三***性***腺癌疗效强有力预测指标

三***性***腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为***性，内分泌治疗和HER2靶向治疗基本无效，晚期患者主要依靠化疗，而且大多数患者一线化疗后仍然进展、复发或转移，二线治疗缓解率仅10%～15%，无进展生存仅2～3个月。近年来，免疫治疗和抗血管生成治疗对晚期三***性***腺癌的疗效令人鼓舞，例如免疫细胞程序性死亡受体PD-1及其配体PD-L1等免疫检查点的***、血管内皮生长因子受体VEGFR的***，已经成为治疗晚期三***性***腺癌的新选择。不过，这些药物仅对部分患者有效，而且价格昂贵，迫切需要强有力的预测指标，选择合适的患者进行治疗，以免浪费金钱、时间和生命。　　2023年11月17日，英国《自然》旗下《信号转导与靶向治疗》在线发表中国工程院院士徐兵河、中国医学科学院肿瘤医院王佳玉和韩逸群、辽宁省肿瘤医院孙涛、湖南省肿瘤医院欧阳取长等学者的TQB2450-Ib-07研究报告，探讨了中国正大天晴原研PD-L1***贝莫苏拜单抗联合VEGFR等多靶点酪氨酸激酶***安罗替尼二线治疗晚期三***性***腺癌客观缓解率和无进展生存的预测指标。TQB2450-Ib-07 (NCT03855358)/ A Phase Ib Study of TQB2450 Injection and Anlotinib Hydrochloride Capsules to Treat Triple Negative Breast Cancer (TNBC)　　该多中心一期临***研究于2019年5月29日～2020年12月31日入组晚期三***性***腺癌一线治疗失败患者34例给予贝莫苏拜单抗＋安罗替尼二线治疗，并且从患者治疗开始前和疾病进展后的外周血液样本收集循环肿瘤DNA，有针对性地进行大规模并行测序，对基因组生物标志物与治疗缓解率和无进展生存的关联进行探索性分析。　　结果，共计31例患者进行大规模并行测序，并对其中29例患者功能驱动突变进行分析，发生率最高的基因突变为TP53（72%）、MLL3（28%）和PIK3CA（17%）。　　通过多因素比例风险回归模型对其他影响因素进行校正后，筛选出两个强有力的预测指标：　　血液肿瘤突变负荷（bTMB）低于与高于6/7个突变每百万碱基的患者相比：

• 客观缓解率高7/14倍（50%比7%，P=0/015）
• 无进展生存长1/78倍（中位7/3比4/1个月，P=0/012）

　　体细胞等位基因突变率最大值（MSAF）低于与高于10%的患者相比：

• 客观缓解率高2/15倍（43%比20%）
• 无进展生存长2/93倍（中位7/9比2/7个月，P</0/001）

　　MSAF和bTMB都较低与都较高的患者相比：

• 客观缓解率高6/36倍（70%比11%，P</0/001）
• 无进展生存长3/79倍（中位11/0比2/9个月，P</0/001）

　　因此，该小样本初步研究结果表明，MSAF和bTMB＋MSAF可以作为将来研究和验证晚期三***性***腺癌患者免疫检查点***联合方案治疗效果的强有力预测指标。

Signal Transduct Target Ther/ 2023 Nov 17/8/429/ IF/ 39/3

Predictive biomarkers of response and survival following immunotherapy with a PD-L1 inhibitor benmelstobart (TQB2450) and antiangiogenic therapy with a VEGFR inhibitor anlotinib for pretreated advanced triple negative breast cancer/

Han Y/ Wang J/ Sun T/ Ouyang Q/ Li J/ Yuan J/ Xu B/

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital/ Chinese Academy of Medical Sciences and Peking Union Medical College/ Beijing/ China/ Liaoning Cancer Hospital &/ Institute/ Shenyang/ Liaoning/ China/ Hunan Cancer Hospital/ Changsha/ Hunan/ China/ Geneplus-Shenzhen/ Shenzhen/ China/

In our phase Ib trial (ClinialTrials/gov Identifier/ NCT03855358)/ benmelstobart (TQB2450)/ a novel humanized IgG1 antibody against PD-L1/ plus antiangiogenic multikinase inhibitor/ anlotinib/ demonstrated promising antitumor activities in pretreated triple negative breast cancer (TNBC) patients/ We conducted explorative analyses of genomic biomarkers to explore the associations with treatment response and survival outcomes/ Targeted next generation sequencing (NGS) was undertaken toward circulating tumor DNA (ctDNA) collected from peripheral blood samples prior to the start of treatment and after disease progression/ A total of 31 patients received targeted NGS and functional driver mutations in 29 patients were analyzed/ The most frequent mutations were TP53 (72%)/ MLL3 (28%)/ and PIK3CA (17%)/ At a blood-based tumor mutational burden (bTMB) cutoff of 6/7 mutations per megabase/ patients with low bTMB showed better response to anlotinib plus TQB2450 (50% vs/ 7%/ P = 0/015) and gained greater PFS benefits (7/3 vs/ 4/1 months/ P = 0/012) than those with high bTMB/ At a maximum somatic allele frequency (MSAF) cutoff of 10%/ a low MSAF indicated a better objective response (43% vs/ 20%) as well as a significantly longer median PFS (7/9 vs/ 2/7 months/ P </ 0/001)/ Patients with both low MSAF and low bTMB showed a notably better objective response to anlotinib plus TQB2450 (70% vs/ 11%/ P </ 0/001) and a significantly longer median PFS (11/0 vs/ 2/9 months/ P </ 0/001) than patients with other scenarios/ Our findings support future studes and validation of MSAF and the combined bTMB-MSAF classification as predictive biomarkers of immune checkpoint inhibitor-based regimens in advanced TNBC patients/

PMID/ 37973901

DOI/ 10/1038/s41392-023-01672-5

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