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Multiple drug resistance in osteogenic sarcoma: INT0133 from the Children's Oncology Group
Cindy L Schwartz1, Richard Gorlick, Lisa Teot
1Hasbro Children's Hospital/Brown Medical School, Providence, RI 02903, USA. cschwartz1@lifespan.org
Purpose:
Multiple drug resistance due to P-glycoprotein (P-gp) expression has been reported to be a cause of disease recurrence in osteosarcoma. Tumor specimens derived from children and young adults with osteosarcoma enrolled onto a national Intergroup trial (INT0133) were analyzed prospectively to determine the role of multiple drug resistance in osteosarcoma.
Patients And Methods:
From October 15, 1992, to November 25, 1997, 685 patients with localized, high-grade osteosarcoma were enrolled onto INT0133. Paraffin-embedded diagnostic tumor specimens were assayed for P-gp using monoclonal antibodies C-494 (139 patients) and JSB-1 (133 patients). Percent necrosis at the time of definitive surgery (NEC), event-free survival (EFS), and overall survival (OS) were evaluated as outcome measures for patients with P-gp-positive disease and were compared with patients with P-gp-negative disease.
Results:
P-gp expression in the biopsy specimen did not significantly increase the risk for adverse outcomes as measured by EFS, OS, or NEC. EFS for those patients with C-494-positive tumors was 59% at 4 years versus 61% at 4 years for patients with C-494-negative tumors (P = .79), or 58% at 4 years versus 61% at 4 years for patients with JSB-1-positive versus JSB-1-negative tumors (P = .65). OS for patients with C-494-positive tumors was 82% at 4 years versus 82% at 4 years for patients with C-494-negative tumors (P = .61).
Conclusion:
Prospective analysis of the role of multiple drug resistance in localized osteosarcoma did not find that immunohistochemical analysis of P-gp expression predicted outcome for patients treated on INT0133.
Insights
P-glycoprotein (P-gp) expression, linked to drug resistance in osteosarcoma, did not predict patient outcomes in a prospective trial. This finding suggests P-gp levels may not be a reliable indicator for treatment decisions in osteosarcoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Multiple drug resistance, mediated by P-glycoprotein (P-gp), is implicated in osteosarcoma recurrence.
- Understanding P-gp's role is crucial for improving treatment strategies in pediatric and young adult osteosarcoma.
Purpose of the Study:
- To prospectively evaluate the prognostic significance of P-gp expression in osteosarcoma.
- To determine if P-gp levels correlate with disease recurrence and survival in patients treated on the INT0133 trial.
Main Methods:
- Analysis of tumor specimens from 685 patients with localized, high-grade osteosarcoma enrolled in the INT0133 trial.
- Immunohistochemical assay for P-gp using monoclonal antibodies C-494 and JSB-1.
- Evaluation of event-free survival (EFS), overall survival (OS), and percent necrosis (NEC) in relation to P-gp expression.
Main Results:
- P-gp expression did not significantly increase the risk of adverse outcomes (EFS, OS, NEC).
- EFS at 4 years was similar for P-gp-positive and P-gp-negative tumors (59% vs. 61% for C-494; 58% vs. 61% for JSB-1).
- Overall survival at 4 years was also comparable between P-gp-positive and P-gp-negative groups (82% vs. 82% for C-494).
Conclusions:
- Prospective analysis indicates that immunohistochemical detection of P-gp does not predict outcomes in osteosarcoma patients treated on INT0133.
- The role of multiple drug resistance via P-gp as a prognostic marker in this patient cohort was not supported.
- Further research may be needed to identify reliable biomarkers for osteosarcoma treatment response.
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