Background: It is recognized that breast cancer is not one disease, but a heterogeneous group that can be classified into different subtypes, with varying clinical outcomes, based on histopathological and molecular features. Estrogen receptor positive (ER+) breast cancer, accounting for 70-80% of all cases, is classified by gene expression profiling into two intrinsic molecular subtypes: luminal A and luminal B. Outcomes are overall poorer in the luminal B subtype in which proliferation rates are overall higher. Arising from this, commercial multigene tests exploit molecular profiling techniques to accurately predict outcome and guide treatment in ER+ breast cancers. However, in Australia, these tests are extremely costly and have a slow turnaround for results.
Aim: To develop an affordable alternative multigene prognostic test to guide treatment recommendations for ER+ breast cancer and to translate this test to clinical application.
Methods: We developed PROSPER, a proliferation-based gene signature test and assessed its association with outcome in public datasets of ER+ breast cancer. Subsequently, PROSPER was measured in total RNA from formalin-fixed paraffin-embedded tissue samples using the highly accurate NanoString platform and correlated with clinical features and outcome. To enhance the applicability of the PROSPER test in the public healthcare setting, we optimised the PROSPER test using cutting-edge multiplex PCR technology.
Results: In silico validation in the METABRIC breast cancer dataset revealed that PROSPER performed as well or better than the predictive signatures underpinning current commercial tests. In a prospective cohort of ER+ breast cancers, PROSPER was significantly correlated with clinical grade, proliferation marker Ki67 and with the results of a commercial multi-gene test. In a retrospective cohort, PROSPER was significantly correlated with Ki67, and disease-specific and overall survival.
Conclusion: Optimization and validation of the PROSPER signature to an easily applied test for effective utilisation in the public pathology setting are underway. A successful outcome of this project will result in considerable benefits to Australian patients and cost savings to the public health system.