BackgroundAdjuvant 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.MethodsComputerized 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.FindingsWith 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.ConclusionThis 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.

BRCA1 is closely related to the pathogenesis of breast cancer, BRCA1 mRNA is reduced in sporadic breast cancer cells despite the lack of mutations. In the present report, we found that overexpression of UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) was closely related to DNA methylation, deacetylation, and methylation of histones, recruitment of an inhibiting transcriptional complex on the BRCA1 promoter in sporadic breast cancer. Overexpression of UHRF1 induced deacetylation of histones H3 and H4, which was facilitated by recruitment of histone deacetylase1 (HDAC1) to the BRCA1 promoter. Loss of acetylation was accompanied by loss of binding of the key transcription factors MyoD, CBP, and p300. UHRF1 also recruited histone lysine methyltransferase G9a to the BRCA1 promoter and histone 3 lysine 4 (H3K4) was demethylated, and histone 3 lysine 9 (H3K9) was methylated. Finally, overexpression of UHRF1 leaded to methylation of BRCA1 promoter by recruitment of DNMT1 to the BRCA1 promoter, locking in marked suppression of BRCA1. It is the first to describe that UHRF1 is responsible for regulating BRCA1 transcription by inducing DNA methylation, histone modifications, and recruitment of transcriptional complex on the BRCA1 promoter, UHRF1 is a new bio-marker in sporadic breast cancer.

Our data indicate that DNMT1 inhibitor AZA and HDAC inhibitor TSA play important roles in restoring sensitivity of the ER alpha negative breast cancer cells to endocrine therapy in vitro and in vivo.

In order to analyze the clinicopathological features of Chinese triple negative tumors, we performed a retrospective study of 1993 female unilateral breast cancer patients undergoing surgery in Cancer Hospital of Fudan University, Shanghai, China. Survival curves were performed with Kaplan-Meier method and annual recurrence hazard was estimated by hazard function. We observed that the rate of larger tumors in triple negative patients was higher than that in HR+/ERBB2- women, but lower than that in ERBB2+ subgroup (P = 0.0001). In addition, 21.83% of triple negative patients had four or more axillary lymph nodes involved as compared to 27.40% of ERBB2+ women and 22.75% of HR+/ERBB2- subgroup (P = 0.0056). In the survival analysis, we found a statistical significance for recurrence-free survival (RFS) among the three subgroups (P = 0.0037), with the rate of 72.89% for ERBB2+ patients, 78.40% for HR+/ERBB2- ones and 75.76% for triple negative ones at the 11th year respectively. When it came to hazard peaks, discrepancies existed in different subgroups. Similar to HR+/ERBB2- patients, triple negative subgroup showed an early major recurrence surge peaking at approximately year 2.5 as opposed to ERBB2+ counterparts with a tapering sharp at the 1st year. Furthermore, the first peak of triple negative tumors was higher than that of HR+/ERBB2- patients, but lower than that of ERBB2+ ones. Therefore, our findings suggested biological characteristics and prognostic outlook of Chinese triple negative breast cancers might be more favorable and somewhat different from those in Western populations.