【佳學基因靶向藥物基因檢測】Merkel 細胞癌的基因組改變和腫瘤突變負擔

基因腫瘤檢測回扣機會

參加學術(shù)會議時成人腫瘤與兒童腫瘤基因檢測順序的異同點《腫瘤治療效果與基因檢測結(jié)果的相關(guān)性》《JAMA Netw Open》在?2023 Jan 3;6(1):e2249674.發(fā)表了一篇題目為《Multicenter Study》腫瘤靶向藥物治療基因檢測臨床研究文章。該研究由Danielle Brazel,?Priyanka Kumar,?Hung Doan,?Tianyu Pan,?Weining Shen,?Ling Gao,?Justin T Moyers等完成。促進了腫瘤的正確治療與個性化用藥的發(fā)展，進一步強調(diào)了基因信息檢測與分析的重要性。

腫瘤基因檢測及靶向藥物治療研究關(guān)鍵詞：

Merkel,細胞癌,MCC,罕見,高度侵襲性,皮膚,神經(jīng)內(nèi)分泌癌

腫瘤治療檢測基因臨床應(yīng)用結(jié)果

重要性：Merkel 細胞癌 (MCC) 是一種罕見且高度侵襲性的皮膚神經(jīng)內(nèi)分泌癌，發(fā)病率不斷增加。細胞毒性化學療法和檢查點抑制劑為轉(zhuǎn)移性環(huán)境提供了治療選擇；然而，目前還沒有經(jīng)過批準的或標準的護理靶向治療方案。目的：確定由 OncoKB 數(shù)據(jù)庫治療證據(jù)水平注釋的與腫瘤突變負荷 (TMB) 相關(guān)的可操作改變。設(shè)計、設(shè)置和參與者：這是一項回顧性研究，橫斷面研究使用來自美國癌癥研究協(xié)會基因組學證據(jù)腫瘤信息交換協(xié)會的數(shù)據(jù)，這是一個多中心國際癌癥聯(lián)盟數(shù)據(jù)庫。 MCC 患者于 2017 年至 2022 年期間入組參與機構(gòu)。數(shù)據(jù)庫 11.0 版的數(shù)據(jù)于 2022 年 1 月發(fā)布，分析時間為 4 月至 2022 年 6 月。主要結(jié)果和測量：主要結(jié)果是高 TMB 患者的百分比和OncoKB 3B 級和 4 級改變。靶向藥物研究的客觀數(shù)據(jù)：數(shù)據(jù)庫中對來自 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 個腫瘤樣本進行了分類。改變的中位數(shù)（范圍）為 4.0 (0.0-178.0)，平均 (SD) 為 13.6 (21.2) 改變。致癌改變占所有改變的 20.2%（4259 個改變中的 862 個）。 55.0% 的患者（172 名患者）的組織起源于原發(fā)性腫瘤，而 39.6% 的患者（124 名患者）的組織起源于原發(fā)性腫瘤。 26.2% 的病例（82 名患者）存在高 TMB（每兆堿基≥10 個突變）。下一代測序確定了 55 名患者 (17.6%) 具有 3B 級變異，用于食品和藥物管理局批準的藥物用于生物標志物批準的適應(yīng)癥或批準的藥物用于另一種適應(yīng)癥。另外 8.6% 的患者（27 名患者）具有 4 級變異?？刹扇⌒袆拥母淖冊诟?TMB 病例中更為常見，82 名患者中有 37 名 (45.1%) 具有 3 級改變，而 231 名低 TMB 患者中只有 18 名 (7.8%)。賊常見的 3B 級基因變異包括 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%]）。賊常見的 4 級變異包括 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%]）?？截悢?shù)改變和融合很少見。在 61.0% 的病例（191 例）中，一條 PanCancer 通路發(fā)生了改變，39.9%（125 例）發(fā)生了多條通路的改變。常見改變的途徑是 RTK-RAS（119 名患者 [38.0%]）、TP53（103 名患者 [32.9%]）、細胞周期（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 錯配修復基因改變。結(jié)論和相關(guān)性：在這項對 MCC 改變和 TMB 的橫斷面回顧性研究中，少數(shù)患者具有潛在的可操作改變。這些發(fā)現(xiàn)支持在選定的 MCC 人群中將靶向治療作為單一藥物或與免疫療法或細胞毒性化學療法聯(lián)合進行研究。

腫瘤發(fā)生與革命國際數(shù)據(jù)庫描述：

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.