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2018年，英国《柳叶刀》肿瘤学分册发表的光明研究主要结果意外发现，对于三阴性乳腺癌术前标准新辅助化疗，加不加多腺苷二磷酸核糖聚合酶（PARP）抑制剂维利帕利似乎不重要，加不加卡铂或许很重要，可能显著提高病理完全缓解比例。不过，三阴性乳腺癌术前标准新辅助化疗是否要加卡铂的决定因素尚不明确。 BrighTNess (NCT02032277): A Randomized, Placebo-Controlled, Double-Blind, Phase 3 Study Evaluating Safety and Efficacy of the Addition of Veliparib Plus Carboplatin Versus the Addition of Carboplatin to Standard Neoadjuvant Chemotherapy Versus Standard Neoadjuvant Chemotherapy in Subjects With Early Stage Triple Negative Breast Cancer (TNBC) 2021年2月18日，《美国医学会杂志》肿瘤学分册在线发表美国哈佛大学、德纳法伯癌症研究所、布莱根医院和波士顿妇女医院、俄亥俄州立大学、艾伯维、圣路易斯华盛顿大学、弗吉尼亚联邦大学、梅西癌症中心、休斯顿卫理公会癌症中心、德克萨斯肿瘤医院、贝勒大学查尔斯萨蒙斯癌症中心、旧金山加利福尼亚大学、耶鲁大学、罗德岛妇婴医院、匹兹堡大学、希尔曼癌症中心、阿勒格尼综合医院、德克萨斯大学MD安德森癌症中心、德国乳腺癌协作组、乌尔姆大学、柏林布赫赫利俄斯医院、马尔堡大学、瑞士圣加仑州立医院的光明研究次要结果分析报告，探讨了分子亚型、肿瘤增殖、免疫表型对早期三阴性乳腺癌患者术前新辅助化疗加入卡铂能否获得病理完全缓解的预测作用。 该国际多中心双盲安慰剂随机对照三期临床研究于2014年4月～2016年3月从15个国家或地区145家医院入组早期（临床II～III期）三阴性乳腺癌治疗前活检确诊女性患者634例（年龄22～78岁，中位51岁），按2∶1∶1随机分入三组进行术前新辅助化疗：紫杉醇＋卡铂＋维利帕利316例、紫杉醇＋卡铂＋安慰剂160例、紫杉醇＋安慰剂158例，随后给予多柔比星＋环磷酰胺。对治疗前活检标本进行全转录组核糖核酸测序。预设主要终点为病理完全缓解及其与基因表达分子亚型（50基因分型和三阴性乳腺癌亚型）的相关性，次要终点为增殖评分和免疫评分，并对免疫表型进行探索分析。数据收集于2014年4月～2016年3月进行，数据分析于2018年1月～2019年3月进行。 结果，其中482例患者（76%）核糖核酸测序数据可评估，与全部意向治疗患者相比，入组时特征相似。 根据50基因分型，基底样癌（386例）与非基底样癌（96例）相比，病理完全缓解比例显著较高（52.3%比35.4%，P=0.003）。 对于卡铂组，基底样癌（289例）与非基底样癌（70例）亚组相比，病理完全缓解比例显著较高（58.1%比40.0%，P=0.007）。 对于非卡铂组，基底样癌（97例）与非基底样癌（26例）亚组相比，病理完全缓解比例相似（35.1%比23.1%，P=0.25）。 基底样与非基底样亚组相比，卡铂获益相似（相互作用分析，P=0.80）。 根据多因素分析，对多柔比星＋环磷酰胺计划疗程、淋巴结分期、入组时体力状态评分、种系BRCA基因变异状态等其他影响因素进行校正，病理完全缓解的独立相关因素包括：
肿瘤病理完全缓解比例：
基因表达免疫表型探索分析表明，杀伤型T淋巴细胞膜受体CD8阳性细胞浸润比例较高的肿瘤，卡铂获益可能较大。 因此，该研究次要结果表明，根据全转录组核糖核酸测序，三阴性乳腺癌基底样亚型和免疫调节亚型的病理完全缓解比例显著较高。根据基底样和免疫调节表型相关生物学过程分析，肿瘤细胞增殖评分和免疫评分是病理完全缓解的独立相关因素；对于全部分子亚型，都可发现卡铂的病理完全缓解获益，不能为治疗决策提供预测信息。故有必要开展进一步研究，对免疫表型与现有生物学标志进行验证，可能有助于提高三阴性乳腺癌患者的治疗水平。 相关链接 JAMA Oncol. 2021 Feb 18. Online ahead of print. Association of Immunophenotype With Pathologic Complete Response to Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: A Secondary Analysis of the BrighTNess Phase 3 Randomized Clinical Trial. Filho OM, Stover DG, Asad S, Ansell PJ, Watson M, Loibl S, Geyer CE Jr, Bae J, Collier K, Cherian M, O'Shaughnessy J, Untch M, Rugo HS, Huober JB, Golshan M, Sikov WM, von Minckwitz G, Rastogi P, Maag D, Wolmark N, Denkert C, Symmans WF. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Brigham and Women's Hospital, Boston, Massachusetts; Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts; The Ohio State University College of Medicine, Columbus; The Ohio State University Comprehensive Cancer Center, Columbus; AbbVie, Inc, North Chicago, Illinois; Washington University, St Louis, Missouri; Massey Cancer Center, Virginia Commonwealth University, Richmond; Houston Methodist Cancer Center, Houston, Texas; Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas; University of California, San Francisco; Yale Cancer Center, New Haven, Connecticut; Women and Infants Hospital of Rhode Island, Providence; University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, Pennsylvania; Allegheny General Hospital, Pittsburgh, Pennsylvania; The University of Texas MD Anderson Cancer Center, Houston; University Medical Center Ulm, Ulm, Germany; German Breast Group, Neu-Isenburg, Germany; Helios Klinikum Berlin-Buch, Berlin, Germany; Philipps-University Marburg and University Hospital of Giessen and Marburg, Marburg, Germany; Cantonal Hospital St Gallen, St Gallen, Switzerland. This prespecified secondary analysis of a phase 3 randomized clinical trial evaluated the association of molecular subtype, tumor proliferation, and immunophenotype with standard neoadjuvant chemotherapy alone vs with carboplatin added for 482 patients with stages II to III triple-negative breast cancer. QUESTION: Does triple-negative breast cancer (TNBC) subtyping inform on chances of achieving a pathologic complete response (pCR) and on the potential benefits of adding carboplatin to