Japanese Journal of Clinical Oncology Advance Access originally published online on May 28, 2009
Japanese Journal of Clinical Oncology 2009 39(8):484-490; doi:10.1093/jjco/hyp052
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© The Author (2009). Published by Oxford University Press. All rights reserved
Long-term Outcome and Pattern of Relapse after Neoadjuvant Chemotherapy in Patients with Human Epidermal Growth Factor Receptor 2-positive Primary Breast Cancer
1 Division of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo
2 Department of Surgery, Osaka National Hospital, Osaka
3 Division of Clinical Trial Design and Management, Translational Research Center, Kyoto University Hospital, Kyoto
4 Department of Pathology, National Cancer Center Hospital
5 Department of Central Laboratory and Surgical Pathology, Osaka National Hospital, Osaka, Japan
For reprints and all correspondence: Chikako Shimizu, Division of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: cshimizu{at}ncc.go.jp
Received February 6, 2009; accepted April 30, 2009
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAUTHOR'S CONTRIBUTIONSFundingConflict of interest statementAcknowledgementsReferences |
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Objective: Determinants of long-term outcome of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who received neoadjuvant chemotherapy (NAC) are not clear. The purpose of this study was to explore the prognostic factors of HER2-positive breast cancer patients administered NAC.
Methods: A retrospective analysis of 125 HER2-positive breast cancer patients treated by NAC using an anthracycline plus taxane with (HCN group, n = 54) or without trastuzumab (non-HCN group, n = 71) was performed. The clinical parameters, including the pathological complete remission (pCR) rate, disease-free survival (DFS) and organ-specific recurrence-free survival, were measured.
Results: According to the results of the univariate analyses, age, clinical stage, pCR and axillary lymph node status were the factors significantly associated with the DFS. The inclusion of trastuzumab in the NAC regimen did not yield a significant difference in the DFS. Only the axillary lymph node status and age were found to be the significant factors affecting the DFS in a multivariate model. There were no significant differences in the patient/tumor characteristics between the HCN and non-HCN groups except for the pCR rate (50% in the HCN group vs. 24% in the non-HCN group) and the median follow-up time (738 days in the HCN group vs. 1579 days in the non-HCN group). Within the first 2 years from the initiation of NAC treatment, the central nervous system (CNS) was the most common site of first recurrence in the HCN group, whereas no cases of CNS metastasis were observed in the non-HCN group.
Conclusions: The pathological axillary node status and age were found to be the significant prognostic factors in HER2-positive breast cancer patients who received NAC. The pattern of recurrence may be different between HCN-treated and non-HCN-treated patients.
Key Words: breast cancer • human epidermal growth factor receptor 2 (her2) • neoadjuvant chemotherapy • pathological response • prognosis
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAUTHOR'S CONTRIBUTIONSFundingConflict of interest statementAcknowledgementsReferences |
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Human epidermal growth factor receptor 2 (HER2) protein overexpression or gene amplification occurs in
20–30% of all breast cancer and is known to be associated with an aggressive phenotype (1,2). Recent randomized controlled studies have shown that trastuzumab, an anti-HER2 monoclonal antibody, given as adjuvant chemotherapy significantly improves the disease-free survival (DFS) and overall survival in patients with HER2-positive primary breast cancer (3,4). Most studies on the use of trastuzumab in a neoadjuvant setting have been single-arm studies without a comparator (5). To the best of our knowledge, only two randomized trials have been reported. Buzdar et al. (6) compared neoadjuvant 5-fluorouracil/epirubicin/cyclophosphamide and paclitaxel chemotherapy with or without trastuzumab for the treatment of HER2-postive, operable breast cancer. The pathological complete remission (pCR) rate, which was the primary endpoint, was strikingly superior in the chemotherapy plus trastuzumab arm, when compared with that in the chemotherapy-alone arm (65% vs. 26%, P = 0.016). Chang et al. (7) conducted a randomized study comparing neoadjuvant docetaxel/carboplatin (DC) therapy with or without trastuzumab in women with locally advanced breast cancer. The pCR rate was 36.4% in the DC plus trastuzumab arm, in contrast to the rate of 9% in the DC-alone arm.
