Abstract 94P
Background
Preoperative radiotherapy (RT) impact on early-stage breast cancer (BC) remains underexplored, holding promise for improved outcomes and innovative treatments. The YOUNGSTER trial aimed to analyze molecular changes induced by preoperative RT across BC subtypes: Luminal A, Luminal B, HER2-enriched, and Basal-like.
Methods
From May 2021 to September 2022, YOUNGSTER enrolled 20 early-stage BC patients eligible for breast-conserving surgery and no prior treatment. The RT boost (5 x 2.67 Gy/fx) was administered preoperatively, followed by core-needle biopsy 3-5 days later. Gene expression was analyzed using a 192-gene panel, including BC and immune-related genes. Additional assessments included Ki67 and CD68 immunohistochemistry, tumor-infiltrating lymphocytes (TILs) via hematoxylin/eosin staining, and RT-induced DNA damage with γH2AX staining. Thirteen surgical samples from primary surgery patients were also analyzed.
Results
At baseline, PAM50 subtypes were distributed as follows: Luminal A (35%), Luminal B (25%), HER2-enriched (20%), and Basal-like (20%). Paired samples (baseline vs post-RT) revealed a significant downregulation in proliferation genes (e.g. MKI67) and the PAM50 proliferation signature. Ki67 IHC staining decreased (p=0.010). Intriguingly, RT upregulated genes such as MDM2, CD86, CD68, and S100A9, consistent across subtypes. Post-RT, a significant increase in DNA damage (p=0.004) occurred. Surgical samples showed a rebound in proliferation genes and MDM2, while sustained macrophage marker and CD86 expression persisted. Notably, immune-related genes (CXCL8, CD4, CD8A, PDCD1, CD79a, IGKC, IGL, IGLV3-25, IGJ) exhibited significant upregulation.
Conclusions
Early changes induced by RT involve reduced proliferation, increased DNA damage, and broad immunomodulation across subtypes. RT upregulation of immune-related genes, sustained macrophage infiltration, and adaptive immune response activation suggest a broader impact than previously recognized.
Legal entity responsible for the study
Hospital Clinic Barcelona.
Funding
Has not received any funding.
Disclosure
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. 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. All other authors have declared no conflicts of interest.