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. 2023 Apr;128(8):1603-1608.
doi: 10.1038/s41416-023-02189-y. Epub 2023 Feb 13.

Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer

Kumiko Umemoto  1 , Yu Sunakawa  2 , Makoto Ueno  3 , Masayuki Furukawa  4 , Nobumasa Mizuno  5 , Kentaro Sudo  6 , Yasuyuki Kawamoto  7 , Takeshi Kajiwara  8 , Koushiro Ohtsubo  9 , Naohiro Okano  10 , Nobuhisa Matsuhashi  11 , Shinji Itoh  12 , Toshihiko Matsumoto  13 , Satoshi Shimizu  14 , Toru Otsuru  15 , Hiroko Hasegawa  16 , Hiroyuki Okuyama  17 , Hideko Ohama  18 , Toshikazu Moriwaki  19 , Takashi Ohta  20 , Justin I Odegaard  21 , Yoshiaki Nakamura  22   23 , Hideaki Bando  22 , Takayuki Yoshino  22 , Masafumi Ikeda  24 , Chigusa Morizane  25
Affiliations

Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer

Kumiko Umemoto et al. Br J Cancer. 2023 Apr.

Abstract

Background: Liquid biopsy is an alternative to tissue specimens for tumour genotyping. However, the frequency of genomic alterations with low circulating-tumour DNA (ctDNA) shedding is shown in pancreatic ductal adenocarcinoma (PDAC). We, therefore, investigated the prevalence of KRAS mutations and ctDNA fraction by the metastatic site in patients with PDAC.

Methods: This study enrolled previously treated PDAC patients from a plasma genomic profiling study; ctDNA analysis was performed using Guardant360 at disease progression before initiating subsequent treatment.

Results: In 512 patients with PDAC, KRAS mutations were detected in 57%. The frequency of KRAS mutation in ctDNA differed depending on the metastatic organ; among patients with single-organ metastasis (n = 296), KRAS mutation detection rate was significantly higher in patients with metastasis to the liver (78%). In addition, the median maximum variant allele frequency (VAF) was higher with metastasis to the liver (1.9%) than with metastasis to the lungs, lymph nodes, peritoneum or with locally advanced disease (0.2%, 0.4%, 0.2% and 0.3%, respectively).

Conclusion: The prevalence of KRAS mutations and maximum VAF were higher in patients with metastasis to the liver than in those with metastasis to other sites. This study indicated the clinical utility of ctDNA analysis, especially in PDAC with liver metastases.

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Conflict of interest statement

