Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six-arm placebo-controlled trial in healthy women

Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.     

Tamoxifen in Mastalgia: A Meta-Analysis

ObjectivesTamoxifen is prescribed for chronic mastalgia at a dosage of one 10- or 20-mg tablet for 3–6 months. A topical preparation of this drug has recently been approved. The aim of this study was to meta-analyze the effectiveness of tamoxifen and its different regimens for the treatment of mastalgia. We also sought to summarize the side effects and the follow-up results of these treatments.Data SourcesWe searched the databases of PubMed/ MEDLINE, Central, Embase, and EBSCO from August 2021 to September 2021.Study SelectionArticles on the effects of tamoxifen in mastalgia were searched, and randomized controlled trials were retrieved for inclusion in this study. PRISMA guidelines were followed, and we selected 9 articles for the meta-analysis.Data Extraction and SynthesisA proforma was prepared for data collection. RevMan 5.4 software was used for methodological quality assessment, statistical analysis, and preparation of forest plots. Oral tamoxifen performed better than placebo (risk ratio [RR] 2.04; 95% CI 1.49–2.78, P < 0.001). No significant difference in efficacy was seen between the 10- and 20-mg dosages (RR 1.08; 95% CI 0.97–1.21, P = 0.18) when used for 3 months.ConclusionOral tamoxifen is helpful in long-standing mastalgia. It is safe and effective at an oral dose of 10 mg.     

甘肃地区乳腺癌患者的CYP2D6基因多态性及代谢表型特征分析

目的:分析乳腺癌患者的CYP2D6基因多态性和代谢表型，为乳腺癌患者进行他莫西芬（TAM）个体化临床治疗提供参考依据。方法:选取2018年1月至2019年1月于我院乳腺科确诊的170例乳腺癌患者外周血，通过Sanger测序技术对CYP2D6基因的9个外显子进行全面具体分析。结果:本研究主要发现有5个CYP2D6等位基因变异位点:CYP2D6*10、CYP2D6*4、CYP2D6*7、CYP2D6*41和CYP2D6*5，其对应的发生频率分别为66.5%、5.9%、2.4%、0.6%和0.6%；其中，CYP2D6*10/*10基因型在乳腺癌患者中占据主导地位，发生频率为60.6%。结论:中国甘肃地区乳腺癌患者，多以CYP2D6*10等位基因、CYP2D6*10/*10基因型、TAM中间代谢型为主，这可为乳腺癌患者选择相应的个体化药物治疗方案以及本地区乳腺癌患者今后大规模的药物遗传基因组学研究提供参考数据。     

IGF-1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER-positive breast cancer

Preclinical studies indicate that activated IGF-1R can drive endocrine resistance in ER-positive (ER+) breast cancer, but its clinical relevance is unknown. We studied the effect of IGF-1R signaling on tamoxifen benefit in patients and we searched for approaches to overcome IGF-1R-mediated tamoxifen failure in cell lines. Primary tumor blocks from postmenopausal ER+ breast cancer patients randomized between adjuvant tamoxifen versus nil were recollected. Immunohistochemistry for IGF-1R, p-IGF-1R/InsR, p-ERα(Ser118), p-ERα(Ser167) and PI3K/MAPK pathway proteins was performed. Multivariate Cox models were employed to assess tamoxifen efficacy. The association between p-IGF-1R/InsR and PI3K/MAPK pathway activation in MCF-7 and T47D cells was analyzed with Western blots. Cell proliferation experiments were performed under various growth-stimulating and -inhibiting conditions. Patients with ER+, IGF-1R-positive breast cancer without p-IGF-1R/InsR staining (n = 242) had tamoxifen benefit (HR 0.41, p = 0.0038), while the results for p-IGF-1R/InsR-positive patients (n = 125) were not significant (HR 0.95, p = 0.3). High p-ERα(Ser118) or p-ERα(Ser167) expression was associated with less tamoxifen benefit. In MCF-7 cells, IGF-1R stimulation increased phosphorylation of PI3K/MAPK proteins and ERα(Ser167) regardless of IGF-1R overexpression. This could be abrogated by the dual IGF-1R/InsR inhibitor linsitinib, but not by the IGF-IR-selective antibody 1H7. In MCF-7 and T47D cells, stimulation of the IGF-1R/InsR pathway resulted in cell proliferation regardless of tamoxifen. Abrogation of cell growth was regained by addition of linsitinib. In conclusion, p-IGF-1R/InsR positivity in ER+ breast cancer is associated with reduced benefit from adjuvant tamoxifen in postmenopausal patients. In cell lines, stimulation rather than overexpression of IGF-1R is driving tamoxifen resistance to be abrogated by linsitinib.     

三苯氧胺与来曲唑治疗ER阳性乳腺癌的临床疗效及对血清雌二醇水平和远期预后的影响

目的探讨三苯氧胺与来曲唑治疗雌激素受体(ER)阳性乳腺癌的临床疗效及对血清雌二醇(E2)水平和远期预后的影响。方法采用简单随机抽样法将110例ER阳性乳腺癌患者分为对照组(n=53)和研究组(n=57)。两组患者均接受长春瑞滨联合顺铂治疗,对照组患者在此基础上接受三苯氧胺治疗,研究组患者在此基础上接受来曲唑治疗,随访3年。比较两组患者的临床疗效、血清肿瘤标志物和E2水平、子宫内膜情况、不良反应发生率及生存情况。结果研究组患者的疾病控制率为92.98%,高于对照组的79.25%,差异有统计学意义(P<0.05)。治疗前,两组患者的血清糖类抗原153(CA153)、癌胚抗原(CEA)及E2水平比较,差异均无统计学意义(P>0.05)。治疗后3个月,两组患者的血清CEA和CA153水平均较本组治疗前降低,且研究组患者的血清CEA和CA153水平均低于对照组,差异均有统计学意义(P<0.05)。治疗后3、6、12个月,研究组患者的血清E2水平均低于治疗前,对照组患者的血清E2水平均高于治疗前,差异均有统计学意义(P<0.05)。病理结果提示,治疗后对照组中子宫内膜息肉2例,内膜不典型增生1例。两组患者恶心呕吐、便秘、肝肾功能不全、血小板减少、粒细胞减少及白细胞降低的发生率比较,差异均无统计学意义(P> 0.05)。研究组患者的3年生存情况优于对照组(P<0.05)。结论来曲唑治疗ER阳性乳腺癌的临床疗效优于三苯氧胺,且可降低血清肿瘤标志物和E2水平,改善远期预后。     

Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30–100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated.

Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed.

Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.     

细胞色素p450家族基因多态性与他莫昔芬临床疗效的关系

目前，他莫昔芬广泛用于雌激素受体阳性的乳腺癌患者，可大幅度降低患者的复发和死亡，已成为抗雌激素治疗的标准用药。p450酶系是他莫昔芬代谢的关键酶，从而影响他莫昔芬的治疗效果。临床上对他莫昔芬治疗的个体反应性存在高度差异，可能与p450家族基因多态性有着密切联系。本文主要对CYP2D6、CYP3A4/5、CYP2C19基因的多态性与他莫昔芬的代谢及疗效之间的关系进行简要阐述。     

GPER-induced signaling is essential for the survival of breast cancer stem cells

G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER⁻/PR⁺ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs.