The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.
University of Nottingham, Nottingham, UK; University Hospitals of Derby and Burton, Derby, UK.
Lancet Oncol. 2020 Nov;21(11):1443-1454. doi: 10.1016/S1470-2045(20)30458-7.
Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki67) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67). The POETIC trial aimed to test these two hypotheses.
POETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0-1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing.
Between Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1-74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75-1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9-92·0) for patients in the POAI group and 90·4% (88·7-91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67 and Ki67 (low-low) was 4·3% (95% CI 2·9-6·3), 8·4% (6·8-10·5) with high Ki67 and low Ki67 (high-low) and 21·5% (17·1-27·0) with high Ki67 and Ki67 (high-high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low-low group was 10·1% (95% CI 3·2-31·3), 7·7% (3·4-17·5) in the high-low group, and 15·7% (10·1-24·4) in the high-high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related deaths were reported.
POAI has not been shown to improve treatment outcome, but can be used without detriment to help select appropriate adjuvant therapy based on tumour Ki67. Most patients with low Ki67 or low POAI-induced Ki67 do well with adjuvant standard endocrine therapy (giving consideration to clinical-pathological factors), whereas those whose POAI-induced Ki67 remains high might benefit from further adjuvant treatment or trials of new therapies.
Cancer Research UK.
术前和围手术期芳香化酶抑制剂（POAI）治疗有可能改善可手术的雌激素受体阳性原发性乳腺癌患者的预后。有研究表明，POAI 治疗 2 周后（Ki67）的肿瘤 Ki67 值比基线 Ki67（Ki67）更能预测患者的个体预后。POETIC 试验旨在检验这两个假设。
POETIC 是一项开放标签、多中心、平行组、随机、3 期临床试验（在英国 130 家医院进行），纳入了至少 50 岁的绝经后、WHO 体力状态 0-1 级、激素受体阳性、可手术的乳腺癌患者，随机分为 POAI（来曲唑 2.5mg/d 或阿那曲唑 1mg/d，术前 14 天开始口服）组或无 POAI（对照组）。辅助治疗根据英国标准的局部实践进行。通过计算机生成的随机分组方法（分组大小为 6 或 9）进行中央随机分组，并按医院分层。治疗分配未设盲。主要终点是复发时间。一个关键的次要目标是探索 Ki67（10% 为界分为两组）与疾病结局的相关性。临床终点的主要分析是根据修改后的意向治疗（排除退出同意的患者）。对于 Ki67 生物标志物相关性和终点分析，可评价人群包括所有随机分组且有配对 Ki67 值的患者。该研究在 ClinicalTrials.gov 注册，NCT02338310；欧洲临床试验数据库，EudraCT2007-003877-21；和 ISRCTN 注册处，ISRCTN63882543。招募工作已经完成，正在进行长期随访。
2008 年 10 月 13 日至 2014 年 4 月 16 日期间，共纳入 4480 名女性患者，并随机分为 POAI（n=2976）或对照组（n=1504）。2018 年 2 月 6 日，中位随访时间为 62.9 个月（IQR 58.1-74.1）。4480 名女性中有 434 人（10%）发生乳腺癌复发（POAI 组 280 例[9%]；对照组 154 例[10%]），风险比为 0.92（95%CI 0.75-1.12）；p=0.40，POAI 组 5 年无乳腺癌复发率为 91.0%（95%CI 89.9-92.0），对照组为 90.4%（88.7-91.9）。在 POAI 治疗的 HER2 阴性亚组中，Ki67 低和 Ki67（低低）的女性 5 年复发风险为 4.3%（95%CI 2.9-6.3），Ki67 高和 Ki67 低（高低）的女性为 8.4%（6.8-10.5），Ki67 高和 Ki67（高高）的女性为 21.5%（17.1-27.0）。在 POAI 治疗的 HER2 阳性亚组中，Ki67 低低组的 5 年复发风险为 10.1%（95%CI 3.2-31.3），Ki67 低低组为 7.7%（3.4-17.5），Ki67 低低组为 15.7%（10.1-24.4）。最常见的 3 级不良事件是热潮红（POAI 组 2801 例中有 20 例[1%]，对照组 1400 例中有 6 例[<1%]）和肌肉骨骼疼痛（POAI 组 29 例[1%] vs 对照组 13 例[1%]）。无治疗相关死亡报告。
POAI 并未显示改善治疗结局，但可用于帮助选择合适的辅助治疗，而不会造成损害，辅助治疗基于肿瘤 Ki67。大多数 Ki67 低或 POAI 诱导的 Ki67 低的患者接受辅助标准内分泌治疗效果良好（考虑临床病理因素），而那些 POAI 诱导的 Ki67 仍然较高的患者可能受益于进一步的辅助治疗或新疗法的试验。
英国癌症研究中心。
