乳腺癌内分泌治疗现状

内分泌治疗是雌激素受体阳性乳腺癌患的重治疗方法.随着新的内分泌药物出现,乳腺癌的内分泌治疗也取得了新的进展.目前,治疗绝经前乳腺癌患的标准用药仍是他莫昔芬,对于绝经后乳腺癌患使用芳香化酶抑制剂会获得更大的临床疗效.本文主阐述内分泌治疗在乳腺癌中的应用.     

Results from a randomized trial of a web-based,tailored decision aid for women at high risk for breast cancer

Objective

To assess the impact of Guide to Decide (GtD), a web-based, personally-tailored decision aid designed to inform women's decisions about prophylactic tamoxifen and raloxifene use.

Methods

Postmenopausal women, age 46–74, with BCRAT 5-year risk ≥1.66% and no prior history of breast cancer were randomized to one of three study arms:intervention (n = 690), Time 1 control (n = 160), or 3-month control (n = 162). Intervention participants viewed GtD prior to completing a post-test and 3 month follow-up assessment. Controls did not. We assessed the impact of GtD on women's decisional conflict levels and treatment decision behavior at post-test and at 3 months, respectively.

Results

Intervention participants had significantly lower decisional conflict levels at post-test (p < 0.001) and significantly higher odds of making a decision about whether or not to take prophylactic tamoxifen or raloxifene at 3-month follow-up (p < 0.001) compared to control participants.

Conclusion

GtD lowered decisional conflict and helped women at high risk of breast cancer decide whether to take prophylactic tamoxifen or raloxifene to reduce their cancer risk.

Practice implications

Web-based, tailored decision aids should be used more routinely to facilitate informed medical decisions, reduce patients’ decisional conflict, and empower patients to choose the treatment strategy that best reflects their own values.     

Modifiable risk factors for adherence to adjuvant endocrine therapy among breast cancer patients

Objective

Breast cancer incidence and mortality are declining due to improvements in early detection and treatment. One advance in treatment is the development of adjuvant endocrine therapy (AET) for women with hormone receptor positive breast cancer. Despite strong evidence linking AET to better health outcomes, AET adherence continues to be suboptimal. This study tests the hypothesis that patient beliefs about medication mediate the relationship between frequency of physician communication and AET adherence.

Methods

This cross-sectional study utilizes data from patient self-report and medical chart abstraction (N = 200). Survey measures included frequency of physician communication, patient beliefs about medicine, AET adherence, and demographic characteristics.

Results

Necessity beliefs mediated the relationship between frequency of physician communication and medication adherence (necessity beliefs β = .18, p < .05; physician communication β = .13, p > .05). There was no evidence of medication concerns mediating the relationship between frequency of physician communication and medication adherence.

Conclusion

More frequent physician communication that shapes what patients believe about AET importance may be associated with greater AET adherence; however, frequent physician communication that shapes patient concerns about side effects may not be associated with greater AET adherence.

Practice implications

Research is needed to enhance understanding of the type of physician communication that is most consistently associated with patient beliefs about medication and AET adherence.     

Hormonal therapy is associated with a lower prevalence of breast arterial calcification on mammography

OBJECTIVE: To bring further understanding to the relationship between hormonal therapy (HT) and breast arterial calcification (BAC). METHODS: Of women arriving for breast cancer screening mammography, 1995 consented to complete a survey and have their mammograms analyzed for the presence of BAC. The survey assessed HT use and major risk factors for CAD. RESULTS: Of the 1919 women with complete data, there were 268 with BAC (14%). When categorized into three age groups, BAC was present in 40.7% of the women > or =65, 10.9% of those 55-64 and 3.0% of those <55. The > or =65 year-old group showed a nearly 50%-point lower prevalence of BAC among HT users compared with women who were not on HT (25.8% versus 74.2%, respectively, p=0.006). With age included as a continuous variable, past use of HT was significantly associated with a lower prevalence of BAC (p<0.03), while the presence of diabetes or a history of stroke were significantly associated with a higher prevalence of BAC (p<0.002). CONCLUSIONS: Well-established cardiovascular risk factors (diabetes, stroke, and age) appear to be associated with a significantly higher incidence of BAC, while HT during the menopausal years appears to be associated with a significantly lower prevalence of BAC.     

