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Mini oral session 1: Breast cancer, metastatic

341MO - Impact of aging on the genetic and transcriptional landscape of advanced breast cancer: an AURORA program (BIG 14-01) subanalysis

Date

15 Sep 2024

Session

Mini oral session 1: Breast cancer, metastatic

Topics

Pathology/Molecular Biology;  Translational Research;  Molecular Oncology

Tumour Site

Breast Cancer

Presenters

Gabriele Zoppoli

Citation

Annals of Oncology (2024) 35 (suppl_2): S357-S405. 10.1016/annonc/annonc1579

Authors

F. Ravera1, F. Santaniello2, L. Ferrando3, D. Venet4, J.A. Seoane5, F. Richard6, E. Munzone7, S. Hatse8, A. Ballestrero9, T. Antoniolli Crestani10, V.S. Adam11, A. Irrthum12, P.G. Aftimos13, A.L. Guerrero Zotano14, D.A. Cameron15, M. Piccart16, C. Desmedt6, M. Benelli17, H. Wildiers6

Author affiliations

  • 1 Department Of Internal Medicine, Università degli Studi di Genova, Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC), 16132 - Genova/IT
  • 2 Department Of Experimental And Clinical Biomedical Sciences, Università degli Studi di Firenze, Fondazione Sandro Pitigliani per la lotta contro i tumori ONLUS, 59100 - Prato/IT
  • 3 Department Of Internal Medicine, Ospedale Policlinico San Martino IRCCS, Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC), 16132 - Genova/IT
  • 4 Breast Cancer Translational Research Laboratory J.c. Heuson, Institute Jules Bordet University Hospital, 1070 - Brussels/BE
  • 5 Cancer Computational Biology Group, Vall d'Hebron Institute of Oncology, 8035 - Barcelona/ES
  • 6 Laboratory For Translational Breast Cancer Research, KU Leuven, 3000 - Leuven/BE
  • 7 Medical Senology Dept., IEO - Istituto Europeo di Oncologia, 20141 - Milan/IT
  • 8 Laboratory Of Experimental Oncology, KU Leuven, 3000 - Leuven/BE
  • 9 Department Of Internal Medicine, Università degli Studi di Genova, Ospedale Policlinico San Martino IRCCS, Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC), 16132 - Genova/IT
  • 10 Medical / Research, Breast International Group (BIG) - AISBL, 1000 - Brussels/BE
  • 11 Research & Development Dept., Breast International Group (BIG) - AISBL, 1000 - Brussels/BE
  • 12 /, Breast International Group (BIG) - AISBL, 1200 - Brussels/BE
  • 13 Clinical Trials Conduct Unit, Institute Jules Bordet, 1070 - Anderlecht/BE
  • 14 Medical Oncology Dept., IVO - Fundación Instituto Valenciano de Oncología, 46009 - Valencia/ES
  • 15 Edinburgh Cancer Centre, Western General Hospital, Crewe Road South, Institute of Genetics and Cancer, University of Edinburgh, EH4 2XU - Edinburgh/GB
  • 16 Department Of Research, Medical Oncology, Medicine Department, Institute Jules Bordet, 1070 - Anderlecht/BE
  • 17 Department Of Experimental And Clinical Biomedical Sciences, Università degli Studi di Firenze,, 59100 - Prato/IT

Resources

This content is available to ESMO members and event participants.

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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