406P - Genomic landscape of endocrine therapy (ET)-resistant BRCA1/2 and PALB2 altered metastatic breast cancer (mBC)

Background

In ER+/HER2- mBC, different genomic mechanisms yield primary and secondary resistance to ET. Data are scarce on different concurrent genomic alterations that may result in ET resistance among BRCA1/2 and PALB2 altered (^ALT) mBC.

Methods

We retrospectively included patients with ET-resistant ER+/HER2- mBC referred to the European Institute of Oncology Molecular Tumor Board (MTB). For a comparative cohort, clinical and genomic data of pre-treated ER+/HER2- mBC was retrieved from the MSK MetTropism study. Only oncogenic genomic alterations were included.8 Results.

Results

Seventeen patients out of 61 (28%) with ER+/HER2- mBC exhibited a BRCA1/2^ALT (BRCA2, n=11; BRCA1, n=3) and PALB2^ALT (n=3) (Group A), while Group B included the remaining 44 patients with wild-type genes. BRCA1/2^ALT and PALB2^ALT consisted of 10 small indels, 6 single nucleotide variants (SNV), and 1 homozygous deletion. Compared to Group B, Group A displayed a lower occurrence of alterations in PIK3CA (5.8% vs. 47.7%, P=0.002), TP53 (5.8% vs. 31.8%, P=0.04), and in the CCND1-FGF19-FGF3 amplicon (P=0.001), along with a lower occurrence of PI3K-AKT-mTOR (15.8% vs. 47.8%, P<0.01) and TP53 (7.6% vs. 42.9%, P<0.01) alterations at the pathway level. In the MSK dataset (n=679), Group A included 27 cases (BRCA2, n=16; BRCA1, n=8; PALB2, n=3), showing a lower occurrence of ESR1^ALT (7.4% vs. 21.8%, P=0.09). At the pathway level, Group A displayed a lower frequency of TP53 (12.7% vs. 24.2%, P <0.001), MAPK (0.7% vs. 21.3%, P<0.001), PI3K-AKT-mTOR (17.3% vs. 22.0%, P=0.13) alterations, while showing a higher occurrence of cell-cycle^ALT (27.8% vs. 23.5%, P=0.03). In the MSK cohort, no gene demonstrated neither mutual exclusivity nor co-occurrence with BRCA1^ALT, BRCA2^ALT, and PALB2^ALT.

Conclusions

Despite the limited sample size, our study suggests that BRCA1/2^ALT and PALB2^ALT -driven ER+/HER2- mBC generally exhibit a lower occurrence of classic alterations in pathways involved in primary and secondary ET resistance, requiring further investigation to detect mechanisms driving ET resistance among this subgroup of mBC to achieve treatment personalization, thus better long-term outcomes further.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Prof. Giuseppe Curigliano.

Funding

Has not received any funding.

Disclosure

A. Marra: Financial Interests, Personal, Advisory Board: Menarini/Stemline; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other, Travel Support: AstraZeneca. N. Fusco: Financial Interests, Personal, Invited Speaker: Merck Sharp & Dohme (MSD), AstraZeneca, Daiichi Sankyo, GSK (GSK), Gilead, Novartis, Roche, Menarini, Lilly, Sysmex; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme (MSD), AstraZeneca, Menarini; Financial Interests, Personal and Institutional, Research Grant: Novartis, Sysmex, Veracyte. E. Guerini Rocco: Financial Interests, Personal, Invited Speaker: AstraZeneca, Exact Sciences, GSK, Illumina, Novartis, Thermo Fisher Scientific; Financial Interests, Personal, Other, travel accommodation and expenses: AstraZeneca, Exact Sciences, GSK, Illumina, Novartis, Roche, Thermo Fisher Scientific; Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Novartis, Roche; Financial Interests, Personal, Writing Engagement: AstraZeneca, Roche; Financial Interests, Institutional, Funding: AstraZeneca, GSK; Financial Interests, Personal and Institutional, Research Grant: Thermo Fisher Scientific; Non-Financial Interests, Institutional, Product Samples: Thermo Fisher Scientific, Illumina, Agilent Technologies, Diatech Pharmacogenetics S.R.L., Biocartis. C. Criscitiello: Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Eli-Lilly, Roche, Gilead; Financial Interests, Personal, Advisory Board: MSD, Seagen, AstraZeneca, Daiichi Sankyo. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad board participant/consultant: ARC Therapeutics, Daichii Sankyo, Eisai, Genentech/Roche, Gilead, Novartis, Sanofi, Seagen; Financial Interests, Personal, Other, Consulting: Aadi BioPharma, Hengrui USA; Financial Interests, Personal, Advisory Board, Ad board participation: Artios, Incyte Corp, BeyondSprings; Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Advisory Board participation: Bayer, Infinity Therapeutics, Sumitovant Biopharmaceuticals, OncXerna, Umoja Biopharma, Zentalis, Natera; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol-Myers Squibb; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory board/consulting: Jazz Pharma; Financial Interests, Personal, Advisory Board: Tango Therapeutics, Systimmune, eFFECTOR, Cullinan Oncology, Arvinas; Financial Interests, Institutional, Funding, And steering committing: AstraZeneca; Financial Interests, Institutional, Funding, And steering committee: Eli Lilly; Financial Interests, Institutional, Funding: Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Bristol Myers Squibb, Eisai, Merck, Novartis; Financial Interests, Personal and Institutional, Steering Committee Member: CytomX; Financial Interests, Institutional, Funding, and steering committee: Gilead, Genentech/Roche; Financial Interests, Institutional, Local PI: Stemline/Menarini. D. Trapani: Other, EMA Healthcare Professional Working Party (HCPWP), member: European Medicines Agency (EMA); Other, EML Cancer Medicines Working Group (CMWG), member: World Health Organization (WHO); Other, Strategic Advisory Group of Experts on In Vitro Diagnostics (SAGE IVD), chair: World Health Organization (WHO). G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Personal, Advisory Board, Advisory Board: Menarini, Gilead; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Coordinating PI, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Officer, Editor of Chief of ESMO Open: ESMO; Non-Financial Interests, Leadership Role, Until the end of 2024: EUSOMA. All other authors have declared no conflicts of interest.