Mazel Benoit, Bertolone Geoffrey, Baurand Amandine, Cosset Elodie, Sawka Caroline, Robert Marion, Gautier Elodie, Lançon Allan, Réda Manon, Favier Laure, Dérangère Valentin, Richard Corentin, Binquet Christine, Boidot Romain, Goussot Vincent, Albuisson Juliette, Ghiringhelli François, Faivre Laurence, Nambot Sophie
Centre de Génétique, FHU-TRANSLAD, Centre Hospitalier Universitaire Dijon-Bourgogne, Dijon, France.
INSERM UMR 1231 GAD, Génétique des Anomalies du Développement, Université Bourgogne Franche-Comté, Dijon, France.
Cancer Med. 2023 Sep;12(18):18786-18796. doi: 10.1002/cam4.6498. Epub 2023 Sep 11.
With the emergence of targeted therapies, there is a need to accurately identify more tumor biomarkers. The EXOMA trial was designed to offer tumor and germline exome sequencing (ES) to patients with solid malignant tumors and facing therapeutic failure. As hereditary cancer predispositions could be identified, with genetic counseling and health management implications, a genetic consultation was systematically established. This design needs to be discussed as genetic human resources are limited and indication of theranostic tests will increase.
Genetic counseling was conducted within 15 days following inclusion in the study for patients recruited between December 2015 and July 2019. In silico analyses from theranostic ES were limited to 317 genes involved in oncogenesis, from both tumor and blood DNA.
Six hundred and sixty six patients had a genetic consultation before ES. In 65/666 patients, 66 germline pathogenic or likely pathogenic (P/LP) variants were identified in 16 actionable genes and seven non-actionable genes according to French guidelines. 24/65 patients had previously received genetic analysis for diagnostic purposes, and for 17 of them, a P/LP variant had already been identified. Among the 48/65 remaining cases for which the EXOMA protocol revealed a previously unknown P/LP variant, only 19 met the criteria for genetic testing for inherited cancer risk after familial survey. These criteria had not been identified by the oncologist in 10 cases. In 21/65 cases, the variant was considered incidental.
In 7.4% of patients, an undiagnosed hereditary genetic predisposition was identified, whether or not related to the clinical presentation, and germline analysis impacted oncological management for only 6.3% of the cohort. This low percentage should be weighed against the burden of systematic genetic consultation and urgent circuits. Information or training tools to form oncologists to the prescription of germline genetic analyses should be explored, as well as information supports and patient preferences.
随着靶向治疗的出现，需要准确识别更多的肿瘤生物标志物。EXOMA试验旨在为患有实体恶性肿瘤且面临治疗失败的患者提供肿瘤和种系外显子组测序（ES）。由于可以识别遗传性癌症易感性，并对遗传咨询和健康管理产生影响，因此系统地建立了遗传咨询。鉴于遗传人力资源有限且治疗诊断测试的适应症将会增加，这种设计需要进行讨论。
对2015年12月至2019年7月招募的患者，在纳入研究后的15天内进行遗传咨询。治疗诊断性ES的计算机分析仅限于肿瘤和血液DNA中涉及肿瘤发生的317个基因。
666例患者在进行ES之前接受了遗传咨询。根据法国指南，在65/666例患者中，在16个可操作基因和7个不可操作基因中鉴定出66个种系致病性或可能致病性（P/LP）变异。24/65例患者先前已接受过诊断性遗传分析，其中17例已鉴定出P/LP变异。在EXOMA方案揭示先前未知的P/LP变异的其余48/65例病例中，只有19例在家族调查后符合遗传性癌症风险基因检测标准。在10例病例中，肿瘤学家未识别出这些标准。在21/65例病例中，该变异被认为是偶然发现的。
在7.4%的患者中，无论是否与临床表现相关，均鉴定出未诊断的遗传性遗传易感性，而种系分析仅对6.3%的队列患者的肿瘤管理产生影响。应权衡这一低比例与系统遗传咨询和紧急流程的负担。应探索用于培训肿瘤学家进行种系遗传分析处方的信息或培训工具，以及信息支持和患者偏好。
