Multicohort Retrospective Validation of a Predictive Biomarker for Topoisomerase I Inhibitors

Area of Science:

• Oncology
• Cancer Biomarkers
• Drug Resistance

Background:

• Camptothecin (CPT) analogs, including topotecan and irinotecan, target topoisomerase I (topoI) and are used for colorectal, gastric, and pancreatic cancers.
• Current response rates for CPT drugs range from 10% to 30%, with no established predictive biomarker for patient selection.
• Understanding CPT drug resistance mechanisms is crucial for developing targeted therapeutic strategies.

Purpose of the Study:

• To develop and validate an immunohistochemistry-based predictive test, P-topoI-Dx, for stratifying patients based on their likelihood of responding to topoI inhibitors.
• To identify patients most likely to benefit from CPT-based therapies, thereby improving treatment efficacy.

Main Methods:

• Retrospective validation studies involved training (n=79) and validation (n=27) cohorts of gastric cancer (GC) patients, plus 8 colorectal cancer (CRC) cohorts (n=176).
• Progression-free survival of 6 months was the endpoint for positive response to CPT therapy.
• Immunohistochemistry was used to stain formalin-fixed, paraffin-embedded slides for phospho-specific topoI-Serine10 (topoI-pS10), followed by quantitative analysis.

Main Results:

• A threshold of 35% positive staining in GC demonstrated high sensitivity (76.6%) and specificity (68.8%) in the training set.
• The GC validation set showed 82.4% sensitivity and 70.0% specificity.
• In CRC cohorts, a 40% threshold yielded 87.5% sensitivity and 70.0% specificity, with a high negative predictive value (87.0%).

Conclusions:

• The P-topoI-Dx immunohistochemical test has demonstrated clinical validity in retrospective analyses of 282 patients.
• This test can effectively identify patients whose tumors are most likely to respond to topoisomerase I inhibitors.
• The P-topoI-Dx test offers a promising tool for patient stratification in CPT-based cancer therapy.