Multicohort Retrospective Validation of a Predictive Biomarker for Topoisomerase I Inhibitors

Koji Ando, Al Ozonoff, Shin Yin Lee, Michael Voisine, Julian Taylor Parker, Ryota Nakanishi, Sho Nishimura, Jing Yang, Zhao Grace, Ben Tran, Thomas J. Diefenbach, Yoshihiko Maehara, Hiroshi Yasui, Tomoyuki Irino, Ravi Salgia, Masanori Terashima, Peter Gibbs, Ramesh K. Ramanathan, Eiji Oki, Masaki MoriMatthew Kulke, Kevan Hartshorn, Ajit Bharti

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Purpose: The camptothecin (CPT) analogs topotecan and irinotecan specifically target topoisomerase I (topoI) and are used to treat colorectal, gastric, and pancreatic cancer. Response rate for this class of drug varies from 10% to 30%, and there is no predictive biomarker for patient stratification by response. On the basis of our understanding of CPT drug resistance mechanisms, we developed an immunohistochemistry-based predictive test, P-topoI-Dx, to stratify the patient population into those who did and did not experience a response. Patients and Methods: The retrospective validation studies included a training set (n = 79) and a validation cohort (n = 27) of gastric cancer (GC) patients, and 8 cohorts of colorectal cancer (CRC) patient tissue (n = 176). Progression-free survival for 6 months was considered a positive response to CPT-based therapy. Formalin-fixed, paraffin-embedded slides were immunohistochemically stained with anti–phospho-specific topoI-Serine10 (topoI-pS10), quantitated, and analyzed statistically. Results: We determined a threshold of 35% positive staining to offer optimal test characteristics in GC. The GC (n = 79) training set demonstrated 76.6% (95% confidence interval, 64-86) sensitivity; 68.8% (41-88) specificity; positive predictive value (PPV) 92.5% (81-98); and negative predictive value (NPV) 42.3% (24-62). The GC validation set (n = 27) demonstrated 82.4% (56-95) sensitivity and 70.0% (35-92) specificity. Estimated PPV and NPV were 82.4% (56-95) and 70.0% (35-92) respectively. In the CRC validation set (n = 176), the 40% threshold demonstrated 87.5% (78-94) sensitivity; 70.0% (59-79) specificity; PPV 70.7% (61-79); and NPV 87.0 % (77-93). Conclusion: The analysis of retrospective data from patients (n = 282) provides clinical validity to our P-topoI-Dx immunohistochemical test to identify patients with disease that is most likely to respond to topoI inhibitors.

Original languageEnglish
Pages (from-to)e129-e138
JournalClinical Colorectal Cancer
Issue number2
Publication statusPublished - 2021 Jun


  • Colorectal cancer
  • Gastric cancer
  • IHC assay
  • P-topoI-Dx

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology


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