These results should be interpreted with caution, because an improvement of the pCR rate does not necessarily translate into a long-term benefit: in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B27 trial, in which the addition of docetaxel after doxorubicin/cyclophosphamide (AC) doubled the pCR rate when compared with the pCR rate obtained after neoadjuvant AC therapy alone, no improvement in the DFS or overall survival was seen (8,9). Therefore, we conducted a retrospective cohort study of HER2-positive breast cancer patients who were administered neoadjuvant chemotherapy (NAC) including anthracycline and taxane with or without trastuzumab. Analysis of patients in neoadjuvant setting allows us to take the objective response to chemotherapy into consideration for predicting the prognosis, which is impossible in the case of analysis in the adjuvant setting. The primary objective of this study was to describe the long-term outcome and to explore the determinants of the clinical outcome in HER2-positive breast cancer patients who received NAC.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAUTHOR'S CONTRIBUTIONSFundingConflict of interest statementAcknowledgementsReferences |
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Study Design
All HER2-positive operable breast cancer patients who were administered NAC containing at least one cycle of an anthracycline plus a taxane between 1998 and 2007 were identified from the databases of the National Cancer Hospital (NCCH) and the Osaka National Hospital (ONH). Information extracted from the medical records of these patients included the patient age, clinical stage before the start of treatment, hormone receptor status before the chemotherapy, the date of chemotherapy initiation, the chemotherapy regimen used, pathological response, the number of metastatic axillary lymph nodes, the date and site of first relapse, and the date of last visit or death. The date of the first relapse in the loco-regional area, central nervous system (CNS) or other distant organ at any time during the follow-up period was also collected. Clinical stage was decided according to the 2003 American Joint Committee on Cancer's guidelines.
This study was conducted in accordance with the National Ethical Guidelines for Epidemiological Research developed by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare.
Pathology Assessment
The pathological assessments were performed by the pathologists at each center. All patients underwent a core needle biopsy (CNB) before receiving the NAC. The estrogen receptor (ER) and progesterone receptor (PgR) expression levels were assessed by immunohistochemistry (IHC). The tumor cells showing positive nuclear staining were counted and the cut-off level for hormone receptor positivity was 10%. HER2 screening was conducted using IHC, and fluorescent in situ hybridization (FISH) was also performed in addition for samples with an IHC score of 2+. Either an IHC score of 3+ or gene amplification by FISH was considered as a positive result. In this study, ‘pCR’ was defined as the complete absence of residual invasive tumor cells in the primary tumor.
Statistical Analysis
The clinical characteristics and treatment outcomes were compared using Fisher's exact test or t-test, as appropriate. Survival estimates were calculated using the Kaplan–Meier method. Relapse was defined as loco-regional, distant or CNS metastasis. DFS was measured from the date on which the NAC was initiated to the date on which disease relapse was first detected at any site, including loco-regional recurrence, or the date of the last follow-up or death. CNS recurrence-free survival was measured from the date on which NAC was initiated to the date of relapse was first detected in the CNS or the date of the last follow-up or death. Differences in DFS according to each clinico-pathological variable were compared using the log-rank test. To explore the factors that might be predictive of the DFS, multivariate analyses were performed using the Cox regression. All statistical analyses were performed using SAS version 9.1.3 (SAS Institute Inc., Cary, NC, USA). All P values were two-sided, and P values <0.05 were considered to be statistically significant.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAUTHOR'S CONTRIBUTIONSFundingConflict of interest statementAcknowledgementsReferences |
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Patient Characteristics
Ninety-three patients from NCCH and 32 patients from ONH were identified. The median patient age was 53 years (range, 26–76 years). Fifty-four patients were administered NAC including trastuzumab (HCN group), and 71 patients were treated with NAC without trastuzumab (non-HCN group). All of the patients in the HCN group, from both treatment centers, received 4 sequential cycles of anthracycline followed by 12 cycles of weekly paclitaxel and trastuzumab. On the other hand, there were some variations of the treatment regimens in the non-HCN group: 36 patients were treated with doxorubicin plus docetaxel (four cycles), and 35 patients received sequential therapy with an anthracycline followed by a taxane. The summary of regimens used as NAC treatment is given in Table 1. Adjuvant endocrine therapy was administered when a CNB or surgical specimen was positive for ER or PgR. None of the patients received trastuzumab post-operatively.
