TY - JOUR
T1 - Multicohort Retrospective Validation of a Predictive Biomarker for Topoisomerase I Inhibitors
AU - Ando, Koji
AU - Ozonoff, Al
AU - Lee, Shin Yin
AU - Voisine, Michael
AU - Parker, Julian Taylor
AU - Nakanishi, Ryota
AU - Nishimura, Sho
AU - Yang, Jing
AU - Grace, Zhao
AU - Tran, Ben
AU - Diefenbach, Thomas J.
AU - Maehara, Yoshihiko
AU - Yasui, Hiroshi
AU - Irino, Tomoyuki
AU - Salgia, Ravi
AU - Terashima, Masanori
AU - Gibbs, Peter
AU - Ramanathan, Ramesh K.
AU - Oki, Eiji
AU - Mori, Masaki
AU - Kulke, Matthew
AU - Hartshorn, Kevan
AU - Bharti, Ajit
N1 - Funding Information:
The Department of Medicine, Boston University Medical School, and Boston University Office of Technology Development supported the publication. The authors also acknowledge the help of Neelabh Bharti for editorial work and for formatting the tables.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
KW - Colorectal cancer
KW - Gastric cancer
KW - IHC assay
KW - P-topoI-Dx
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U2 - 10.1016/j.clcc.2020.11.005
DO - 10.1016/j.clcc.2020.11.005
M3 - Article
C2 - 33731288
AN - SCOPUS:85102579648
SN - 1533-0028
VL - 20
SP - e129-e138
JO - Clinical Colorectal Cancer
JF - Clinical Colorectal Cancer
IS - 2
ER -
