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-month letrozole, 55 pre-/2-week/posttreatment matched samples; TEAM IIa: 3- to 6-month exemestane, 49 pre-/28 posttreatment paired samples; and NEWEST: 16-week fulvestrant, 39 pretreatment 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 qRT-PCR. Approximately one third of ER-positive patients had a functionally inactive ER pathway activity score (ERPAS), which was associated with a nonresponding status. Quantitative ERPAS decreased significantly upon therapy (P < 0.001 Edinburgh and TEAM IIa). Responders had a higher pretreatment ERPAS and a larger 2-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 ER-positive 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.

dx.doi.org/10.1158/1535-7163.MCT-19-0318, hdl.handle.net/1765/124657
Molecular Cancer Therapeutics
Erasmus MC: University Medical Center Rotterdam

Inda, M.A. (Márcia A), Blok, E.J. (Erik J.), Kuppen, P.J.K, Charehbili, A, den Biezen-Timmermans, E.C. (Eveline C.), van Brussel, A. (Anne), … van de Stolpe, A. (2020). Estrogen Receptor Pathway Activity Score to Predict Clinical Response or Resistance to Neoadjuvant Endocrine Therapy in Primary Breast Cancer. Molecular Cancer Therapeutics, 19(2), 680–689. doi:10.1158/1535-7163.MCT-19-0318