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P-glycoprotein expression: critical determinant in the response to osteosarcoma chemotherapy
H S Chan1, T M Grogan, G Haddad
1Department of Pediatrics, The Hospital for Sick Children and University of Toronto, ON, Canada.
Background:
Fewer than 20% of patients with bone cancer who are treated with surgery alone are cured. Even with the best current treatment, surgery combined with chemotherapy, only 60%-80% of patients with nonmetastatic bone cancer and 10% of patients with metastatic bone cancer are cured. Thus far, the reason for treatment failure in the nonresponding subset has not been identified. It has been hypothesized that P-glycoprotein, which confers multidrug resistance, might be the cause. We sought to determine whether the expression of P-glycoprotein is associated with poor treatment outcome in osteosarcoma.
Methods:
In a retrospective study, we correlated P-glycoprotein expression with the outcome of conventional chemotherapy in 62 consecutive, clinically staged patients diagnosed as having osteosarcoma between 1980 and 1989.
Results:
P-glycoprotein was overexpressed in 27 patients but not in another 34 patients, and expression was ambiguous in the sample from one patient. At a median follow-up of 8.9 years, the 34 patients whose tumors did not express P-glycoprotein had significantly better relapse-free rates than the 27 subjects whose tumors expressed the protein (87% versus 0%; P<.00001) and had improved survival rates (94% versus 35%; P<.00001). Among the 46 patients who received chemotherapy before surgery, the 23 whose tumors were negative for P-glycoprotein showed significantly better long-term outcomes (P<.00002), although differences in tumor necrosis in response to therapy were only of borderline significance (P = .057).
Conclusions:
P-glycoprotein expression does correlate with treatment failure in patients with osteosarcoma. This correlation raises the possibility that inhibiting the action of P-glycoprotein as part of therapy for this disease would improve outcome.
Insights
P-glycoprotein expression in bone cancer is linked to treatment failure. Identifying and inhibiting this protein could improve outcomes for osteosarcoma patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Surgery alone cures fewer than 20% of bone cancer patients.
- Current treatments (surgery + chemotherapy) have limited success rates, especially for metastatic disease.
- The cause of treatment failure in nonresponding patients is unknown, with P-glycoprotein (multidrug resistance) as a hypothesis.
Purpose of the Study:
- To investigate the association between P-glycoprotein expression and treatment outcomes in osteosarcoma.
- To determine if P-glycoprotein is a factor in chemotherapy resistance in bone cancer.
Main Methods:
- Retrospective study of 62 osteosarcoma patients diagnosed between 1980-1989.
- Correlation of P-glycoprotein expression with outcomes of conventional chemotherapy.
- Analysis of relapse-free rates, survival rates, and tumor response to therapy.
Main Results:
- P-glycoprotein was overexpressed in 27 patients; 34 patients did not express it.
- Patients without P-glycoprotein expression had significantly better relapse-free (87% vs 0%) and survival rates (94% vs 35%).
- Pre-operative chemotherapy in P-glycoprotein-negative patients showed significantly better long-term outcomes.
Conclusions:
- P-glycoprotein expression is significantly correlated with treatment failure in osteosarcoma.
- This finding suggests P-glycoprotein plays a role in chemotherapy resistance.
- Inhibiting P-glycoprotein may represent a novel therapeutic strategy to improve osteosarcoma treatment outcomes.