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乳腺癌内分泌治疗：他莫昔芬(转载)
浸润性乳腺癌Ⅰ、ⅡA、ⅡB或T3N1M0系统性辅助治疗 内分泌治疗 他莫昔芬Tamoxifen他莫昔芬The most firmly established adjuvant endocrine therapy is tamoxifen for both premenopausal and postmenopausal women. In women with ER-positive breast cancer, adjuvant tamoxifen decreases the annual odds of recurrence by 39% and the annual odds of death by 31% irrespective of the use of chemotherapy, patient age, menopausal status, or ALN status. In patients receiving both tamoxifen and chemotherapy, chemotherapy should be given first, followed by sequential tamoxifen. Prospective randomized trials have demonstrated that 5 years of tamoxifen is more effective than 1 to 2 years of tamoxifen.对于绝经前和绝经后女性最稳固确立的辅助内分泌治疗都是他莫昔芬。在ER阳性乳腺癌女性中，辅助他莫昔芬降低年复发率39%和年死亡率31%不论化疗的使用、患者年龄、绝经情况或腋淋巴结情况。在接受他莫昔芬和化疗的患者中，应该首先给予化疗，然后序贯他莫昔芬。前瞻性随机试验已经证明他莫昔芬5年比1-2年更有效。The ATLAS trial randomly allocated women to continue tamoxifen up to 10 years or to discontinue tamoxifen (control). The outcome analyses of 6846 women with ER-positive disease showed that by extending adjuvant treatment to 10 years, the risk of relapse and breast cancer-related mortality was reduced. The risk of recurrence during years 5 to 14 was 21.4% for women receiving tamoxifen versus 25.1% for controls (absolute recurrence reduction 3.7%). Patients receiving tamoxifen beyond 10 years of treatment had a greater reduction in risk of progression, possibly due to a “carryover effect.” The reduction in risk of recurrence was 0.90 (95% CI, 0.79-1.02) during 5 to 9 years of tamoxifen treatment and 0.75 (0.62-0.90) after 10 years. Furthermore, reduced mortality was apparent after completion of 10 years of treatment with tamoxifen. With regards to toxicity, the most important adverse effects noted in all women in the ATLAS trial were an increased risk for endometrial cancer after treatment with 10 years of tamoxifen and pulmonary embolism. The recurrence rate ratios for incidence of adverse events (hospitalization or death) were: pulmonary embolus 1.87 (95% CI, 1.13-3.07, P = .01 [including 0.2% mortality in both treatment groups]), stroke 1.06 (0.83-1.36), ischemic heart disease 0.76 (0.60-0.95, P = .02), and endometrial cancer 1.74 (1.30- 2.34, P = .0002). The cumulative risk for endometrial cancers during 5 to 14 years was 3.1%, with a mortality of 0.4% associated with endometrial cancer, higher than what was noted in the control group of patients receiving only 5 years of therapy (cumulative risk: 1.6%; mortality: 0.2%). The results of the aTTom trial confirm the ATLAS reduction in recurrence and death from breast cancer.ATLAS试验随机分配延续他莫昔芬至10年或停止他莫昔芬(对照)。6846例ER阳性疾病女性的预后分析显示通过延伸辅助治疗至10年，复发危险和乳腺癌相关死亡降低。在5-14年期间复发风险接受他莫昔芬的女性是21.4%而对照组是25.1%(绝对复发率降低3.7%)。接受他莫昔芬治疗超过10年的患者进展风险降低更显著，可能是由于“延滞效应。”复发风险降低在他莫昔芬治疗的5-9年期间是0.90(95% CI，0.79-1.02)在10年以后是0.75(0.62-0.90)。此外，在他莫昔芬10年治疗结束以后死亡率降低是明显的。至于毒性，ATLAS试验指出在所有的女性中最重要的不良反应是在他莫昔芬治疗10年后子宫内膜癌和肺栓塞风险增加。不良事件发生率/复发率比值(住院治疗或死亡)是：肺栓塞1.87(95% CI，1.13-3.07，P=.01[两个治疗组中都包括0.2%死亡率])、卒中1.06(0.83-1.36)、缺血性心脏病0.76(0.60-0.95，P =.02)和子宫内膜癌1.74(1.30-2.34，P =.0002)。在5-14年期间子宫内膜癌累积风险是3.1%，与子宫内膜癌相关的死亡率0.4%，高于只接受5年治疗的对照组患者(累积风险：1.6%；死亡率：0.2%)。aTTom试验结果证实ATLAS试验降低乳腺癌复发和死亡的结果。In women who are premenopausal at diagnosis, the NCCN Panel recommends tamoxifen treatment with or without ovarian suppression/ablation. Ovarian ablation may be accomplished by surgical oophorectomy or by ovarian irradiation. Ovarian suppression utilizes luteinizing hormone-releasing hormone (LHRH) agonists that result in suppression of luteinizing hormone (LH) and release of follicle- stimulating hormone (FSH) from the pituitary and reduction in ovarian estrogen production. Available LHRH agonists in theUnited & Statesinclude goserelin and leuprolide and, when used for ovarian suppression, both agents should be given as monthly injections as the 3-month depots do not reliably suppress estrogen levels in all patients.