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Pathological information was obtained from 123 patients. The overall pCR rate was 35%, and 60% of the patients were pathologically confirmed to have node-negative surgical specimens. The median follow-up period for the entire cohort was 1233 days, and the overall 1- and 2-year DFS rates were 92% and 78%, respectively.
The patient characteristics are summarized in Table 2.
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Effect of Clinico-pathological Factors on the DFS
Individually, pCR and a negative axillary lymph node status after pre-operative chemotherapy were significantly associated with a longer DFS [hazard ratio (HR) for pCR over non-pCR, 0.32; 95% confidence interval (CI), 0.12–0.82, P = 0.02; HR for negative axillary lymph nodes, 0.25; 95% CI, 0.12–0.53, P < 0.001]. Patients older than 50 years (HR 0.46, P = 0.03) or with Stage II disease (HR, 0.64; 95% CI, 0.32–1.27, P = 0.20) tended to have a better DFS. In contrast, the hormone receptor status, concomitant or sequential administration of an anthracycline plus taxane, and the inclusion of HCN in the pre-operative treatment did not have any significant influence on the DFS. Figure 1 shows the Kaplan–Meier estimates of the DFS stratified according to the pathological response, nodal status and the use/non-use of trastuzumab in all patients.
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In a multivariate model including the age, stage, pCR, axillary lymph node status and treatment group (HCN vs. non-HCN), only the axillary lymph node status and age were found to be significantly associated with the DFS (Table 3).
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Exploratory Comparison of DFS Between the HCN and Non-HCN Groups
As shown in Table 2, there were no significant differences in the age, clinical stage or hormone-receptor status between the HCN and non-HCN groups. The median follow-up time was significantly shorter in the HCN group (738 vs. 1579 days, P < 0.0001). The pCR rate [50% vs. 24%; odds ratio, 3.18; 95% CI, 1.47–6.86, P = 0.0039] and the proportion of pathologically node-negative patients (52% vs. 23%, P = 0.0015) were significantly higher in the HCN group than in the non-HCN group.
The HR for DFS in the pCR patients over non-pCR patients was 0.09 (95% CI, 0.01–0.70) in the HCN group and 0.62 (95% CI, 0.21–1.83) in the non-HCN group (P = 0.10 according to a test of interaction). The HR for DFS in patients with a negative axillary lymph node status over node-positive patients was 0.16 (95% CI, 0.05–0.59) in the HCN group and 0.31 in the non-HCN group (P = 0.44 according to a test of interaction) (Fig. 2).
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Patterns of Recurrence
Throughout the follow-up period, 17 loco-regional and 41 distant-organ metastases including 15 CNS metastases occurred. The HRs for recurrence-free survival according to the pathological response (pCR vs. non-pCR) were 0.24 (95% CI, 0.06–1.07, P = 0.06) for loco-regional recurrence, 0.31 (95% CI, 0.07–1.40, P = 0.13) for CNS recurrence and 0.33 (95% CI, 0.11–0.95, P = 0.04) for recurrence in other distant organs.
