Wenjin Yin

Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials.

Background Adjuvant trastuzumab therapy has yielded conflicting results for overall survival, concerns about central nervous system (CNS) metastasis, and questions about optimal schedule. Therefore, we carried out a meta-analysis to assess the benefits of concurrent or sequential trastuzumab with adjuvant chemotherapy for early breast cancer patients with HER2-positive tumors. Methods Computerized and manual searches were performed to identify randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in HER2-positive early breast cancer patients. Odds ratios were used to estimate the association between the addition of trastuzumab to adjuvant chemotherapy and various survival outcomes. The fixed-effects or random-effects model was used to combine data. Findings With six eligible studies identified, this analysis demonstrated that patients with HER2-positive breast cancer derived benefit in disease-free survival, overall survival, locoregional recurrence and distant recurrence (all P<0.001) from the addition of trastuzumab to adjuvant chemotherapy, whereas trastuzumab did worse in CNS recurrence as compared to the control group (P = 0.018). Furthermore, concomitant use of trastuzumab significantly lowered the hazard of death (P<0.001) but bore a higher incidence of CNS recurrence (P = 0.010), while statistical significance failed to be discerned for either overall survival (P = 0.069) or CNS metastasis (P = 0.374) between the sequential and observation arms. Conclusion This analysis verifies the efficacy of trastuzumab in the adjuvant setting. Additionally, our findings indirectly corroborate the superiority of concurrent trastuzumab to sequential use and also illuminate that prolonged survival is the possible reason for the higher incidence of CNS with trastuzumab versus observation.

The efficacy of zoledronic acid in breast cancer adjuvant therapy: A meta-analysis of randomised controlled trials

BACKGROUND The effect of zoledronic acid in breast cancer adjuvant therapy concerning improvement of patient survival has yet to be confirmed. We performed a meta-analysis of published and unpublished randomised controlled trials with the aim of accurate evaluation between clinical outcome and the association of the addition of zoledronic acid to adjuvant therapy. METHODS We searched PubMed (from 1966 to present) and online abstracts from the proceeding Annual Meetings of the American Society of Clinical Oncology (ASCO) (years 1992-2010) and online abstracts from San Antonio Breast Cancer Symposium (years 2004-2010). A total of five eligible studies including 3676 subjects and 3678 controls met our search criteria and were evaluated. Random and fixed-effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. The primary study end-points were the disease free survival (DFS). Secondary end-points were overall survival (OS), distant or loco-regional recurrence free survival and bone metastasis free survival. FINDINGS Compared with the control arm, adjuvant breast cancer treatment with zoledronic acid did not significantly improve overall survival, disease free survival, bone metastasis free survival, distant and locoregional recurrence free survival. However, in the postmenopausal subgroup, the addition of zoledronic acid to standard therapy could significantly improve DFS (relative risk (RR) = 0.763, 95% confidence interval (CI) 0.658-0.884, p < 0.001) and reduce the risk of distant (RR = 0.744, 95%CI 0.611-0.906, p = 0.003) and locoregional recurrence (RR = 0.508, 95%CI 0.340-0.760, p = 0.001). INTERPRETATION Adjuvant zoledronic acid did not significantly improve the prognosis of breast cancer patients. Due to the highly variable definitions of menopause utilised in different studies, we hypothesise that zoledronic acid may have a potential effect on postmenopausal patients. Additional studies are needed to evaluate the value of adjuvant treatment of zoledronic acid in premenopausal counterparts, differing disease stages and various pathological types of breast cancer.

