Abstract 35P
Background
Genomic alterations in ESR1 are enriched in endocrine therapy (ET)-resistant, estrogen receptor-positive (ER+) metastatic breast cancer (mBC). In the present analysis, we investigated clinical and genomic differences among ESR1 wild type (ESR1 WT ) and ESR1-mutated (ESR1 MUT ) ER+ mBCs.
Methods
Clinical and genomic data was retrieved from cBioPortal using the MSK MetTropism dataset. Metastatic, post-ET ER+/HER2- tumor samples were included in the analysis. Oncogenic and likely oncogenic alterations according to OncoKB were included in the analysis. False discovery rate (FDR) correction was applied for multiple hypothesis testing.
Results
Among 707 ER+/HER2- mBCs, 136 ESR1 MUT in 131 tumors were found, of whom 85.29% (116/136) consisted in alterations located in helices 11 and 12 (H11-12), 10.29% (14/136) in H5 (E380X), and 4.41% (6/136) in other domains of the ESR1 gene. The frequency of ESR1 MUT was higher in ductal vs. lobular mBC (20.1% vs. 13.2%; P=0.04) and enriched in liver metastasis compared to other sites (22.5% vs. 12.7%; q=0.02). ESR1 MUT tumors showed higher fraction of genome altered (FGA) (0.28 [IQR 0.15 0.43] vs. 0.22 [0.11-0.38]; P=0.04) and tumor mutational burden (TMB) (4.89 [IQR 3.46-6.85] vs. 3.92 [2.59-6.05] mut/Mb; P=0.001) compared to ESR1 WT mBC. Tumors harboring E380X alterations had higher TMB compared to those with H11-12 alterations (8.24 [IQR 5.06-15.3] vs. 4.89 [3.46-6.75] mut/Mb; P=0.01). In both ESR1 MUT and ESR1 WT tumors, PIK3CA represented the most common altered gene (38% and 42%). TP53 gene alterations were enriched in ESR1 WT tumors (36% vs. 14%) (Odd Ratio (OR) 3.17, 95% CI 1.88-5.64, q=0.001). Considering signaling pathways, ESR1 MUT tumors showed a lower occurrence of TP53-pathway (OR 0.48, 95%CI 0.30-0.74; q=0.003) and MAPK (OR 0.29, 95%CI 0.11-0.65; q=0.009) alterations. TP53 (q<0.001), CDH1 (q<0.001) and ERBB2 (q<0.001) demonstrated mutual exclusivity with ESR1 MUT .
Conclusions
ER+/HER2- mBCs carrying ESR1MUT exhibit a divergent genomic background, such as a low number of TP53 and MAPK pathway alterations. Less common ESR1 alterations falling outside the H11-H12 region seem to occur in tumors with high TMB, deserving further investigation to understand their real actionability.
Legal entity responsible for the study
L. Boscolo Bielo.
Funding
Has not received any funding.
Disclosure
C. Criscitiello: Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Eli Lilly, Roche, Gilead; Financial Interests, Personal, Advisory Board: MSD, Seagen, AstraZeneca, Daiichi Sankyo. A. Marra: Financial Interests, Personal, Advisory Board: Menarini/Stemline; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other, Travel Support: AstraZeneca. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; 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, Invited Speaker, 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, Member of Board of Directors, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Officer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Officer, ESMO Clinical Practice Guidelines Chair: ESMO; Non-Financial Interests, Member of Board of Directors, Chair of Clinical Practice Guidelines Committee: ESMO. All other authors have declared no conflicts of interest.