循环肿瘤 DNA 中 BRCA 和 ATM 突变状态在晚期胰腺癌治疗选择中的临床应用。
Clinical utility of BRCA and ATM mutation status in circulating tumour DNA for treatment selection in advanced pancreatic cancer.
发表日期：2024 Aug 28
作者：
Kentaro Sudo, Yoshiaki Nakamura, Makoto Ueno, Masayuki Furukawa, Nobumasa Mizuno, Yasuyuki Kawamoto, Naohiro Okano, Kumiko Umemoto, Akinori Asagi, Masato Ozaka, Koushiro Ohtsubo, Satoshi Shimizu, Nobuhisa Matsuhashi, Shinji Itoh, Toshihiko Matsumoto, Taroh Satoh, Hiroyuki Okuyama, Masahiro Goto, Hiroko Hasegawa, Yoshiyuki Yamamoto, Justin I Odegaard, Hideaki Bando, Takayuki Yoshino, Masafumi Ikeda, Chigusa Morizane
来源：
BRITISH JOURNAL OF CANCER
摘要：
同源重组缺陷（HRD）的鉴定仍然是晚期胰腺癌（APC）的一个挑战。我们研究了循环肿瘤 DNA (ctDNA) 分析在评估 BRCA1/2 和 ATM 突变状态以及 APC 治疗选择中的效用。我们分析了 GOZILA 中纳入的 702 名 APC 患者的临床和 ctDNA 数据，GOZILA 是一项使用 Guardant360 的 ctDNA 分析研究分别在 4.8%（推定种系，3.7%）和 4.4%（推定种系，0.9%）的患者中检测到失活 BRCA1/2 和 ATM 突变。推定种系 BRCA1/2 (gBRCA) 突变的患者对含铂化疗的客观缓解 (63.2% vs. 16.2%) 和 PFS (HR 0.55, 95% CI 0.32-0.93) 明显优于无突变患者。相比之下，假定的 gBRCA 突变对吉西他滨联合白蛋白结合型紫杉醇的疗效没有影响。在 2 名接受含铂治疗的患者中，检测到推定的 BRCA2 回复突变。七名患有体细胞 BRCA 突变的患者中，有三名对含铂疗法有反应，而四名具有推定种系 ATM 突变的患者中只有一名有反应。三分之一的体细胞 ATM 突变发生在与克隆造血相关的基因组位点。全面的 ctDNA 分析提供了有关 HRD 状态的临床相关信息。它可以成为 APC 中 HRD 筛查的实用、方便的选择。© 2024。作者，获得 Springer Nature Limited 的独家许可。
Identification of homologous recombination deficiency (HRD) remains a challenge in advanced pancreatic cancer (APC). We investigated the utility of circulating tumour DNA (ctDNA) profiling in the assessment of BRCA1/2 and ATM mutation status and treatment selection in APC.We analysed clinical and ctDNA data of 702 patients with APC enroled in GOZILA, a ctDNA profiling study using Guardant360.Inactivating BRCA1/2 and ATM mutations were detected in 4.8% (putative germline, 3.7%) and 4.4% (putative germline, 0.9%) of patients, respectively. Objective response (63.2% vs. 16.2%) and PFS (HR 0.55, 95% CI 0.32-0.93) on platinum-containing chemotherapy were significantly better in patients with putative germline BRCA1/2 (gBRCA) mutation than those without. In contrast, putative gBRCA mutation had no impact on the efficacy of gemcitabine plus nab-paclitaxel. In 2 patients treated with platinum-containing therapy, putative BRCA2 reversion mutations were detected. Three of seven patients with somatic BRCA mutations responded to platinum-containing therapy, while only one of four with putative germline ATM mutations did. One-third of somatic ATM mutations were in genomic loci associated with clonal haematopoiesis.Comprehensive ctDNA profiling provides clinically relevant information regarding HRD status. It can be a practical, convenient option for HRD screening in APC.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.