Site-specific relapse pattern of the triple negative tumors in Chinese breast cancer patients

BackgroundIt has been reported that triple negative phenotype is characterized by aggressive clinical history in Western breast cancer patients, however its pattern of metastatic spread had never been reported in the Chinese population. Considering racial disparities, we sought to analyze the spread pattern for different sites of first recurrence in Chinese triple negative breast cancers.MethodsA retrospective study of 1662 patients was carried out from a large database of breast cancer patients undergoing surgery between January 1, 2000 and March 31, 2004 at the Cancer Hospital, Fudan University, Shanghai, China. Survival curves were generated using the Kaplan-Meier method and annual relapse hazards were estimated by the hazard function.ResultsWe found a statistically significant difference in relapse-free survival (RFS) for locoregional and visceral recurrence (P = 0.007 and P = 0.025, respectively) among the triple negative, ERBB2+ and HR+/ERBB2- subgroups in univariate analysis. In the multivariate Cox proportional hazards regression analysis, RFS for either locoregional or visceral relapse in the triple negative category was inferior to that in HR+/ERBB2- patients (P = 0.027 and P = 0.005, respectively), but comparable to that in ERBB2+ women (both P > 0.05). Furthermore, the early relapse peak appeared later in the triple negative group than that in the ERBB2+ counterpart for both locoregional and visceral relapse. On the other hand, when compared with triple negative breast cancers, a significantly lower risk of developing bone relapse was discerned for ERBB2+ women (P = 0.048; HR = 0.384, 95% CI 0.148-0.991), with the borderline significance for HR+/ERBB2- breast cancers (P = 0.058; HR = 0.479, 95% CI 0.224-1.025). In terms of bone metastasis, the hazard rate remained higher for the triple negative category than that for the ERBB2+ subtype.ConclusionBased on the site-specific spread pattern in different subgroups, the triple negative category of breast cancers in the Chinese population exhibits a different pattern of relapse, which indicates that different organotropism may be due to the different intrinsic subtypes. A better knowledge of the triple negative category is warranted for efficacious systemic regimens to decrease and/or delay the relapse hazard.

The predictive role of phosphatase and tensin homolog (PTEN) loss, phosphoinositol-3 (PI3) kinase (PIK3CA) mutation, and PI3K pathway activation in sensitivity to trastuzumab in HER2-positive breast cancer: a meta-analysis

Abstract Objective: Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be related to trastuzumab resistance in in vitro studies; however, this issue in clinical studies is controversial. Therefore, we conducted a meta-analysis to assess the association between PTEN loss, PIK3CA mutation and the efficacy of trastuzumab-based treatment in HER2-positive breast cancer patients. Methods: A computerized search was performed through the PubMed database, the online proceedings of the American Society of Clinical Oncology Annual Meetings, the San Antonio Breast Cancer Symposium and the International St. Gallen Breast Cancer Conference. Ten eligible studies including 1889 cases were identified. Results: In HER2-positive locally advanced breast cancer patients, neither PTEN loss, PIK3CA mutation nor PI3K activation was associated with the response rate of trastuzumab-based neoadjuvant treatment (PTEN loss: RR = 0.687, 95% CI: 0.439–1.074, P = 0.099; PIK3CA mutation: RR = 1.114, 95% CI: 0.453–2.735, P = 0.814; PI3K activation: RR = 0.787, 95% CI: 0.417–1.484, P = 0.459; RR = 0.772, 95% CI: 0.387–1.539, P = 0.462). In HER2-positive early stage breast cancer patients, PTEN loss was not associated with the disease-free survival (DFS) rate of trastuzumab-based adjuvant treatment (HR = 1.096, 95% CI: 0.706–1.700, P = 0.684). In HER2-positive recurrent or metastatic breast cancer patients, PTEN loss was significantly correlated with poorer efficacy of trastuzumab-based salvage treatment (RR = 0.682, 95% CI: 0.550–0.846, P = 0.000). Conclusions: In HER2-positive recurrent or metastatic breast cancer patients PTEN loss might indicate resistance to trastuzumab-based salvage treatment. Due to the small sample size and the considerable heterogeneity in the chemotherapy treatment regimens, further research is needed to clarify the association between PTEN loss, PIK3CA mutation and the efficacy of trastuzumab-based treatment in neoadjuvant and adjuvant settings.