在诊断时绝经前女性中，NCCN小组推荐他莫昔芬治疗±卵巢抑制/去势。卵巢去势可通过外科卵巢切除或卵巢放射实现。利用黄体生成素释放激素(LHRH)激动剂抑制黄体生成素(LH)和垂体释放促卵泡激素(FSH)从而抑制卵巢并减少卵巢产生雌激素。在美国可获得的LHRH激动剂包括戈舍瑞林和亮丙瑞林并且，当用于卵巢抑制时，两个药物都应该每月注射一次给药因为3个月缓释库不能可靠地抑制全部患者的雌激素水平。The EBCTCG performed a meta-analysis of randomized studies of ovarian ablation or suppression alone versus no additional systemic adjuvant therapy for early-stage breast cancer.EBCTCG完成了一项单纯卵巢切除去势或抑制对比无其他全身性辅助治疗治疗早期乳腺癌随机研究的荟萃分析。Analysis of ovarian suppression versus no adjuvant therapy did not demonstrate significant reduction in recurrence (0.72, 95% CI, 0.49-1.04) or death (HR 0.82, 95% CI, 0.47-1.43). In addition, data on ovarian suppression with tamoxifen, chemotherapy, or both showed no significant reduction in reduced recurrence or death.卵巢抑制对比无辅助治疗的分析未显示明显降低复发(0.72，95% CI，0.49-1.04)或死亡(HR 0.82，95% CI，0.47-1.43)。另外，他莫昔芬、化疗或两者卵巢抑制的数据都证明复发或死亡无明显降低。Studies in premenopausal women of ovarian ablation or suppression alone versus CMF (cyclophosphamide/methotrexate/fluorouracil) chemotherapy alone generally demonstrate similar antitumor efficacy in patients with hormone receptor-positive tumors and superior outcomes with CMF in patients with hormone receptor-negative tumors. There is also the suggestion that the benefits of ovarian suppression/ablation may be greater in the younger premenopausal group. Studies in premenopausal women of ovarian ablation/suppression plus tamoxifen versus chemotherapy alone generally demonstrate no difference in rates of recurrence or survival.在绝经前女性中单纯卵巢切除去势或抑制对比CMF(环磷酰胺/甲氨蝶呤/氟尿嘧啶)单独化疗的研究普遍证明在激素受体阳性的肿瘤患者中抗肿瘤活性相似而在激素受体阴性肿瘤患者中CMF转归占优势。还提示在更年轻的绝经前组中卵巢抑制/去势的获益可能更显著。在绝经前女性中卵巢去势/抑制加他莫昔芬对比单独化疗的研究普遍证明在复发率或生存率方面没有差异。A large intergroup study in premenopausal women with hormone receptor-positive, node-positive breast cancer studied adjuvant CAF (cyclophosphamide/doxorubicin/5-fluorouracil) chemotherapy versus CAF plus ovarian suppression with goserelin (CAF-Z) versus CAF-Z plus tamoxifen (CAF-ZT). The results demonstrated no improvement in time to recurrence or OS comparing CAF with CAF-Z. There was improvement in time to recurrence (HR, 0.73; 95% CI, 0.59-0.90; P & .01) but not OS with CAF-Z compared with CAF-ZT (HR, 0.91; 95% CI, 0.71-1.15; P = .21). This study did not include a CAF plus tamoxifen arm, so the contribution of the goserelin to the improved time to recurrence in the CAF-ZT arm cannot be assessed. The addition of ovarian suppression/ablation has also been subjected to meta-analysis by the EBCTCG. They identified no statistically significant reduction in annual rates of recurrence or death with the addition of ovarian suppression or ablation to chemotherapy in women less than 40 years or 40 to 49 years of age.一项在激素受体阳性、淋巴结阳性、绝经前乳腺癌女性中的大型组间研究研究了辅助CAF(环磷酰胺/阿霉素/5-氟尿嘧啶)化疗与CAF加戈舍瑞林卵巢抑制(CAF-Z)以及CAF-Z加他莫昔芬(CAF-ZT)对比。比较CAF与CAF-Z结果显示在至复发时间或总生存期方面没有改善。与CAF-ZT相比CAF-Z改善至复发时间(HR，0.73；95% CI，0.59-0.90；P&.01)但是OS未改善(HR，0.91；95% CI, 0.71-1.15；P =.21)。本研究没有包括CAF加他莫昔芬组，因此不能评估戈舍瑞林在CAF-ZT组对改善至复发时间的贡献。卵巢抑制/去势的加入已成为EBCTCG荟萃分析的主题。他们发现在年龄小于40岁或40-49岁的女性中化疗外加卵巢抑制或切除统计上没有显著降低年复发率或死亡率。