Pathway activity profiling can predict neoadjuvant endocrine therapy response in HR+ HER2- postmenopausal early stage breast cancer

To improve patient selection for neoadjuvant endocrine therapy (NET), signal transduction pathway profiles of estrogen receptor (ER)-, androgen receptor (AR), were studied and compared to standard immunohistochemistry (IHC) in postmenopausal patients with HR+ (IHC ER ≥ 50%, progesterone receptor any), HER2- breast cancer of the NEOLBC trial (NCT03283384). After two weeks of NET with letrozole, patients with Ki67 (Ki67-2 W) ≥ 1% IHC were randomized to receive letrozole + ribociclib or standard chemotherapy until surgery, while patients with Ki67-2 W < 1% continued NET (letrozole monotherapy). Baseline, two week- and resection FFPE samples of 82 patients were analyzed using mRNA-based OncoSIGNal profiling test, providing the pathway activity score (PAS). Despite samples being ER-IHC ≥ 50%, the ER-PAS varied over a range of 32–78 (scale from 0 to 100) with 20% of the patients showing low ER-PAS (32–45; similar to triple negative breast cancer tissue). At 2 weeks, 89% (73/82) of the patients showed a decreased ER-PAS (11.6 ± 8.6) compared to baseline (p < 0.001), whereas ER-IHC remained unchanged. Patients with complete response (RECIST1.1) appeared to have a higher ER-PAS at baseline compared to those with stable disease (p = 0.03), ROC analysis confirmed ER-PAS at baseline as an acceptable predictive factor for MRI response (AUC ≥ 0.7). Lastly, baseline and 2-week pathway activity profiling could identify targetable escape mechanisms for NET non-responders, which could improve personalized treatment strategies. ER IHC+ does not correlate to ER-PAS and ER-PAS is a more dynamic marker that appears to reflect variable NET response more accurately than IHC.