MiR-206 suppresses epithelial mesenchymal transition by targeting TGF-β signaling in estrogen receptor positive breast cancer cells

Background: Previous reports have shown a mutual negative feedback loop between microRNA (miR)-206 and estrogen receptor (ER) expression. Furthermore, decreased miR-206 expression in breast cancer (BC) is associated with the advanced clinical stage and lymph node metastasis. However, its role and the mechanism underlying the migration and invasion of ER positive BC remain unclear. Results: In this study, miR-206 was stably transfected into ER positive cell lines MCF-7 and T47D to investigate the effect of miR-206. The results showed that miR-206 overexpression markedly impaired the migration and invasive abilities of these cells, followed by suppression of the epithelial mesenchymal transition (EMT). Mechanistic analyses showed that miR-206 inhibited the autocrine production of transforming growth factor (TGF)-β as well as the downstream expression of neuropilin-1 (NRP1) and SMAD2, responsible for the decreased migration, invasion, and EMT in these cells. Conclusions: Our data demonstrate that miR-206 inhibits TGF-β transcription and autocrine production, as well as downstream target genes of EMT. Restoring miR-206 expression may provide an effective therapeutic strategy for ER positive BC.

For or against Adjuvant Trastuzumab for pT1a-bN0M0 Breast Cancer Patients with HER2-Positive Tumors: A Meta-Analysis of Published Literatures

Background Although the prognosis of patients with small (≤1cm) tumors is generally favorable, emerging data suggests that biological behavior varies between intrinsic subtypes in such patients. Furthermore, it still remains unclear whether HER2-positive pT1a-bN0M0 patients could benefit from adjuvant trastuzumab. For further evaluation, we sought to conduct a meta-analysis so as to get a better understanding of the prognosis for HER2-positive pT1a-bN0M0 patients and their survival benefit from adjuvant trastuzumab, accordingly, offering the implications for current practice. Methods The PubMed database, the online proceedings of the American Society of Clinical Oncology (ASCO) Annual Meetings, the online proceedings of the San Antonio Breast Cancer Symposium, and the CD proceedings of the International St. Gallen Breast Cancer Conference were searched for all relevant studies published before September 2012. Relative risks (RRs) were used to compare the prognosis of different intrinsic subtypes for pT1a-bN0M0 breast cancer. Analyses were also performed to estimate the association between adjuvant trastuzumab and various survival outcomes. Results With eight eligible studies identified, this meta-analysis demonstrated a deleterious effect of HER2+ phenotype on disease-free survival (DFS; RR = 3.677, 95% CI 2.606–5.189, p <0.001) and distant disease-free survival (DDFS; RR = 3.824, 95% CI 2.249–6.501, p<0.001) as compared to HR+/HER2- subgroup. However, significant difference failed to be achieved in terms of any endpoint between HER2+ and triple negative breast cancer (TNBC). Besides, a marked improvement in DFS was observed with the addition of trastuzumab for HER2-positive pT1a-bN0M0 patients (RR = 0.323, 95% CI 0.191–0.547, p<0.001). Conclusion This meta-analysis clarifies that intrinsic subtypes might be a reliable marker to predict the prognosis in pT1a-bN0M0 breast cancer. Besides, even for such early stage HER2-positive patients, adjuvant trastuzumab might bring significant survival benefit.

The clinical significance of Ki-67 as a marker of prognostic value and chemosensitivity prediction in hormone-receptor-positive breast cancer: a meta-analysis of the published literature

