Abstract PS17-04: Clinical and Genomic Features of ER-Positive/HER2-negative Metastatic Breast Cancer in AURORA Molecular Screening Initiative (BIG 14-01): Mechanisms of Endocrine Therapy Resistance and Implications for Adjuvant Approaches
Authors: Guerrero-Zotano Angel , Benelli Matteo , Irrthum Alexandre , Cameron David , Ferrando Lorenzo , Romagnoli Dario , Paoli Marta , Llinas Arnau , Dadiani Maya , Fimereli Danai , Oliveira Mafalda , Caballero Carmela , Crestani Thayane , Agostinetto Elisa , Martins-Branco Diogo , Hilbers Florentine , Gal-Yam Einav , Balic Marija , Cardoso Fatima , Reis-Filho Jorge , Sotiriou Christos , Curigliano Giuseppe , Linderholm Barbro , de Azambuja Evandro , Knox Susan , Rotaru Cristina , Ciruelos Eva , Davidson Nancy E , Viale Giuseppe , Taylor Donatienne , Canon Jean-Luc , Calvo Lourdes , Albanell Joan , Colleoni Marco , Duhem Caroline , Harbeck Nadia , Herremans Catherine , Loibl Sibylle , Marreaud Sandrine , Scheepers Elsemieke , Raimbault Alice , Goulioti Theodora , Vingiani Andrea , Biagioni Chiara , Vosberg Sebastian , Zoppoli Gabriele , Seoane Jose , Venet David , Aftimos Philippe , Piccart Martine 
Published: May 2024

Abstract
Background:
Up to 30% of patients (pts) with ER-positive early breast cancers develop metastatic relapse. The molecular differences between endocrine therapy (ET)-sensitive and ET-resistant relapses, as well as the impact of specific adjuvant ET-based therapies, remain unclear.
Methods:
The AURORA program (NCT02102165) analyzed multi-omics data of paired primary (prim) and metastatic (meta) tumor tissue, along with plasma samples, from 1,156 patients with metastatic breast cancer (MBC). Targeted genome sequencing (TGS), RNA sequencing, and circulating tumor DNA analysis were performed. ET-resistance at MBC diagnosis was defined following the 5th ESO-ESMO ABC Guidelines.
Results:
We studied 628 pts with metastatic ER+/HER2- disease. Patient´s median age was 56 years, 133 (21%) were premenopausal, 314 (50%) had ET-resistance at recurrence (9% primary, 41% secondary), 132 (21%) had ET-sensitive recurrence, and the rest were ET-naive recurrences or de novo MBC. Adjuvant treatment was aromatase inhibitor (AI) +/- ovarian function suppression (OFS) in 288 (46%) pts, while 159 (25%) had tamoxifen only (+/- OFS).
Gene expression correlation significantly differed (p &lt; 0.005) based on ET-resistance in 92 paired samples. ET-sensitive (n=11) and de-novo tumors (n=41) showed higher correlation than primary (n=7) and secondary ET-resistance (n=32), regardless of adjuvant ET type.
Prim and meta showed concordance in 91% of IHC subtypes and 62% of intrinsic subtypes. Intrinsic subtype showed 9% of prim luminal tumors switching to meta non-luminal, with 66% of Luminal A switching to Luminal B. Neither IHC nor intrinsic subtype switching was associated with the type of adjuvant ET or ET resistance. Pts with meta non-luminal intrinsic subtype (18%) had worse PFS on CDK4/6i (HR 4.0, 95% CI 1.9-8.7) and OS (HR 3.6, 95% CI 2.0-5.7) than luminal subtypes.
TGS was performed in 534 meta (365 before 1L, 305 pairs). In meta before 1L, the dN/dS algorithm revealed selection in 17 genes, including TP53, PIK3CA, and ESR1. Mutations (mut) in ESR1, ERBB2, ERBB3, and RB1 among others, were specifically identified in meta. The incidence of ESR1mut was 3% in prim, 12.6% before 1L, 23.4% after 1L, and 4.7% in meta from ET-naive tumors (Table). Before 1L, ESR1mut was higher after adjuvant AI vs tamoxifen (21% vs. 4%, p&lt; 0.001). ESR1mut incidence varied with ET-resistance (16% primary, 19% secondary, 9% sensitive, 4% ET-naïve/de novo, p&lt; 0.01). Paired samples showed that ESR1mut were mainly acquired events and associated with higher ER mRNA signaling (hallmark estrogen response) compared to ESR1wt (p &lt; 0.05).
The agreement between ESR1mut detected in ctDNA and tissue was high before 1L (90%), and slightly lower after 1L (84%).
In a multivariate model with relevant clinical factors, ESR1mut were associated with worse OS (HR 1.76, 95% CI 1.2-2.5, p=0.003), independently of TP53 and PIK3CA mutational status.
Conclusion:
AURORA study sheds light on metastatic tumor alterations acquired under anti-cancer therapy, in ER+/HER2- MBC. We observed a high prevalence of acquired ESR1mut prior to the initiation of first-line therapy, particularly in tumors exposed to adjuvant AI or with primary or secondary ET_resistance. The association of ESR1muts with poorer OS underscores the importance of implementing effective adjuvant ET strategies to prevent the emergence of these mutations.
Frequency of driver gene mutations in primary and metastastic tumors before 1st-line treatment according to adjuvant ET and type of ET resistance
Table.
Citation Format: Angel Guerrero-Zotano, Matteo Benelli, Alexandre Irrthum, David Cameron, Lorenzo Ferrando, Dario Romagnoli, Marta Paoli, Arnau Llinas, Maya Dadiani, Danai Fimereli, Mafalda Oliveira, Carmela Caballero, Thayane Crestani, Elisa Agostinetto, Diogo Martins-Branco, Florentine Hilbers, Einav Gal-Yam, Marija Balic, Fatima Cardoso, Jorge Reis-Filho, Christos Sotiriou, Giuseppe Curigliano, Barbro Linderholm, Evandro de Azambuja, Susan Knox, Cristina Rotaru, Eva Ciruelos, Nancy E Davidson, Giuseppe Viale, Donatienne Taylor, Jean-Luc Canon, Lourdes Calvo, Joan Albanell, Marco Colleoni, Caroline Duhem, Nadia Harbeck, Catherine Herremans, Sibylle Loibl, Sandrine Marreaud, Elsemieke Scheepers, Alice Raimbault, Theodora Goulioti, Andrea Vingiani, Chiara Biagioni, Sebastian Vosberg, Gabriele Zoppoli, Jose Seoane, David Venet, Philippe Aftimos, Martine Piccart. Clinical and Genomic Features of ER-Positive/HER2-negative Metastatic Breast Cancer in AURORA Molecular Screening Initiative (BIG 14-01): Mechanisms of Endocrine Therapy Resistance and Implications for Adjuvant Approaches [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-04.