The expression of Ki-S1 and BCL-2 and the response to primary tamoxifen therapy in elderly patients with breast cancer

Ki-S1, a marker of proliferation, and bcl-2, thegene product of which is an antagonist ofapoptosis, have been measured in 51 ER-positive primarybreast cancers before and during tamoxifen treatment andthen related to clinical response. Both markers weredetected in the majority of tumours before treatmentand, quantitatively, initial expression of Bcl-2 protein, butnot Ki-S1, was significantly related to the percentagereduction in tumour volume as assessed by ultrasound.Staining for both markers was lower in posttreatment samples than in those taken prior totreatments, but concordant decreases in staining indices wereseen in only 11 of the 51 tumours.The results demonstrate, using clinical material, that theresponse to tamoxifen may involve changes in proliferationand/or susceptibility to cell-death.     

Dual targeting of EphA2 and ER restores tamoxifen sensitivity in ER/EphA2-positive breast cancer

Overexpression and altered function of EphA2 receptor tyrosine kinase are critical in the progression of breast cancer and provide a target for breast cancer therapy. We have previously demonstrated that EphA2 overexpression decreases estrogen dependence and Tamoxifen sensitivity both in vitro and in vivo. EA5, a novel monoclonal antibody that mimicks the binding of ephrin A to EphA2, reverses the effect of EphA2 overexpression and restores Tamoxifen sensitivity in EphA2-transfected MCF-7 cells in vitro. To explore the role of EphA2 overexpression on ER-dependent mechanisms, we used two different ER+/EphA2-transfected cell line models (MCF-7^neo/MCF-7^EphA2 and T47D^neo/T47D^EphA2). EA5 inhibits primary tumor growth and restores Tamoxifen sensitivity in the MCF-7^EphA2 xenografts. Using the T47D^EphA2 in vitro model, we verified that EphA2 decreases ER activation in response to E2 stimulation consistent with our earlier results in MCF-7^EphA2 model. We found no direct interaction between ER and EphA2 and no difference in expression of canonical ER-dependent proteins or ER co-regulators. However, E2 stimulation phosphorylates FAK^Tyr925 only in ER+/EphA2+ cell lines. Treatment of T47D^EphA2 cells with EA5 and Tamoxifen leads to dephosphorylation of FAK^Tyr925 in response to E2. Our data demonstrate that dual targeting of EphA2 and ER is a promising approach for delaying resistance to Tamoxifen. The data support our hypothesis that EphA2 impacts ER function via a FAK dependent pathway.     

戈舍瑞林联合三苯氧胺治疗绝经前ER+PR+及ER+PR-复发转移性乳腺癌疗效观察

目的:探讨戈舍瑞林联合三苯氧胺辅助内分泌治疗绝经前雌激素(ER)、孕激素(PR)双阳性及ER+/PR-两种复发转移乳腺癌的临床疗效,对比两种乳腺癌的治疗效果.方法:将104例绝经前、原癌基因(c-erbB-2)均为(+)、淋巴结1-3个阳性的复发转移乳腺癌患者分成两组,52例ER+/PR+,52例为ER+/PR-.两组患者均为手术后和辅助化疗后发现复发转移的乳腺癌接受戈舍瑞林3.6mg皮下注射,每28天1次,连续6个月以上;联合三苯氧胺口服,10mg/次,每日2次,连用6个月以上.结果:104例患者完全缓解(CR)3例,部分缓解(PR)31例,稳定(SD)31例,进展(PD)39例,总有效率(OR=CR+PR)为32.7%,临床获益率(CBR=CR+PR+SD≥6个月)62.5%;其中ER+、PR-组,CR 2例,PR 21例,SD 16例,PD 13例,OR为44.1%,CBR 74.9%;ER+、PR-组CR 1例,PR 10例,SD 15例,PD 26例,OR 21.1%,CBR 49.9%.结论:戈舍瑞林联合三苯氧胺辅助内分泌治疗绝经前ER阳性、淋巴结1-3阳性、复发转移性的乳腺癌患者临床疗效显著,而ER+/PR+组患者效果明显优于ER+、PR-组患者,临床治疗效果更佳.对于在辅助内分泌治疗期间发生PD,应立即中止辅助内分泌治疗,进行手术、解救化疗、放疗或分子靶向等治疗后再序贯内分泌治疗.     