Abstract Objectives: Hormone-receptor (HR)-positive breast cancer is associated with a poor response to adjuvant chemotherapy. Thus, it is important to identify HR-positive patients who can benefit from chemotherapy and the Ki-67 index may help to predict chemotherapy efficacy in such populations. However, controversies exist regarding the prognostic and predictive role of Ki-67 and its exact cut-off value in HR-positive patients. Therefore, we conducted this study. Methods: The meta-analysis included 4512 patients in five trials. Due to different data formats provided by studies, we classified the trials into two groups to facilitate analysis. Group 1 included the PACS01, USON 01062, and IBCSG VIII and IX trials, while Group 2 included the BCIRG001, USON 01062, and IBCSG VIII and IX trials. Results: In Group 1, Ki-67 high patients had a worse prognosis in disease-free survival (DFS) than Ki-67 low counterparts (risk ratio [RR] = 1.62, 95% confidence index [CI] = 1.36–1.94, P < 0.001). In Group 2, Ki-67 high patients had a better prognosis in DFS (RR = 0.53, 95% CI = 0.45–0.61, P < 0.001) and overall survival (OS) (RR = 0.32, 95% CI = 0.25–0.42, P < 0.001). In Ki-67 high patients administered anthracycline/taxane-based chemotherapy, the experimental group (FAC → T, AC → TX) achieved a better DFS than the control group (FAC, AC → T, respectively) (RR = 0.60, 95% CI = 0.39–0.90, P = 0.014). With a cut-off point ≥19%, Ki-67 high patients achieved a worse DFS (RR = 1.49, 95% CI = 1.28–1.72, P < 0.001). Conclusion: This study had limitations due to its retrospective nature and the lack of standardized Ki-67 measurement methods. Nevertheless, our findings indicate that Ki-67 high patients have a worse prognosis and may be more sensitive to anthracycline/taxane-based regimens. The ideal Ki-67 cut-off point for predicting chemosensitivity may be a certain value among a range of values ≥19% in HR-positive patients.

Some common mutations of RAD50 and NBS1 in western populations do not contribute significantly to Chinese non-BRCA1/2 hereditary breast cancer

To the editor Breast cancer is one of the main causes of cancer-related deaths among women worldwide, with 5–10% of cases being attributed to germline mutations in major genes. Former genetic linkage analysis revealed that the etiology of a relatively large proportion of Chinese potential hereditary breast cancers could not be explained by BRCA1 or BRCA2 mutations [1]. RAD50 is one of the highly conserved DNA double-strand (DSB) break repair factors. Together with NBS1 and MRE11, it composes the Mre11 complex and functions in sensing and early processing of DSB, cell cycle checkpoints, DNA recombination, and maintenance of telomeres [2]. Heterozygosity for deleterious mutations in components of the RAD50-MRE11-NBS1 complex seems to influence risk of breast cancer. The initial finding of mutations in Rad50 and NBS1 associated with breast cancer risk is consistent with the involvement of DNA repair genes in carcinogenesis [3], and mutations in those genes seem to be moderately penetrant but infrequent. This study is a continuation of our efforts to determine the role of some known common mutations of RAD50 and NBS1 in western populations in the development of non-BRCA1/2 Chinese families with signs of hereditary susceptibility to breast cancer. High-risk breast cancer patients were recruited and collected through four different medical centers which were described in our previous study [4]. The index cases included should match the following criteria: (1) at least one firstor second-degree relatives with breast cancer and/or ovarian cancer, regardless of age; or (2) breast cancer diagnosed below 35 years of age. Written informed consent was obtained from all subjects in accordance with institutional guidelines. Previous testing had confirmed the included cases to be BRCA1/2 mutation negative. Altogether 192 cases came from independent families were identified, the average age at diagnosis of breast cancer was 42.2 years, ranging between 23 and 81. The family histories concerning four-generation pedigrees of all the eligible cases were retrieved from the medical records and standard questionnaires, ascertained by the families and/or the patients personally. Six of the families in our study were breast-ovarian cancer families. A total of 192 women with no personal or family history of cancer were enrolled as normal control from Cancer Hospital of Fudan University between 2003 and 2007. This project has been approved by the Scientific and Ethical Committee of the Cancer Hospital of Fudan University. Oligonucleotide primers and polymerase chain reaction (PCR) conditions as former publications were used to amplify the specific segments which spanned the three mutation spots (RAD50 687delT, NBS1 657del5 and NBS1 I171 V) [3, 5, 6]. The PCR and DNA sequencing analysis were performed as described previously [4]. Full sequencing of all the index cases did not revealed the Rad50 687delT mutation in any case, and we did not find any other deleterious mutations in exon 5 of RAD50. In addition, our analysis of sequence variations in the 5 and 6th exon of NBS1 indicated that 657del5 and I171 V were not present in our cohort of high-risk breast cancer cases and control individuals, and the common polymorphismQ185E identified in our study had a similar frequency in cases and controls, which implied that it was unlikely to be associated with an increased risk for breast cancer in Chinese population (Table 1). A.-Y. Cao Z. Hu W.-J. Yin W. Jin Z.-M. Shao (&) Breast Cancer Institute, Cancer Hospital/Cancer Institute, Department of Oncology, Shanghai Medical College, Institutes of Biomedical Science, Fudan University, 270 Dong’an Road, 200032 Shanghai, People’s Republic of China e-mail: zhimingshao@yahoo.com

