Capalbo Carlo, Belardinilli Francesca, Raimondo Domenico, Milanetti Edoardo, Malapelle Umberto, Pisapia Pasquale, Magri Valentina, Prete Alessandra, Pecorari Silvia, Colella Mariarosaria, Coppa Anna, Bonfiglio Caterina, Nicolussi Arianna, Valentini Virginia, Tessitore Alessandra, Cardinali Beatrice, Petroni Marialaura, Infante Paola, Santoni Matteo, Filetti Marco, Colicchia Valeria, Paci Paola, Mezi Silvia, Longo Flavia, Cortesi Enrico, Marchetti Paolo, Troncone Giancarlo, Bellavia Diana, Canettieri Gianluca, Giannini Giuseppe
Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
Department of Medical Oncology Sant' Andrea Hospital, I-00189 Rome, Italy.
Cancers (Basel). 2019 Jan 27;11(2):147. doi: 10.3390/cancers11020147.
The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on and/or genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of , the expected response is much worse compared to patients with exclusive mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy.
转移性结直肠癌（mCRC）对一线传统联合治疗的反应高度可变，反映出该疾病高度的异质性。通过组学方法已全面表征了这种异质性背后的基因改变，这些方法需要大量精力和成本。为了将结直肠癌分子异质性的知识转化为实用的临床方法，我们利用了一个基于简化下一代测序（NGS）的平台，对77例接受一线传统治疗的患者队列进行筛查。使用一组通常与结直肠癌相关的22个基因的热点和靶向区域对样本进行测序。这揭示了51例携带可操作基因突变的患者，其中22例携带可用药改变。这些突变经常与其他基因改变相关。为了考虑这种分子复杂性并在无偏倚的生物信息学分析辅助下，我们定义了携带不同分子模式的三个患者亚组。我们证明这三个分子亚组与对一线传统联合治疗的不同反应相关。仅携带 和/或 基因上突变的患者取得了最佳结果。相比之下，在携带任何其他基因中的突变（单独或与 突变相关）的患者中，与仅携带 突变的患者相比，预期反应要差得多。此外，我们的数据表明，标准方法对该面板中包含的基因无任何突变的患者疗效有限。总之，我们确定了一种可靠且易于使用的方法，用于对mCRC患者进行基于分子的简化分层，该方法可预测一线传统联合治疗的疗效。
