226P - Prevalence and characteristics of HR+/HER2- MBC with ESR1 mutations post-CDK inhibitor therapy

Background

Activating mutations of the ESR1 gene can be detected in up to 40% of endocrine therapy (ET)-resistant hormone receptor-positive, HER2-negative (HR+/ HER2-) metastatic breast cancer (MBC). Our aim was to investigate the role of ESR1^mut in HR+/HER2- MBC patients (pts) who have developed resistance to ET in combination with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i).

Methods

We retrospectively collected data and/or samples from pts with HR+/HER2- MBC treated at 4 institutions in Italy who had undergone a biopsy upon progression to first or second-line CDK4/6i plus ET prior to initiating a new treatment or within one month of beginning it. We assessed the presence of ESR1^mut in the biopsy samples using NGS and/or ddPCR panels assays targeting all the hotspot regions. The time to treatment failure (TTF) was calculated as the interval from the initiation of CDK4/6i therapy to its conclusion. A significance level of p<0.05 was established for correlative analyses.

Results

Of the 39 pts enrolled in the study (age 45-58, median 51 years), 26 (67%) had ESR1^mut in their metastatic sites. 57% of these pts had visceral metastases. After progression to CDK4/6i, 7 pts received ET (monotherapy or in combination treatments), while 17 received other therapies (including chemotherapy and PARP inhibitors). p.D538G and p.Y537S ESR1 activating mutations were the most prevalent mutations, present in 35% and 27% of the pts, respectively. The prevalence of liver metastases was similar in ESR1^mut and ESR1^WT tumors (70% vs 65%). There were no significant differences in TTF based on the type of therapy received after CDK4/6i, nor according to the duration of prior CDK4/6i (cutoff of 12 months). Additionally, the type of ESR1^mut did not affect the clinical outcome (p=0.16). Pts with concurrent mutations in both ESR1 and PIK3CA (n=4) exhibit a worse survival compared to the non-mutated counterpart, although the difference was not statistically significant (p=0.40).

Conclusions

This real-world study illuminates on the clinical characteristics and outcomes of pts with HR+/HER2- MBC according to the presence and type of ESR1^mut. We are expanding the cohort to include a broader spectrum of pts, enhancing the clinical relevance of our findings.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

C. De Angelis: Financial Interests, Personal, Advisory Board: Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Daicii-Sankyo, Gilead, and GSK; Financial Interests, Personal, Invited Speaker: Roche, Lilly, Novartis, Pfizer, Seagen, GSK, Gilead, and Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Novartis, Gilead, and Daiichi Sankyo . U. Malapelle: Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientifics, Eli Lilly, GSK, Merck, AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientifics, Eli Lilly, Diaceutics, GSK, Merck, AstraZeneca, Janssen, Diatech, Novartis, Hedera. A. Marra: Financial Interests, Personal, Advisory Board: Menarini/Stemline; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other, Travel Support: AstraZeneca. E. Guerini Rocco: Financial Interests, Personal, Invited Speaker: AstraZeneca, AstraZeneca, Exact Sciences, GSK, Illumina, Novartis, Roche, 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, 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. 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. N. Fusco: Financial Interests, Personal, Invited Speaker: Merck Sharp & Dohme (MSD), AstraZeneca, Daiichi Sankyo, 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. All other authors have declared no conflicts of interest.