芳香化酶抑制剂相关骨关节症状的免疫调节机制研究

目的　探讨乳腺癌患者应用芳香化酶抑制剂（ＡＩｓ）所致骨关节症状的免疫调节机制。方法　选择Ⅰ ～Ⅲ期绝经后乳腺癌患者５１例,３３例应用ＡＩｓ治疗,分为有较严重骨关节症状组１６例（ＢＰＩ-ＳＦ疼痛评分＞７）和未出现骨关节症状组１７例,另１８例为未进行ＡＩｓ治疗受体阴性组。同时设对照组（健康人）１６例。取各组研究对象的外周血,检测血中雌激素（Ｅ２）水平;应用ＥＬＩＳＡ方法检测血清中ＩＦＮ-γ、ＩＬ-４浓度以及骨钙素（ＢＧＰ）、骨碱性磷酸酶（ＢＡＬＰ）和Ⅰ型胶原羧基端前肽（ＣＩＣＰ）的浓度;应用流式细胞仪检测ＣＤ４＋ＣＤ２５＋调节性Ｔ细胞表达率。结果　有症状组的Ｅ２水平为（７２.８±５８.９）ｐｍｏｌ／Ｌ,无症状组为（６７.４±５７.６）ｐｍｏｌ／Ｌ,均低于对照组的（２０６.９±１１９.４）ｐｍｏｌ／Ｌ（Ｐ＜０.０１）,但有症状组与无症状组之间差异无统计学意义（Ｐ＞０.０５）。有症状组的ＩＦＮ-γ浓度为（８２.８３±５.５３）ｐｇ／ｍｌ,明显高于无症状组和受体阴性组（Ｐ＜０.０５）;有症状组的ＩＬ-４浓度为（２２.８３±１.０９）ｐｇ／ｍｌ,低于无症状组和受体阴性组（Ｐ＜０.０５）。流式细胞仪检测结果显示,有症状组外周血ＣＤ４＋ＣＤ２５＋Ｔ细胞的表达率为（５.６±１.１）％,低于无症状组的（１２.１±２.３）％和受体阴性组的（１４.９±３.５）％,差异均有统计学意义（Ｐ＜０.０１）。有症状组的骨代谢指标ＢＡＬＰ和ＣＩＣＰ水平分别为（６２.１±５.５）Ｕ／Ｌ和（１５６.８±４１.１）ｎｇ／ｍｌ,均高于无症状组的（４５.２±４.６）Ｕ／Ｌ和（１３７.５±３６.９）ｎｇ／ｍｌ,差异有统计学意义（Ｐ＜０.０５）,但有症状组的ＢＧＰ水平与无症状组无明显差异（Ｐ＞０.０５）。结论　应用ＡＩｓ产生的相关骨关节症状可能与患者机体的免疫功能调节异常密切相关,其确切机制有待进一步的研究阐明。     

芳香化酶抑制剂治疗乳腺癌研究进展

全文综述了三代芳香化酶抑制剂用于乳腺癌治疗的现状以及最新研究进展。     

芳香化酶抑制剂治疗乳腺癌研究进展

第3代芳香化酶抑制剂与其他内分泌制剂相比，具有疗效高、选择性强、毒副作用少等特点，已成为绝经后乳腺癌患者内分泌治疗的主要措施之一。现综述新一代芳香化酶抑制剂的抗肿瘤机制、药理学特性及在绝经后乳腺癌的治疗进展。     

乳腺癌芳香化酶抑制剂耐药分子机制研究进展

芳香化酶抑制剂（ aromatase inhibitors,AIs）在绝经后雌激素依赖性乳腺癌的治疗中取得了令人鼓舞的疗效。大型的临床试验ATAC和BIG 1-98均证明第三代芳香化酶抑制剂作为绝经后乳腺癌的辅助治疗可明显提高患者的无病生存期,疗效优于他莫昔芬。随着AIs在临床广泛应用及用药时间的延长,AIs耐药也成了临床医生不可回避的问题,至今国内尚没有对AIs耐药分子机制的详细报道,本文通过对国内外一些实验室和临床研究结果的综述,拟概述乳腺癌AIs耐药分子机制的研究进展。     

