Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up.
Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up.
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DOI：
10.1016/s1470-2045(11)70270-4
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发表时间：
2011-11
期刊：
影响因子：
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通讯作者：
International Breast Cancer Study Group (IBCSG)
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作者：
Regan MM;Neven P;Giobbie-Hurder A;Goldhirsch A;Ejlertsen B;Mauriac L;Forbes JF;Smith I;Láng I;Wardley A;Rabaglio M;Price KN;Gelber RD;Coates AS;Thürlimann B;BIG 1-98 Collaborative Group;International Breast Cancer Study Group (IBCSG)
患有激素受体阳性早期乳腺癌的绝经后妇女具有持续、长期的乳腺癌复发和死亡风险。因此，评估该患者群体内分泌治疗的试验需要长期随访。我们介绍了国际乳腺组织 (BIG) 1-98 研究中中位随访 8.1 年的疗效结果的更新。 BIG 1-98 是一项随机、III 期、双盲试验，受试者为 8010 名患有激素受体阳性早期乳腺癌的绝经后妇女，该试验比较了五年他莫昔芬或来曲唑单药治疗或序贯治疗与其中一种药物的两年治疗，随后另一种药物的三年治疗。主要疗效终点是无病生存期（DFS：事件包括浸润性乳腺癌复发、第二次原发[对侧乳腺癌和非乳腺癌]或无既往癌症事件的死亡），次要终点是总生存期 (OS)、远处无复发间隔 (DRFI) 和无乳腺癌间隔 (BCFI)。单药治疗比较包括随机接受他莫昔芬 × 5 年 (n=2459) 或来曲唑 × 5 年 (n=2463) 治疗的患者。 2005 年，据报道来曲唑与他莫昔芬相比具有显着的 DFS 益处，一项方案修订促进了仍在单独接受他莫昔芬治疗的患者交叉使用来曲唑； Cox 模型和 Kaplan-Meier 估计以及截尾权重逆概率 (IPCW) 用于解释他莫昔芬组 619 名患者选择性交叉至来曲唑的情况。序贯治疗与来曲唑单药治疗的比较包括参加试验四臂方案的患者，并随机接受来曲唑×5年（n=1546）、来曲唑×2年随后他莫昔芬×3年（n=1540）或他莫昔芬×2年随后来曲唑×3年（n=1548）。所有患者均已完成研究治疗；对于那些参加四臂选项的人，后续行动仍在继续。 BIG 1-98 已在 ClinicalTrials.gov NCT00004205 上注册。随机分组后中位随访时间为 8.7 年（范围 0-12.4），无论是使用 IPCW 还是意向治疗 (ITT) 分析，来曲唑单药治疗均显着优于他莫昔芬 [IPCW：DFS HR 0.82 (95% CI 0.74-0.92)，OS HR 0.79 (0.69-0.900，DRFI HR 0.79) (0.68–0.92)，BCFI HR 0.80 (0.70–0.92)；ITT：DFS HR 0.86 (0.78–0.96)，OS HR 0.87 (0.77–0.999)，DRFI HR 0.86 (0.74–0.998)，BCFI HR 0.86 (0.76–0.98)]。在随机化后 8.0 年的中位随访（范围 0–11.2）中，与来曲唑单药治疗相比，任一序列的四个终点均没有统计学显着差异。对于 DFS 为 78.6%、77.8%、77.3%；对于 DRFI 为 87.5%、87.7%、85.9%；对于 BCFI 为 86.1%、85.3%、84.3%。与他莫昔芬相比，来曲唑单药治疗可降低乳腺癌复发率和死亡率。与来曲唑单药治疗相比，涉及他莫昔芬和来曲唑的序贯治疗并不能改善预后，但考虑到个体患者的复发风险和治疗耐受性，可能是有用的策略：他莫昔芬导致更多的血栓栓塞事件、阴道出血、潮热和盗汗，而更多的阴道干燥、骨折、骨质疏松症、关节痛/肌痛，以及来曲唑导致的更严重的心脏事件，美国国家癌症研究所，国际乳腺癌研究组。
Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast cancer recurrence and death. Therefore, trials evaluating endocrine therapies for this patient population require extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8.1 years median follow-up. BIG 1-98 is a randomized, phase III, double-blind trial of 8010 postmenopausal women with hormone receptor-positive early breast cancer that compares five years of tamoxifen or letrozole monotherapy or sequential treatment with two years of one of these agents followed by three years of the other. The primary efficacy endpoint is disease-free survival (DFS: events comprise invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without prior cancer event), and secondary endpoints are overall survival (OS), distant recurrence-free interval (DRFI) and breast cancer-free interval (BCFI). The monotherapy comparison includes patients randomized to tamoxifen × 5 years (n=2459) or letrozole × 5 years (n=2463). In 2005, after significant DFS benefit was reported for letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to letrozole of 619 patients in the tamoxifen arm. The comparison of sequential treatments to letrozole monotherapy includes patients enrolled in the four-arm option of the trial and randomized to letrozole × 5 years (n=1546), letrozole × 2 years followed by tamoxifen × 3 years (n=1540), or tamoxifen × 2 years followed by letrozole × 3 years (n=1548). All patients have completed study treatment; follow up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.gov NCT00004205. At a median follow-up of 8.7 years from randomization (range 0–12.4), letrozole monotherapy is significantly better than tamoxifen, whether using IPCW or intention-to-treat (ITT) analysis [IPCW: DFS HR 0.82 (95% CI 0.74–0.92), OS HR 0.79 (0.69–0.900, DRFI HR 0.79 (0.68–0.92), BCFI HR 0.80 (0.70–0.92); ITT: DFS HR 0.86 (0.78–0.96), OS HR 0.87 (0.77–0.999), DRFI HR 0.86 (0.74–0.998), BCFI HR 0.86 (0.76–0.98)]. At a median follow-up of 8.0 years from randomization (range 0–11.2), there were no statistically significant differences in any of the four endpoints for either sequence compared with letrozole monotherapy. Eight-year ITT estimates [each with SE ≤ 1.1%] for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78.6%, 77.8%, 77.3% for DFS; 87.5%, 87.7%, 85.9% for OS; 89.9%, 88.7%, 88.1% for DRFI; and 86.1%, 85.3%, 84.3% for BCFI. For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared to tamoxifen. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but may represent useful strategies considering individual patient’s risk of recurrence and treatment tolerability: more thromboembolic events, vaginal bleeding, hot flushes and night sweats with tamoxifen, while more vaginal dryness, bone fractures, osteoporosis, arthralgia/myalgia, and higher grade cardiac events with letrozole. Novartis, United States National Cancer Institute, International Breast Cancer Study Group.