In two randomized trials (TEXT and SOFT), premenopausal women with hormone receptor-positive early-stage breast cancer were assigned to receive exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The DFS was 92.8% in the exemestane plus ovarian suppression group, as compared with 88.8% in the tamoxifen plus ovarian suppression group (HR for recurrence, 0.66; 95% CI, 0.55-0.80; P & .001). The OS did not differ significantly between the two groups (HR for death in the exemestane plus ovarian suppression group, 1.14; 95% CI, 0.86-1.51; P = .37). Women at high risk of recurrence who received prior chemotherapy had improved outcomes with ovarian suppression. Their chance of remaining disease-free at 5 years was 78% with tamoxifen alone, 82.5% with tamoxifen and ovarian suppression, and 85.7% with exemestane and ovarian suppression. In the cohort of women with no prior chemotherapy, no meaningful benefit was seen from ovarian suppression, as women who received tamoxifen alone demonstrated a 95% chance of remaining disease-free for 5 years.在两项随机试验(TEXT和SOFT)中，绝经前激素受体阳性的早期乳腺癌女性被分配至接受依西美坦加卵巢抑制或他莫昔芬加卵巢抑制治疗5年。通过使用促性腺激素释放激素激动剂曲普瑞林、卵巢切除或卵巢放射达到抑制卵巢雌激素的产生。DFS依西美坦加卵巢抑制组是92.8%，而他莫昔芬加卵巢抑制组是88.8%(复发HR，0.66；95% CI，0.55-0.80；P & .001)。OS两组间没有显著差别(依西美坦加卵巢抑制组死亡HR，1.14；95% CI，0.86-1.51；P =.37)。复发高危女性既往接受化疗者卵巢抑制改善转归。在5年时其无残留疾病的可能性单独他莫昔芬是78%，他莫昔芬加卵巢抑制是82.5%，而依西美坦加卵巢抑制是85.7%。在既往未曾化疗的女性组中，没有观察到卵巢抑制有意义的获益，因为单纯他莫昔芬治疗的女性显示5年无残留疾病的可能性95%。Several studies have evaluated aromatase inhibitors in the treatment of postmenopausal women with early-stage breast cancer. These studies have utilized the aromatase inhibitors as initial adjuvant therapy, as sequential therapy following 2 to 3 years of tamoxifen, or as extended therapy following 4.5 to 6 years of tamoxifen. The aromatase inhibitors are not active in the treatment of women with functioning ovaries and should not be used in women whose ovarian function cannot reliably be assessed owing to treatment-induced amenorrhea. The results from two prospective, randomized, clinical trials have provided evidence of an OS benefit for patients with early-stage breast cancer receiving initial endocrine therapy with tamoxifen followed sequentially by anastrozole (HR, 0.53; 95% CI, 0.28-0.99; P = .045) or exemestane (HR, 0.83; 95% CI, 0.69-1.00; P = .05 [excluding patients with ER-negative disease]) when compared with tamoxifen as the only endocrine therapy. In addition, the NCIC-CTG MA-17 trial demonstrated a survival advantage with extended therapy with letrozole compared with placebo in women with ALN-positive (but not lymph node-negative), ER-positive breast cancer. However, no survival differences have been reported for patients receiving initial adjuvant therapy with an aromatase inhibitor versus first-line tamoxifen. Tamoxifen and aromatase inhibitors have different side effect profiles. Both contribute to hot flashes and night sweats and may cause vaginal dryness. Aromatase inhibitors are more commonly associated with musculoskeletal symptoms, osteoporosis, and increased rate of bone fracture, while tamoxifen is associated with an increased risk for uterine cancer and deep venous thrombosis.若干研究评估了芳香化酶抑制剂治疗绝经后早期乳腺癌女性。这些研究利用芳香化酶抑制剂作为初始辅助治疗、作为他莫昔芬2-3年之后的序贯治疗或作为他莫昔芬4.5-6年之后的扩展治疗。在卵巢有功能的女性治疗中芳香化酶抑制剂不是有效的而且不应用于由于治疗引起闭经不能可靠地评估卵巢功能的女性。对于早期乳腺癌患者，与他莫昔芬作为唯一的内分泌治疗相比，两项前瞻性、随机临床试验提供的证据显示，初始内分泌治疗接受他莫昔芬序贯阿那曲唑(HR，0.53；95% CI，0.28-0.99；P =.045)或依西美坦(HR，0.83；95% CI，0.69-1.00；P =.05[不包括ER阴性疾病患者])OS获益。另外，NCIC-CTG MA-17试验显示在腋淋巴结阳性(而非淋巴结阴性)、ER阳性乳腺癌女性中与安慰剂相比用来曲唑长期治疗具有生存优势。但是，已报道对于用一种芳香化酶抑制剂初始辅助治疗的患者与一线他莫昔芬比较无生存差异。他莫昔芬和芳香化酶抑制剂具有不同的副作用。两者都可导致潮热和盗汗并可引起阴道干涩。芳香化酶抑制剂肌肉骨骼症状、骨质疏松以及骨折率增加更常见，而他莫昔芬子宫癌和深静脉血栓形成风险增加。