哌柏西利＋氟维司群疗效预测指标
哌柏西利属于周期蛋白依赖型激酶4/6（CDK4/6）口服抑制剂，可以阻断激素受体阳性乳腺癌细胞有丝分裂周期由健身视频DNA合成前期（G1）进入DNA合成期（S）而停止分裂增殖毛桃图片。根据国际多中心随机双盲安慰剂对照III期研究（PALOMA-3，NCT01942135）结果，选择性雌激素受体降解剂氟维司群＋哌柏西利与氟维司群＋安慰剂相比，对于既往内分泌治疗失败的激素受体阳性HER2阴性转移性乳腺癌，中位无进展生存显著延长4.9个月（9.5比4.6个月），进展或死亡风险减少54%（风险比：0.46，P<0.0001）。不过，哌柏西利＋氟维司群二线治疗激素受体阳性转移性乳腺癌的效果预测指标尚不明确。
2019年2月26日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表英国皇家马斯登医院、伦敦大学癌症研究院、澳大利亚墨尔本大学彼得麦卡伦癌症中心、意大利米兰大学欧洲肿瘤研究院、德国乳腺癌研究协作组、慕尼黑大学、美国宾夕法尼亚大学、西北大学综合癌症中心、法国古斯塔夫鲁西研究院的PALOMA-3研究大型基因组表达分析报告，探讨了哌柏西利＋氟维司群二线治疗激素受体阳性转移性乳腺癌的效果预测指标。
该研究于2013年10月7日～2014年8月26日从17个国家144个研究中心入组既往内分泌治疗
失败的激素受体阳性转移性乳腺癌患者521例，随机分配接受哌柏西利＋氟维司群或安慰剂＋氟维司群。首先根据信号转导通路和既往研究证据对10个基因（CCND1、CDK4、CDK6、RB1、CDKN2A、CCNE1、CCNE2、CDK2、CCND3、ESR1）进行初步分析，随后对进读2534个癌症相关基因进行全基因组系统分析。通过多因素比例风险回归模型分析，评估基因表达与哌柏西利对无进展生存影响的相关性，将基因表达作为连续变量或通过中位值进行二等分。最后，通过术前哌柏西利（POP）随机对照II期研究61例原发性乳腺癌患者哌柏西利治疗2周的独立乳腺癌队列进行验证。
∙PALOMA-3: Palbociclib (PD-0332991) Combined With Fulvestrant In Hormone Receptor+ HER2-Negative Metastatic Breast Cancer After Endocrine Failure (NCT01942135)
∙POP: Randomized Pha II Study to Asss PD 0332991 in Breast Cancer (NCT02008734)
结果，PALOMA-3研究对302例患者进行了肿瘤组织基因组表达分析（哌柏西利组194例患者，安慰剂组108例患者）。
其中，周期蛋白E1（CCNE1）编码基因信使核糖核酸（mRNA）海参的作用表达水平高于中位与低于中位的患者相比，哌柏西利＋氟维司群的中位无进展生存显著较短：钢琴入门教材
∙哌柏西利＋氟维司群：7.6比14.1个月
∙安慰剂＋氟维司群：4.0比4.8个月
∙流离失所是什么意思相互影响分析：校正前P=0.00238，假发现率校正后P=0.0238
转移灶物业管理经理与原发灶存档活检组织标本相比，CCNE1 mRNA的预测作用更显著。两种治疗方案与CDK4、CDK6、CCNED1、RB1表达水平之间的相互影响不显著。哌柏西利对管腔A型和管腔B型肿瘤均有效。
根据POP研究的独立乳腺癌队列验证结果，神经元结构CCNE1 mRNA表达水平高于中位与低于中位的患者相比，哌柏西利的抗增殖活性显著较差（P=0.005）。
因此，虽然哌柏西利＋氟维司群对所有生物标志分组患者都有效，但是CCNE1 mRNA高表达与哌柏西利耐药相关，CCNE1 mRNA表达水平或可成为哌柏西利＋氟维司群的疗效预测指标。
J Clin Oncol. 2019 Feb 26. [Epub ahead of print]
Cyclin E1 Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor-Positive Metastatic Breast Cancer.
Turner NC, Liu Y, Zhu Z, Loi S, Colleoni M, Loibl S, DeMichele A, Harbeck N, André F, Bayar MA, Michiels S, Zhang Z, Giorgetti C, Arnedos M, Huang Bartlett C, Cristofanilli M.
Royal Marsden Hospital and Institute of Cancer Rearch, London, United Kingdom; Pfizer, La Jolla, CA; Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Istituto Europeo di Oncologia, Milan, Italy; German Breast Group, Neu-Inburg, Germany; University of Pennsylvania, Philadelphia, PA; Ludwig Maximilian University of Munich, Munich, Germany; Institut Gustave Roussy, Villejuif, France; Pfizer, Milan, Italy; Pfizer, New York, NY; Robert H Lurie Comprehensive Cancer Center, Chicago, IL.
PURPOSE: A large-panel gene expression analysis was conducted to identify biomarkers associated with the effectiveness of adding palbociclib to fulvestrant.
METHODS: The PALOMA-3 (v identifier: NCT01942135) trial randomly assigned 521 endocrine-pretreated patients with metastatic breast cancer to receive palbociclib plus fulvestrant or placebo plus fulvestrant. Primary analysis was first conducted on 10 genes on the basis of pathway biology and evidence from previous studies followed by a systematic panel-wide arch among 2,534 cancer-related genes. The association of gene expression with the effect of palbociclib on progression-free survival (PFS) was evaluated using Cox proportional hazards regression analysis, with gene expression as a continuous variable or dichotomized by median. An independent breast cancer cohort from the Preoperative Palbociclib (POP) Clinical Trial (v identifier: NCT02008734) was ud for validation, in 61 patients with primary breast cancer treated with 2 weeks of palbociclib.
RESULTS: In the PALOMA-3 trial, 302 patients had tumor tissue analyzed (palbociclib arm, 194 patients; placebo arm, 108 patients). Palbociclib efficacy was lower in patients with high versus low cyclin E1 (CCNE1) mRNA expression (median PFS: palbociclib arm, 7.6 v 14.1 months; placebo arm, 4.0 v 4.8 months, respectively; interaction P unadjusted
= 0.00238; fal discovery rate-adjusted P = 0.0238). CCNE1 mRNA was more predictive in metastatic than in archival primary biopsy tissue samples. No significant interaction was found between treatment and expression levels of CDK4, CDK6, cyclin D1, and RB1. Palbociclib was efficacious in both luminal A and luminal B tumors. High CCNE1 mRNA expression was associated with poor antiproliferative activity of palbociclib in the POP trial (P = 0.005).
CONCLUSION: Addition of palbociclib to fulvestrant demonstrated efficacy in all biomarker groups, although high CCNE1 mRNA expression was associated with relative resistance to palbociclib.
