Germline variants in cancer-predisposing genes in pancreatic cancer patients with a family history of cancer
Germline variants in cancer-predisposing genes in pancreatic cancer patients with a family history of cancer
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有癌症家族史的胰腺癌患者中癌症易感基因的种系变异
DOI：
10.1093/jjco/hyac110
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发表时间：
2022
影响因子：
2.4
通讯作者：
Furuse Junji
中科院分区：
文献类型：
--
作者：
Terashima Takeshi;Morizane Chigusa;Ushiama Mineko;Shiba Satoshi;Takahashi Hideaki;Ikeda Masafumi;Mizuno Nobumasa;Tsuji Kunihiro;Yasui Kohichiroh;Azemoto Nobuaki;Satake Hironaga;Nomura Shogo;Yachida Shinichi;Sugano Kokichi;Furuse Junji
背景我们的第二阶段试验（FABRIC研究）未能验证吉西他滨加奥沙利铂（GEMOX）在有胰腺癌、乳腺癌、卵巢癌或前列腺癌家族史或个人史的胰腺导管腺癌（PDAC）患者中的疗效，这表明家族和个人病史可能不足以确定对铂的反应-该辅助分析旨在研究同源重组修复（HRR）的生殖系变异的患病率。相关基因，并阐明生殖系变异与GEMOX疗效和PDAC患者预后的关系。在FABRIC研究的45例患者中，27例患者登记在此辅助analysis.ResultsOf识别的变异在HR相关基因，一个变异被认为是致病性的，在6例患者（22%）的8个变异的变异意义不明（VUS）。GEMOX的客观反应在7名患者中达到43%，并且倾向于高于没有此类变体的患者（25%）。HRR相关基因的致病/VUS变异是一个独立的有利因素，无进展生存期（风险比，0.322;P= 0.047）和总生存期（风险比，0.195;P= 0.023）在多变量analysis.ConclusionsThe生殖系变异的患病率在PDAC患者是非常低的，即使在患者的家族/个人历史的胰腺癌，乳腺癌，卵巢癌或前列腺癌。在HRR相关基因中存在一个或多个种系变异的患者被归类为致病性或VUS，可能有可能获得对GEMOX更好的应答，并获得更好的结局。
BackgroundOur phase II trial (FABRIC study) failed to verify the efficacy of gemcitabine plus oxaliplatin (GEMOX) in patients with pancreatic ductal adenocarcinoma (PDAC) with a familial or personal history of pancreatic, breast, ovarian or prostate cancer, which suggested that a family and personal history may be insufficient to determine response to platinum-based chemotherapy.MethodsThis ancillary analysis aimed to investigate the prevalence of germline variants of homologous recombination repair (HRR)-related genes and clarify the association of germline variants with the efficacy of GEMOX and patient outcome in PDAC patients. Of 45 patients enrolled in FABRIC study, 27 patients were registered in this ancillary analysis.ResultsOf the identified variants in HRR-related genes, one variant was considered pathogenic and eight variants in six patients (22%) were variants of unknown significance (VUS). Objective response to GEMOX was achieved by 43% of the seven patients and tended to be higher than that of patients without such variants (25%). Pathogenic/VUS variant in HRR-related genes was an independent favorable factor for progression-free survival (hazard ratio, 0.322;P= 0.047) and overall survival (hazard ratio, 0.195;P= 0.023) in multivariable analysis.ConclusionsThe prevalence of germline variants in PDAC patients was very low even among patients with a familial/personal history of pancreatic, breast, ovarian or prostate cancer. Patients with one or more germline variants in HRR-related genes classified as pathogenic or VUS may have the potential to obtain better response to GEMOX and have better outcomes.