Two studies have examined initial adjuvant endocrine treatment with either tamoxifen or an aromatase inhibitor. The ATAC trial demonstrated that anastrozole is superior to tamoxifen or the combination of tamoxifen and anastrozole in the adjuvant endocrine therapy of postmenopausal women with hormone receptor-positive breast cancer. With a median of 100 months follow-up, results in 5216 postmenopausal women with hormone receptor-positive, early-stage breast cancer enrolled in the ATAC trial demonstrated fewer recurrences (HR for DFS, 0.85; 95% CI, 0.76-0.94; P = .003) with anastrozole compared with tamoxifen. No difference in survival has been observed (HR, 0.90; 95% CI, 0.75-1.07; P = .2). Patients in the combined tamoxifen and anastrozole group gained no benefit over those in the tamoxifen group, suggesting a possible deleterious effect from the weak estrogenic effect of tamoxifen in patients with near complete elimination of endogenous estrogen levels. ATAC trial sub-protocols show a lesser effect of anastrozole compared with tamoxifen o similar effects of anastrozole and tamoxifen on quality of life, with most patients reporting that overall quality of life was not si a greater loss of bone mineral dens a small pharmacokinetic interference of anastrozole in the presence of tamoxifen of
and no evidence for an interaction between prior chemotherapy and anastrozole.两项研究已经试验了用他莫昔芬或一种芳香化酶抑制剂初始辅助内分泌治疗。ATAC试验显示激素受体阳性的绝经后乳腺癌女性辅助内分泌治疗阿那曲唑优于他莫昔芬或他莫昔芬联合阿那曲唑。ATAC试验入组的5216例激素受体阳性的绝经后早期乳腺癌女性中位随访100个月结果显示与他莫昔芬相比阿那曲唑更少复发(DFS HR，0.85；95% CI，0.76-0.94；P =.003)。没有观察到生存差异(HR，0.90；95% CI，0.75-1.07；P=.2)。他莫昔芬与阿那曲唑联合组患者获益未超过他莫昔芬组，提示在接近完全消除内源性雌激素水平的患者中他莫昔芬的弱雌激素样作用可能具有有害影响。ATAC试验附属协议显示与他莫昔芬相比阿那曲唑对子宫内膜组织的影响更少；阿那曲唑与他莫昔芬对生活质量的影响相似，大多数患者报告总体生活质量未显著受损；阿那曲唑骨密度降低更显著；不清楚在有他莫昔芬存在的情况下阿那曲唑药代动力学些微干扰的意义；既往化疗与阿那曲唑之间的相互作用没有证据。BIG 1-98 is a randomized trial testing the use of tamoxifen alone for 5 years, letrozole alone for 5 years, or tamoxifen for 2 years followed sequentially by letrozole for 3 years, or letrozole for 2 years followed sequentially by tamoxifen for 3 years. An early analysis compared tamoxifen alone versus letrozole alone, including those patients in the sequential arms during their first 2 years of treatment only. With 8010 women included in the analysis, DFS was superior in the letrozole-treated women (HR, 0.81; 95% CI, 0.70- 0.93; log rank P = .003). No interaction between PR expression and benefit was observed. No difference in OS was observed. A comparison of the cardiovascular side effects in the tamoxifen and letrozole arms of the BIG 1-98 trial showed that the overall incidence of cardiac adverse events was similar (letrozole, 4.8%; tamoxifen, 4.7%). However, the incidence of grade 3 to 5 cardiac adverse events was significantly higher in the letrozole arm, and both the overall incidence and incidence of grade 3 to 5 thromboembolic events was significantly higher in the tamoxifen arm. In addition, a higher incidence of bone fracture was observed for women in the letrozole arm compared with those in the tamoxifen arm (9.5% vs. 6.5%). After a longer follow-up (median 71 months) no significant improvement in DFS was noted with either tamoxifen followed by letrozole or the reverse sequence as compared with letrozole alone (HR for tamoxifen followed by letrozole, 1.05; 99% CI, 0.84-1.32; HR for letrozole followed by tamoxifen, 0.96; 99% CI, 0.76-1.21).BIG 1-98是一项随机试验研究单纯使用他莫昔芬5年、单纯来曲唑5年或他莫昔芬2年序贯来曲唑3年或来曲唑2年序贯他莫昔芬3年。一项早期分析比较单独他莫昔芬与单纯来曲唑，包括那些在序贯组中仅仅治疗最初2年的者。在该分析中包括8010例女性，在来曲唑治疗的女性中DFS占优(HR，0.81；95% CI，0.70-0.93；卡方检验P =.003)。PR表达与观察到的获益之间无交互作用。未观察到OS差异。BIG 1-98试验他莫昔芬与来曲唑组心血管副作用比较显示总的心脏不良事件发生率相似(来曲唑，4.8%；他莫昔芬，4.7%)。但是，3至5度心脏不良事件的发生率来曲唑组显著更高，而3至5度血栓栓塞事件的发生率与总的发病率他莫昔芬组显著更高。另外，与他莫昔芬组相比来曲唑组女性观察到骨折的发生率更高(9.5%对6.5%)。在更长时间的随访以后(中位数71个月)与单纯来曲唑相比较他莫昔芬序贯来曲唑或相反次序观察到DFS无显著改善(他莫昔芬序贯来曲唑HR，1.05；99%CI，0.84-1.32；来曲唑序贯他莫昔芬HR，0.96；99%CI，0.76-1.21)。