CirculatingTP53mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX

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.

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

“…We found that, the correlation coefficient r and the κ value for the concordance between mutations of the 5 most frequently mutated genes in matched tumor and blood samples ranged from 0.49 to 0.93 and from 0.48 to 0.76, respectively, which is in line with previous studies [ 41 , 64 ]. This suggests that mutations in ctDNA could well reflect and serve as surrogate for the mutations in the deriving tumor.…”

“…In this study, we found that in patients with mPDAC TP53 mutations in ctDNA at initial diagnosis and the third measurement but not in tumor predicted shorter OS, both in univariable and multivariable analyses, which is in line with a previous study [ 63 ]. TP53 -mutated ctDNA at baseline predicted early tumor progression in patients with PDAC receiving FOLFIRINOX chemotherapy [ 64 ]. Through both univariable and multivariable analyses, we also revealed that high CDKN2A and SMAD4 mutation abundances in ctDNA but not in tumor and high ARID1A mutation abundances in both ctDNA and tumor at baseline and/or the second measurement were linked to inferior OS and/or PFS.…”

“…As of now, FOLFIRINOX or gemcitabine in combination with albumin-bound paclitaxel represents the mainstream chemotherapy for advanced/metastatic pancreatic cancer. van der Sijde et al [ 64 ] reported that in 48 patients with PDACs of all stages, TP53 ctDNA mutation before FOLFIRINOX was linked to early tumor progression in multivariable analysis. Wei et al [ 36 ] showed that in 38 patients with advanced PDAC receiving first-line FOLFIRINOX treatment, the mutant allele fraction for altered loci in ctDNA before treatment correlated with cancer stage, metastatic burden, and OS.…”

“…In this prospective study specifically focusing on patients with metastatic PDAC receiving NPS treatment, we adopted novel sensitive thresholds for ctDNA and first analyzed the significance of mutations with high abundance versus those with low/no abundance, and the findings might not be easily integrated with previous researches [ 36 , 48 , 51 , 64 , 76 , 81 – 84 ] mostly analyzing mutation versus non-mutation in ctDNA and/or focusing on patients with resected PDAC receiving neoadjuvant and/or adjuvant chemotherapy. Few studies had a study design similar to ours.…”

Overexpression of CENPL mRNA potentially regulated by miR-340-3p predicts the prognosis of pancreatic cancer patients

“…The pathogenesis, early diagnosis and precise treatment remain challenging. Studies have revealed that TP53 mutation occurred in approximately 70% of patients with PAAD and was one of the major factors involved in development and progression of PAAD [ 28 – 31 ]. In this study, CENPL was rarely mutated in PAAD.…”