雌激素孕激素受体阳性与雌激素受体阳性孕激素受体阴性乳腺癌的临床研究

目的探讨雌激素孕激素受体阳性与雌激素受体(ER)阳性孕激素受体(PR)阴性乳腺癌的临床病理特征及预后因素分析。方法收集2012年1月至2015年12月山东省肿瘤医院收治的398例女性乳腺癌患者的临床资料,分析病理学特征。应用χ2检验比较不同组的差异;应用COX回归模型分析疾病进展相关因素。结果低ER水平(HR 5.59,95%CI:2.42~12.95,P0.001)、低PR水平(HR 0.19,95%CI:0.04~0.90,P0.05)和高Ki-67增殖指数(HR 5.84,95%CI:1.91~17.85,P0.05)的患者复发率更高。ER+/PR+患者与ER+/PR-患者在肿瘤体积(P0.001)、病理分期(P0.001)、Ki-67水平(≥20%)(P0.001)、Her-2阳性表达(P0.05)等方面比较,差异有统计学意义。结论 ER+/PR-乳腺肿瘤比ER+/PR+乳腺肿瘤具有更强的侵袭性。     

Drug resistance to tamoxifen during breast cancer therapy

Summary Breast cancer is the most common malignancy occurring in Western women, and is one of the leading causes of cancer mortality. The nonsteroidal antiestrogen tamoxifen has been shown to be an effective treatment for pre and postmenopausal women with all stages of the disease. Tamoxifen provides effective palliation when used to treat patients with advanced disease, and adjuvant tamoxifen therapy produces significant increases in both disease-free and overall survival (Early Breast Cancer Trialists Collaborative Group. Lancet 339:1-15, 71-85, 1992). Data from the laboratory have shown that the primary action of tamoxifen is tumoristatic rather than tumoricidal, and long-term therapy is therefore recommended. Unfortunately, many patients experience disease progression while taking tamoxifen. Some tamoxifen resistant tumors may remain sensitive to alternative endocrine therapies, while others may become refractory to any hormonal manipulation. Many models have been developedin vitro andin vivo to study the progression of breast cancer growth from tamoxifen sensitive to tamoxifen resistant. We and others have used long-term estrogen deprivation and long-term tamoxifen exposure to develop cell lines and tumors capable of growth in the presence of clinically relevant tamoxifen concentrations. Recently our laboratory has also shown that mutations in the estrogen receptor can cause an antiestrogen-occupied receptor to behave as though it were occupied by an estrogen. Breast cancer is a highly heterogeneous disease and it is likely that the mechanisms which cause tamoxifen resistant growth are equally heterogeneous. Several of the models from our laboratory and others which may contribute to an understanding of this complex phenomenon are discussed here.     

Loss in MCL-1 function sensitizes non-Hodgkin's lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199)

As a population, non-Hodgkin''s lymphoma (NHL) cell lines positive for the t(14;18) translocation and/or possessing elevated BCL2 copy number (CN; BCL2^High) are exquisitely sensitive to navitoclax or the B-cell lymphoma protein-2 (BCL-2)-selective inhibitor venetoclax. Despite this, some BCL2^High cell lines remain resistant to either agent. Here we show that the MCL-1-specific inhibitor A-1210477 sensitizes these cell lines to navitoclax. Chemical segregation of this synergy with the BCL-2-selective inhibitor venetoclax or BCL-X_L-selective inhibitor A-1155463 indicated that MCL-1 and BCL-2 are the two key anti-apoptotic targets for sensitization. Similarly, the CDK inhibitor flavopiridol downregulated MCL-1 expression and synergized with venetoclax in BCL2^High NHL cell lines to a similar extent as A-1210477. A-1210477 also synergized with navitoclax in the majority of BCL2^Low NHL cell lines. However, chemical segregation with venetoclax or A-1155463 revealed that synergy was driven by BCL-X_L inhibition in this population. Collectively these data emphasize that BCL2 status is predictive of venetoclax potency in NHL not only as a single agent, but also in the adjuvant setting with anti-tumorigenic agents that inhibit MCL-1 function. These studies also potentially identify a patient population (BCL2^Low) that could benefit from BCL-X_L (navitoclax)-driven combination therapy.     

Arena: Overprolonged adjuvant tamoxifen therapy in breast cancer

While adjuvant tamoxifen therapy given continuously for 2–3years can lead to a modest improvement in survival rates inearly breast cancer, there is no evidence that prolonging tamoxifenadministration beyond that time is likely to improve survivalrates any further in unselected cases. In the case of advanceddisease, an alternating tamoxifen/progestagen regimen has beenshown to increase the response rate and also its duration, beyondthat to be expected from either agent alone. The next generationof adjuvant trials in breast cancer needs to explore the potentialof an alternating tamoxifen/megestrol regimen. breast cancer, tamoxifen therapy, progestagen therapy, megestrol therapy, adjuvant therapy     

Application of single and combination therapy of clarithromycin and tamoxifen to suppress breast cancer cell proliferation and metabolism

