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2017年1月4日，美国临床肿瘤学会官方期刊《临床肿瘤学杂志》在线发表贝勒医学院、MD安德森癌症中心、拉雷多医院、德克萨斯大学、梅奥医院、华盛顿大学、堪萨斯城圣卢克医院、罗氏诊断、旧金山加利福尼亚大学、英国伦敦皇家马斯登医院、克利夫兰医院、凯斯西储大学、达纳法伯癌症研究所、北卡罗来纳大学、杜克大学、纳什维尔乳腺中心、圣伊丽莎白医疗中心、新墨西哥大学、马里兰大学起草的美国外科医师学会（ACS）肿瘤学组（ACOSOG）Z1031研究报告，发现对于雌激素受体阳性早期乳腺癌，如果芳香酶抑制剂新辅助治疗2～4周但是Ki67表达升高，转为化疗后病理学完全缓解率低于预期。 MKI67基因（Ki67）是1983年德国基尔大学病理学研究所和生物化学研究所用鼠源单克隆抗体检测一种来自霍奇金淋巴瘤系细胞核抗原时首次发现的，Ki源于研究者当时所在的德国基尔（Kiel），67是当时96孔板中发现该抗原相对应的单克隆抗体编号。Ki67与其他肿瘤分子标记物相结合，能较好的反映肿瘤增殖活性、对判断肿瘤的恶性程度、预后和指导肿瘤术后辅助治疗有极其重要的意义。Ki67高表达是乳腺癌治疗无效、预后不良的指标。 对于临床Ⅱ或Ⅲ期、雌激素受体阳性的绝经后乳腺癌患者，芳香酶抑制剂新辅助内分泌疗法是一种可以替代化疗的选择，同样能够增加保乳机会，虽然毒性低，但是临床应用较少。雌激素受体阳性乳腺癌原发灶的病理学完全缓解是新辅助治疗的重要评价指标，为了确定：1、芳香酶抑制剂新辅助治疗2～4周后如果Ki67≥10%换用化疗能否提高病理学完全缓解？2、基于Ki67的术前内分泌预后指数（PEPI）能否检验复发风险？ACOSOG开展了Z1031研究。 该研究分为Z1031A和Z1031B两个阶段：Z1031A入组Ⅱ或Ⅲ期、雌激素受体阳性、激素受体状态的奥尔雷德（Allred）评分6～8的乳腺癌绝经后女性，随机接受三种芳香酶抑制剂（阿那曲唑、来曲唑、依西美坦）新辅助治疗；Z1031B将方案修改为在芳香酶抑制剂治疗2～4周后测定肿瘤Ki67，如果Ki67＞10%，患者改为新辅助化疗。 预先设定病理学完全缓解率＞20%为疗效临界值。在完成芳香酶抑制剂新辅助治疗的患者中，使用分层Cox模型评定PEPI为0（肿瘤大小为T1或T2、淋巴结状态为N0、Ki67＜2.7%、激素受体状态的奥尔雷德评分＞2）与＞0的疾病复发时间是否不同。 结果发现，在Z1031B中，35例改为新辅助化疗的患者获得病理学完全缓解仅2例（5.7%，95%置信区间：0.7%～19.1%）。 中位随访5.5年后，109例PEPI为0的患者复发率仅3.7%（4例），341例PEPI＞0的患者复发率达14.4%（49例），复发风险相差将近4倍（风险比：0.27，95%置信区间：0.092～0.764，P=0.014）。 因此，雌激素受体阳性乳腺癌对芳香酶抑制剂无效后，化疗效果低于预期，应该进一步研究这些患者的最佳疗法。 此外，对于PEPI为0的患者，单用辅助内分泌疗法、不用化疗的5年复发风险仅为3.6%。 上述根据Ki67和PEPI进行分类的方法，正被ALTERNATE（绝经后女性临床Ⅱ或Ⅲ期雌激素受体阳性乳腺癌新辅助治疗替代方案Ⅲ期研究：NCT01953588）进一步明确。 相关阅读 J Clin Oncol. 2017 Jan 4. [Epub ahead of print] Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance). Ellis MJ, Suman VJ, Hoog J, Goncalves R, Sanati S, Creighton CJ, DeSchryver K, Crouch E, Brink A, Watson M, Luo J, Tao Y, Barnes M, Dowsett M, Budd GT, Winer E, Silverman P, Esserman L, Carey L, Ma CX, Unzeitig G, Pluard T, Whitworth P, Babiera G, Guenther JM, Dayao Z, Ota D, Leitch M, Olson JA Jr, Allred DC, Hunt K. Baylor College of Medicine; MD Anderson Cancer Center, Houston; Doctor's Hospital of Laredo, Laredo; University of Texas Southwestern Campus, Dallas, TX; Mayo Clinic, Rochester MN; Washington University School of Medicine, St Louis; St Lukes Hospital, Kansas City, MO; Roche Diagnostics, Mountain View; University of California San Francisco, San Francisco, CA; Royal Marsden Hospital, London, UK; Cleveland Clinic; Case Western Reserve University, Cleveland OH; Dana-Farber Cancer Institute, Boston MA; University of North Carolina, Chapel Hill; Duke University, Durham, NC; Nashville Breast Center, Nashville, TN; St Elizabeth Medical Center, Edgewood, KY; University of New Mexico, Albuquerque, NM; University of Maryland School of Medicine and Greenebaum Cancer Center, Baltimore, MD. Purpose: To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) -positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods: The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results: Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion: Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588). PMID: 28045625 DOI: 10.1200/JCO.2016.69.4406
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