芳香化酶抑制剂治疗乳腺癌研究进展

芳香化酶抑制剂(AI)是作用于绝经后雄激素向雌激素转化的主要途径芳香化酶的一类药物，现主要介绍AI的研究进展及其在乳腺癌治疗中的应用、药理学特点和临床价值。     

芳香化酶抑制剂治疗乳腺癌研究进展

芳香化酶抑制剂(AI)是作用于绝经后雄激素向雌激素转化的主要途径芳香化酶的一类药物,现主要介绍AI的研究进展及其在乳腺癌治疗中的应用、药理学特点和临床价值.     

芳香化酶抑制剂致乳腺癌患者关节痛的病因及防治

芳香化酶抑制剂（AIs）已经广泛用于绝经后雌激素受体阳性的乳腺癌患者的术后辅助治疗.与单独应用他莫昔芬相比,AIs能显著地提高治疗效果,但同时也会带来骨肌系统的副作用,主要包括骨丢失和关节痛,而这已成为导致治疗中断的主要因素.本文对芳香化酶抑制剂导致关节痛的可能病因及治疗进展进行综述.     

芳香化酶抑制剂治疗相关的骨丢失及其防治

临床研究显示对于激素受体阳性的绝经后乳腺癌患者芳香化酶抑制剂的疗效优于他莫昔芬,但芳香化酶抑制剂进一步降低循环中雌激素水平,对骨代谢产生不良影响,导致骨成分丢失增加,增加骨质疏松症和骨折的风险,尤其是高龄女性及低骨密度者。本文就芳香化酶抑制剂治疗与骨丢失的关系及其监测和防治进行综述。     

芳香化酶抑制剂的耐药机制及对策

芳香化酶抑制剂（aromatase inhibitors，AIs）在绝经后激素反应性乳腺癌妇女的辅助内分泌治疗和解救治疗效果优于三苯氧胺（tamoxifen，TAM）。然而，随着药物治疗的深入，AIs的耐药也逐渐显现。近年研究发现：AIs的原发耐药可能与芳香化酶基因多态性有关，但具体的原理还不甚清楚。AIs的继发耐药可能与雌激素受体（ER）和多个生长因子通路的交叉通话相关。针对AIs的耐药，许多学者进行了逆转耐药的研究，本文就AIs的原发与继发耐药机制及逆转耐药的策略进行综述。     

芳香化酶抑制剂在绝经后乳腺癌妇女内分泌治疗的策略

在肿瘤治疗领域很少有药物能改变疾病的过程，而第三代芳香化酶抑制剂的出现则改变了乳腺癌的治疗程式。大量随机、前瞻、大样本临床试验结果的出现，使临床医师开始重新认识激素受体阳性和阴性乳腺癌在发病机制、治疗策略和预后方面的不同。     

Pilot study of duloxetine for treatment of aromatase inhibitor-associated musculoskeletal symptoms

BACKGROUND:

Approximately 50% of postmenopausal women with hormone receptor‐positive early stage breast cancer treated with an aromatase inhibitor (AI) develop musculoskeletal symptoms. Standard analgesics are relatively ineffective. Duloxetine is a serotonin norepinephrine reuptake inhibitor with proven efficacy for treatment of multiple chronic pain states. The authors investigated the hypothesis that duloxetine is efficacious for treatment of AI‐associated musculoskeletal symptoms.

METHODS:

The authors performed a single‐arm, open‐label phase 2 study of duloxetine in postmenopausal women with breast cancer who developed new or worsening pain after treatment with an AI for at least 2 weeks. Patients were treated with duloxetine for 8 weeks (30 mg for 7 days, then 60 mg daily). The primary endpoint was a 30% decrease in average pain score over 8 weeks, and secondary outcomes included change in average and worst pain, pain interference, depression, sleep quality, and hot flashes. Statistical analysis was done with t tests for paired data.