MF, KO, N Matsuhashi, SI, T Matsumoto, T Otsuru, HH, H Okuyama and H Ohama have nothing to disclose. KU reports honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical and Yakult Honsha. YS reports honoraria from Takeda Pharmaceutical, Eli Lilly Japan, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, Bayer, Daiichi Sankyo and Merck Biopharma; and grants from IQVIA and Parexel; and contributions or endowed chair from Takeda Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan, Sanofi and EN Otsuka Pharma. MU reports grants and personal fees from Taiho Pharmaceutical, AstraZeneca, Merck Biopharma, MSD, Ono Pharmaceutical, Incyte Corporation and Chugai Pharmaceutical; and personal fees from Nihon Servier; and grants from Astellas Pharma, Eisai and DFP. N Mizuno reports grants and personal fees from AstraZeneca, Novartis, Yakult Honsha, Ono Pharmaceutical, Taiho Pharmaceutical; and grants from MSD, Dainippon Sumitomo Pharma, ASLAN Pharmaceuticals, Incyte Corporation. and Seagen; and personal fees from Teijin Pharma, FUJIFILM Toyama Chemical, outside the submitted work. KS reports honoraria from Ono Pharmaceutical and Yakult Honsha; and grants (for the institution) from Bristol-Myers Squibb/Ono Pharmaceutical, Eisai and Incyte corporation. YK reports honoraria from Taiho Pharmaceutical, Incyte, Merck Biopharma, Yakult Honsha, and Eli Lilly; and grants from Takeda Pharmaceutical. TK reports honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical and Eli Lilly. NO reports honoraria from Taiho Pharmaceutical, Eli Lilly, Eisai, Bayer Yakuhin, Chugai Pharmaceutical, Ono Pharmaceutical and Takeda Pharmaceutical; and advisory board from GlaxoSmithKline. SS reports grants from AstraZeneca, Incyte Corporation and Delta-Fly Pharma. T Moriwaki reports honoraria from Taiho Pharmaceutical, Eli Lilly Japan, Takeda Pharmaceutical, Chugai Pharmaceutical, Sanofi, Bayer Yakuhin, Merck Biopharma, Ono Pharmaceutical and Yakult Honsha; and grants from Taiho Pharmaceutical, MSD, Takeda Pharmaceutical, and Yakult Honsha. T Ohta reports honoraria from Chugai Pharmaceutical, Teijin Pharma, Takeda Pharmaceutical, Eisai, Yakult-Honsha, Daiichi Sankyo, Merck Biopharma, Ono Pharmaceutical, Taiho Pharmaceutical and Bristol-Myers Squibb; and grants from Takeda Pharmaceutical. JIO reports from, and stock interests in, Guardant Health. YN reports grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Guardant Health, Genomedia, Daiichi Sankyo, Seagen, Roche Diagnostics. HB reports honoraria from Taiho Pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical; and grants from Ono Pharmaceutical outside the submitted work. TY reports honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical and MSD; and grants from Ono Pharmaceutical, Sanofi, Daiichi Sankyo, Parexel International, Pfizer Japan, Taiho Pharmaceutical, MSD, Amgen, Genomedia, Sysmex, Chugai Pharmaceutical and Nippon Boehringer Ingelheim. MI reports honoraria from Bayer, Bristol-Myers Squibb, Eli Lilly, Eisai, Sumitomo Dainippon Pharma, EA Pharma, Teijin Pharma, Yakult Honsha, Taiho Pharmaceutical, Otsuka, MSD, Mylan, Nihon Servier, Chugai Pharmaceutical, AstraZeneca, AbbVie, Abbott, Takeda, Novartis and Astellas Pharma; and advisory roles with Bayer, Eli Lilly, Eisai, Chugai Pharmaceutical, AstraZeneca, Takeda Pharmaceutical, Ono Pharmaceutical, GlaxoSmithKline and Nihon Servier; and grants from Bayer, Bristol-Myers Squibb, Eli Lilly, Eisai, Takeda Pharmaceutical, AstraZeneca, Chugai Pharmaceutical, Merck Biopharma, ASLAN Pharmaceuticals, Novartis, Yakult Honsha, Taiho Pharmaceutical, Ono Pharmaceutical, MSD, Merus N.V., Nihon Servier, Pfizer, Chiome Bioscience, Delta-Fly Pharma, and J-Pharma. CM reports honoraria from Nihon Servier, Novartis, Yakult Honsha, Teijin Pharma, Taiho Pharmaceutical, Eisai and MSD; advisory roles with Yakult Honsha, Novartis, Servier, Taiho Pharmaceutical and Abbvie; and grants from Eisai, Yakult Honsha, Ono Pharmaceutical, Taiho Pharmaceutical, J-Pharma, Daiichi Sankyo, HITACHI, AstraZeneca and Merck Biopharma.

Figures

Fig. 1
Fig. 1. Genomic alterations identified with ctDNA analysis in patients with PDAC.
Overall frequency of genomic alterations (n = 512) (a). The distribution of KRAS mutation, RAS wild-type and no alterations (b). ctDNA, circulating DNA, PDAC pancreatic ductal adenocarcinoma, SNV single-nucleotide variant, HRD homologous recombination deficiency.
Fig. 2
Fig. 2. The maximum VAF (%) and frequencies of the detection of KRAS mutation in ctDNA in patients with metastasis to a single site (n = 296).
Left and right box plots represent the maximum VAF in all patients and patients with KRAS mutation in ctDNA according to each metastatic site, respectively. Max VAF maximum variant allele frequency, KRAS mt KRAS mutation. *Max VAF calculated in population excluded germline mutation. **In GOZILA study, we define subclonal with the clonality as ≤0.3 and set the cut-off value of max VAF as 0.6%. ***Kruskal–Wallis test.
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