standard neoadjuvant chemotherapy? FINDINGS: This prespecified secondary analysis of a randomized clinical trial of 634 patients with stages II to III TNBC found that in 482 women with evaluable RNA sequencing, basal-like and immunomodulatory subtypes were associated with higher pCR rates. After analyzing important biological processes related to these phenotypes, tumor cell proliferation and immune scores were identified as independent factors informing on chances of achieving pCR; TNBC subtyping was not informative for treatment decision. MEANING: With further validation and long-term survival data, RNA-based proliferation and immune scores may inform the development of novel therapies for patients with TNBC. IMPORTANCE: Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) likely benefits a subset of patients; however, determinants of benefit are poorly understood. OBJECTIVE: To define the association of molecular subtype, tumor proliferation, and immunophenotype with benefit of carboplatin added to NAC for patients with stages II to III TNBC. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of a phase 3, double-blind, randomized clinical trial (BrighTNess) that enrolled 634 women across 145 centers in 15 countries. Women with clinical stages II to III TNBC who had undergone pretreatment biopsy were eligible to participate. Whole transcriptome RNA sequencing was performed on the biopsy specimens. The prespecified end point was association of pathologic complete response (pCR) with gene expression-based molecular subtype, with secondary end points investigating established signatures (proliferation, immune) and exploratory analyses of immunophenotype. Data were collected from April 2014 to March 2016. The study analyses were performed from January 2018 to March 2019. INTERVENTIONS: Neoadjuvant chemotherapy with paclitaxel followed by doxorubicin and cyclophosphamide, or this same regimen with carboplatin or carboplatin plus veliparib. MAIN OUTCOMES AND MEASURES: Association of gene expression-based molecular subtype (PAM50 and TNBC subtypes) with pCR. RESULTS: Of the 634 women (median age, 51 [range, 22-78] years) enrolled in BrighTNess, 482 (76%) patients had evaluable RNA sequencing data, with similar baseline characteristics relative to the overall intention-to-treat population. Pathologic complete response was significantly more frequent in PAM50 basal-like vs nonbasal-like cancers overall (202 of 386 [52.3%] vs 34 of 96 [35.4%]; P = .003). Carboplatin benefit was not significantly different in basal-like vs nonbasal-like subgroups (P = .80 for interaction). In multivariable analysis, proliferation (hazard ratio, 0.36; 95% CI, 0.21-0.61; P < .001) and immune (hazard ratio, 0.62; 95% CI, 0.49-0.79; P < .001) signatures were independently associated with pCR. Tumors above the median for proliferation and immune signatures had the highest pCR rate (84 of 125; 67%), while those below the median for both signatures had the lowest pCR rate (42 of 125; 34%). Exploratory gene expression immune analyses suggested that tumors with higher inferred CD8+ T-cell infiltration may receive greater benefit with addition of carboplatin. CONCLUSIONS AND RELEVANCE: In this secondary analysis of a randomized clinical trial, triple-negative breast cancer subtyping revealed high pCR rates in basal-like and immunomodulatory subsets. Analysis of biological processes related to basal-like and immunomodulatory phenotypes identified tumor cell proliferation and immune scores as independent factors associated with achieving pCR; the benefit of carboplatin on pCR was seen across all molecular subtypes. Further validation of immunophenotype with existing biomarkers may help to escalate or de-escalate therapy for patients with TNBC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02032277 PMID: 33599688 DOI: 10.1001/jamaoncol.2020.7310 |
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