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The genomic landscape of HER2 negative metastatic breast cancer with loss of estrogen and progesterone receptors.

Ilenia Migliaccio·Marta Paoli·Chiara Biagioni·Cristina Guarducci·Francesca Galardi·Giulia Anichini·Laura Biganzoli·Matteo Benelli·Luca Malorni
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Abstract

INTRODUCTION: Loss of estrogen receptor (ER) and/or progesterone receptor (PR) might occur during the metastatic progression of ER positive and HER2 negative (ER+/HER2-) breast cancer (BC), but the underpinning molecular alterations remain elusive. We explored the genomic context of HER2- tumors with ER and/or PR loss to investigate potential drivers and actionable alterations that might help personalize treatment of ER+/HER2- BC. METHODS: We accessed data from metastatic HER2- BC included in the MSK-2018 dataset to compare outcome, tumor characteristics and genomic alterations of BC with loss of ER (ER+/-, n = 66) to those maintaining ER positivity (ER+/+, n = 364) or ER negativity (ER-/-, n = 50). We also compared metastatic ER+/+ BC with loss of PR (PR+/-, n = 111) to those maintaining PR positivity (PR+/+, n = 192) or PR negativity (PR-/-, n = 41). RESULTS: In line with previous reports, ER+/- BC was associated with aggressive clinico-pathological characteristics and poor outcome. ER+/- BC showed significantly higher frequency of TP53 and RB1 mutations and lower frequency of PIK3CA and GATA3 mutations compared to ER+/+. ER+/- or PR+/- status was mutually exclusive with ESR1 mutations and was associated with a significantly higher tumor mutational burden. Moreover, ER+/- BC were enriched in driver alterations in the genes of the Notch and Retinoblastoma pathways and showed a significantly lower frequency of level 1 actionable alterations according to OncoKB. CONCLUSIONS: Loss of ER and/or PR may identify a distinct evolutionary trajectory of ER+/HER2- metastatic progression, largely non-overlapping with ESR1-mutant endocrine resistance. Further studies on matched primary and metastatic samples are warranted.

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HumansFemaleReceptors, ProgesteroneBreast NeoplasmsErb-b2 Receptor Tyrosine KinasesReceptors, EstrogenMiddle AgedMutationGATA3 Transcription FactorClass I Phosphatidylinositol 3-KinasesAdultBiomarkers, TumorAgedGenomicsNeoplasm MetastasisTumor Suppressor Protein p53Breast cancerESR1Estrogen receptorProgesterone receptorJournal Article

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Ilenia Migliaccio, Marta Paoli, Chiara Biagioni, Cristina Guarducci, Francesca Galardi, Giulia Anichini, Laura Biganzoli, Matteo Benelli, Luca Malorni. 2026-08-10. The genomic landscape of HER2 negative metastatic breast cancer with loss of estrogen and progesterone receptors.. https://doi.org/10.1016/j.breast.2026.104897

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