Bonneville-Levard Alice, Frappaz Didier, Tredan Olivier, Lavergne Emilie, Corset Véronique, Agrapart Vincent, Chabaud Sylvie, Pissaloux Daniel, Wang Qing, Attignon Valery, Cartalat Stéphanie, Ducray François, Thomas-Maisonneuve Laure, Honnorat Jérôme, Meyronet David, Taillandier Luc, Blonski Marie, Viari Alain, Baudet Christian, Sohier Emilie, Lantuejoul Sylvie, Paindavoine Sandrine, Treilleux Isabelle, Rodriguez Christine, Pérol David, Blay Jean-Yves
Department of Medical Oncology, Leon Bérard Cancer Centre, 28, rue Laennec, 69373, Lyon, France.
Department of Clinical Research and Innovation, Léon Bérard Cancer Centre, Lyon, France.
Med Oncol. 2021 Nov 5;39(1):4. doi: 10.1007/s12032-021-01536-4.
Immunohistochemistry and recent molecular technologies progressively guided access to personalized anti-tumoral therapies. We explored the feasibility, efficacy, and the impact of molecular profiling in patients with advanced brain tumors. This multicentric prospective trial ProfiLER enrolled patients with primary brain tumors, who have been pre-treated with at least one line of anti-cancer treatment, and for whom molecular profiles had been achieved using next-generation sequencing and/or comparative genomic hybridization on fresh or archived samples from tumor, relapse, or biopsies. A molecular tumor board weekly analyzed results and proposed molecular-based recommended therapy (MBRT). From February 2013 to December 2015, we enrolled 141 patients with primary brain tumor and analyzed 105 patients for whom tumor genomic profiles had been achieved. Histology mainly identified glioblastoma (N = 46, 44%), low-grade glioma (N = 26, 25%), high-grade glioma (N = 12, 11%), and atypical and anaplastic meningioma (N = 8, 8%). Forty-three (41%) patients presented at least one actionable molecular alteration. Out of 61 alterations identified, the most frequent alterations occurred in CDKN2A (N = 18), EGFR (N = 12), PDGFRa (N = 8), PTEN (N = 8), CDK4 (N = 7), KIT (N = 6), PIK3CA (N = 5), and MDM2 (N = 3). Sixteen (15%) patients could not be proposed for a MBRT due to early death (N = 5), lack of available clinical trials (N = 9), or inappropriate results (N = 2). Only six (6%) of the 27 (26%) patients for whom a MBRT had been proposed finally initiated MBRT (everolimus (N = 3), erlotinib (N = 1), ruxolitinib (N = 1), and sorafenib (N = 1)), but discontinued treatment for toxicity (N = 4) or clinical progression (N = 2). High-throughput sequencing in patients with brain tumors may be routinely performed, especially when macroscopic surgery samples are available; nevertheless delays should be reduced. Criteria for clinical trial enrollment should be reconsidered in patients with brain tumors, and a panel of genes specifically dedicated to neurologic tumors should be developed to help decision-making in clinical practice.
免疫组织化学和近期的分子技术逐步引领了个性化抗肿瘤治疗的发展。我们探讨了分子谱分析在晚期脑肿瘤患者中的可行性、疗效及影响。这项多中心前瞻性试验ProfiLER纳入了原发性脑肿瘤患者，这些患者至少接受过一线抗癌治疗，且已通过新一代测序和/或比较基因组杂交技术对来自肿瘤、复发灶或活检的新鲜或存档样本进行了分子谱分析。一个分子肿瘤委员会每周分析结果并提出基于分子的推荐治疗方案（MBRT）。从2013年2月至2015年12月，我们纳入了141例原发性脑肿瘤患者，并对其中105例已获得肿瘤基因组谱的患者进行了分析。组织学检查主要确诊为胶质母细胞瘤（N = 46，44%）、低级别胶质瘤（N = 26，25%）、高级别胶质瘤（N = 12，11%）以及非典型和间变性脑膜瘤（N = 8，8%）。43例（41%）患者存在至少一种可采取行动的分子改变。在鉴定出的61种改变中，最常见的改变发生在CDKN2A（N = 18）、表皮生长因子受体（EGFR，N = 12）、血小板衍生生长因子受体α（PDGFRa，N = 8）、磷酸酶和张力蛋白同源物（PTEN，N = 8）、细胞周期蛋白依赖性激酶4（CDK4，N = 7）、原癌基因c-KIT（KIT，N = 6）、磷脂酰肌醇-3激酶催化亚基α（PIK3CA，N = 5）和小鼠双微体2（MDM2，N = 3）。16例（15%）患者因早期死亡（N = 5）、缺乏可用的临床试验（N = 9）或结果不合适（N = 2）而无法被推荐接受MBRT。在被推荐接受MBRT的27例（26%）患者中，只有6例（6%）最终开始接受MBRT（依维莫司（N = 3）、厄洛替尼（N = 1）、芦可替尼（N = 1）和索拉非尼（N = 1）），但因毒性（N = 4）或临床进展（N = 2）而停止治疗。对脑肿瘤患者进行高通量测序可以常规开展，尤其是在有宏观手术样本的情况下；然而，应减少延迟。对于脑肿瘤患者，应重新考虑临床试验入组标准，并应开发一组专门针对神经肿瘤的基因，以帮助临床实践中的决策制定。
