Clinical utility of BRCA and ATM mutation status in circulating tumour DNA for treatment selection in advanced pancreatic cancer

期刊论文
发表日期：

2024年8月28日

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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

摘要

Background

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.

Methods

We analysed clinical and ctDNA data of 702 patients with APC enroled in GOZILA, a ctDNA profiling study using Guardant360.

Results

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.

Conclusion

Comprehensive ctDNA profiling provides clinically relevant information regarding HRD status. It can be a practical, convenient option for HRD screening in APC.