Multicohort Retrospective Validation of a Predictive Biomarker for Topoisomerase I Inhibitors
| Autor: | Yoshihiko Maehara, Masaki Mori, Julian Taylor Parker, Eiji Oki, Zhao Grace, Thomas J. Diefenbach, Ravi Salgia, Michael Voisine, Sho Nishimura, Jing Yang, Ramesh K. Ramanathan, Tomoyuki Irino, Shin Yin Lee, Ryota Nakanishi, Ben Tran, Ajit Bharti, Masanori Terashima, Hiroshi Yasui, Peter Gibbs, Matthew H. Kulke, Kevan L. Hartshorn, Al Ozonoff, Koji Ando |
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| Rok vydání: | 2020 |
| Předmět: |
Oncology
Male medicine.medical_specialty Colorectal cancer Antineoplastic Agents Risk Assessment 03 medical and health sciences 0302 clinical medicine Stomach Neoplasms Pancreatic cancer Internal medicine medicine Biomarkers Tumor Humans Predictive testing Retrospective Studies business.industry Gastroenterology Cancer Middle Aged medicine.disease Confidence interval Progression-Free Survival Irinotecan Pancreatic Neoplasms DNA Topoisomerases Type I 030220 oncology & carcinogenesis 030211 gastroenterology & hepatology Topotecan business Colorectal Neoplasms Camptothecin medicine.drug |
| Zdroj: | Clinical colorectal cancer. 20(2) |
| ISSN: | 1938-0674 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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