Cell-free DNA Predicts Prolonged Response to Multi-agent Chemotherapy in Pancreatic Ductal Adenocarcinoma.

Abstract

The treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) is frequently characterized by significant toxicity and rapid development of resistance to current approved therapies. More reliable biomarkers of response are needed to guide clinical decision making. We evaluated cell-free DNA (cfDNA) using a tumor-agnostic platform and traditional biomarkers (CEA and CA19-9) levels in 12 patients treated at Johns Hopkins University on NCT02324543 "Study of Gemcitabine/Nab-Paclitaxel/Xeloda (GAX) in Combination With Cisplatin and Irinotecan in Subjects With Metastatic Pancreatic Cancer." The pretreatment values, levels after 2 months of treatment, and change in biomarker levels with treatment were compared with clinical outcomes to determine their predictive value. The variant allele frequency (VAF) of KRAS and TP53 mutations in cfDNA after 2 months of treatment was predictive of progression-free survival (PFS) and overall survival (OS). In particular, patients with a lower-than-average KRAS VAF after 2 months of treatment had a substantially longer PFS than patients with higher posttreatment KRAS VAF (20.96 vs. 4.39 months). Changes in CEA and CA19-9 after 2 months of treatment were also good predictors of PFS. Comparison via concordance index demonstrated KRAS or TP53 VAF after 2 months of treatment to be better predictors of PFS and OS than CA19-9 or CEA. This pilot study requires validation but suggests cfDNA measurement is a useful adjunct to traditional protein biomarkers and imaging evaluation and could distinguish between patients who are likely to achieve prolonged responses versus those that will have early progression and may benefit from a change in treatment approach.

Significance:

We report on the association of cfDNA with response durability for patients undergoing treatment with a novel metronomic chemotherapy regimen (gemcitabine, nab-paclitaxel, capecitabine, cisplatin, irinotecan; GAX-CI) for metastatic PDAC. This investigation offers encouraging evidence that cfDNA may prove to be a valuable diagnostic tool to guide clinical management.

• Authors: Eric S Christenson, Su Jin Lim, Jennifer Durham, Ana De Jesus-Acosta, Katherine Bever, Daniel Laheru, Amy Ryan, Parul Agarwal, Robert B Scharpf, Dung T Le, Hao Wang
• Journal: Cancer research communications (Cancer Res Commun) Vol. 2 Issue 11 Pg. 1418-1425 (11 2022) ISSN: 2767-9764 [Electronic] United States
• PMID: 36970054 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Irinotecan
• Cisplatin
• Deoxycytidine
• Cell-Free Nucleic Acids
• CA-19-9 Antigen
• Proto-Oncogene Proteins p21(ras)
• Capecitabine

Topics

• Humans
• Irinotecan (therapeutic use)
• Cisplatin (therapeutic use)
• Deoxycytidine (therapeutic use)
• Cell-Free Nucleic Acids (genetics)
• CA-19-9 Antigen (therapeutic use)
• Pilot Projects
• Proto-Oncogene Proteins p21(ras) (genetics)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Pancreatic Neoplasms (drug therapy)
• Carcinoma, Pancreatic Ductal (drug therapy)
• Capecitabine