Five trials have studied the use of tamoxifen for 2 to 3 years followed sequentially by a third-generation aromatase inhibitor versus continued tamoxifen in postmenopausal women. The Italian Tamoxifen Anastrozole (ITA) trial randomized postmenopausal women with breast cancer who had completed 2 to 3 years of tamoxifen to either continue tamoxifen or to switch to anastrozole to complete a total of 5 years of endocrine therapy. The HR for relapse strongly favored sequential treatment with anastrozole (HR, 0.35; 95% CI, 0.18-0.68; P = .001) with a trend towards fewer deaths (P = .10). Updated results from this study show the HR for relapse-free survival as 0.56 (95% CI, 0.35-0.89; P = .01); P value for OS analysis remained at 0.1. The IES trial randomized 4742 postmenopausal women with breast cancer who had completed a total of 2 to 3 years of tamoxifen to either continue tamoxifen or to switch to exemestane to complete a total of 5 years of endocrine therapy. The results at a median of 55.7 months of follow-up demonstrated the superiority of sequential exemestane in DFS (HR, 0.76; 95% CI, 0.66-0.88; P = .0001) with a significant difference in OS in only patients with ER-positive tumors (HR, 0.83; 95% CI, 0.69-1.00; log rank P = .05). A prospectively planned, combined analysis of 3224 patients enrolled in the ABCSG 8 trial and the Arimidex Nolvadex (ARNO 95) trial has also been reported. Patients in this combined analysis had been randomized following 2 years of tamoxifen to complete 5 years of adjuvant tamoxifen or 3 years of anastrozole. With 28 months of median follow-up available, event-free survival was superior with crossover to anastrozole (HR, 0.60; 95% CI, 0.44-0.81; P = .0009). No statistically significant difference in survival has been observed. An analysis of the ARNO 95 trial alone after 58 months of median follow-up demonstrated that switching from tamoxifen to anastrozole was associated with significant increases in both DFS (HR, 0.66; 95% CI, 0.44-1.00; P = .049) and OS (HR, 0.53; 95% CI, 0.28-0.99; P = .045). A meta-analysis of ABCSG 8, ARNO 95, and ITA studies showed significant improvement in OS (HR, 0.71; 95% CI, 0.52-0.98; P = .04) with a switch to anastrozole.5项试验研究了在绝经后女性中使用他莫昔芬2-3年序贯一个第三代芳香化酶抑制剂对比继续使用他莫昔芬。意大利他莫昔芬阿那曲唑(ITA)试验对已经完成他莫昔芬2-3年的绝经后乳腺癌女性随机分配至继续他莫昔芬或转换至阿那曲唑直至完成总共5年的内分泌治疗。复发HR强烈支持阿那曲唑序贯治疗(HR，0.35；95% CI，0.18-0.68；P=.001)具有更少的死亡倾向(P=.10)。本研究更新的结果显示无复发生存HR为0.56(95% CI，0.35-0.89；P=.01)；OS分析P值仍然是0.1。IES试验对已经完成他莫昔芬总共2-3年的4742例绝经后乳腺癌女性随机分配至继续他莫昔芬或转换至依西美坦直至完成总共5年的内分泌治疗。中位随访55.7个月时的结果显示序贯依西美坦在DFS方面具有优势(HR，0.76；95% CI，0.66-0.88；P=.0001)，只有在ER阳性肿瘤患者中OS有显著差异(HR，0.83；95% CI，0.69-1.00；卡方检验P=.05)。ABCSG 8试验与阿那曲唑他莫昔芬(ARNO 95)试验中入组的3224例患者的一项前瞻性计划的联合分析也已发表。在该联合分析中患者随机接受接着2年的他莫昔芬至完成5年的他莫昔芬辅助治疗或3年的阿那曲唑治疗。可获得的中位随访28个月，转换至阿那曲唑无事件生存占优势(HR，0.60；95% CI，0.44-0.81；P=.0009)。没有观察到统计上显著意义的生存差异。在中位随访58个月以后单独ARNO 95试验的一项分析显示从他莫昔芬转换至阿那曲唑显著增加DFS(HR，0.66；95% CI，0.44-1.00；P=.049)以及OS(HR，0.53；95% CI，0.28-0.99；P=.045)。ABCSG 8、ARNO 95以及ITA研究的一项荟萃分析显示转换至阿那曲唑显著改善OS(HR，0.71；95% CI，0.52-0.98；P=.04)。The TEAM trial compared treatment of exemestane alone versus sequential therapy of tamoxifen for 2.5 to 3.0 years followed by exemestane to complete 5 years of hormone therapy. At the end of 5 years, 85% of patients in the sequential group versus 86% in the exemestane group were disease free (HR, 0.97; 95% CI, 0.88-1.08; P = .60). This is consistent with the data from the BIG 1-98 trial, in which tamoxifen followed by letrozole or the reverse sequence of letrozole followed by tamoxifen was not associated with significant differences in efficacy versus letrozole monotherapy after a median follow-up of 71 months.TEAM试验比较了单独依西美坦治疗与他莫昔芬2.5-3.0年序贯依西美坦直至完成5年的激素治疗。在5年末时，序贯组85%的患者与依西美坦组86%的患者是无病的(HR，0.97；95% CI，0.88-1.08；P=.60)。