术前芳香酶抑制剂能否改善乳腺癌结局

　　芳香酶抑制剂可抑制芳香酶将雄激素催化为雌激素的芳香化反应，已被广泛用于可手术雌激素受体阳性原发乳腺癌术后内分泌治疗。有学者推测，术前芳香酶抑制剂治疗也可能改善可手术雌激素受体阳性原发乳腺癌女性结局。此外，还有学者推测，术前芳香酶抑制剂治疗2周后的肿瘤增殖指数Ki67与基线（随机入组前）Ki67相比，对于预测患者芳香酶抑制剂治疗结局的效果更好。

　　2020年11月，英国《柳叶刀》肿瘤学分册正式发表皇家马斯登医院、伦敦大学癌症研究院、诺丁汉大学、独立癌症患者之声、普尔医院、利物浦大学医院、贝克斯利癌症中心、曼彻斯特大学医院、格拉斯哥大学伊丽莎白女王医院、德比和伯顿大学医院、皇家伯恩茅斯和克赖斯特彻奇医院、伯明翰大学和皇家伍尔弗汉普顿医院的POETIC研究报告，探讨了激素敏感型早期乳腺癌绝经后女性术前内分泌治疗的长期结局和Ki67的预后价值。

POETIC: Trial of Perioperative Endocrine Therapy - Individualising Care (NCT02338310、EudraCT2007-003877-21、ISRCTN63882543)

　　该多中心非盲平行分组随机对照三期临床研究于2008年10月13日～2014年4月16日从英国130家医院入组年龄≥50岁、世界卫生组织体力状态评分0～1分、绝经后女性、激素受体阳性可手术乳腺癌患者4480例，按2∶1随机分为两组：

  • 干预组2976例：术前服用芳香酶抑制剂2周（每天口服来曲唑2.5毫克或阿那曲唑1毫克）

  • 对照组1504例：术前不用芳香酶抑制剂

　　手术后根据英国当地医院治疗标准给予辅助治疗。按计算机随机生成的置换区组（可变区组大小为6或9）集中进行分组，并按医院进行分层。治疗方法分配非盲。主要终点为复发时间。关键次要终点为Ki67≥10%或<10%与疾病结局的相关性。对改良意向治疗患者（剔除撤回同意患者）进行主要终点分析。对全部随机入组且Ki67已匹配的患者进行Ki67生物标志相关性和终点分析。入组已经完成，长期随访正在进行。

　　结果，截至2018年2月6日，中位随访62.9个月（四分位58.1～74.1），乳腺癌复发434例（10%）。

　　干预组与对照组相比：

  • 复发例数：280例比154例

  • 总复发率：9.4%比10.2%

  • 复发风险：低8%（风险比：0.92，95%置信区间：0.75～1.12，P=0.40）

  • 5年无复发率：91.0%比90.4%（95%置信区间：89.9～92.0、88.7～91.9）

　　对于干预组HER2阴性亚组患者，5年复发风险：

  • Ki67前低后低：4.3%（95%置信区间：2.9～6.3）

  • Ki67前高后低：8.4%（95%置信区间：6.8～10.5）

  • Ki67前高后高：21.5%（95%置信区间：17.1～27.0）

　　对于干预组HER2阳性亚组患者，5年复发风险：

  • Ki67前低后低：10.1%（95%置信区间：3.2～31.3）

  • Ki67前高后低：7.7%（95%置信区间：3.4～17.5）

  • Ki67前高后高：15.7%（95%置信区间：10.1～24.4）

　　对4201例（94%）患者进行绝经症状评定，其中干预组2801例与对照组1400例相比，发生率最高的3级不良反应：

  • 潮热：20例（0.7%）比6例（0.4%）

  • 肌肉骨骼疼痛：29例（1%）比13例（1%）

　　未见治疗相关死亡。

　　因此，该研究结果表明，术前芳香酶抑制剂虽然不能改善治疗结局，但是可以根据治疗2周后的肿瘤Ki67，选择合适的手术后辅助治疗方法。对于基线Ki67较低或术前芳香酶抑制剂治疗2周后Ki67较低的大多数患者，手术后标准内分泌辅助治疗即可（考虑临床病理因素），而对于术前芳香酶抑制剂治疗2周后Ki67仍然较高的患者，可能获益于手术后加强辅助治疗或新药研究。

　　对此，西班牙乳腺癌研究协作组、奥古斯特·皮·桑尼尔生物医学研究所、巴塞罗那医院、巴塞罗那大学发表同期评论：实施乳腺癌术前内分泌治疗。

Lancet Oncol. 2020 Nov 2;21(11):1443-1454.

Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial.

Smith I, Robertson J, Kilburn L, Wilcox M, Evans A, Holcombe C, Horgan K, Kirwan C, Mallon E, Sibbering M, Skene A, Vidya R, Cheang M, Banerji J, Morden J, Sidhu K, Dodson A, Bliss JM, Dowsett M.

The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK; University of Nottingham, Nottingham, UK; Independent Cancer Patients Voice, London, UK; Poole Hospital NHS Foundation Trust, Poole, UK; Liverpool University Hospitals Foundation Trust, Liverpool, UK; Bexley Cancer Centre, Leeds, UK; University of Manchester and Manchester University NHS Foundation Trust, Manchester, UK; Queen Elizabeth University Hospital Glasgow, Govan, UK; University Hospitals of Derby and Burton, Derby, UK; Royal Bournemouth and Christchurch NHS Foundation Trust, Bournemouth, UK; University of Birmingham and Royal Wolverhampton NHS Trust, Wolverhampton, UK.

BACKGROUND: 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 (Ki672W) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67B). The POETIC trial aimed to test these two hypotheses.

METHODS: 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.

FINDINGS: 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 Ki67B and Ki672W (low-low) was 4.3% (95% CI 2.9-6.3), 8.4% (6.8-10.5) with high Ki67B and low Ki672W (high-low) and 21.5% (17.1-27.0) with high Ki67B and Ki672W (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.

INTERPRETATION: 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 Ki67B or low POAI-induced Ki672W do well with adjuvant standard endocrine therapy (giving consideration to clinical-pathological factors), whereas those whose POAI-induced Ki672W remains high might benefit from further adjuvant treatment or trials of new therapies.

FUNDING: Cancer Research UK.

PMID: 33152284

DOI: 10.1016/S1470-2045(20)30458-7

Lancet Oncol. 2020 Nov 2;21(11):1390-1392.

Implementing preoperative endocrine therapy in breast cancer.

Munoz M, Prat A.

August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; SOLTI Breast Cancer Research Group, Barcelona, Spain; Hospital Clinic of Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain.

PMID: 33152280

DOI: 10.1016/S1470-2045(20)30478-2

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