148P - Diversity of genomic mechanisms of resistance to endocrine therapy in ER+ breast cancer

Background

Mutations in the ESR1 gene drive estrogen-independent tumor proliferation, conferring resistance to Aromatase Inhibitor (AI) therapy in estrogen receptor-positive (ER+) breast cancer. ESR1 mutations are strongly selected in cancers with previously sustained response to AI. We investigated the emergence of ESR1 mutations in response to therapy and the selective pressures that drive the development of endocrine resistance.

Methods

ESR1 mutations were identified in 182 plasma samples from metastatic patients sequenced using a custom targeted-capture panel and 665 whole-genome sequenced tumor samples in the Hartwig metastatic cohort. Mutations in plasma samples were determined using VarScan, a custom script and prior ESR1 mutations detected using digital droplet PCR assay. The neoantigen presentation of seven hotspot ESR1 mutations was summarised by the Patient Harmonic-mean Best Rank (PHBR) score. GISTIC copy number analysis, dNdScv driver gene quantification and DeconstructSigs was used to examine mutational processes that drive ESR1 mutant and ESR1 wild-type (WT) cancer.

Results

The landscape of plasma ESR1 mutations were more diverse than in tumours. In tumours, ESR1 amplification was found in 21% of the ESR1 WT group, and was not observed in the ESR1 mutant group. Mutations in ERBB2 (6%) and MAPK-associated genes, such as NF1 (9%), were identified as drivers in ESR1 WT but not mutant patients. APOBEC activity was reduced in ESR1 mutant patients (SBS2 (p=0.00059), SBS13 (p=0.00033)), however, clock-like signatures (SBS1 (p=0.0018), SBS15 (p=0.011)) were enriched in comparison to ESR1 WT patients. The immune presentation in the plasma samples was poor with no significant differences for patients with or without each of the hotspot mutations, except patients with Y537S who had significantly higher PHBR scores (p=0.0074).

Conclusions

The landscape of ESR1 mutations was more diverse in plasma at the point of endocrine resistance. ESR1 mutant cancers showed lower APOBEC and high clock-like mutational signatures, suggesting distinct genomic drivers of evolution. ESR1 WT cancers demonstrated copy gains in ESR1 and driver mutations related to MAPK activation, highlighting potential alternative genomic pathways to endocrine resistance.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The Institute of Cancer Research.

Funding

Pfizer.

Disclosure

S. Chia: Financial Interests, Personal, Funding: Novartis, Pfizer, Eli Lilly; Financial Interests, Personal, Research Grant: Exact Sciences. G. Schiavon: Financial Interests, Personal, Ownership Interest: AstraZeneca; Financial Interests, Personal, Full or part-time Employment: AstraZeneca. S.R.D. Johnston: Financial Interests, Personal, Research Grant: Eli Lilly, Pfizer, Puma Biotechnology; Financial Interests, Personal, Funding: AstraZeneca, Novartis, Sanofi Genzyme, Eisai. N. Turner: Financial Interests, Personal, Advisory Board: AstraZeneca, Eli Lilly, Pfizer, Roche/Genentech, Novartis, GSK, Repare Therapeutics, Relay Therapeutics, Zentalis, Gilead, Inivata, Guardant, Exact Sciences; Financial Interests, Personal, Funding: AstraZeneca, Pfizer, Roche/Genentech, Merck Sharpe & Dohme, Guardant Health, Invitae, Inivata, Personalis, Natera. B. O'Leary: Financial Interests, Personal, Other, Consulting: Merck Sharpe & Dohme, Oliver Whyman; Financial Interests, Personal, Speaker’s Bureau: Merck Sharpe & Dohme; Financial Interests, Personal, Research Grant: Pfizer. All other authors have declared no conflicts of interest.