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Molecular profiling in gastric cancer: examining potential targets for chemotherapy
John T Miura1, Fabian M Johnston, James Thomas
1Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
Background And Objectives:
Current NCCN guidelines recommend epirubicin (E), cisplatin (C), and 5-fluorouracil (F) as a first-line therapeutic approach for operable gastric adenocarcinoma (GC). Molecular profiling (MP) was used to evaluate the expression of chemotherapy targeted biomarkers associated with ECF therapy and other first-line cytotoxic regimens for GC.
Methods:
GC specimens were analyzed by immunohistochemistry (IHC) for TOP2A, TS, ERCC1, PGP, and TOPO1 expression (Caris Life Sciences, Phoenix, AZ) from 2009 to 2012.
Results:
A total of 230 GC specimens were analyzed. The median age of patients was 61 (IQR: 50-72) years with the majority being male (n = 139, 60%). IHC actionable targets included: 60% (n = 138) high TOP2A, 55% (n = 127) negative ERCC1, and 63% (n = 145) negative TS, indicating potential benefit from E, C, and F, respectively. Simultaneous expression analysis demonstrated only 24% (n = 55) of patients had gene expression levels that suggested uniform sensitivity to ECF. Biomarker results of 6.5% (n = 15) of patients revealed a potential complete lack of sensitivity to first-line ECF.
Conclusions:
MP of GC has the potential to define patients who would derive the greatest benefit from current therapies. Prospective controlled studies are required to validate the role of biomarkers in the management of GC patients.
Insights
Molecular profiling of gastric adenocarcinoma (GC) can identify patients likely to benefit from standard chemotherapy. However, only a small fraction of patients show sensitivity to the recommended epirubicin, cisplatin, and 5-fluorouracil regimen.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacogenomics
Background:
- Current NCCN guidelines recommend epirubicin (E), cisplatin (C), and 5-fluorouracil (F) as first-line therapy for operable gastric adenocarcinoma (GC).
- Molecular profiling (MP) can assess biomarkers relevant to chemotherapy response in GC.
Purpose of the Study:
- To evaluate chemotherapy-targeted biomarker expression in GC specimens.
- To assess the potential of MP to guide first-line therapy selection for GC patients.
Main Methods:
- Immunohistochemistry (IHC) was used to analyze 230 GC specimens for TOP2A, TS, ERCC1, PGP, and TOPO1 expression.
- Analysis focused on biomarkers associated with ECF therapy and other first-line regimens.
Main Results:
- 60% of patients had high TOP2A, 55% negative ERCC1, and 63% negative TS, suggesting potential benefit from E, C, and F respectively.
- Only 24% of patients demonstrated gene expression levels indicating uniform sensitivity to ECF.
- 6.5% of patients showed biomarker results suggesting a complete lack of sensitivity to first-line ECF therapy.
Conclusions:
- Molecular profiling of GC holds promise for identifying patients who will benefit most from current therapies.
- Prospective controlled studies are necessary to validate the utility of biomarkers in managing GC patients.