Abstract 49P
Background
The efficacy of Selective Estrogen Receptor Degraders (SERDs) in ESR1-non-mutated (ESR1-non-mut) tumors is uncertain. To address this gap, we used DNADX, a DNA NGS phenotypic profiling tool that identifies 150 distinct signatures and categorizes tumors into 5 subtypes (Nat Commun 2023) using DNA copy number (CN) profiles from ctDNA. Our research focuses on comparing ESR1 mutated (ESR1mut) and ESR1-non-mut tumors using genomic features.
Methods
This study used 126 patients (pts) with advanced HR+ MBC after progression on CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET). Plasma ctDNA samples were characterized for ESR1mut status by Guardant-360 liquid biopsy assay and profiled by the DNADX assay (cohort 1). In this cohort, we developed an ESR1mut genomic predictor using the DNADX assay. Validation of the ESR1mut predictor was conducted in three independent cohorts: a plasma dataset of 132 HR+/HER2- BCs before starting CDK4/6i plus ET (cohort 2), and a tumor tissue dataset of 381 pts (MSKCC, cohort 3). The DNADX ESR1mut genomic predictor was also compared with the DNADX 5-subtype classification.
Results
ESR1mut tumors had higher DNADX plasma tumor fraction than ESR1-non-mut tumors (p=0.008). In plasma, ESR1mut tumors displayed increased activity in DNA luminal-related signatures and decreased activity in Basal-like-related signatures, with no notable differences in proliferation-based signatures compared to ESR1-non-mut tumors. DNADX ESR1mut genomic predictor demonstrated an Area Under the Curve of 0.764 in the training dataset and 0.710 in the validation dataset for ESR1mut identification. Notably, 30-40% of ESR1-non-mut tumors had high DNADX ESR1mut genomic scores, indicating biological similarity to ESR1mut tumors. ESR1mut tumors distribution across the DNADX's 5-subtype classification varied significantly, with the lowest prevalence in the aggressive Cluster-3 subtype (4% vs. 20.4%; p<0.001).
Conclusions
Metastatic ESR1mut and non-mut tumors show biological heterogeneity in ctDNA CN landscapes. A subset of ESR1-non-mut tumors share molecular features with ESR1-mut tumors. DNADX profiling could be crucial in guiding SERDs development beyond ESR1mut focus.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
I. Garcia Fructuoso: Financial Interests, Personal, Invited Speaker, And travel expenses: Novartis; Financial Interests, Personal, Invited Speaker, And Travel expenses: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Other, Travel expenses: Gilead, Lilly. O. Martínez-Sáez: Financial Interests, Personal, Invited Speaker: Novartis, Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Personal, Other, Medical advisory: Reveal Genomics. L. Pare Brunet: Financial Interests, Institutional, Full or part-time Employment: Reveal Genomics S.L.; Financial Interests, Institutional, Other, Patent pending: In vitro method for the prognosis of patients suffering from HER2-positive breast cancer - 905333: SOLTI; Financial Interests, Institutional, Other, Patent filed: EP23382703: Reveal Genomics S.L.; Financial Interests, Institutional, Other, Patent filed: EP23383369: Reveal Genomics S.L. G. Villacampa Javierre: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. P. Villagrasa Gonzalez: Financial Interests, Personal, Full or part-time Employment, CEO and co-founder of the company: Reveal Genomics S.L.; Financial Interests, Personal, Ownership Interest: Reveal Genomics S.L.; Financial Interests, Personal, Royalties, PCT/EP2021/086493 - in vitro method for the prognosis of patients suffering from HER2-positive breast cancer: Reveal Genomics S.L. J. Parker: Financial Interests, Personal, Other, Advisory: Reveal Genomics, Bristol Myers Squibb; Financial Interests, Personal, Full or part-time Employment: LifeEdit Therapeutics; Financial Interests, Personal, Ownership Interest: Reveal Genomics, GeneCentric; Financial Interests, Personal, Royalties: Veracyte. C.M. Perou: Financial Interests, Personal, Member of Board of Directors: GeneCentric Therapeutics; Financial Interests, Personal, Stocks/Shares: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics; Financial Interests, Personal, Royalties, from PAM50 licensing: Bioclassifier LLC; Financial Interests, Personal, Royalties: GeneCentric Therapeutics; Non-Financial Interests, Advisory Role: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics. A. Vivancos: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb, Guardant Health, Bayer, INCYTE; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Bristol Myers Squibb, Roche, INCYTE. A. Prat: Financial Interests, Personal, Invited Speaker: Roche, 1TRIALSP, S.L.; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca, Reveal Genomics; Financial Interests, Personal, Member of Board of Directors, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Royalties: Reveal Genomics, International Oncology Bureau, S.L.,; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Financial Interests, Institutional, Funding: Reveal Genomics; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA; Non-Financial Interests, Personal, Other, Research Foundation that gives grants to researchers: FERO. F. Brasó-Maristany: Financial Interests, Personal, Full or part-time Employment, part time employment: Reveal Genomics SL; Financial Interests, Personal, Other, Patents filed: EP23382703 and EP23383369: Reveal Genomics SL; Financial Interests, Personal, Other, Patents filed: PCT/EP2022/086493, PCT/EP2023/060810: Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer. All other authors have declared no conflicts of interest.