Therapeutic strategies in male breast cancer: Clinical implications of chromosome 17 gene alterations and molecular subtypes

Male breast cancer (MBC) is a rare disease. To date, therapy is mainly based on studies and clinical experiences with breast cancer in women. Only little is known about molecular typing of MBC, particularly with regard to potential biological predictors for adjuvant therapy. In female breast cancer tumors with chromosome 17 centromere (CEP17) duplication, HER2 and/or Topoisomerase II alpha (Topo II-α) gene alterations have been suggested to be associated with poor prognosis and increased sensitivity to anthracycline-containing regimens.In a well characterized cohort of 96 primary invasive MBC, we studied CEP17, HER2 and Topo II-α alterations by fluorescence in-situ hybridization (FISH), and expression of hormone receptors (HR), HER2 and Ki67 by immunohistochemistry to define molecular subtypes. Tumor characteristics and follow-up data were available and correlated with molecular findings.HER2 amplification and Topo II-α amplification/deletion were exceptionally rare in MBC (6.3% and 3.1%, respectively). CEP17 polysomy were found in 9.4% of tumors. HER2, Topo II-α and CEP17 gene alterations were not correlated to patients outcome. 96.9% of our cases were HR positive. Triple negative tumors were found in only 3.1% of the cases. In nodal negative tumors luminal A subtypes were significantly associated with better overall survival.Our results provide evidence for a predominant male breast cancer phenotype, characterized by HR expression and a lack of HER2/Topo II-α alterations and CEP17 duplicates. Therefore, the impact of anthracycline sensitivity linked to HER2/Topo II-α alterations as found in female breast cancer has low clinical significance for this specific male breast cancer phenotype.     

Prolonged clinical benefit from the maintenance hormone therapy in patients with metastatic breast cancer

ObjectiveWe investigated the efficacy of maintenance hormone therapy (MHT), which was given to hormone positive metastatic breast cancer (MBC) patients in non-progression status to the previous chemotherapy.MethodsThis study retrospectively analyzed 76 MBC patients who had been treated with MHT from 2006 to 2010 at a single institute.ResultsFor the 76 patients reviewed, the median progression free survival (PFS) to MHT was 14.4 months (95% CI, 11.6–17.3). Prolonged PFS was associated with less previous palliative chemotherapy, fewer metastatic sites, and the absence of visceral metastasis in univariate analysis. Multivariate analysis showed that only the number of previous palliative chemotherapy (HR 1.73, 95% CI, 1.00–2.98; P = 0.04) remained as a significant variable. MHT was generally well tolerated.ConclusionsMHT showed considerable efficacy and tolerability in this study. Further randomized prospective study is warranted.     

Randomized phase II study of sunitinib versus standard of care for patients with previously treated advanced triple-negative breast cancer

PurposeThis randomized, open-label phase II study compared the efficacy of sunitinib monotherapy with that of single-agent standard-of-care (SOC) chemotherapy in patients with previously treated advanced triple-negative breast cancer (TNBC).MethodsPatients with advanced TNBC, relapsed after anthracycline- and taxane-based chemotherapy, were randomized to receive either sunitinib (37.5 mg/day) or the investigator's choice of SOC therapy. Progression-free survival was the primary endpoint.ResultsMedian progression-free survival was 2.0 months with sunitinib and 2.7 months with SOC chemotherapy (one-sided P = 0.888). Median overall survival was not prolonged with sunitinib (9.4 months) compared with SOC chemotherapy (10.5 months; one-sided P = 0.839). The objective response rate was 3% with sunitinib and 7% with SOC chemotherapy (one-sided P = 0.962).ConclusionsSunitinib monotherapy did not improve efficacy compared with SOC chemotherapy in patients with previously treated advanced TNBC, for which identification of effective treatments and therapeutic targets remains an urgent need.Trial registrationNCT00246571.     

