Abstract PD2-07: Multi-omics characteristics of ER+/HER2- breast cancer switching to metastatic non-luminal subtype: findings from the AURORA study (BIG14-01)

Abstract Background ER+/HER2− breast cancer with luminal primary tumors (P) can undergo intrinsic subtype switching, with metastases (M) displaying non-luminal intrinsic subtypes associated with a more aggressive behavior and poorer therapeutic responses. We investigated the molecular characteristics of intrinsic subtype switching from luminal P to non-luminal M among patients (pts) with ER+/HER2- breast cancer. Methods The AURORA study (NCT02102165) collected multi-omics data from paired P and M and plasma samples from 1148 pts. We focused on paired RNA-seq data from pts with ER+/HER2- LumA or LumB (L) P. PAM50 intrinsic subtype assignments were verified for reliability. Overall survival (OS) was calculated from the date of diagnosis of metastatic disease. Fisher’s exact, comet, Wilcoxon, and log-rank tests were used to assess statistical associations where appropriate. Results Of 131 pts, 16% (n=21) had a non-luminal M subtype, mainly HER2-enriched (LH, 14%, n=18), while 84% (n=110) remained luminal (LL). IHC subtype switching occurred in 55% of LH, with 33% losing ER and 22% acquiring HER2. Pts with LH tumors had a higher frequency of relapse while on adjuvant endocrine therapy (ET) or within 1 year of ET completion (p<0.001) compared to pts with LL tumors. Pts with LH tumors had worse OS than pts with LL tumors, even after excluding pts with de novo disease (p<0.001, HR=2.7, 95% CI: 1.5-4.9). LH tumors showed a higher frequency of TP53 mutations in both P and M compared to LL (p<0.001), with no significant difference observed for PIK3CA mutations. No ESR1 mutations (ctDNA or M) were detected in LH, while 18% of LL were ESR1 mutated (p=0.02). MAPK pathway mutations were more frequent in LH compared to LL (p=0.07 in M), particularly when compared to LL with detected ESR1 mutation (p=0.05). Gene expression analysis showed less similarity between P and M pairs in LH tumors (median Pearson's correlation R=0.70) compared to LL (R=0.80) (p=0.002). LH showed decreased ESR1 (paired p<1e-5) and increased ERBB2 (p<1e-4) expression in M compared to P counterparts. P from LH had higher levels of epithelial-mesenchymal transition and immune (q<1e-15) and lower estrogen receptor response (q<1e-10) signatures compared to LL. Discussion ER+/HER2- tumors that switched from luminal P to HER2-enriched subtype at metastasis had worse clinical outcomes and distinct molecular profiles, including TP53/MAPK mutations and immune related signatures already present in primary tumors, and reduced ER signaling and higher ERBB2 expression in metastases. ESR1 mutations were found only in tumors that remained luminal, suggesting that the luminal to HER2-enriched subtype switch may represent a distinct mechanism of ET resistance. Our findings highlight key features of primary tumors that may predict this subtype switching, guiding future research toward tailored (neo)adjuvant strategies. Citation Format: M. Benelli, A. Guerrero-Zotano, F. Santaniello, D. Cameron, A. Llinas-Bertran, M. Dadiani, M. Paoli, L. Ferrando, D. Romagnoli, M. Oliveira, C. Caballero, T. Crestani, E. Agostinetto, D. Martins-Branco, E. Nili Gal-Yam, F. Hilbers, M. Balic, F. Cardoso, C. Sotiriou, G. Curigliano, B. Linderholm, E. de Azambuja, S. Knox, V. Adam, E. Ciruelos, N. Davidson, G. Viale, F. Duhoux, B. Rojas, S. Servitja, J. Albanell, M. Colleoni, C. Duhem, N. Harbeck, S. Loibl, S. Marreaud, S. Fielding, P. Bedard, O. Johannsson, J. Bliss, S. Loi, A. Raimbault, T. Goulioti, C. Dauccia, A. Vingiani, D. Venet, G. Zoppoli, J. Seoane, P. Aftimos, M. Piccart. Multi-omics characteristics of ER+/HER2- breast cancer switching to metastatic non-luminal subtype: findings from the AURORA study (BIG14-01) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD2-07.