Information needs of post-menopausal women with hormone receptor positive early-stage breast cancer considering adjuvant endocrine therapy

Objective

To identify questions that post-menopausal women with receptor-positive early-stage breast cancer want answered before their adjuvant-endocrine-therapy decision is made.

Methods

We surveyed patients eligible for adjuvant-endocrine therapy in the previous 3–18 months. Participants rated the importance of getting each of 95 questions answered before the decision is made (options: essential/desired/not important or no opinion/avoid). For each question rated “essential”/“desired”, the participant also identified the purpose(s) for the answer: to help her understand, decide, plan, or other reason(s).

Results

The response rate was 55% (188/343). Participants rated a mean of 57 (range: 1–95) questions “essential”, 80 (range: 1–95) “essential” or “desired”, and 2 (range: 0–27) “avoid”. Every question was “essential” to ≥31% of participants, and “essential”/“desired” to ≥63%. All but eleven questions were rated as “avoid” by ≥1 participant. The most frequent purposes for “essential” questions were to: understand their situations (mean 45, range: 0–95), decide (mean 18, range: 0–94), and plan (mean 13, range: 0–95).

Conclusion

Many patients want a lot of information before this decision is made but there is wide variation within the group in both the number and in which questions they want answered.

Practice implications

Patient education in this setting needs to be tailored to the needs of the individual patient.     

Androgen receptor amplification is associated with increased cell proliferation in prostate cancer

Mechanisms of prostate cancer progression during hormonal therapy and the pathobiologic consequences of androgen receptor (AR) gene amplification are inadequately known. To further investigate the hypothesis that AR gene amplification is associated with increased cell proliferation, we analyzed 123 paraffin-embedded prostate cancer specimens from men who experienced tumor relapse during androgen withdrawal therapy. We used fluorescence in situ hybridization to quantify AR gene copy number and Ki-67 immunohistochemistry to determine cell proliferation. One third of the tumors showed AR gene amplification. Among tumors with AR amplification, the mean cell proliferation rate was 19.8 (SD, 12.3; 95% confidence interval [CI], 15.4-24.1), whereas it was 13.0 (SD, 15.9; 95% CI, 9.1-16.8) in tumors without amplification (P = .032). In the best fitting logistic regression model, only proliferation remained significant (P = .040). When the median Ki-67 labeling index (6.7%) of all tumors was used as a cutoff point, the tumors with AR amplification were more frequently highly proliferating than tumors with no amplification (P = .010; odds ratio, 3.4; 95% CI, 1.4-8.3). Our results imply that progression of prostate cancer during androgen withdrawal therapy is associated with AR gene amplification and increased cell proliferation rate in one third of tumors. We suggest that AR gene amplification is an important molecular mechanism underlying the increase in proliferation rate of a substantial fraction of recurrent prostate carcinomas. However, efforts should be targeted to develop prostate cancer cell lines to study causal relationships between AR gene amplification and various biologic variables.     

不同治疗方法对绝经后乳腺癌患者骨密度的影响

目的 探讨不同治疗方法 对绝经后乳腺癌患者骨密度(BMD)的影响.方法 研究分为健康对照组(50例)、肿瘤组[48例,其中24例再行他莫昔芬(TAM)组治疗].采用双能X线骨密度仪(DEXA)测定所有研究对象的基线BMD.肿瘤组术后均进行辅助化疗,其中24例(TAM组)化疗后继续使用TAM行内分泌治疗.用DEXA测量腰椎和左髋部位的BMD,比较肿瘤组化疗前、后以及TAM组行内分泌治疗8个月后BMD变化.结果 肿瘤组化疗后腰椎部位BMD(0.87±0.15)g/cm2比化疗前(0.93±0.15)g/cm2明显降低(P<0.05);TAM组行内分泌治疗8个月后腰椎BMD(0.90±0.04)g/cm2和股骨颈(0.74±0.05)g/cm2等左髋部位的BMD均有明显增加(P<0.05).结论 化疗可能导致绝经后乳腺癌患者BMD的下降,而TAM治疗能缓解化疗引起的BMD降低.     