RESULTS:

Twenty‐one of 29 evaluable patients (72.4%) achieved at least a 30% decrease in average pain, and 18 of 23 patients (78.3%) who completed protocol‐directed treatment continued duloxetine. The mean percentage reduction in average pain severity between baseline and 8 weeks was 60.9% (95% confidence interval [CI], 48.6%‐73.1%), and in maximum pain severity it was 59.9% (95% CI, 47.0‐72.7%). The most common adverse events were grade 1 or 2 fatigue, xerostomia, nausea, and headache.

CONCLUSIONS:

Duloxetine appears to be effective and well tolerated for treatment of AI‐associated musculoskeletal symptoms. Future randomized, placebo‐controlled studies are warranted. Cancer 2011;. © 2011 American Cancer Society.     

A prospective study of aromatase inhibitor‐associated musculoskeletal symptoms and abnormalities on serial high‐resolution wrist ultrasonography

BACKGROUND:

Nearly half of women treated with aromatase inhibitors (AI) develop AI‐associated musculoskeletal symptoms (AIMSS) such as arthralgias, but to the authors' knowledge the etiology is unclear. The upper extremities are frequently affected, especially the wrists, hands, and fingers. AI use may also increase the risk of developing carpal tunnel syndrome. Tendon sheath fluid and tenosynovial changes have been demonstrated by imaging symptomatic patients who were treated with AIs. The authors hypothesized that these abnormalities are correlated with AIMSS.

METHODS:

Thirty consecutive patients in whom adjuvant therapy with letrozole or exemestane was initiated on a prospective clinical trial enrolled in a pilot study evaluating tendon and joint abnormalities at baseline and after 3 months of AI therapy. Patients underwent high‐resolution ultrasonography of the wrists bilaterally and completed the Health Assessment Questionnaire (HAQ) and pain Visual Analog Scale (VAS). AIMSS were defined as an increase in the HAQ or VAS score during AI therapy that exceeded a predefined cutoff.

RESULTS:

Twenty‐five patients completed both the baseline and 3‐month assessments. During the first 12 months of AI therapy, 15 patients developed AIMSS, and 13 discontinued therapy because of musculoskeletal symptoms. There was a trend toward an association between the presence of tendon sheath abnormalities on wrist ultrasound at baseline and the development of AIMSS (P = .06).

CONCLUSIONS:

Clinically relevant musculoskeletal symptoms develop in women treated with AIs, leading to treatment discontinuation in a substantial percentage of these patients. However, in the current study, patient‐reported symptoms were not found to be associated with changes visible on wrist ultrasonography. Cancer 2010. © 2010 American Cancer Society.     

A prospective pilot study investigating the musculoskeletal pain in postmenopausal breast cancer patients receiving aromatase inhibitor therapy

Background

Although arthralgia is a known adverse effect of aromatase inhibitor (ai) treatment in postmenopausal breast cancer patients, few studies have carried out a comprehensive evaluation of the nature, onset, and incidence of musculoskeletal (msk) pain in these patients. We therefore used a pilot study to identify conditions or markers predictive of pain.

Methods

For 24 weeks, we monitored 30 eligible postmenopausal women starting ai therapy. Pre-existing and incident msk conditions and pain were assessed clinically and with ultrasonography of the hands and wrists. In addition, patient questionnaires were used to assess pain before and during ai therapy. Biochemical markers were measured at baseline and at regular intervals after anastrozole therapy began. Gene profiling studies were carried out before and 48 hours after the initial ai administration.

Results

Over the 24-week study period, 20 participants (67%) showed no pain symptoms; 5 (17%) experienced low or moderate pain at baseline, which did not increase with ai treatment; and during therapy, 5 (17%) showed exacerbation of pain attributable to osteoarthritis of the hand and to finger flexor tenosynovitis. Although all 30 participants had some degree of msk conditions before anastrozole therapy started, the pre-existing conditions did not necessarily predispose the women to increased pain during anastrozole treatment. Higher levels of urinary N-telopeptides of type i collagen were associated with the groups presenting pain, suggesting a higher extent of pre-existing bone resorption, without significant evolution over the 24-week treatment period. Slightly higher levels of 1,25(OH)₂ vitamin D₃ were observed at baseline in patients with pain increase, but did not significantly change during treatment; however, average levels of 25(OH) vitamin D₃ increased, likely because of supplementation. Although biochemical markers did not discriminate efficiently between pain groups, a signature of 166 genes in peripheral blood mononuclear cells was identified that could stratify patients into the various groups observed in this pilot study. The gene signature was enriched in components of inflammatory signalling and chemokine expression, of antitumoural immunity pathways, and of metabolic response to hormones and xenobiotics, although no clinically significant association could be made in the present study, considering the small number of patients. Nevertheless, the observed trend suggests the feasibility of developing surrogate predictive markers of msk pain. Patient compliance was high in this study and was not affected by pain exacerbation.