GPR30/EGFR在多囊卵巢综合征患者卵巢组织中的表达

目的:探讨雌激素膜受体G蛋白偶联受体30(GPR30)及表皮生长因子(EGFR)在多囊卵巢综合征(PCOS)患者卵巢组织中的表达。方法:选取2012~2015年在青岛市妇女儿童医院生殖中心行手术治疗的PCOS患者25例,以及同期因良性卵巢肿瘤行剥除术的25例患者为对照组。采用实时荧光定量PCR技术检测卵巢组织中ERα、ERβ、GPR30及EGFR mRNA的表达水平;Western blot法检测卵巢组织中ERα、ERβ、GPR30及EGFR蛋白表达;免疫组化法检测卵巢组织中ERα、ERβ、GPR30及EGFR蛋白的表达定位。结果:PCOS卵巢组织中GPR30及EGFR mRNA和蛋白表达水平均显著高于对照组,差异均有统计学意义(P0.05)。始基卵泡及初级卵泡中,GPR30蛋白主要定位表达于卵母细胞胞浆与胞膜以及颗粒细胞的细胞核,始基卵泡卵母细胞表达明显高于初级卵泡卵母细胞,较对照组GPR30在PCOS组卵母细胞及颗粒细胞中表达均升高;EGFR蛋白主要表达于颗粒细胞的细胞核,在PCOS组表达升高。结论:GPR30及EGFR在PCOS患者的卵泡发育障碍过程中可能具有重要作用。     

May progesterone receptor membrane component 1 (PGRMC1) predict the risk of breast cancer?

Objective: Our and other studies have pointed on an important role of progesterone receptor membrane component 1 (PGRMC1) in development of breast cancer, especially in hormone therapy. To investigate if PGRMC1 could be used to predict the risk for getting breast cancer, we assessed in tissues of patients with primary invasive breast cancer, if the expression of PGRMC1 may be associated with the expression of estrogen receptor alpha (ERα), progesterone receptor (PR), and ki67.

Methods: Samples from 109 patients with breast cancer between the years 2008 and 2014 were obtained with the patients’ consent. Each sample was evaluated for the ERα, PR, Ki67, and PGRMC1 expression by immunohistochemistry using serial sections from the ame paraffin block comparing malignant tissue to benign tissue.

Results: Expression of PGRMC1 is increased in tumor area compared with non-cancerous tissue and positively correlates with ERα expression (OR?=?1.42 95%CI 1.06–1.91, p?=?0.02). No association was obtained between expression of PGRMC1 and PR or Ki67.

Conclusion: It can be suggested that women with breast epithelium highly expressing PGRMC1 and in interaction with ERα may have an increased risk to develop breast cancer, especially when treated with hormone therapy.     

Endocrine therapy for hormone treatment-naïve advanced breast cancer

A proportion of patients with hormone receptor-positive locally advanced or metastatic breast cancer will not have received prior endocrine therapy. However, there are limited clinical data specifically in these patients. We conducted a review of randomized phase II and III clinical studies of anastrozole, letrozole, exemestane, palbociclib, and fulvestrant to determine the evidence base supporting use of specific endocrine therapies in this patient population. From our findings, there is a paucity of clinical studies in patients with endocrine therapy-naïve disease; however, it appears that first-line treatment effects are consistent between patients who have and have not received prior endocrine treatment.     

大麻素受体激动剂WIN55,212-2联合金诺芬对人肝癌细胞HepG2增殖与凋亡的影响

目的 探讨大麻素受体激动剂WIN55,212-2(WIN)联合金诺芬(AF)对人肝癌细胞HepG2增殖和凋亡的影响,并对其机制进行初步研究.方法 分别用5 μmol/L WIN、0.25 μmol/L AF、5μmol/L WIN联合0.25μmol/L AF处理HepG2细胞24h和48 h后,MTS法检测细胞活力;采用AnnexinV-FITC和PI双染色法并通过流式细胞仪分析细胞凋亡;Western blot检测凋亡相关蛋白(Bcl-2、Bip、ATF4、PARP、Caspase-3、Caspase-8、Caspase-9)表达的变化.分别用5μmol/L WIN联合0.25 μmol/L AF、Z-VAD-FMK以及Z-VAD-FMK预处理1h后再用5 μmol/L WIN联合0.25 μmol/L AF处理HepG2细胞24 h,Western blot检测蛋白PARP、Caspase-3、Caspase-8、Caspase-9的变化.结果 与两药单独使用相比,WIN联合AF明显抑制细胞增殖,诱导细胞凋亡,可以引起Bcl-2蛋白表达水平下调,内质网应激反应相关蛋白Bip、ATF4蛋白表达水平上调,以及活化Caspase-3、Caspase-8、Caspase-9,引起PARP蛋白的切割.加入Caspase广谱抑制剂Z-VAD-FMK处理细胞后,能部分逆转联合用药的细胞凋亡比例.结论 大麻素受体激动剂WIN联合AF能有效诱导肝癌细胞凋亡,其机制可能与Bcl-2表达下调、内质网应激反应和Caspase系统活化相关.     

