罗氏新药治疗三阴性乳腺癌疗效标志
2018年发表于美国麻省医学会《新英格兰医学杂志》的IMpassion130研究证实，罗氏旗下基因泰克研发的免疫细胞程序性死亡蛋白配体（PD-L1）抑制剂阿替利珠单抗＋白蛋白结合型纳米颗粒紫杉醇一线治疗晚期三阴性乳腺癌，可显著延长患者的无进展生存，并可显著延长PD-L1阳性患者的总生存。因此，进一步了解肿瘤免疫微环境和BRCA相关DNA修复缺陷对免疫检查点抑制剂临床活性的影响，可能有助于优化晚期三阴性乳腺癌的患者选择和治疗选择。
2021年2月1日，美国《国家癌症研究所杂志》在线发表美国基因泰克、匹兹堡大学医疗中心、旧金山加利福尼亚大学、哈佛大学达纳法伯癌症研究所、纽约大学珀尔马特癌症中心、澳大利亚墨尔本大学彼得麦卡伦癌症中心、德国癌症研究中心、国家肿瘤疾病中心、海德堡大学医院、法国居里学院、尤金马奎斯癌症中心、日本爱知癌症中心、巴西南里奥格兰德天主教大学圣卢卡斯医院、俄罗斯阿尔汉格尔斯克地区肿瘤医院、瑞士罗氏、英国伦敦大学玛丽王后学院巴特癌症研究所的IMpassion130研究分析报告，对阿替利珠单抗＋白蛋白紫杉醇或安慰剂＋白蛋白紫杉醇一线治疗晚期三阴性乳腺癌的免疫生物标志和BRCA突变与临床获益进行了评估。
IMpassion130 (NCT02425891): A Phase III, Multicenter, Randomized, Placebo-Controlled Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Nab-Paclitaxel Compared With Placebo With Nab-Paclitaxel for Patients With Previously Untreated Metastatic Triple-Negative Breast Cancer
该研究将902例晚期三阴性乳腺癌尚未治疗患者按1∶1随机分入两组，接受白蛋白紫杉醇＋阿替利珠单抗或白蛋白紫杉醇＋安慰剂，直至疾病进展或出现毒性反应。根据免疫细胞和肿瘤细胞的PD-L1、肿瘤内杀伤型T淋巴细胞CD8受体、肿瘤间质浸润淋巴细胞、BRCA突变，对无进展生存和总生存进行比较。
结果，原发或转移肿瘤组织免疫细胞PD-L1阳性与阴性相比，阿替利珠单抗＋白蛋白紫杉醇的无进展生存和总生存获益显著较大。
免疫细胞PD-L1阳性比例较低的243例（26.9%）与较高的125例（13.9%）患者相比，生存结局改善相似。
肿瘤内CD8和肿瘤间质浸润淋巴细胞阳性率与免疫细胞PD-L1阳性率成正比；阿替利珠单抗＋白蛋白紫杉醇与安慰剂＋白蛋白紫杉醇相比，仅对CD8阳性和间质肿瘤浸润淋巴细胞阳性且免疫细胞PD-L1阳性患者可见生存结局改善。
其中612例患者BRCA突变89例（14.5%）与免疫细胞PD-L1状态无关，无论BRCA突变状态如何，免疫细胞PD-L1阳性患者都对阿替利珠单抗＋白蛋白紫杉醇获益。
因此，该研究分析结果表明，虽然阿替利珠单抗＋白蛋白紫杉醇对肿瘤微环境免疫细胞较丰富的患者更为有效，但是仅对肿瘤免疫细胞PD-L1阳性患者可见临床获益。
对弈，美国贝勒医学院发表同期评论：乳腺癌PD-L1通往完美生物标志的道路充满不确定性。
相关链接
J Natl Cancer Inst. 2021 Feb 1. Online ahead of print.
Atezolizumab and nab-Paclitaxel in Advanced Triple-Negative Breast Cancer: Biomarker Evaluation of the IMpassion130 Study.
Emens LA, Molinero L, Loi S, Rugo HS, Schneeweiss A, Diéras V, Iwata H, Barrios CH, Nechaeva M, Duc AN, Chui SY, Husain A, Winer EP, Adams S, Schmid P.
University of Pittsburgh Medical Center, Hillman Cancer Center/Magee Women's Hospital, Pittsburgh, PA; Genentech, Inc., South San Francisco, CA; Peter MacCallum Cancer Centre, and University of Melbourne, Melbourne, Victoria, Australia; University of California San Francisco, San Francisco, CA; National Center for Tumor Diseases, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany; Institut Curie, Paris, and Centre Eugene Marquis, Rennes, France; Aichi Cancer Center Hospital, Nagoya, Japan; Hospital Sao Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil; Arkhangelsk Regional Clinical Oncology Dispensary, Arkhangelsk, Russia; Roche, Basel, Switzerland; Dana-Farber Cancer Institute, Boston, MA; Perlmutter Cancer Center, New York University School of Medicine, New York, NY; Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
BACKGROUND: Understanding the impact of the tumor immune microenvironment and BRCA-related DNA repair deficiencies on the clinical activity of immune checkpoint inhibitors may help optimize both patient and treatment selection in metastatic triple-negative breast cancer (mTNBC). In this substudy from the phase 3 IMpassion130 trial, immune biomarkers and BRCA alterations were evaluated for association with clinical benefit with atezolizumab (A) + nab-paclitaxel (nP) vs placebo + nP in unresectable locally advanced or mTNBC.
METHODS: Patients were randomized 1:1 to nab-paclitaxel 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) + atezolizumab 840 mg every 2 weeks or placebo until progression or toxicity. Progression-free survival (PFS) and overall survival (OS) were evaluated based on programmed death-ligand 1 (PD-L1) expression on immune cells (IC) and tumor cells (TC), intratumoral CD8, stromal tumor-infiltrating lymphocytes (sTILs), and BRCA1/2 mutations.
RESULTS: PD-L1 IC+ in either primary or metastatic tumor tissue was linked to PFS and OS benefit with A+nP. PD-L1 IC+ low (26.9%; 243 of 902 patients) and high (13.9%; 125 of 902 patients) populations had improved outcomes that were comparable. Intratumoral CD8 and sTILs positivity were associated with PD-L1 IC+ status; A+nP vs P+nP improved outcomes were observed only in CD8+ and sTIL+ patients who were also PD-L1 IC+. BRCA1/2 mutations (occurring in 14.5% [89 of 612 patients]) were not associated with PD-L1 IC status, and PD-L1 IC+ patients benefited from A+nP regardless of BRCA1/2 mutation status.
CONCLUSIONS: Although A+nP was more efficacious in patients with richer tumor immune microenvironment, clinical benefit was only observed in patients whose tumors were PD-L1 IC+.
PMID: 33523233
DOI: 10.1093/jnci/djab004
J Natl Cancer Inst. 2021 Feb 1. Online ahead of print.
PD-L1 in Breast Cancer: The road to the perfect biomarker is fraught with uncertainty.
Lim B.
Baylor College of Medicine, Houston, TX.
PMID: 33523229
DOI: 10.1093/jnci/djab005