Endocrine therapy is important for management of patients with estrogen receptor (ER) positive breast cancer, however positive ER staining does not reliably predict therapy response. We assessed the potential to improve prediction of response to endocrine treatment of a novel test that
quantifies functional ER pathway activity from mRNA levels of ER pathway-specific target genes.
ER pathway activity was assessed on datasets from three neoadjuvant treated ER-positive breast cancer patient cohorts. Edinburgh: 3 months letrozole, 55 pre-/two-week/post-treatment matched samples; TEAM IIa: 3-6 months exemestane, 49 pre-/28 post-treatment paired samples; NEWEST: 16 weeks fulvestrant, 39 pre-treatment samples. ER target gene mRNA levels were measured in Fresh Frozen tissue (Edinburgh, NEWEST) with Affymetrix microarrays, and in Formalin Fixed Paraffin Embedded samples (TEAM IIa) with RT-qPCR.
Approximately one third of ER-positive patients had a functionally inactive ER pathway activity score (ERPAS), which was associated with a non-responding status. Quantitative ERPAS decreased significantly upon therapy (p<0.001 Edinburgh and TEAM IIa). Responders had a higher pretreatment ERPAS and a larger two-week decrease in activity (p=0.02 Edinburgh). Progressive disease
was associated with low baseline ERPAS (p=0.03 TEAM IIa; p=0.02 NEWEST) which did not decrease further during treatment (p=0.003 TEAM IIa). In contrast, the staining-based ER Allred score was not significantly associated with therapy response (p=0.2).The ERPAS identified a subgroup of ERpositive patients with a functionally inactive ER pathway associated with primary endocrine resistance. Results confirm the potential of measuring functional ER pathway activity to improve prediction of response and resistance to endocrine therapy.
- Estrogen Receptor positive breast cancer
- signal transduction pathways
- endocrine therapy response
- neoadjuvant treatment
- Bayesian modeling