Circulating tumor and invasive cell expression profiling predicts effective therapy in pancreatic cancer

Cancer. 2022 Aug 1;128(15):2958-2966. doi: 10.1002/cncr.34269. Epub 2022 Jun 1.

Abstract

Background: Pancreatic adenocarcinoma (PDAC) remains a refractory disease; however, modern cytotoxic chemotherapeutics can induce tumor regression and extend life. A blood-based, pharmacogenomic, chemosensitivity assay using gene expression profiling of circulating tumor and invasive cells (CTICs) to predict treatment response was previously developed. The combination regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel (G/nab-P) are established frontline approaches for treating advanced PDAC; however, there are no validated biomarkers for treatment selection. A similar unmet need exists for choosing second-line therapy.

Methods: The chemosensitivity assay was evaluated in metastatic PDAC patients presenting for frontline treatment. A prospective study enrolled patients (n = 70) before receiving either FOLFIRINOX or G/nab-P at a 1:1 ratio. Six milliliters of peripheral blood was collected at baseline and at time of disease progression. CTICs were isolated, gene-expression profiling was performed, and the assay was used to predict effective and ineffective chemotherapeutic agents. Treating physicians were blinded to the assay prediction results.

Results: Patients receiving an effective regimen as predicted by the chemosensitivity assay experienced significantly longer median progression-free survival (mPFS; 7.8 months vs. 4.2 months; hazard ratio [HR], 0.35; p = .0002) and median overall survival (mOS; 21.0 months vs. 9.7 months; HR, 0.40; p = .005), compared with an ineffective regimen. Assay prediction for effective second-line therapy was explored. The entire study cohort experienced favorable outcomes compared with historical controls, 7.1-month mPFS and 12.3-month mOS.

Conclusions: Chemosensitivity assay profiling is a promising tool for guiding therapy in advanced PDAC. Further prospective validation is under way (clinicaltrials.gov NCT03033927).

Keywords: chemotherapy; circulating tumor and invasive cells; gene expression modeling; pancreatic cancer; personalized medicine.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma* / drug therapy
  • Adenocarcinoma* / genetics
  • Albumins
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Deoxycytidine
  • Fluorouracil
  • Humans
  • Leucovorin
  • Paclitaxel
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Prospective Studies

Substances

  • Albumins
  • Deoxycytidine
  • Paclitaxel
  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Pancreatic Carcinoma

Associated data

  • ClinicalTrials.gov/NCT03033927