Endocrine therapy for breast cancer patients is currently determined based on positive estrogen receptor alpha (ER) staining measured by immunohistochemistry. However, not all selected patients will respond to this therapy, suggesting that ER staining is not an optimal predictor for therapy response. We previously described a new method to measure functional signal transduction pathways based on a Bayesian inference from measurements of mRNA levels (microarray, qPCR) of the specific ER pathway related target genes. Initial evaluation suggested that ER pathway activity score of the primary biopsy is related to clinical response. In this study, this association is confirmed together with the observation that only the ER pathway activity is targeted by endocrine therapy, making this pathway activity score a possible candidate for response prediction to this therapy.
The Edinburgh Breast Cancer Unit collected pre-treatment biopsies of 29 post-menopausal patients with primary localized ER-positive breast cancer. Patients received neo-adjuvant letrozole treatment and clinical outcome was assessed at 3 months follow-up based on 3D ultrasound measurements (single clinician) and translated into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Archival RNA from fresh frozen (FF) biopsy samples was used to measure gene expression of target genes from several pathways (ER, AR, FOXO, HH, TGFb and Wnt) using RT-qPCR. Pathway activity scores were computed and expressed on a 0-100 scale.
A high ER pathway activity score was correlated with a higher decrease in tumour size (Pearson 0.4; p = 0.02), and low ER pathway score was clearly associated with PD (ER score of 20.2 in PD vs 43.8 in non-PD, two-sided t-test p = 0.03) with an AUC of 0.84 (CI 95% 0.63-1). Similar results were obtained by comparing CR/PR vs SD/PD. Other measured pathway activities did not correlate to clinical response confirming the ER pathway as primary target for endocrine therapy.
This study confirms the potential use of ER pathway activity score from a primary biopsy of ER-positive breast cancer patients as an improved biomarker in the prediction of neoadjuvant endocrine therapy response.
Philips Electronics Nederland B.V., acting through its HealthWorks Molecular Pathway Dx.
Has not received any funding.
D. Keizer, M.A. Inda, D. Clout A. van de Stolpe: Employee: Philips Reasearch. All other authors have declared no conflicts of interest.