Tissue inhibitors of metalloproteinase expression in human breast cancer: TIMP-3 is associated with adjuvant endocrine therapy success

Tissue inhibitors of matrix metalloproteinase (TIMPs) may be involved in tumour growth, apoptosis, angiogenesis, invasion, and the development of metastases. This study has evaluated the association of the expression levels of the TIMP forms 1, 2, 3, and 4, measured by quantitative real-time RT-PCR, with classical clinicopathological characteristics, ie age, menopausal status, tumour size, histological grade, number of involved lymph nodes, and steroid hormone receptor status, and with disease progression and treatment sensitivity in 273 breast cancer patients. The mRNA levels of TIMP-1 and TIMP-2 were not associated with any known clinicopathological tumour feature. TIMP-3 and TIMP-4 levels were significantly higher in steroid hormone receptor-positive samples, although the levels of TIMP-4 were much lower than those of the other TIMPs. Only TIMP-3 predicted relapse-free survival (RFS) time differently depending on post-surgical treatment as, in particular, the interaction of TIMP-3 with endocrine therapy (p = 0.008, HR = 0.24, 95% CI = 0.09-0.69) contributed significantly to RFS in multivariate Cox regression analysis. In subgroup analyses, the 107 patients treated with tamoxifen differed greatly in prognosis after dichotomization by the median TIMP-3 level (p = 0.0003). Thus, high tumour levels of the matrix metalloproteinases inhibitor and pro-apoptotic factor TIMP-3 are associated with successful tamoxifen treatment of patients with breast cancer.     

内分泌治疗乳腺癌患者的衰老感知及相关因素

目的:探索内分泌治疗的乳腺癌患者衰老感知水平及相关因素。方法:正在接受内分泌治疗的乳腺癌患者110例,使用宾夕法尼亚大学关节疼痛相关的衰老感知量表(PAAS)、医院用焦虑抑郁量表(HADS)、简明疼痛评估量表(BPI)、自我同情量表简化版(SCS-SF)进行评估。结果:PAAS总分中位数为8(1,24);SCS-SF总分中位数为38.5(22,51)。多元回归分析显示,人均月收入与抑郁得分均与衰老感知正向关联(β=0.20、0.39),自我同情得分与衰老感知负向关联(β=-0.34)。结论:在乳腺癌患者中,收入水平、抑郁和自我同情都与衰老感知相关。     

Factors associated with patient involvement in surgical treatment decision making for breast cancer

OBJECTIVE: To evaluate factors associated with women's reported level of involvement in breast cancer surgical treatment decision making, and the factors associated with the match between actual and preferred involvement in this decision. METHODS: Survey data from breast cancer patients in Detroit and Los Angeles was merged with surgeon data for an analytic dataset of 1101 patients and 277 surgeons. Decisional involvement and the match between actual and preferred amount of involvement were analyzed as three-level dependent variables using multinomial logistic regression controlling for clustering within surgeons. Independent variables included patient demographic and clinical factors, surgeon demographic and practice factors, cancer program designation, and two measures of patient-surgeon communication. RESULTS: We found variation in women's actual decisional involvement and match between actual and preferred involvement. Women with a surgeon-based or patient-based (versus shared) decision were significantly (p < or = 0.05) younger. Women who had too little decisional involvement (versus the right amount) were younger, while women with too much involvement had less education. Patient-surgeon communication variables were significantly associated with both involvement and match, and higher surgeon volume as associated with too little involvement. CONCLUSION: Patient factors and patient-surgeon communication influence women's perception of their involvement in breast cancer surgical treatment decision making. PRACTICE IMPLICATIONS: Decision tools are needed across surgeons and practice settings to elicit patients' preferences for involvement in treatment decisions for breast cancer.     

