Gene expression before and after neoadjuvant chemotherapy or endocrine therapy and survival outcomes in hormone receptor-positive, HER2-negative breast cancer: the NEOENDO study

Abstract

Background Neoadjuvant chemotherapy (NACT) and endocrine therapy (NET) are sometimes used to shrink hormone receptor-positive (HoR+)/HER2-negative breast cancer (BC) before surgery. These treatments can change the tumor on a molecular level, but the impact on patient outcomes remains unclear. There is also a lack of detailed comparison between the changes induced by both therapies.Methods We studied 186 patients with early-stage BC treated at our Institution with either NACT or NET. Changes in clinical and gene expression (GE) features before/after treatment were assessed. GE findings were confirmed in HoR+/HER2-negative BC cell lines. Associations with event-free survival (EFS) were conducted with the Kaplan-Meier method, log-rank tests, and Cox regressions. GE comparisons were assessed with SAM analysis. We considered p < 0.05 and a false discovery rate (FDR) < 5% as statistically significant.Results Patients treated with NACT had more aggressive cancer at baseline but also showed higher rates of pathological complete response compared to those treated with NET (18.6% vs. 3.4%, p = 0.001). Both treatments shifted the tumor types towards less aggressive forms (i.e., PAM50 Luminal A/Normal-like) and lowered the risk of recurrence in terms of PAM50 risk-of-relapse score (ROR-P) (all p < 0.001). NACT induced more profound mean reduction in ROR-P than NET. Both treatments induced a significant upregulation of selected immune genes and PAM50 Basal-like-related signature and genes, while a significant downregulation was observed for proliferation-, luminal- and HER2-related genes/signatures (all FDR < 5%). A net reduction in proliferation-related genes and ROR-P was confirmed in cell lines with CT and ET. Higher rates of pathologic responses were achieved with NACT in patients with higher initial levels of ROR-P and proliferation-related genes, while responders to NET showed an upregulation of luminal-related genes vs. NACT responders. Decreasing the risk of recurrence and transitioning the tumor subtype to resemble normal tissue (i.e., PAM50 Normal-like) suggested improved EFS.Conclusions NACT was more effective in molecularly and dimensionally 'downstaging' the cancer compared to NET but baseline genomic features associated to differential responses according to treatment strategy. Examining baseline and post-treatment GE might help tailoring neo/adjuvant systemic treatments, potentially leading to more personalized and effective care.

Unraveling the clinicopathological and molecular changes induced by neoadjuvant chemotherapy and endocrine therapy in hormone receptor-positive/HER2-low and HER2-0 breast cancer

“…mixed HER2-low and HER2-0 populations). 13 In that same analysis, we observed an encouraging trend towards better survival outcomes associated with such a molecular downstaging. 13 In a small study from Hilal et al., 28 NET induced a reduction in ER and PgR, consistent with our findings, though a slight increase in molecular risk of relapse, as detected with the 21-gene Oncotype DX® assay, was observed.…”

“… 13 In that same analysis, we observed an encouraging trend towards better survival outcomes associated with such a molecular downstaging. 13 In a small study from Hilal et al., 28 NET induced a reduction in ER and PgR, consistent with our findings, though a slight increase in molecular risk of relapse, as detected with the 21-gene Oncotype DX® assay, was observed. Although this might seem contradictory with our findings, we should note that PAM50 ROR-P and Oncotype molecular risk score (RS) rely on gene modules that only partially overlap.…”

“…A consecutive cohort of patients with stage I-IIIB HR+/HER2-negative BC treated as per standard-of-care NACT or NET at the Hospital Clinic of Barcelona (HCB) between 2014 and 2018 was included in the NEOENDO retrospective observational study, as elsewhere reported in detail. 13 NACT consisted of standard anthracycline and/or taxane-based regimens. NET consisted of 3-6 months of an aromatase inhibitor (AI) or tamoxifen +/− gonadotropin-releasing hormone analogue (GnRHa).…”