ER、PR、HER-2、Ki-67与乳腺癌新辅助化疗疗效相关性分析

目的  探讨雌激素受体（ER）、孕激素受体（PR）、人表皮生长因子受体2（HER-2）、Ki67抗原（Ki-67）与乳腺癌新辅助化疗疗效相关性分析。方法  采用免疫组织化学方法检测81例乳腺癌新辅助化疗前后ER、PR、HER-2、Ki-67的表达情况,并评估其与乳腺癌新辅助化疗有效率的关系。结果  81例患者中临床RR79％,术后pCR（9.9％）,tpCR（6.2％）。达到pCR+tpCR率,（ER阴性）23.0%>（ER阳性）12.7%,（PR阴性）28.6%>（PR阳性）9.4%;ER、PR、HER-2及Ki67等与新辅助化疗疗效之间差异无统计学意义。新辅助化疗前后ER、PR、HER-2的状态改变不明显,差异无统计学意义（P >0.05）,而Ki67的表达数量有统计学意义（P <0.05）,其降低了Ki67的表达水平。结论  乳腺癌新辅助化疗可有效控制肿瘤,ER或PR阴性者较阳性者可获得更高的pCR+tpCR率,Ki67可作为化疗药物敏感性和耐药性的预测指标。

     

Membrane insertion and topology of the p7B movement protein of Melon Necrotic Spot Virus (MNSV)

Cell-to-cell movement of the Melon Necrotic Spot Virus (MNSV) is controlled by two small proteins working in trans, an RNA-binding protein (p7A) and an integral membrane protein (p7B) separated by an amber stop codon. p7B contains a single hydrophobic region. Membrane integration of this region was observed when inserted into model proteins in the presence of microsomal membranes. Furthermore, we explored the topology and targeting mechanisms of full-length p7B. Here we present evidence that p7B integrates in vitro into the ER membrane cotranslationally and with an Nt-cytoplasmic/Ct-luminal orientation. The observed topology was monitored in vivo by fusing GFP to the Ct of p7B, enabling the overexpression in Escherichia coli cultures. Finally, the topology of a putative p14 movement protein was established by replacing the amber stop codon located between p7A and p7B.     

Prediction of Human Brain Penetration of P-glycoprotein and Breast Cancer Resistance Protein Substrates Using In Vitro Transporter Studies and Animal Models

Four P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrates with human cerebrospinal fluid (CSF) concentrations and preclinical neuropharmacokinetics were used to assess in vitro–in vivo extrapolation of brain penetration in preclinical species and the ability to predict human brain penetration. Unbound brain (C_b,u), unbound plasma (C_p,u), and CSF compound concentrations (C_CSF) were measured in rats and nonhuman primates (NHPs), and the unbound partition coefficients (C_b,u/C_p,u and C_CSF/C_p,u) were used to assess brain penetration. The results indicated that for P-gp and BCRP dual substrates, brain penetration was severally impaired in all species. In comparison, for P-gp substrates that are weak or non-BCRP substrates, improved brain penetration was observed in NHPs and humans than in rats. Overall, NHP appears to be more predictive of human brain penetration for P-gp substrates with weak or no interaction with BCRP than rat. Although C_CSF does not quantitatively correspond to C_b,u for efflux transporter substrates, it is mostly within 3-fold higher of C_b,u in rat and NHP, suggesting that C_CSF can be used as a surrogate for C_b,u. Taken together, a holistic approach including both in vitro transporter and in vivo neuropharmacokinetics data enables a better estimation of human brain penetration of P-gp/BCRP substrates.