Abstract
Background:Biomarkers predicting treatment response may be used to stratify pancreatic ductal adenocarcinoma (PDAC) patients for therapy. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations that associate with tumor progression during FOLFIRINOX chemotherapy, and overall survival (OS).Methods:Circulating cell-free DNA was analyzed with a 57 gene next-generation sequencing panel using plasma samples of 48 PDAC patients of all disease stages. Patients received FOLFIRINOX as initial treatment. Chemotherapy response was determined on CT scans as disease control (n = 30) or progressive disease (n = 18) within eight cycles of FOLFIRINOX, based on RECIST 1.1 criteria.Results:Detection of a TP53 ctDNA mutation before start of FOLFIRINOX [odds ratio (OR) 10.51, 95% confidence interval (CI) 1.40–79.14] and the presence of a homozygous TP53 Pro72Arg germline variant (OR 6.98, 95% CI 1.31–37.30) were predictors of early tumor progression during FOLFIRINOX in multivariable analysis. Five patients presented with the combination of a TP53 ctDNA mutation before start of FOLFIRINOX and the homozygous Pro72Arg variant. All five patients showed progression during FOLFIRINOX. The combination of the TP53 mutation and TP53 germline variant was associated with shorter survival (median OS 4.4 months, 95% CI 2.6–6.2 months) compared with patients without any TP53 alterations (median OS 13.0 months, 95% CI 8.6–17.4 months).Conclusion:The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort.
Highlights
Some advances have been made in the treatment of pancreatic ductal adenocarcinoma (PDAC), the prognosis of patients remains very poor.[1,2] The standard first-line treatment for locally advanced pancreatic cancer (LAPC) and metastatic PDAC is FOLFIRINOX chemotherapy, a combination of fluorouracil, leucovorin, Fleur van der Sijde Bas Groot Koerkamp Quisette P
Patient characteristics In total, Circulating cell-free DNA (ccfDNA) isolated from plasma from 48 patients was sequenced both before and after the first cycle of FOLFIRINOX, resulting in 96 samples
CtDNA detection In disease control patients ccfDNA concentrations increased from 6.32 ng/ml plasma [interquartile range (IQR) 4.15–14.73 ng/ml plasma] before start of FOLFIRINOX to 14.25 ng/ml plasma (IQR 8.57–21.58 ng/ml plasma, p = 0.028) after one cycle of FOLFIRINOX
Summary
Some advances have been made in the treatment of pancreatic ductal adenocarcinoma (PDAC), the prognosis of patients remains very poor.[1,2] The standard first-line treatment for locally advanced pancreatic cancer (LAPC) and metastatic PDAC is FOLFIRINOX chemotherapy, a combination of fluorouracil, leucovorin, Fleur van der Sijde Bas Groot Koerkamp Quisette P. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations that associate with tumor progression during FOLFIRINOX chemotherapy, and overall survival (OS). Five patients presented with the combination of a TP53 ctDNA mutation before start of FOLFIRINOX and the homozygous Pro72Arg variant. Conclusion: The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort
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