ER-α30和ER-α36在乳腺癌组织的表达及意义

目的探讨新型雌激素受体亚型ER-α30和ER-α36在乳腺癌中的表达及与他莫昔芬治疗预后的关系。方法收集2015年1月至2015年11月间在河北北方学院附属第一医院接受他莫昔芬内分泌治疗的Luminal A型乳腺癌患者75例,并收集同时期30例ER(-)乳腺癌患者组织。采用免疫组化染色SP法检测ER-α30和ER-α36蛋白表达。分析ER-α30和ER-α36蛋白表达与Luminal A型乳腺癌临床病理特征的关系。随访患者的无病生存时间(DFS)。采用Cox风险比例回归模型分析影响DFS的因素。结果Luminal A型乳腺癌组织中ER-α30蛋白阳性表达率为32.0%(24/75),低于ER(-)乳腺癌组织(P<0.05)。ER-α30蛋白表达与TNM分期、肿瘤直径、浸润深度、淋巴结转移、孕激素受体状态有关(P<0.05)。ER-α36蛋白阳性表达率为52.0%(39/75),与ER(-)乳腺癌组织比较差异无统计学意义(P>0.05)。ER-α36蛋白表达与TNM分期和肿瘤直径有关(P<0.05)。随访时间为11~54个月,患者48个月无病生存率为64.0%(48/75)。ER-α30阳性患者48个月无病生存率为33.33%(8/24),阴性患者为78.43%(40/51),差异具有统计学意义(P=0.001)。ER-α36阳性患者48个月无病生存率为48.7%(19/39),阴性患者为80.6%(29/36),差异具有统计学意义(P=0.002)。Cox风险比例回归分析显示,ER-α30、ER-α36是影响Luminal A型乳腺癌患者DFS的独立预后因素(P<0.05)。结论Luminal A型乳腺癌ER-α30和ER-α36阳性表达者接受他莫昔芬治疗无病生存期较短,其有望成为预测他莫昔芬治疗反应性的重要指标。     

Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer

Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G₁, G₁/S, G₂, and G₂/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.     

Toxicidad retiniana por tamoxifeno. Seguimiento mediante estudio por imagen multimodal

IntroductionTamoxifen is a non-steroidal anti-oestrogen that acts as an antagonist in breast tissue, neurosensory retina, and retinal pigment epithelium (RPE). The reported incidence of its ocular effects varies between 0.9% and 11%.MethodsCase series. Multimodal image studies were used to evaluate three female patients who were receiving tamoxifen for breast cancer for the purpose of monitoring and determining whether there are changes after discontinuation of treatment.ResultsAll three patients showed signs of crystalline retinopathy using spectral domain optical coherence tomography (SD-OCT) during follow-up.ConclusionThe follow-up using multimodal imaging studies allowed evaluating the progression of the changes, providing a prognostic assessment. The findings reported (visual acuity and multimodal imaging) confirmed the results of previous studies, indicating that, at a certain level of toxicity, the damage was irreversible.     

Tamoxifen related side effects and their impact on breast cancer incidence: A retrospective analysis of the randomised IBIS-I trial

BackgroundStudies in the adjuvant setting have shown that endocrine therapy related side effects predict breast cancer recurrence risk. Here, we assess the relationship between early reported side effects and incidence of breast cancer in women randomised to tamoxifen for cancer prevention in the International Breast Intervention Study (IBIS)–I trial.MethodsWomen randomised to tamoxifen in the IBIS-I trial and for whom side effect status was known at the 6-month follow-up visit were included in this analysis. Side effects included in this analysis were hot flushes, vaginal discharge, and vaginal dryness. The primary endpoint was all breast cancer and secondary endpoint was oestrogen receptor (ER) positive breast cancer. Cox proportional hazard models were used to investigate breast cancer incidence in the tamoxifen group with and without side effects reported within 6 months of randomisation.ResultsWomen randomised to tamoxifen and reporting hot flushes at the 6-month follow-up visit had a non-statistically significant increase in breast cancer compared to those without hot flushes (HR = 1.26 (0.98–1.62), P = 0.08). A significant higher breast cancer risk was observed for postmenopausal women who reported hot flushes at the 6-month follow-up visit compared to those without hot flushes (HR = 1.59 (1.12–2.26), P = 0.01). A higher risk was observed for ER-positive breast cancer in postmenopausal women (HR = 1.81 (1.19–2.74), P = 0.01). No significant associations between gynaecological side effects and breast cancer occurrence was observed.ConclusionsOverall, no association between side effects reported at 6 months and subsequent breast cancer occurrence was observed. Some side effects might be useful markers for breast cancer occurrence in postmenopausal women.     

Soy Foods Might Weaken the Sensitivity of Tamoxifen in Premenopausal Patients With Lumina A Subtype of Breast Cancer

Background

Based on estrogen active substances, many women consume soy foods in the belief that it could prevent breast cancer (BC). Women with different molecular subtypes would be likely to have diverse reactions to soy foods, especially those with the estrogen-receptor-positive (ER⁺) subtype. The aim of the current study is to identify the differentially expressed genes (DEGs) on soy foods in premenopausal patients with Lumina A subtype of BC (LABC) after soy food treatment, and to further investigate the critical molecule change.

Underutilisation of breast cancer prevention medication in Australia

Increased implementation of proven prevention strategies is required to combat rising breast cancer incidence. We assessed use of risk reducing medication (RRMed) by Australian women at elevated breast cancer risk. Only 2.4% had ever used RRMed. Higher breast cancer risk was statistically significantly associated with use of RRMed (OR 1.82, 95%CI: 1.08–3.07, p = 0.02 for ≥30% lifetime risk compared with 16%–29% lifetime risk), but parity, education level and family history of breast cancer were not. Breast cancer prevention medications are underutilised. Efforts are needed to incorporate breast cancer risk assessment and risk management discussions into routine health assessments for women.     