内分泌和化疗对乳腺肿瘤患者干细胞的影响

BACKGROUND:Tumor stem cells are the root of cancer recurrence and metastasis, so clinical researches should focus on the effects of different treatments on tumor stem cells. OBJECTIVE:To explore the effects of endocrine therapy and chemotherapy on stem cells in patients with breast cancer. METHODS:After recovery and cultivation of estrogen receptor-positive human breast cancer cell lines MCF-7, passage 3 cells in logarithmic phase were selected and divided into three groups containing control, estradiol and estradiol with tamoxifen groups. The estradiol group was divided into three subgroups: 10^-7, 10^-8 and 10^-9 mol/L estradiol was added into the medium, respectively; the estradiol with tamoxifen group was divided into three subgroups: 10^-7, 10^-8 and 10^-9 mol/L estradiol with 10^-6 mol/L tamoxifen were added into the medium, respectively. The same amount of absolute ethyl ethanol was added into the medium of control group. Fifteen female patients with late recurrence and metastasis of breast cancer received chemotherapy as recurrence and metastasis group. Another 15 healthy volunteers were selected as healthy control group. RESULTS AND CONCLUSION:The proportion of CD44⁺CD24^-/low cell subsets in the estradiol and estradiol with tamoxifen groups was significantly higher than that of the control group (P < 0.05), and the proportion of CD44⁺CD24^-/low cell subsets in the estradiol group was significantly higher than that of the estradiol with tamoxifen group at the same concentration (P < 0.05). The proportion of CD44+CD24-/low cell subsets had no significant differences among groups at 10 and 20 days of culture (P < 0.05). The proportion of CD44⁺CD24^-/low cell subsets significantly increased in MCF-7 cells after 24-hour intervention with different chemotherapy drugs. But only the proportion of CD44⁺CD24^-/low cell subsets in the paclitaxel and doxorubicin groups was significantly higher than that of the control group after 20-day intervention (P < 0.05). Besides, the proportion of CD44⁺CD24^-/low cell subsets in the peripheral blood of healthy volunteers was significantly lower than that of the recurrence and metastasis group (P < 0.05). Among 15 patients with late recurrence and metastatic of breast cancer, 9 had stable disease, 5 had partial remission, 1 had failed chemotherapy and cancer progression. Moreover, the proportion of CD45^-CD44⁺CD24^-/low cell subsets in the peripheral blood of patients sensitive for chemotherapy was significantly lower than that before treatment (P < 0.05). In conclusion, both endocrine therapy and chemotherapy exert a certain effect on the CD44⁺CD24^-/low cell subsets of breast cancer positive for estrogen receptor. Given that CD44⁺CD24^-/low cell subsets in MCF-7 cells resist chemotherapy drugs, the proportion of CD45^-CD44⁺CD24^-/low cells in the peripheral blood of patients sensitive for chemotherapy is decreased.     

Capecitabine maintenance therapy in patients with recurrent or metastatic breast cancer

Our objective was to investigate the efficacy and safety of capecitabine maintenance therapy (CMT) after capecitabine-based combination chemotherapy in patients with metastatic breast cancer. The clinical data of 139 metastatic breast cancer patients treated from March 2008 to May 2012 with capecitabine-based combination chemotherapy were retrospectively analyzed. When initial disease control was achieved by the combination chemotherapy, we used CMT for 50 patients, while 37 patients were treated with a different (non-CMT) maintenance therapy. We compared time to progression (TTP), objective response rate, disease control rate, clinical benefit rate, and safety of the two groups, and a sub-group analysis was performed according to pathological characteristics. Sixty-four percent of the patients received a median of six cycles of a docetaxel+capecitabine combination chemotherapy regimen (range 1-45); the median TTP (MTTP) for the complete treatment was 9.43 months (95%CI=8.38-10.48 months) for the CMT group and 4.5 months (95%CI=4.22-4.78 months; P=0.004) for the non-CMT group. The MTTPs for the maintenance therapies administered after the initial capecitabine combined chemotherapy were 4.11 months (95%CI=3.34-4.87 months) for the CMT group and 2.0 months (95%CI=1.63-2.38 months) for the non-CMT group. Gastrointestinal side effects, decreased white blood cells and palmar-plantar erythrodysesthesia were the main adverse reactions experienced with the combination chemotherapies, CMT and non-CMT treatments. No significant differences in the incidence of adverse reactions were detected in the CMT and non-CMT patients. After initial disease control was achieved with the capecitabine-based combination chemotherapy, CMT can significantly prolong TTP rates with a favorable safety profile.     

