Abstract 341MO
Background
The AURORA program, established by the Breast International Group (BIG), seeks to characterize the molecular and clinical landscape of advanced breast cancer (aBC). Matched primary tumors and metastatic lesions were prospectively collected, together with extensive clinical information. Here, mutational and transcriptional features of aBC samples were evaluated according to age at aBC diagnosis, to identify aging-associated molecular processes.
Methods
Lasso regression was used for mutational feature selection. Associations with age as continuous variable at metastatic biopsy were tested via Firth logistic models adjusted for clinico-pathological variables. The interaction between mutation acquisition in aBC and age was analyzed in cases with matched samples. Age correlations with transcriptional signatures were explored using linear models. The Benjamini-Hochberg method with FDR≤ 0.1 was applied across all analyses.
Results
A total of 830 cases (1,333 samples) assessed by January 2024 were analyzed. Younger age at aBC diagnosis correlated with primary nodal status and grade, whereas primary lobular histology was linked to older age. Adjusting for primary grade, nodal status, histology, metastatic subtype, de novo status, subtype switch, mutations in 13 genes were associated with older age: PIK3CA, CDH1, SETD2, CARD11, KDM6A, EPHB1, PTPRT, ESR1, PIK3R1, MYH11, KMT2A, LRP1B, and ARID1A. ERCC4 and PTCH1 mutations were enriched in younger patients. Hedgehog and G2M checkpoint signatures were associated with younger age at aBC presentation, whereas the PI3K signature correlated with older age. In the 503 matched cases, aBC-acquired mutations in CARD11, MYH11, ARID1A, KAT6B, KDM6A, KMT2A, ERBB4, GNAS, PTEN, BRCA2, and EPHB6 were enriched in older patients, while acquired PTCH1 and ERCC4 mutations were more frequent in younger patients.
Conclusions
aBC in older patients is characterized by distinct molecular features, like the enrichment of actionable mutations in PI3K, estrogen receptor, and ephrin receptor signaling, as well as rarer but potentially actionable mutations like those in CARD11. The signatures of aBC in the aging population are coherent with less activation of proliferative and DNA damage pathways.
Clinical trial identification
NCT02102165. Breast International Group (BIG) identifier: BIG 14-01.
Editorial acknowledgement
Legal entity responsible for the study
Breast International Group (BIG).
Funding
Breast Cancer Research Foundation® (BCRF); Fondation Cancer (Luxembourg); Pfizer grant for non-drug research; Fondation contre le Cancer (Belgium); National Lottery (Belgium); NIF Foundation; Barrie & Dena Webb; Candriam; the Fund Friends of BIG (King Baudouin Foundation); Martine Piccart; the Hotimsky family; Sogerim; Think Pink Belgium (SMART Fund); Cognizant Foundation; Eurofins Foundation; Fondation Futur 21; & many individual donors.
Disclosure
G. Zoppoli: Financial Interests, Personal, Stocks/Shares: Immunomica Ltd. E. Munzone: Financial Interests, Personal, Advisory Board: Eisai, Exact Science, MSD Oncology, Daiichi Sankyo/AstraZeneca, Pfizer, Seagen. T. Antoniolli Crestani: Financial Interests, Institutional, Full or part-time Employment, Scientific Advisor: Breast International Group (BIG); Financial Interests, Institutional, Research Grant: AstraZeneca, Roche/Genentech, Tesaro, Novartis, Pfizer, SERVIER, Biovica, GSK, Sanofi/Aventis. V.S. Adam: Financial Interests, Personal, Full or part-time Employment, I am an employee of the Breast International Group (BIG).: Breast International Group (BIG); Financial Interests, Institutional, Funding, My institution receives funding from AstraZeneca for OlympiA.: AstraZeneca; Financial Interests, Institutional, Funding, My institution receives funding from GSK for BRAVO.: GSK; Financial Interests, Institutional, Funding, My institution receives funding from Novartis for ALPHABET, ALTTO, and DIANER.: Novartis; Financial Interests, Institutional, Funding, My institution receives funding from Pfizer for PALLAS and PYTHIA.: Pfizer; Financial Interests, Institutional, Funding, My institution receives funding from Roche for DECRESCENDO, ALEXANDRA/IMpassion030, and APHINITY.: Roche; Financial Interests, Institutional, Funding, My institution received funding from Novartis for AMEERA-6.: Sanofi; Financial Interests, Institutional, Funding, My institution receives funding from Genentech for LORELEI.: Genentech; Non-Financial Interests, Member, I am a member of the American Society for Clinical Oncology (ASCO).: American Society for Clinical Oncology (ASCO). A. Irrthum: Financial Interests, Full or part-time Employment: Breast International Group (BIG). P.G. Aftimos: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Macrogenics, Roche, Novartis, Amcure, Servier, G1 Therapeutics, Radius, Deloitte, Menarini, Gilead, Novartis, Eisai, Lilly; Financial Interests, Personal, Invited Speaker: Synthon, Amgen; Financial Interests, Institutional, Research Grant: Roche. A.L. Guerrero Zotano: Financial Interests, Research Grant: Pfizer; Financial Interests, Speaker, Consultant, Advisor: Novartis, Astrazeneca, Exact Sciences, Pierre Fabre, Lilly; Financial Interests, Leadership Role: GEICAM. M. Piccart: Financial Interests, Personal, Invited Speaker: AstraZeneca, Lilly, MSD, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Menarini, Seattle Genetics, Seagen, Gilead, NBE Therapeutics, Frame Therapeutics; Financial Interests, Personal, Advisory Board, Consultant and invited speaker: Roche-Genentech; Financial Interests, Personal, Member of Board of Directors, Scientific Board: Oncolytics; Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Gilead; Financial Interests, Institutional, Funding: Menarini, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon. C. Desmedt: Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Other, Translational Steering Committee MonarchE: Lilly; Financial Interests, Institutional, Advisory Board: AstraZeneca; Non-Financial Interests, Other, Co-chair: European Lobular Breast Cancer Consortium. M. Benelli: Financial Interests, Personal, Other, Personal fees for consultancy on bioinformatics analyses: Novartis. H. Wildiers: Financial Interests, Institutional, Other, Consultancy: Roche, Gilead, Pfizer, Immutep Limited, Novartis, Augustine Therapeutics, Stemline Therapeutics Switzerland, MediMix BV, NV Hict; Financial Interests, Institutional, Advisory Board, + Consultancy: Lilly, AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: Astrazeneca, E Squared Communications LLC, PSI CRO AG; Financial Interests, Institutional, Invited Speaker: Seagen; Financial Interests, Institutional, Research Grant, Grant to the Leuven Breast Center to support the research database: Roche; Financial Interests, Institutional, Research Grant, Grant to institute to perform a multicentric national academic trial: Novartis; Financial Interests, Institutional, Local PI: Syneos Health; Other, Travel & accomodations: Pfizer; Other, Subscription fee: Gilead; Other, Travel support: Daiichi Sankyo. All other authors have declared no conflicts of interest.
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