Objective This study compares the anti-tumor effects of single and combination use of clarithromycin and tamoxifen on estrogen receptor (ER) positive breast cancer cell lines,BT-483 and MCF-7 as well as triple negative cell line,MBA-MD-231,which acts as a negative control.The effect of solid breast tumor inhibition by clarithromycin is also studied.Method BT-483,MCF-7 and MBA-MD-231 were cultured in 6-well plates in a 37 ℃ humidified incubator without CO2 for 24 h prior to the addition of the test drugs.The test groups were clarithromycin (Group 1),tamoxifen (Group 2),clarithromycin and tamoxifen (Group 3),and control (Group 4).Group 3 was prepared in 1 to 1 ratio at a concentration of 1.5 mmol/L clarithromycin and 25 μmol/L tamoxifen.On the other hand,1 mm3 solid breast tumors were submerged into various groups as above for 24 h.On the harvest day,the proliferation of cancer cells and solid breast tumor samples were measured by WST-1 proliferation reagent while ATP bioluminescence assay was employed to measure the metabolic rate of the three cell lines.Results The proliferation of BT-483 and MCF-7 was suppressed most by combination use of clarithromycin and tamoxifen with statistical significance.The two drugs did not have an inhibitory effect on the hormonal negative cancer cells.For solid breast tumor samples,all the test groups showed reduced metabolic rate as compared with the control group (P<0.05).Conclusion Combination use of tamoxifen and clarithromycin are effective in suppressing cell proliferation and metabolism rate of breast cancer cells while single use of clarithromycin effectively inhibits the proliferation of solid breast tumor.     

Decreased expression of EZH2 is associated with upregulation of ER and favorable outcome to tamoxifen in advanced breast cancer

The purpose of this study is to investigate EZH2 in a large series of breast cancer patients for its prognostic and predictive value, and to evaluate its functional role in treatment response in vitro. EZH2 levels were measured using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) in primary breast cancer specimens and related to clinicopathologic factors and disease outcome. EZH2 expression was downregulated with siRNAs in MCF7, to assess expression alterations of putative EZH2 downstream genes and to determine cell numbers after treatment with the anti-estrogen ICI 164384. In 688 lymph node-negative patients who did not receive adjuvant systemic therapy, EZH2 was not significantly correlated with metastasis-free survival (MFS). In 278 patients with advanced disease treated with first-line tamoxifen monotherapy, the tertile with highest EZH2 levels was associated with the lowest clinical benefit (OR = 0.48; P = 0.02) and with a shorter progression-free survival (PFS) in both univariate (HR = 1.80; P < 0.001) and multivariate analysis, including traditional factors (HR = 1.61; P = 0.004). In vitro, EZH2 silencing in MCF7 caused a 38% decrease in cell numbers (P < 0.001) whereas ICI 164384 treatment resulted in a 25% decrease (P < 0.001) compared to controls. Combining EZH2 silencing with ICI treatment reduced cell numbers with 67% (P < 0.001) compared to control conditions. EZH2 downregulation was associated with an almost two-fold upregulation of the estrogen receptor alpha (ER) (P = 0.001). In conclusion, EZH2 has no prognostic value in breast cancer. High levels of EZH2 are associated with poor outcome to tamoxifen therapy in advanced breast cancer. Downregulated EZH2 leads to upregulation of the ER and better response to anti-estrogens.     

Overprolonged adjuvant tamoxifen therapy in breast cancer.

While adjuvant tamoxifen therapy given continuously for 2-3 years can lead to a modest improvement in survival rates in early breast cancer, there is no evidence that prolonging tamoxifen administration beyond that time is likely to improve survival rates any further in unselected cases. In the case of advanced disease, an alternating tamoxifen/progestagen regimen has been shown to increase the response rate and also its duration, beyond that to be expected from either agent alone. The next generation of adjuvant trials in breast cancer needs to explore the potential of an alternating tamoxifen/megestrol regimen.     

Predicting adherence to tamoxifen for breast cancer adjuvant therapy and prevention

Treatment with the selective estrogen receptor modulator (SERM) tamoxifen for 5 years has produced dramatic breast cancer-related benefits in (a) the adjuvant setting, with 30% to 50% reductions in recurrence, contralateral disease, and mortality and (b) the prevention setting of healthy high-risk women, where tamoxifen reduces the risk of invasive and noninvasive breast cancer by 50%. Despite these striking data, adherence to tamoxifen is low, and low adherence is associated with poor survival. Although toxicity is a major predictor of poor adherence after starting therapy, pretreatment (baseline) predictors of poor tamoxifen adherence have been minimally studied. The adherence-survival link underscores the critical need to identify early predictors of poor adherence, and recent work is beginning to address this need. A major baseline predictor of poor adherence to prevention is current smoking, which is interestingly absent from studies of adherence to adjuvant therapy. Other important prevention adherence factors include breast cancer risk, extremes of age, non-white ethnicity, low socioeconomic status, and alcohol use. The strongest adjuvant therapy predictors are age (especially very young), ethnicity, and socioeconomic status. Future studies involving prospective systematic evaluation of these and other potential predictors in endocrine chemoprevention (e.g., other SERMs and aromatase inhibitors) are critical, as is the development of effective/targeted interventions to improve adherence and thus treatment outcomes in at-risk women.     

