【佳学基因靶向药物基因检测】Merkel 细胞癌的基因组改变和肿瘤突变负担

基因肿瘤检测回扣机会

参加学术会议时成人肿瘤与儿童肿瘤基因检测顺序的异同点《肿瘤治疗效果与基因检测结果的相关性》《JAMA Netw Open》在 2023 Jan 3;6(1):e2249674.发表了一篇题目为《Multicenter Study》肿瘤靶向药物治疗基因检测临床研究文章。该研究由Danielle Brazel, Priyanka Kumar, Hung Doan, Tianyu Pan, Weining Shen, Ling Gao, Justin T Moyers等完成。促进了肿瘤的精准治疗与个性化用药的发展，进一步强调了基因信息检测与分析的重要性。

肿瘤基因检测及靶向药物治疗研究关键词：

Merkel,细胞癌,MCC,罕见,高度侵袭性,皮肤,神经内分泌癌

肿瘤治疗检测基因临床应用结果

重要性：Merkel 细胞癌 (MCC) 是一种罕见且高度侵袭性的皮肤神经内分泌癌，发病率不断增加。细胞毒性化学疗法和检查点抑制剂为转移性环境提供了治疗选择；然而，目前还没有经过批准的或标准的护理靶向治疗方案。目的：确定由 OncoKB 数据库治疗证据水平注释的与肿瘤突变负荷 (TMB) 相关的可操作改变。设计、设置和参与者：这是一项回顾性研究，横断面研究使用来自美国癌症研究协会基因组学证据肿瘤信息交换协会的数据，这是一个多中心国际癌症联盟数据库。 MCC 患者于 2017 年至 2022 年期间入组参与机构。数据库 11.0 版的数据于 2022 年 1 月发布，分析时间为 4 月至 2022 年 6 月。主要结果和测量：主要结果是高 TMB 患者的百分比和OncoKB 3B 级和 4 级改变。靶向药物研究的客观数据：数据库中对来自 313 名 MCC 患者（107 名女性 [34.2%]；287 名白人患者 [91.7%]；7 名黑人患者 [2.2%]）的 324 个肿瘤样本进行了分类。改变的中位数（范围）为 4.0 (0.0-178.0)，平均 (SD) 为 13.6 (21.2) 改变。致癌改变占所有改变的 20.2%（4259 个改变中的 862 个）。 55.0% 的患者（172 名患者）的组织起源于原发性肿瘤，而 39.6% 的患者（124 名患者）的组织起源于原发性肿瘤。 26.2% 的病例（82 名患者）存在高 TMB（每兆碱基≥10 个突变）。下一代测序确定了 55 名患者 (17.6%) 具有 3B 级变异，用于食品和药物管理局批准的药物用于生物标志物批准的适应症或批准的药物用于另一种适应症。另外 8.6% 的患者（27 名患者）具有 4 级变异。可采取行动的改变在高 TMB 病例中更为常见，82 名患者中有 37 名 (45.1%) 具有 3 级改变，而 231 名低 TMB 患者中只有 18 名 (7.8%)。最常见的 3B 级基因变异包括 PIK3CA（12 名患者 [3.8%]）、BRCA1/2（13 名患者 [4.2%]）、ATM（7 名患者 [2.2%]）、HRAS（5 名患者 [1.6%]）、和 TSC1/2（6 名患者 [1.9%]）。最常见的 4 级变异包括 PTEN（13 名患者 [4.1%]）、ARID1A（9 名患者 [2.9%]）、NF1（7 名患者 [2.2%]）和 CDKN2A（7 名患者 [2.2%]）。拷贝数改变和融合很少见。在 61.0% 的病例（191 例）中，一条 PanCancer 通路发生了改变，39.9%（125 例）发生了多条通路的改变。常见改变的途径是 RTK-RAS（119 名患者 [38.0%]）、TP53（103 名患者 [32.9%]）、细胞周期（104 名患者 [33.2%]）、PI3K（99 名患者 [31.6%]）和 NOTCH（ 93 名患者 [29.7%]）。此外，8.0% 的病例（25 名患者）存在致癌 DNA 错配修复基因改变。结论和相关性：在这项对 MCC 改变和 TMB 的横断面回顾性研究中，少数患者具有潜在的可操作改变。这些发现支持在选定的 MCC 人群中将靶向治疗作为单一药物或与免疫疗法或细胞毒性化学疗法联合进行研究。

肿瘤发生与革命国际数据库描述：

Importance: Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine carcinoma with increasing incidence. Cytotoxic chemotherapy and checkpoint inhibitors provide treatment options in the metastatic setting; however, there are no approved or standard of care targeted therapy treatment options.Objective: To identify actionable alterations annotated by the OncoKB database therapeutic evidence level in association with tumor mutation burden (TMB).Design, setting, and participants: This is a retrospective, cross-sectional study using data from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange, a multicenter international cancer consortium database. Patients with MCC were enrolled in participating institutions between 2017 and 2022. Data from version 11.0 of the database were released in January 2022 and analyzed from April to June 2022.Main outcomes and measures: The main outcome was the percentage of patients with high TMB and OncoKB level 3B and 4 alterations.Results: A total of 324 tumor samples from 313 patients with MCC (107 women [34.2%]; 287 White patients [91.7%]; 7 Black patients [2.2%]) were cataloged in the database. The median (range) number of alterations was 4.0 (0.0-178.0), with a mean (SD) of 13.6 (21.2) alterations. Oncogenic alterations represented 20.2% of all alterations (862 of 4259 alterations). Tissue originated from primary tumor in 55.0% of patients (172 patients) vs metastasis in 39.6% (124 patients). TMB-high (≥10 mutations per megabase) was present in 26.2% of cases (82 patients). Next-generation sequencing identified 55 patients (17.6%) with a level 3B variation for a Food and Drug Administration-approved drug for use in a biomarker-approved indication or approved drug in another indication. An additional 8.6% of patients (27 patients) had a level 4 variation. Actionable alterations were more common among high TMB cases, with 37 of 82 patients (45.1%) harboring level 3 alterations compared with only 18 of 231 patients (7.8%) with low TMB. The most common level 3B gene variants included PIK3CA (12 patients [3.8%]), BRCA1/2 (13 patients [4.2%]), ATM (7 patients [2.2%]), HRAS (5 patients [1.6%]), and TSC1/2 (6 patients [1.9%]). The most common level 4 variants include PTEN (13 patients [4.1%]), ARID1A (9 patients [2.9%]), NF1 (7 patients [2.2%]), and CDKN2A (7 patients [2.2%]). Copy number alterations and fusions were infrequent. In 61.0% of cases (191 cases), a PanCancer pathway was altered, and 39.9% (125 cases) had alterations in multiple pathways. Commonly altered pathways were RTK-RAS (119 patients [38.0%]), TP53 (103 patients [32.9%]), cell cycle (104 patients [33.2%]), PI3K (99 patients [31.6%]), and NOTCH (93 patients [29.7%]). In addition, oncogenic DNA mismatch repair gene alterations were present in 8.0% of cases (25 patients).Conclusions and relevance: In this cross-sectional retrospective study of alterations and TMB in MCC, a minority of patients had potentially actionable alterations. These findings support the investigation of targeted therapies as single agent or in combination with immunotherapy or cytotoxic chemotherapy in selected MCC populations.