The sites of first recurrence from the first day of NAC throughout the follow-up period and within the first 2 years from the start of NAC treatment were counted (Table 4). The number was recounted when simultaneous multiple recurrent sites occurred. In the HCN group, metastasis occurred in CNS, loco-regional area and liver metastasis as the sites of first recurrence, within the first 2 years in five, four and one patient, respectively. In the non-HCN group, on the other hand, metastasis occurred in the liver, loco-regional area, lung, bone and adrenal gland within the first 2 years in seven, six, four, two and one patient, respectively, metastasis, but there were no cases of CNS metastases occurred within this time period in this group.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAUTHOR'S CONTRIBUTIONSFundingConflict of interest statementAcknowledgementsReferences |
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Our study is, to the best of our knowledge, the largest study until date to examine the long-term outcome of HER2-positive breast cancer patients administered NAC. The axillary nodal status after pre-operative chemotherapy and patient age were the only significant prognostic factors influencing the long-term outcome after NAC in this cohort. According to the univariate, but not multivariate, analysis, the pathological response of the primary tumor (pCR or not) was associated with the DFS.
Identification of prognostic markers after NAC has been discussed in several previously published studies in the literature but previous studies have not taken the biological subtypes of the tumors into account, except for the study by Leidtke et al. (10) in which the response to NAC and long-term survival were compared between patients with triple-negative breast cancer (TNBC) and non-TNBC. In their study, the pCR rates were higher in the patients with TNBC than in the non-TNBC patients. Patients with pCR had excellent survival, regardless of the tumor subtype (TNBC or non-TNBC), but the prognosis in patients with residual disease was worse among the non-TNBC patients (10). Their data suggest that HER2-positive breast cancer patients without HR expression in the tumor who did not receive trastuzumab may have a worse prognosis as in patients with TNBC, but the prognostic factors in patients with HER2-positive disease were beyond the scope of their discussion (10). Because of the worse prognosis in patients with HER2-positive disease, we consider that it would be worthwhile identifying the prognostic factors in HER2-positive breast cancer patients who were administered NAC.
Younger age was associated with a worse outcome in the present study. Age under 35 years old is known as a marker of worse prognosis in general. Other studies have suggested that age, the clinical stage, histologic grade and histologic type (ductal or lobular), ER status, p53 expression status and clinical response to NAC are potential prognostic markers, but the data are inconsistent and it is inconclusive that age is robust enough as prognostic marker (11–13).
On the other hand, the number of metastatic lymph nodes in the axilla was identified as a predictor of the DFS after NAC in a Cox proportional hazards model in several studies not specifying the biological subtypes of the tumors (11–13). In our previous study which included all biological subtypes of breast cancer, the pre-treatment clinical stage, clinical response to NAC and post-treatment pathological nodal status were found to be strong predictors of the DFS (14). Pathological response in the primary lesion using any pathological response criteria and age failed to yield a statistically significant difference in the long-term outcome in our previous study (14). The result in the HER2-positive patient cohort in this study was consistent with our observation in patients with all subtypes of breast cancer.
In an exploratory comparison of the HCN and non-HCN groups, the HCN group yielded a higher pCR rate for the primary tumor and a higher proportion of patients with negative axillary node status than the non-HCN group, but this difference was not correlated with the DFS. There are two possible explanations for this observation, other than the possible lack of statistical power of this study: the duration of trastuzumab administration and the difference in the patterns of recurrence between the HCN and non-HCN groups.
The efficacy of short courses of adjuvant trastuzumab is controversial. Large randomized controlled studies using adjuvant trastuzumab have demonstrated a benefit of adjuvant trastuzumab therapy administered for at least 1 year (3,4). One small-sized (n = 231) randomized study demonstrated the superiority of 9-week trastuzumab administration regimen in an adjuvant setting (15); however, no randomized studies directly comparing different durations of trastuzumab treatment have not been reported yet.