这与BIG 1-98试验的数据一致，该试验在中位随访71个月后，他莫昔芬序贯来曲唑或相反次序的来曲唑序贯他莫昔芬与来曲唑单药治疗的疗效无显著差异。Results of the MA-17 trial in 5187 women who had completed 4.5 to 6 years of adjuvant tamoxifen demonstrated that extended therapy with letrozole provides benefit in postmenopausal women with hormone receptor-positive, early-stage breast cancer. At a median follow-up of 2.5 years, the results showed fewer recurrences or new contralateral breast cancers with extended letrozole (HR, 0.58; 95% CI, 0.45- 0.76; P & .001). No difference in OS was demonstrated (HR, 0.82; 95% CI, 0.57-1.19; P = .3), although there was a survival advantage in the subset of patients with ALN-positive disease (HR 0.61; 95% CI, 0.38- 0.98; P = .04). In a separate cohort analysis of the MA-17 trial, the efficacy of letrozole versus placebo was evaluated after un-blinding of the study in the 1579 women who had been randomly assigned to placebo after 4.5 to 6 years of tamoxifen. The median time since completion of tamoxifen was 2.8 years. Both DFS and distant DFS were significantly improved in the group receiving letrozole, thereby providing some evidence for the efficacy of letrozole in patients who had received 4.5 to 6 years of tamoxifen therapy followed by no endocrine therapy for an extended period. A formal quality-of-life analysis demonstrated reasonable preservation of quality of life during extended endocrine therapy, although women may experience ongoing menopausal symptoms and loss of bone mineral density. No data are available regarding use of aromatase inhibitors for more than 5 years or long-term toxic effects from extended treatment. In addition, the ATLAS trial data do not provide clear direction for treatment of postmenopausal women. There are no data available to suggest that an aromatase inhibitor for 5 years is better for long-term benefit than 10 years of tamoxifen.MA-17试验中5187例已经结束4.5-6年的辅助他莫昔芬女性的结果显示在激素受体阳性的绝经后早期乳腺癌女性中来曲唑延长治疗带来获益。在中位随访2.5年时，结果显示延长来曲唑治疗乳腺癌复发或新发对侧乳腺癌更少(HR，0.58；95%CI，0.45-0.76；P＜.001)。OS未显示差异(HR，0.82；95% CI，0.57-1.19；P=.3)，尽管在腋淋巴结阳性患者亚组中有生存优势(HR 0.61；95% CI，0.38-0.98；P=.04)。在一项MA-17试验的独立群组分析中，该研究1579例女性他莫昔芬4.5-6年后随机分入安慰剂在揭盲以后与安慰剂相比评价来曲唑的疗效。自他莫昔芬结束的中位时间是2.8年。来曲唑组DFS与远处DFS均显著改善，从而提供了在已经接受4.5-6年的他莫昔芬治疗之后无内分泌治疗的患者中延长来曲唑持续时间的一些疗效证据。一项正规的生活质量分析显示在延长的内分泌治疗期间适当保护生活质量，尽管可能经历绝经症状与骨密度降低。关于使用芳香化酶抑制剂超过5年或长期治疗的长期毒性作用无可用资料。另外，对于绝经后女性的治疗ATLAS试验数据没有提供明确的方向。没有可用数据建议一种芳香化酶抑制剂5年长期获益优于他莫昔芬10年。In the extension study of ABCSG trial 6, hormone receptor-positive postmenopausal patients received 5 years of adjuvant tamoxifen and were randomized to 3 years of anastrozole or no further therapy. At a median follow-up of 62.3 months, women who received anastrozole (n = 387) were reported to have a statistically significantly reduced risk of recurrence compared with women who received no further treatment (n = 469; HR, 0.62; 95% CI, 0.40-0.96; P = .031).在ABCSG试验6的扩展研究中，接受5年的辅助他莫昔芬激素受体阳性的绝经后患者然后被随机分入3年的阿那曲唑或不进一步治疗。在中位随访62.3个月时，报道与无进一步治疗的女性相比接受阿那曲唑的女性(n＝387)统计上显著降低复发风险(n＝469；HR，0.62；95%CI，0.40-0.96；P=.031)。The differences in design and patient populations among the studies of the aromatase inhibitors do not allow for the direct comparison of the results of these studies. A meta-analysis of adjuvant trials of aromatase inhibitors versus tamoxifen alone versus after 2 or 3 years of tamoxifen documented lower recurrence rates with the aromatase inhibitor-containing regimen, with no clear impact on OS. It is not known whether initial, sequential, or extended use of adjuvant aromatase inhibitors is the optimal strategy.在芳香化酶抑制剂的这些研究当中设计与患者人群的差异不允许直接比较这些研究结果。一项对比在2或3年他莫昔芬后芳香化酶抑制剂与单独他莫昔芬辅助试验的荟萃分析证明含芳香化酶抑制剂方案复发率较低，对OS没有明显影响。