雌激素诱导蛋白pS2表达与ER阳性原发乳腺癌患者辅助内分泌治疗疗效的关系

目的:探讨雌激素诱导蛋白pS2的表达与乳腺癌临床参数和辅助三苯氧胺TAM治疗疗效的关系,明确pS2对辅助内分泌治疗的指导地位。方法:采用免疫组化S蛳P法检测81例ER阳性原发乳腺癌的石蜡切片pS2的表达, 统计学分析其与预后的关系。结果:原发乳腺癌pS2的阳性表达率为66.7 %,其表达与手术年龄(P=0.037)、月经状态(P=0.016)、肿瘤大小(P=0.029)、PR表达情况(P<0.001)密切相关,年龄小于50岁、绝经前、小肿瘤、PR阳性的患者pS2阳性率高。单因素分析和多因素分析均表明pS2是预测OS的独立预后因子。同时pS2对DFS也具有独立预后价值(P=0.023)。结论:pS2是预测ER阳性乳腺癌患者辅助内分泌治疗疗效的独立指标。     

Myocardial infarction risk and tamoxifen therapy for breast cancer

Tamoxifen prevents recurrence after breast cancer and breast cancer among high-risk women, and may prevent myocardial infarction (MI). To assess the impact of tamoxifen on MI risk, we conducted a case-control study of first MI after breast cancer nested among women diagnosed with breast cancer, while enrolled in a health maintenance organisation from 1980 to 2000. We obtained information on breast cancer treatment and MI risk factors through medical record reviews and interviews. Data were analysed using conditional logistic regression. Of 11,045 women with breast cancer, 134 met MI criteria and were matched to two MI-free control subjects on year of birth and breast cancer diagnosis. After adjusting for smoking, hypertension and diabetes, tamoxifen was unassociated with MI (odds ratio (OR)=1.2, 95% confidence interval (CI)=0.7-1.9). Duration, cumulative dose and recency of use were not associated with MI. Radiation therapy was associated with MI (OR=2.0, 95% CI=1.1-3.5), an association that varied slightly but not statistically significantly by tamoxifen use (radiation with tamoxifen, OR=2.0, 95% CI=0.9-4.4; radiation without tamoxifen, OR=2.9, 95% CI=1.2-7.5). Tamoxifen treatment for breast cancer does not appear to increase or decrease MI risk, although radiation therapy appears to increase MI risk.     

Relationship of PS2 with response to tamoxifen therapy in patients with recurrent breast cancer.

PS2, an oestrogen-inducible protein, was measured in the cytosol of 230 primary tumours from patients who were subjected to first-line tamoxifen therapy for advanced disease without prior adjuvant therapy with tamoxifen. PS2 correlated positively with oestrogen receptor (ER, P < 0.01) and progesterone receptor content (PgR, P < 0.001), and with the length of progression-free survival (PFS, P = 0.05). Although not statistically significant, higher levels of PS2 (> or = 10 ng mg-1 protein) were also associated with increased probability of response to tamoxifen treatment and a longer total post-relapse survival (PRS). ER, PgR, menopausal status, site of disease and prior adjuvant chemotherapy were all associated with response to tamoxifen therapy and with PFS. In multivariate analysis for PFS, low levels of ER and PgR, visceral metastasis, a disease-free interval of less than 1 year and prior adjuvant chemotherapy were all significantly associated with an increased probability of a rapid disease progression after start of tamoxifen therapy. In the subset of 83 tumours with intermediate levels of ER and PgR (both > or = 10, but not both > or = 75 fmol mg-1 protein), PS2 was positively related with the length of PFS (P < 0.01) and PRS (P < 0.05). PS2 remained the strongest factor in multivariate analysis for PFS (P < 0.01) in this ER/PgR intermediate subgroup, but was not of predictive value in univariate or multivariate analysis for both PFS and PRS in tumours classified as ER/PgR low or high (> or = 75 fmol mg-1 protein). It is concluded that PS2 status may be used as a parameter, additional to ER and PgR, for better refinement of prediction of response to tamoxifen treatment in advanced breast cancer patients especially with intermediate ER/PgR levels in their primary tumour.