Interestingly, CNS metastasis within 2 years of the initiation of NAC was more frequent in the HCN group than in the non-HCN group. This result is compatible with the results of a meta-analysis of trials of adjuvant trastuzumab, in which the likelihood of brain metastasis was found to be 1.82-fold higher (95% CI, 1.16–2.85) in the trastuzumab arm (16). Early CNS events in the HCN group may have worsened the DFS in this group. Our data lend support to the hypothesis that trastuzumab may contribute to the eradication of extracranial disease, but not prevent CNS metastasis. Whether the shorter CNS recurrence-free survival period in the HCN group was due to a biological effect of trastuzumab treatment on the HER2-positive tumor cells, a delay in the manifestation of CNS metastasis in the non-HCN group because of the effect of the systemic treatment on relapsed disease, or mere chance, remains uncertain.
A high incidence (10–48%) of CNS metastasis has been reported in trastuzumab-treated HER2-positive metastatic breast cancer patients (15). Recently, Dawood et al. (16) reported a retrospective study of a cohort of breast cancer patients treated at a single institution; all of the patients had developed CNS metastases and had a confirmed HER2-status (n = 598). In their study, the patients with HER2-positive tumors treated with trastuzumab showed longer interval until the development of CNS metastases, when compared with those who had never received trastuzumab. Our results seem to be contradictory to these findings, but since patients who received trastuzumab in the adjuvant/neoadjuvant setting were excluded from Dawood et al.'s study, it is possible that trastuzumab-treated early breast cancer patients may manifest CNS metastases earlier during the course of the disease. Because of the sample size, we were not able to calculate the hazard function of recurrence and death by time, but such analysis comparing trastuzumab-treated and non-trastuzumab-treated HER2-positive breast cancer patients may be of interest. Our study has some limitations: the sample size was small and the patients were not prospectively randomized. There was also an imbalance in the follow-up times between the HCN and non-HCN groups because trastuzumab has only been approved for use in Japan since 2001. However, we consider that the comparison of outcomes among the HCN and non-HCN groups within the first 2 years was appropriate and was not affected by the follow-up time.
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CONCLUSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAUTHOR'S CONTRIBUTIONSFundingConflict of interest statementAcknowledgementsReferences |
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In conclusion, the pathological axillary node status and age were found to be the significant prognostic factors in HER2-positive breast cancer patients administered NAC. A pathological response to NAC was associated with a better DFS. Although the use of trastuzumab increased the pCR rate, it did not yield any significant difference in the DFS. It appears that the patterns of relapse might differ according to the inclusion/non-inclusion of HER2-targeted drugs in the NAC, and further studies to determine the mechanism of CNS metastasis in patients with HER2-positive breast cancer and the development of alternative or additional strategies to prevent CNS metastasis are needed.
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AUTHOR'S CONTRIBUTIONS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAUTHOR'S CONTRIBUTIONSFundingConflict of interest statementAcknowledgementsReferences |
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C.S. conceived of the study and participated in its design and coordination, collected the data and drafted the manuscript. N.M. participated in the design, collected the data and helped to draft the manuscript. K.Y. carried out the statistical analysis and helped to draft the manuscript. H.T. and M.M. approved of the pathological diagnosis of the studied cohort. M.A. and K.T. contributed to the analysis and interpretation of the data and to the drafting of the manuscript. Y.F. provided the administrative and financial support for this study. All of the authors have read and approved of the final manuscript.
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Funding |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAUTHOR'S CONTRIBUTIONSFundingConflict of interest statementAcknowledgementsReferences |
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This study was supported by the Health and Labour Science Grants for Research in Advanced Medical Technology (H17-pharmaco-006).
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAUTHOR'S CONTRIBUTIONSFundingConflict of interest statementAcknowledgementsReferences |
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None declared.
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Acknowledgements |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAUTHOR'S CONTRIBUTIONSFundingConflict of interest statementAcknowledgementsReferences |
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We thank Tsutomu Kouno, Noriyuki Katsumata and Tadahiko Shien from NCCH, and Jun Yamamura and Hiroko Masuda from ONH for their support in collecting the clinical data.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAUTHOR'S CONTRIBUTIONSFundingConflict of interest statementAcknowledgementsReferences |
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