初始、序贯或扩展使用辅助芳香化酶抑制剂是否是最佳策略尚不清楚。The optimal duration of aromatase inhibitor treatment is also not known, nor is the optimal use vis-¨¤-vis chemotherapy established. Further, the long-term (greater than 5-year) safety and efficacy of these agents are still under investigation. The various studies are consistent in demonstrating that the use of a third-generation aromatase inhibitor in postmenopausal women with hormone receptor-positive breast cancer lowers the risk of recurrence, including ipsilateral breast tumor recurrences, contralateral breast cancer, and distant metastatic disease when used as initial adjuvant therapy, sequential therapy, or extended therapy. The panel finds no compelling evidence that there is meaningful efficacy or toxicity differences between the aromatase inhibitors, anastrozole, letrozole, and exemestane. All three have shown similar anti-tumor efficacy and toxicity profiles in randomized studies in the adjuvant settings.芳香化酶抑制剂治疗的最佳持续时间也不知道，和确定化疗的优化使用也不清楚。此外，这些药物长期(＞5年)的疗效和安全性仍在研究中。各种各样的研究一致证明在激素受体阳性的绝经后乳腺癌女性中当使用一个第三代芳香化酶抑制剂作为初始辅助治疗、序贯治疗或延长治疗时降低复发风险，包括同侧乳腺肿瘤复发、对侧乳腺癌以及远处转移。小组发现在芳香化酶抑制剂阿那曲唑、来曲唑和依西美坦之间有意义的疗效或毒性差异没有令人信服的证据。在辅助治疗随机研究中已经证明所有三个药物抗肿瘤疗效和毒性特征相似。NCCN recommendations for adjuvant endocrine therapy for postmenopausal women: The NCCN Guidelines for Breast Cancer recommend the following adjuvant endocrine therapy options for women with early-stage breast cancer who are postmenopausal at diagnosis: an aromatase inhibitor as initial adjuvant therapy for 5 years (category 1); tamoxifen for 2 to 3 years followed by one of the following options: an aromatase inhibitor to complete 5 years of adjuvant endocrine therapy (category 1) or 5 years of aromatase inhibitor therapy (category 2B); or tamoxifen for 4.5 to 6 years followed by 5 years of an aromatase inhibitor (category 1) or consideration of tamoxifen for up to 10 years. In postmenopausal women, the use of tamoxifen alone for 5 years (category1) or up to 10 years is limited to those who decline or who have a contraindication to aromatase inhibitors.对于绝经后女性辅助内分泌治疗NCCN建议：对于诊断时绝经后早期乳腺癌女性乳腺癌NCCN指南推荐以下辅助内分泌治疗方案：一种芳香化酶抑制剂作为初始辅助治疗5年(1类)；他莫昔芬2-3年序贯以下方案之一：一种芳香化酶抑制剂至完成5年的辅助内分泌治疗(1类)或5年的芳香化酶抑制剂治疗(2B类)；或他莫昔芬4.5-6年序贯5年的一种芳香化酶抑制剂(1类)或考虑他莫昔芬长达10年。在绝经后女性中，单纯使用他莫昔芬5年(1类)或达10年限于那些有芳香化酶抑制剂禁忌症者。NCCN recommendations for adjuvant endocrine therapy for premenopausal women: For women premenopausal at diagnosis, the NCCN Guidelines for Breast Cancer recommend 5 years of tamoxifen (category 1) with or without ovarian suppression (category 2B). The NCCN Panel has noted in a footnote that ovarian suppression plus an aromatase inhibitor for 5 years may be considered as an option for premenopausal women. Women who are premenopausal at diagnosis and who become amenorrheic with chemotherapy may have continued estrogen production from the ovaries without menses. Serial assessment of circulating LH, FSH, and estradiol to assure a true postmenopausal status is mandatory if this subset of women is to be considered for therapy with an aromatase inhibitor.对于绝经前女性辅助内分泌治疗NCCN建议：对于诊断时绝经前期女性，乳腺癌NCCN指南建议5年的他莫昔芬(1类)±卵巢抑制(2B类)。NCCN小组在一个脚注中指出对于绝经前女性可以考虑卵巢抑制加一种芳香化酶抑制剂5年作为一个选择。诊断时绝经前女性和由于化疗而闭经者卵巢可能继续产生雌激素却没有月经。如果此亚组的女性将考虑用一种芳香化酶抑制剂治疗，必须连续评估循环LH、FSH和雌二醇以保证真正的绝经后状态。After 5 years of initial endocrine therapy, for women who are postmenopausal at that time (including those who have become postmenopausal during the 5 years of tamoxifen therapy), the NCCN Panel recommends considering extended therapy with an aromatase inhibitor for up to 5 years (category 1) or based on the data from the ATLAS trial considering tamoxifen for an additional 5 years. For those who remain premenopausal after the initial 5 years of tamoxifen, the panel recommends considering continuing up to 10 years of tamoxifen therapy.