Targeted epidermal growth factor receptor nanoparticle bioconjugates for breast cancer therapy

Selective drug delivery is an important approach with great potential for overcoming problems associated with the systemic toxicity and poor bioavailability of antineoplastic drugs. Nanomedicine plays a pivotal role by delivering drugs in a targeted manner to the malignant tumor cells thereby reducing the systemic toxicity of the anticancer drugs. The objective of this study was to prepare and characterize rapamycin loaded polymeric poly(lactide-co-glycolide) (PLGA) nanoparticles (NP) that were surface conjugated with antibodies to epidermal growth factor receptor (EGFR), highly expressed on breast cancer cells, using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) mediated cross linking agents. To potentiate the anticancer efficiency of the formulations, in vitro cytotoxicity of native rapamycin, rapamycin loaded nanoparticles and EGFR antibody conjugated rapamycin loaded nanoparticles (EGFR-Rapa-NPs) were evaluated on malignant MCF 7 breast cancer cell lines. IC₅₀ doses as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay showed the superior antiproliferative activity of EGFR-Rapa-NPs over unconjugated nanoparticles and native rapamycin due to higher cellular uptake on malignant breast cancer cells. Cell cycle arrest and cellular apoptosis induced by the above formulations were confirmed by flow cytometry. Molecular basis of apoptosis studied by western blotting revealed the involvement of a cytoplasmic protein in activating the programmed cell death pathway. Thus it was concluded that EGFR-Rapa-NPs provide an efficient and targeted delivery of anticancer drugs, presenting a promising active targeting carrier for tumor selective therapeutic treatment in near future.     

精神分裂症的认知行为治疗个案报告

本文介绍了1例康复期精神分裂症患者在利培酮治疗基础上联合认知行为治疗的整个治疗过程.在12次的认知行为治疗过程中,在前、中、后三个阶段如何进行治疗设置、不同阶段的治疗重点、具体治疗方法的应用以及效果评估进行了案例示范,并对该案例治疗的不足和精神分裂症认知行为疗法的未来发展进行了讨论.     

Effects of supervised exercise therapy in patients receiving radiotherapy for breast cancer

PURPOSE: Postoperative radiotherapy for breast cancer has a number of associated complications. This study examined whether supervised moderate-intensity exercise could mitigate the complications that occur during radiotherapy. PATIENTS AND METHODS: Forty women were randomized before radiotherapy after various operations for breast cancer. Seventeen patients who were assigned to the exercise group performed supervised moderate-intensity exercise therapy for 50 min 3 times per week for 5 weeks. Twenty-three patients in the control group were asked to perform self-shoulder stretching exercise. The World Health Organization Quality of Life-BREF (WHOQOL-BREF), brief fatigue inventory (BFI), range of motion (ROM) of the shoulder, and pain score were assessed before and after radiotherapy. RESULTS: There were no significant differences noted at baseline between groups. In the exercise group, there was an increase in the WHOQOL-BREF and shoulder ROM and decrease in BFI and pain score after radiotherapy. On the other hand, patients in the control group showed decrease in the WHOQOL-BREF and shoulder ROM and increase in BFI and pain score after radiotherapy. There were statistically significant differences in the changes in the WHOQOL, BFI, shoulder ROM, and pain score between the groups. CONCLUSION: Patients receiving radiotherapy for breast cancer may benefit in physical and psychological aspects from supervised moderate-intensity exercise therapy.     

