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大约70%的乳腺癌为雌激素受体阳性，雌激素受体可进一步调节肿瘤增殖相关基因表达，内分泌治疗（包括芳香化酶抑制剂、选择性雌激素受体调节剂或降解剂）是治疗雌激素受体阳性乳腺癌最有效的方法。不过，大多数激素受体阳性乳腺癌或早或晚都可对内分泌治疗产生耐药。细胞周期蛋白依赖性激酶4和6（CDK 4/6）过度活跃是内分泌治疗耐药原因之一，CDK4/6抑制剂联合内分泌治疗已经成为治疗雌激素受体阳性乳腺癌的新选择。不幸的是，激素受体阳性乳腺癌对CDK4/6抑制剂或早或晚仍可产生耐药。磷脂酰肌醇3激酶（PI3K）、哺乳动物雷帕霉素靶蛋白（mTOR）过度活跃也是内分泌治疗耐药原因之一，那么CDK4/6抑制剂＋PI3K抑制剂＋mTOR抑制剂＋内分泌治疗能否成为治疗雌激素受体阳性晚期乳腺癌的新希望？ 
2024年3月25日，英国《柳叶刀》肿瘤学分册在线发表美国德克萨斯大学MD安德森癌症中心、南佛罗里达大学莫菲特癌症中心、旧金山加利福尼亚大学综合癌症中心、伯明翰阿拉巴马大学奥尼尔综合癌症中心、西雅图华盛顿大学弗雷德哈钦森癌症中心、北卡罗来纳大学莱恩伯格综合癌症中心、科罗拉多大学医院、俄亥俄州立大学综合癌症中心的B2151009研究报告，首次探讨了PI3K和mTOR双抑制剂格达托利＋CDK4/6抑制剂哌柏西利＋内分泌治疗对激素受体阳性HER2阴性晚期乳腺癌的有效性和安全性。 B2151009 (NCT02684032): A Study To Assess The Tolerability And Clinical Activity Of Gedatolisib In Combination With Palbociclib/Letrozole Or Palbociclib/Fulvestrant In Women With Metastatic Breast Cancer (Phase 1b study to assess the safety, tolerability, and clinical activity of gedatolisib in combination with palbociclib and either letrozole or fulvestrant in women with metastatic or locally advanced/recurrent breast cancer) 该多中心非盲非随机1b期临床研究于2017年12月19日～2019年6月19日从美国17个地点入组年龄≥18岁女性、美国东部肿瘤协作组体力状态评分为0～1分的激素受体阳性HER2阴性晚期乳腺癌患者103例分为四组： A组31例（一线治疗、未用CDK4/6抑制剂）格达托利连续＋哌柏西利＋来曲唑 B组13例（一或二线、未用CDK4/6抑制剂）格达托利连续＋哌柏西利＋氟维司群 C组32例（至少二线、已用CDK4/6抑制剂）格达托利连续＋哌柏西利＋氟维司群 C组27例（至少二线、已用CDK4/6抑制剂）格达托利间歇＋哌柏西利＋氟维司群
A、B、C组每28天第1、8、15、22天静脉注射格达托利180毫克，D组每28天第1、8、15天静脉注射格达托利180毫克。来曲唑、氟维司群、哌柏西利都按标准剂量和疗程给药。 
主要终点为研究者根据实体肿瘤疗效评价标准（RECIST）1.1版对肿瘤大小可测量者评定的客观缓解率。 结果，A、B、C、D组相比： 因此，该小样本非对照研究结果表明，与已经发表的标准治疗方案研究结果相比，格达托利＋哌柏西利＋内分泌治疗的客观缓解率令人鼓舞、安全性可接受，故有必要进一步开展大样本随机对照临床研究进行验证。 同期，英国伦敦大学癌症研究院、皇家马斯登医院、法国巴黎大学古斯塔夫鲁西研究院、美国纽约纪念医院斯隆凯特林癌症中心、北卡罗来纳大学莱恩伯格综合癌症中心发表长篇综述：雌激素受体阳性晚期乳腺癌PI3K-AKT和mTOR靶向治疗最佳方案。Lancet Oncol. 2024 Mar 25;25(4):474-487. IF: 51.1Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study.Rachel M Layman, Hyo S Han, Hope S Rugo, Erica M Stringer-Reasor, Jennifer M Specht, E Claire Dees, Peter Kabos, Samuel Suzuki, Sarah C Mutka, Brian F Sullivan, Igor Gorbatchevsky, Robert Wesolowski.The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Moffit Cancer Center, Tampa, FL, USA; University of California, San Francisco Comprehensive Cancer Center, San Francisco, CA, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA; Fred Hutch Cancer Center, University of Washington, Seattle, WA, USA; University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA; University of Colorado Hospital, Aurora, CO, USA; Celcuity, Minneapolis, MN, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.BACKGROUND: The PI3K-mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)-mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K-mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein.METHODS: This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1-2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A-C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B-D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with ClinicalTrials.gov, NCT02684032.FINDINGS: Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16.6 months (IQR 5.7-48.4) for group A, 11.0 months (7.6-16.9) for group B, 3.6 months (1.8-7.5) for group C, and 9.4 months (5.3-16.7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85.2%; 90% CI 69.2-94.8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61.5%; 90% CI 35.5-83.4) of 13 evaluable group B participants, seven (25.0%; 12.4-41.9) of 28 evaluable group C participants, and 15 (55.6%; 38.2-72.0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3-4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3-4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event.INTERPRETATION: Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile.FUNDING: Pfizer and CelcuityDOI: 10.1016/S1470-2045(24)00034-2Lancet Oncol. 2024 Mar 25;25(4):e139-e151. IF: 51.1Optimal targeting of PI3K-AKT and mTOR in advanced oestrogen receptor-positive breast cancer.Iseult M Browne, Fabrice André, Sarat Chandarlapaty, Lisa A Carey, Nicholas C Turner.Institute of Cancer Research, London, UK; The Royal Marsden Hospital NHS Foundation Trust, London, UK; Institut Gustave Roussy, Université Paris Saclay, Villejuif, France; Memorial Sloan Kettering Cancer Centre, New York, NY, USA; University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.The growing availability of targeted therapies for patients with advanced oestrogen receptor-positive breast cancer has improved survival, but there remains much to learn about the optimal management of these patients. The PI3K-AKT and mTOR pathways are among the most commonly activated pathways in breast cancer, whose crucial role in the pathogenesis of this tumour type has spurred major efforts to target this pathway at specific kinase hubs. Approvals for oestrogen receptor-positive advanced breast cancer include the PI3K inhibitor alpelisib for PIK3CA-mutated tumours, the AKT inhibitor capivasertib for tumours with alterations in PIK3CA, AKT1, or PTEN, and the mTOR inhibitor everolimus, which is used irrespective of mutation status. The availability of different inhibitors leaves physicians with a potentially challenging decision over which of these therapies should be used for individual patients and when. In this Review, we present a comprehensive summary of our current understanding of the pathways and the three inhibitors and discuss strategies for the optimal sequencing of therapies in the clinic, particularly after progression on a CDK4/6 inhibitor.DOI: 10.1016/S1470-2045(23)00676-9
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