Preoperative detection of KRAS G12D mutation in ctDNA is a powerful predictor for early recurrence of resectable PDAC patients

Abstract

BACKGROUND: About 25-37% of resectable pancreatic ductal adenocarcinoma (PDAC) had a great chance of early recurrence after radical resection, which is mainly due to preoperative micrometastasis. We herein demonstrated the profiles of ctDNA in resectable PDAC and use of ctDNA to identify patients with potential micrometastasis. METHODS: A total of 113 and 44 resectable PDACs were enrolled in discovery and validation cohorts, separately. A panel containing 50 genes was used to screen ctDNA by an NGS-based assessment with high specificity. RESULTS: In the discovery cohort, the overall detection rate was 38.05% (43/113). Among positive ctDNA, KRAS mutation had the highest detection rate (23.01%, 26/113), while the others were <5%. Survival analysis showed that plasma KRAS mutations, especially KRAS G12D mutation, had significant association with OS and RFS of resectable PDAC. Plasma KRAS G12D mutation showed a strong correlation with early distant metastasis. In the validation cohort, survival analysis showed similar association between plasma KRAS G12D mutation and poor outcomes. CONCLUSIONS: This study demonstrated that plasma KRAS mutations, especially KRAS G12D mutation, served as a useful predictive biomarker for prognosis of resectable PDAC. More importantly, due to high correlation with micrometastasis, preoperative detection of plasma KRAS G12D mutation helps in optimising surgical selection of resectable PDAC.

Prognostic value of circulating tumor DNA in pancreatic cancer: a systematic review and meta-analysis

“…A total of 33 studies were excluded according to the inclusion and exclusion criteria. Thus, a total of 25 eligible studies that included 2326 patients were enrolled in this meta-analysis [ 18 – 42 ]. The characteristics of the included studies are summarized in Table 1 .…”

“…All of the included studies had OS outcomes, while 5 of them had PFS prognostic data [ 21 , 28 , 32 , 35 , 36 ]. Seven studies included patients with PC of all stages (stage: I - IV) [ 23 – 26 , 29 , 32 , 33 ], 8 studies included patients with resectable PC (stage: I - II) [ 21 , 22 , 27 , 31 , 35 , 37 , 38 , 42 ], and 12 studies included patients with advanced PC (stage: III - IV) [ 18 – 20 , 22 , 28 , 30 , 31 , 34 , 36 , 39 – 41 ]. All of the included studies sampled at baseline, and 4 of them had postoperative data [ 21 , 31 , 35 , 38 ].…”

“…Several studies have reported that a type of K-ras mutations, the K-ras G12V mutation, is an independent prognostic factor in PC [ 19 , 25 , 35 ]. Cheng et al [ 20 ] and Guo et al [ 42 ] showed that the K-ras G12D mutation also has a significant prognostic value, although Kinugasa et al [ 25 ] suggested that there is no significant association between the K-ras G12D mutation and OS in PC patients. According to the results of this meta-analysis, we considered that the detection of the K-ras G12D mutation is a significant prognostic factor in PC (HR = 1.77; 95% CI, 1.22-2.58, I 2 = 55.6%), although more studies are needed to further confirm this finding.…”

Meta-analysis of the studies dedicated to the predictive significance of circulating tumor DNA in pancreatic cancer

“…Однако частота обнаружения mKRAS цДНК в данном исследовании с помощью метода цифровой капельной ПЦР составила всего 26% (8/31), при этом в большинстве случаев цоДНК выявлялась при метастатическом процессе [10]. В нескольких исследованиях для выявления цоДНК применяли мультигенные панели [14,16,21,23], в то время как в остальных исследованиях цоДНК определялась по наличию мутаций в гене KRAS. В когорте 118 пациентов с метастатическим РПЖ независимыми факторами, связанными с ОВ, оказались мутация KRAS G12V (p=0,019, ОР 1,45), а также мутация в 17 экзоне гена ERBB2 (р=0,035, ОВ 1,61), уровень CA19-9 (p=0,022, ОР 0,71), CA-125 (p=0,007, ОР 0,62), проведение химиотерапии (p=0,011, ОР 0,52) и количество метастазов (p=0,023, ОР 0,67) [4].…”

“…Также уровень цоДНК после операции был повышен в случае нерадикально выполненной операции [19,26]. Другой возможной причиной наличия цоДНК после операции может быть наличие микрометастазов, не выявляемых традиционными методами лучевой диагностики [23].…”