The incidence of breast cancer and changes in the use of hormone replacement therapy: A review of the evidence

Even though a link between hormone replacement therapy (HRT) and breast cancer has been well documented in the epidemiological literature since the 1980s, it was not until publication of the results of the Women's Health Initiative (WHI) study in 2002 and the Million Women Study in 2003 that women and doctors started reconsidering the use of HRT and sales of HRT started to drop. This paper evaluates the impact of the publication of these two landmark studies on the expected and observed changes in the incidence of breast cancer.Between 2001–2002 and 2005–2006, sharp and significant reductions in the incidence of breast cancer of up to 22% were reported in many US and European populations, temporally consistent with the drop in usage of HRT. Declines in the rates of breast cancer were strongest for 50–60-year-old women (those most likely to be current users of HRT), affected mainly ER+ and PR+ cancers (those most strongly associated with HRT use), and were largest among women with the highest pre-decline prevalence of HRT use and the sharpest decline in its use.A considerable amount of scientific evidence supports the hypothesis that the decline in the incidence of breast cancer is in large part attributable to the sudden drop in HRT use following publication of the WHI and Million Women studies. Nevertheless, the problem of how to advise women contemplating HRT use today remains. Medical relief will remain necessary for many women with menopausal complaints, and so new therapeutic options need to be explored.     

Docetaxel-loaded nanoparticles based on star-shaped mannitol-core PLGA-TPGS diblock copolymer for breast cancer therapy

A star-shaped biodegradable polymer, mannitol-core poly(d,l-lactide-co-glycolide)-d-α-tocopheryl polyethylene glycol 1000 succinate (M-PLGA-TPGS), was synthesized in order to provide a novel nanoformulation for breast cancer chemotherapy. This novel copolymer was prepared by a core-first approach via three stages of chemical reaction, and was characterized by nuclear magnetic resonance, gel permeation chromatography and thermogravimetric analysis. The docetaxel-loaded M-PLGA-TPGS nanoparticles (NPs), prepared by a modified nanoprecipitation method, were observed to be near-spherical shape with narrow size distribution. Confocal laser scanning microscopy showed that the uptake level of M-PLGA-TPGS NPs was higher than that of PLGA NPs and PLGA-TPGS NPs in MCF-7 cells. A significantly higher level of cytotoxicity was achieved with docetaxel-loaded M-PLGA-TPGS NPs than with commercial Taxotere®, docetaxel-loaded PLGA-TPGS and PLGA NPs. Examination of the drug loading and encapsulation efficiency proved that star-shaped M-PLGA-TPGS could carry higher levels of drug than linear polymer. The in vivo experiment showed docetaxel-loaded M-PLGA-TPGS NPs to have the highest anti-tumor efficacy. In conclusion, the star-like M-PLGA-TPGS copolymer shows potential as a promising drug-loaded biomaterial that can be applied in developing novel nanoformulations for breast cancer therapy.     

乳腺癌保乳术后不同放射治疗计划剂量学研究

目的研究乳腺癌不同放射治疗计划的剂量学差异。方法对18例保乳手术的患者分别设计常规切线野计划、正向调强计划、逆向调强计划,处方剂量均为5000cGy。利用剂量体积直方图来比较各种计划中临床靶区、危机器官的剂量学差异。结果常规切线野计划、正向调强计划、逆向调强计划的靶区覆盖率V95％分别为84.35％、98.37％、96．71％．剂量不均匀性指数分别为15．870％、7．189％、10．820％;逆向调强计划与常规切线野计划、正向调强计划相比危机器官的受照射量与体积明显增加．各指标组间比较差异有统计学意义（P〈0．05）;正向调强更能有效降低各危机器官的平均受照射量和体积,与常规切线野计划相比对侧肺、脊髓、心脏的Dmean差异有统计学意义（P〈0.05）。结论正向调强计划能够有效地提高靶区覆盖率和剂量分布均匀性,也能降低正常组织、器官的受照剂量和体积;逆向调强计划有待进一步完善。     

认知疗法治疗抑郁性神经症

对18例抑郁性神经症门诊病人,采用 Beck 认知疗法和阿米替林治疗进行了初步对照研究,结果二组均有明显疗效,但认知治疗组优于药物组,此法适合中国国情及文化背景,可进一步应用。