在5年的初始内分泌治疗以后，对于在那时绝经后女性(包括那些在5年他莫昔芬治疗期间已经成为绝经后者)，NCCN小组推荐考虑用一种芳香化酶抑制剂延长治疗达5年(1类)或根据ATLAS试验数据考虑追加5年他莫昔芬。对于那些在初始5年他莫昔芬以后仍然是绝经前者，专家组推荐考虑继续他莫昔芬治疗达到10年。Response to adjuvant endocrine therapy: The measurement of the nuclear antigen, Ki-67 by IHC, gives an estimate of the tumor cells in the proliferative phase (G1, G2, and M phases) of the cell cycle. Studies have demonstrated the prognostic value of Ki-67 as a biomarker and its usefulness in predicting response and clinical outcome. One small study suggests that measurement of Ki-67 after short-term exposure to endocrine treatment may be useful to select patients with tumors resistant to endocrine therapy and those who may benefit from additional interventions. However, these data require larger analytic and clinical validation. In addition, standardization of tissue handling and processing is required to improve the reliability and value of Ki-67 testing. At this time, there is no conclusive evidence that Ki-67 alone, especially baseline Ki-67 as an individual biomarker, helps to select the type of endocrine therapy for an individual patient. Therefore, the NCCN Breast Cancer Panel does not currently recommend assessment of Ki- 67.对辅助内分泌治疗的应答：通过IHC测定核抗原Ki-67，评估细胞周期中增殖期(G1、G2和M期)的肿瘤细胞。研究已经证明Ki-67作为一个生物标志物的预后价值及其在预测应答和临床预后方面的有效性。一项小型研究提示在短期暴露于内分泌治疗以后测定Ki-67对于选择对内分泌治疗耐药以及那些可能受益于其他干预的肿瘤患者可能是有用的。但是，这些数据需要更大量的分析和临床验证。另外，组织处理与加工的标准化是提高Ki-67检测可靠性和价值所必需的。在这个时候，单独Ki-67，特别是基线Ki-67作为一个独立的生物标志物，对于一例具体患者，帮助选择内分泌治疗的类型并没有确凿证据。因此，NCCN乳腺癌小组目前不推荐评估Ki-67。The cytochrome P-450 (CYP450) enzyme, CYP2D6, is involved in the conversion of tamoxifen to endoxifen. Over 100 allelic variants of CYP2D6 have been reported in the literature. Individuals with wild-type CYP2D6 alleles are classified as extensive metabolizers of tamoxifen. Those with one or two variant alleles with either reduced or no activity are designated as intermediate metabolizers and poor metabolizers, respectively. A large retrospective study of 1325 patients found that time to disease recurrence was significantly shortened in poor metabolizers of tamoxifen. However, the BIG 1-98 trial reported on the outcome based on CYP2D6 genotype in a subset of postmenopausal patients with endocrine-responsive, early invasive breast cancer. The study found no correlation between CYP2D6 allelic status and disease outcome or between CYP2D6 allelic status and tamoxifen-related adverse effects. A genetic analysis of the ATAC trial found no association between CYP2D6 genotype and clinical outcomes. Given the limited and conflicting evidence at this time, the NCCN Breast Cancer Panel does not recommend CYP2D6 testing as a tool to determine the optimal adjuvant endocrine strategy. This recommendation is consistent with the ASCO Guidelines. When prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid potent and intermediate CYP2D6 inhibiting agents, particularly paroxetine and fluoxetine, if an appropriate alternative exists.细胞色素P450(CYP450)酶，CYP2D6，与他莫昔芬转化为吲哚昔芬有关。已在文献中报道的CYP2D6等位基因变异体超过100种。具有野生型CYP2D6 等位基因的个体被列为他莫昔芬的快代谢型。那些具有一个或两个或活性降低或无活性的变异型等位基因者分别被命名为中间代谢型和慢代谢型。一项1325例患者的大型回顾性研究发现在他莫昔芬慢代谢型中至疾病复发时间显著缩短。但是，BIG 1-98试验报道了在一个绝经后、内分泌应答的、早期浸润性乳腺癌患者亚群中基于CYP2D6基因型的预后。本研究发现在CYP2D6等位基因状态和疾病预后之间或者在CYP2D6等位基因状态和他莫昔芬相关的不良反应之间无关。ATAC试验的一项遗传分析发现在CYP2D6基因型与临床转归之间无相关性。考虑到在这个时候证据有限且冲突，NCCN乳腺癌小组不推荐CYP2D6检测作为一个确定最佳辅助内分泌策略的手段。该推荐与ASCO指南一致。当处方一种选择性5-羟色胺再摄取抑制剂(SSRI)时，如果有恰当的替代药物，避免处方强效与中效CYP2D6抑制剂特别是帕罗西汀和氟西汀是合理的。Breast cancer NCCN 2015v3
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