High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study

Abstract

Aims We previously showed that the nab-paclitaxel plus S-1 (NPS) regimen had promising effects against metastatic pancreatic ducal adenocarcinoma (mPDAC), whose efficacy however could not be precisely predicted by routine biomarkers. This prospective study aimed to investigate the values of mutations in circulating tumor DNA (ctDNA) and their dynamic changes in predicting response of mPDAC to NPS chemotherapy. Methods Paired tumor tissue and blood samples were prospectively collected from patients with mPDAC receiving first-line NPS chemotherapy, and underwent next-generation sequencing with genomic profiling of 425 genes for ctDNA. High mutation allelic frequency (MAF) was defined as ≥ 30% and ≥ 5% in tumor tissue and blood, respectively. Kappa statistics were used to assess agreement between mutant genes in tumor and ctDNA. Associations of mutations in ctDNA and their dynamic changes with tumor response, overall survival (OS), and progression-free survival (PFS) were assessed using the Kaplan–Meier method, multivariable-adjusted Cox proportional hazards regression, and longitudinal data analysis. Results 147 blood samples and 43 paired tumor specimens from 43 patients with mPDAC were sequenced. The most common driver genes with high MAF were KRAS (tumor, 35%; ctDNA, 37%) and TP53 (tumor, 37%; ctDNA, 33%). Mutation rates of KRAS and TP53 in ctDNA were significantly higher in patients with liver metastasis, with baseline CA19-9 ≥ 2000 U/mL, and/or without an early CA19-9 response. κ values for the 5 most commonly mutated genes between tumor and ctDNA ranged from 0.48 to 0.76. MAFs of the genes mostly decreased sequentially during subsequent measurements, which significantly correlated with objective response, with an increase indicating cancer progression. High mutations of KRAS and ARID1A in both tumor and ctDNA, and of TP53, CDKN2A, and SMAD4 in ctDNA but not in tumor were significantly associated with shorter survival. When predicting 6-month OS, AUCs for the 5 most commonly mutated genes in ctDNA ranged from 0.59 to 0.84, larger than for genes in tumor (0.56 to 0.71) and for clinicopathologic characteristics (0.51 to 0.68). Repeated measurements of mutations in ctDNA significantly differentiated survival and tumor response. Among the 31 patients with ≥ 2 ctDNA tests, longitudinal analysis of changes in gene MAF showed that ctDNA progression was 60 and 58 days ahead of radiologic and CA19-9 progression for 48% and 42% of the patients, respectively. Conclusions High mutations of multiple driving genes in ctDNA and their dynamic changes could effectively predict response of mPDAC to NPS chemotherapy, with promising reliable predictive performance superior to routine clinicopathologic parameters. Inspiringly, longitudinal ctDNA tracking could predict disease progression about 2 months ahead of radiologic or CA19-9 evaluations, with the potential to precisely devise individualized therapeutic strategies for mPDAC.

THZ1: Towards KRAS mutation‐based precision medicine against pancreatic ductal adenocarcinoma

“…2 Genetic analyses have revealed that KRAS mutation importantly drives the pathogenesis of PDAC, prompting an increasing number of investigations into the potential of targeted therapies addressing this genetic alteration. 3,4 Recent advances in molecular targeted therapies, in particular Cyclin Dependent Kinase inhibitors, have shown promise in preclinical studies. 5,6 The recent study by Huang et al 7 presented a compelling application for the targeted agent THZ1, a smallmolecule covalent CDK7/12/13 inhibitor, and provided intriguing insights into its efficacy.…”

“…It is also critical to investigate the long-term safety and efficacy of THZ1 and its impact on patient quality of life. The development of liquid biopsy biomarkers that predict response to THZ1 with high specificity is necessary for pancreatic cancer, 3 which can help with the development of personalized therapeutic regi-mens. The understanding of the mechanism of action of THZ1 should also be further enhanced through molecularlevel experiments, to identify the key genes and proteins that are altered following THZ1 treatment.…”