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Multicohort Retrospective Validation of a Predictive Biomarker for Topoisomerase I Inhibitors
Koji Ando1, Al Ozonoff2, Shin-Yin Lee3
1Division of Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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.
Insights
A new immunohistochemistry test, P-topoI-Dx, can predict patient response to topoisomerase I (topoI) inhibitors like irinotecan and topotecan for colorectal and gastric cancers.
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.