吡格列酮联合他莫昔芬治疗多囊卵巢综合征的疗效观察

目的探讨盐酸吡格列酮片联合枸橼酸他莫昔芬片治疗多囊卵巢综合征的临床疗效。方法选取2014年9月—2017年10月江油市人民医院妇科收治的多囊卵巢综合征患者100例为研究对象,将所有患者随机分为对照组和治疗组,每组各50例。对照组患者于月经周期开始的第5天口服枸橼酸他莫昔芬片,20 mg/次,1次/d。治疗组患者在对照组治疗的基础上早餐后口服盐酸吡格列酮片,30 mg/次,1次/d。以21 d为1个疗程,两组患者均连续治疗3个疗程。比较两组治疗前后排卵情况、临床症状、卵巢情况、性激素水平、胰岛素抵抗指标和不良反应发生情况。结果治疗后,对照组患者成熟卵泡数为(1.6±0.5)个,排卵率为64.0%;治疗组患者成熟卵泡数为(2.2±0.5)个,排卵率为88.0%,两组排卵情况比较差异有统计学意义(P0.05)。治疗后,两组月经稀发、痤疮、多毛例数均显著降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗后治疗组临床症状例数均显著少于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组卵巢体积显著降低,子宫内膜厚度显著增加,同组治疗前后比较差异有统计学意义(P0.05);且治疗后治疗组卵巢情况显著优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组黄体生成素(LH)、睾酮(T)水平明显降低,促卵泡激素(FSH)、雌二醇(E2)水平明显升高,同组治疗前后比较差异有统计学意义(P0.05);且治疗后治疗组性激素水平改善显著优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组空腹血糖(FPG)、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)均显著降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗后治疗组胰岛素抵抗指标显著低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,治疗组不良反应发生率为6.0%,明显低于对照组的16.0%,两组比较差异具有统计学意义(P0.05)结论盐酸吡格列酮片联合枸橼酸他莫昔芬片治疗多囊卵巢综合征疗效显著,可显著改善患者的临床症状,促进性激素紊乱和胰岛素抵抗情况的恢复,具有一定的临床推广应用价值。     

A phase I pharmacokinetics study of lapatinib and tamoxifen in metastatic breast cancer (EORTC 10053 Lapatam study)

ObjectiveThis phase I study assessed the pharmacokinetic (PK), tolerability, safety and preliminary clinical activity of tamoxifen (T) and lapatinib (L) in patients with metastatic breast cancer (MBC).MethodsPatients (pts) with hormone receptor positive MBC, irrespective of HER-2 status, were randomly assigned to T → T + L group, tamoxifen in cycle 1 for 28 days then adding lapatinib on day 1 of cycle 2; or L → T + L group, lapatinib in cycle 1 for 14 days, then adding tamoxifen on day 1 of cycle 2 to evaluate the potential drug–drug PK interaction at steady-state. The dose of tamoxifen was 20 mg/day and lapatinib 1500 mg/day.ResultsTwenty-five pts were enrolled of which 23 started treatment, five (22%) of them were HER-2 positive. Median age was 59 years and 96% had PS ≤1. Eleven (91.7%) pts in the T → T + L group and 10 (76.9%) in L → T + L group received at least 2 cycles of treatment. The most frequently reported drug-related adverse events (>25% of patients) were diarrhoea (62%), anaemia (56%), rash (52%), fatigue (52%), dermatology other (34%) and leukopenia (28%). Grade 3–4 drug-related toxicities were infrequent (<10%). No cardiotoxicity was observed. T plasma concentrations did not appeared to be affected by the presence of lapatinib. L steady-state plasma concentrations were 20% lower after 28 days of co-administration with T. Eight (36.4%) patients experienced stable disease and median progression free survival was 2.7 months.ConclusionsThe combination of L and T was safe and clinically active. T affected L plasma concentrations, which remained within the therapeutic index.     

Effects of tamoxifen on tricarboxylic acid cycle enzymes in the brain of rats submitted to an animal model of mania induced by amphetamine

The neurobiological basis of bipolar disorder (BD) remains unknown; nevertheless, mitochondrial dysfunction has been identified in this disorder. Inactivation of any step in the tricarboxylic acid (TCA) cycle can impair mitochondrial ATP production. There is recent evidence indicating that PKC is an important therapeutic target for bipolar disorder. Therefore, we evaluated the effects of tamoxifen (TMX—a PKC inhibitor) on the activities of enzymes in the TCA cycle of rat brains subjected to an animal model of mania induced by amphetamine. In the reversal treatment, Wistar rats were first treated with d-AMPH or saliratsne (Sal) for 14 days. Thereafter, between days 8 and 14, the rats were administered TMX or Sal. The citrate synthase, succinate dehydrogenase, and malate dehydrogenase were evaluated in the frontal cortex, hippocampus, and striatum. The d-AMPH administration inhibited TCA cycle enzymes activity in all analyzed structures, and TMX reversed d-AMPH-induced dysfunction. In addition, we observed a negative correlation between d-AMPH-induced hyperactivity and the activity of these enzymes in the rat's brain. These findings suggested that TCA cycle enzymes inhibition can be an important link for the mitochondrial dysfunction seen in BD, and TMX exert protective effects against the d-AMPH-induced TCA cycle enzymes dysfunction.