IBTR. Patients with ER-positive and HER2-negative tumors had a favorable prognosis, whereas patients who developed IBTR after NAC had significantly worse overall survival. If these results are confirmed in further studies, then these data will provide useful information for adequate decision-making in patients who plan to receive NAC with the expectation of BCT.
This work was supported by a Grant-in-Aid for research of cancer treatment from the Ministry of Health, Labor, and Welfare of Japan (21-7-4).