Conclusions

Baseline msk assessment showed pre-existing causes for pain in most of the study patients before initiation of the ai. Exacerbation of existing osteoarthritis pain and tenosynovial symptoms was the primary cause of pain increase. Musculoskeletal pain assessment at baseline and prompt treatment of pain symptoms may help to optimize adherence to ai therapy. The value of routinely assessing inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate was not supported by our pilot study. Gene expression profiles in peripheral blood mononuclear cells may be further explored in larger-scale studies as stratification markers to identify patients at risk of developing arthralgia.     

Early operable breast cancer in elderly women treated with an aromatase inhibitor letrozole as sole therapy

Background:

Primary endocrine therapy (PET) with aromatase inhibitors (AIs) is an option in elderly patients unfit for or unwilling to undergo surgery. We studied the outcome of patients treated with letrozole as PET.

Methods:

Patients with early oestrogen receptor (ER)/progesterone receptor (PR)-positive breast cancer treated with letrozole from February 2001 to September 2009 were reviewed. Inoperable and locally advanced tumours were excluded. Reasons for offering PET, response, survival, cause of death, time to initial and best response, fracture incidence, and late failure rates were studied.

Results:

In all, 104 patients received PET due to frailty (n=48), comorbidity (n=30), old age (n=9), and patient preference (n=17). Median follow-up was 56 months (4–106). Eighty-five cancers responded to letrozole (stable disease (SD, n=19), reduction in size (PR, n=42), and complete response ((CR), n=24)). Median survival was 51 months (4–103), time to initial response (PR/CR) 4.5 months (2–24), and time to best response 8.5 months (3–50). Letrozole was stopped in 25 patients due to progressive disease (n=19), side effects (n=5), and patient choice (n=1). Only 12 of 49 deaths were from breast cancer.

Conclusion:

Letrozole is a reasonable alternative in elderly women with early ER/PR-positive invasive breast cancer who are unfit or unwilling to undergo standard therapy.     

The effects of aromatase inhibitors and antiestrogens in the nude mouse model

The effects of antiestrogens, tamoxifen and ICI 182,780, and aromatase inhibitors, arimidex (anastrozole ZD1033) and letrozole (CGS 20,267), on the growth of tumors were studied in nude mice. In this model, estrogen dependent MCF-7 human breast cancer cells stably transfected with the aromatase gene were inoculated in four sites per mouse. Sufficient estrogen is produced from aromatization of androstenedione supplement (0.1 mg/mouse/day) by the cells to stimulate their proliferation, tumor formation, and maintain the uterus similar to that of the intact mouse. Once the tumors reached a measurable size, the mice were injected with antiestrogen or inhibitor for 35–56 days. Tumor volumes were measured weekly. At autopsy, the tumors were removed, cleaned, and weighed. Statistical data was determined from tumor weights. Both antiestrogens were effective in reducing tumor growth in these mice. Tamoxifen appears to be more effective than ICI 182,780, although the former stimulated the uterine weight whereas the pure antiestrogen did not. However, both aromatase inhibitors were more effective than the antiestrogens. Tumor regression was observed with letrozole. Thus, after-treatment tumor weights were less than those of a group of mice at the start of treatment. The aromatase inhibitors also reduced the weight of the uterus, suggesting that these compounds, as well as the pure antiestrogen, may not cause endometrial proliferation, unlike tamoxifen. These aromatase inhibitors may not only benefit patients who have relapsed from tamoxifen, but may be more effective in patients as first line agents for suppressing the effects of estrogen.