First Efficacy Results of Capecitabine with Anthracycline- and Taxane-Based Adjuvant Therapy in High-Risk Early Breast Cancer: A Meta-Analysis

Background Capecitabine is effective and indicated for the salvage treatment of metastatic breast cancer. Therefore, it is essential to evaluate the efficacy of capecitabine in the adjuvant setting. There have been two large randomized studies to determine whether patients with high-risk early breast cancer benefit from the addition of capecitabine to standard chemotherapy, but they have yielded inconsistent results. We first undertook a meta-analysis to evaluate the efficacy of the addition of capecitabine over standard treatment. Methods PubMed, EBSCO, Web of Science, conference proceedings and key trials were searched from 1998 to 2011. The hazard ratio (HR) was used to evaluate the efficacy of a taxane-anthracycline regimen and a taxane-anthracycline-capecitabine regimen in early breast cancer. All of the data from each study use either fixed-effects or random-effects by Stata. Findings We found significant improvement in the additional capecitabine arm versus control in disease-free survival (DFS) (HR = 0.83, 95% CI: 0.71–0.98, P = 0.027), overall survival (OS) (HR = 0.71, 95% CI: 0.57–0.88, P = 0.002), distant recurrence (HR = 0.79, 95% CI: 0.66–0.94, P = 0.008) and the death from breast cancer only (HR = 0.65, 95% CI: 0.51–0.83, P = 0.001). Meanwhile, the subgroup analysis revealed that capecitabine improved the DFS in triple negative (HR = 0.71, 95% CI: 0.53–0.96, P = 0.028), hormone receptor negative (HR = 0.73, CI: 0.56–0.94, P = 0.017) and HER2 negative (HR = 0.81, CI: 0.67–0.98, P = 0.034) patients. Conclusion Due to the synergistic effect of taxane and capecitabine, taxane-anthracycline-capecitabine regimen may effectively improve the efficacy in the adjuvant setting and may be a novel generation of adjuvant chemotherapy regimen. The results of the current meta-analysis support this hypothesis and indicate that taxane-based regimen with capecitabine may be an effective, convenient, and well tolerated regimen in patients with early breast cancer.

Postoperative Fever: The Potential Relationship with Prognosis in Node Negative Breast Cancer Patients

Background Postoperative fever may serve as an indirect sign to reflect the alterations of the host milieu caused by surgery. It still remains open to investigation whether postoperative fever has a bearing on prognosis in patients with lymph node negative breast cancers. Methods We performed a retrospective study of 883 female unilateral patients with lymph node negative breast cancer. Fever was defined as an oral temperature ≥38 in one week postoperation. Survival curves were performed with Kaplan-Meier method, and annual relapse hazard was estimated by hazard function. Findings The fever patients were older than those without fever (P<0.0001). Hypertensive patients had a propensity for fever after surgery (P = 0.011). A statistically significant difference was yielded in the incidence of fever among HR+/ERBB2-, ERBB2+, HR-/ERBB2- subgroups (P = 0.012). In the univariate survival analysis, we observed postoperative fever patients were more likely to recur than those without fever (P = 0.0027). The Cox proportional hazards regression analysis showed that postoperative fever (P = 0.044, RR = 1.89, 95%CI 1.02–3.52) as well as the HR/ERBB2 subgroups (P = 0.013, HR = 1.60, 95%CI 1.09–2.31) was an independent prognostic factor for relapse-free survival. Conclusion Postoperative fever may contribute to relapse in node negative breast cancer patients, which suggests that changes in host milieu related to fever might accelerate the growth of micro-metastatic foci. It may be more precise to integrate both tumor- and host-related factors for the evaluation of relapse risk.