416P - Prognostic impact of liquid biopsy (LB) biomarkers at relapse on second-line (2L) treatment (Tx) after progression to endocrine therapy (ET) in metastatic breast cancer (mBC): Ancillary analysis of the MAGNETIC.1 study

Background

With the increasing availability of new therapies and the absence of reliable biomarkers for ET, determining the 2L Tx algorithm for luminal-like (HRpos) mBC has become more challenging. This study aimed to assess the impact of LB biomarkers at the diagnosis of metastatic relapse before first line (1L) ET on 2L progression free survival (PFS2) and overall survival (OS2).

Methods

The prospective multicenter MAGNETIC.1 trial (NCT05814224) enrolled 148 patients (pts) with HRpos mBC treated with 1L ET and longitudinally characterized through LB. The prognostic impact of clinical and LB features was evaluated using Cox regression analysis. Survival estimates were generated using the Kaplan-Meier method.

Results

Overall, 88 pts (59%) experienced disease progression (PD) to 1L. 2L Tx options were chemotherapy (CT) (53%), CDK4/6i beyond PD (20%), ET alone (15%), ET + everolimus (8%), and ET + alpelisib (1%). The main baseline (BL) metastatic (mts) sites were bone (73%) and lymph nodes (55%), while new mts sites at PD included liver (44%), bone (19%) and lung (8%). LB biomarkers significantly associated with PFS2 were BL methylation of ESR1 promoter A (PromA) and promoter B (PromB) dichotomized at 75th percentile (high versus low) (respectively P=0.05 and P=0.022), PromA at 6 months (T5) (P=0.013), and BL Actin short (As) fragments (P=0.007). The latter was confirmed after correction for 2L Tx type (CT versus ET) and 1L progression free survival (PFS1) (P=0.007). PromA dynamics was also prognostic, regardless of BL Prom A (P=0.013). No impact of clinical features emerged for PFS2. Liver mts, 2L Tx type, BL As, BL AKT1 and BL ERBB2 mutational status were prognostic for OS2. Significance was confirmed at multivariable analysis corrected for PFS1 for BL As (P=<0.001), BL AKT1 (P=0.001) and BL ERBB2 (P=0.003).

Conclusions

LB biomarkers at relapse exhibit prognostic significance not only for 1L but also for 2L Tx, independently of main clinical features. Characterization through plasma As fragments may offer insights into both PFS2 and OS2, potentially guiding Tx sequencing beyond the 1L.

Clinical trial identification

NCT05814224. Release date: not applicable.

Editorial acknowledgement

Legal entity responsible for the study

Centro di Riferimento Oncologico (CRO), IRCCS - Aviano (PN), Italy.

Funding

Italian Ministry of Health (Ricerca finalizzata).

Disclosure

S. Spazzapan: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, MSD, Novartis, Pfizer, Seagen, Mundipharma; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Daiichi Sankyo, MSD, Novartis, Pfizer, Seagen, Mundipharma; Financial Interests, Personal, Research Grant: AstraZeneca, Daiichi Sankyo, MSD, Novartis, Pfizer, Seagen, Mundipharma. A.M.M. Minisini: Financial Interests, Personal, Advisory Board: Novartis, MSD, BMS, Merck, PierreFabre, Gilead, Seagen; Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, MSD, BMS, Merck, Sunpharma, Sanofi, PierreFabre; Financial Interests, Personal, Other: MSD, AstraZeneca, Pharmamar, GSK; Financial Interests, Personal, Advisory Role: Sunpharma; Financial Interests, Personal, Other, Travel grant: PierreFabre, Gilead. L. Gerratana: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Eli Lilly, GSK, Incyte, Novartis, Pfizer, Merck Sharp & Dohme, Menarini Stemline, Abbvie; Financial Interests, Personal and Institutional, Research Funding: Menarini Silicon Biosystems; Financial Interests, Personal, Other, Travel expenses: Menarini Stemline. F. Puglisi: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Daiichi Sankyo, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Italfarmaco, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, Viatris; Financial Interests, Personal and Institutional, Research Funding: Astrazeneca, Eisai, Roche; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Daiichi Sankyo, Celgene, Eli Lilly, Exact Sciences, Gilead, Ipsen, Italfarmaco, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, Viatris; Financial Interests, Personal, Other, Travel grant: Amgen, AstraZeneca, Daiichi Sankyo, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Italfarmaco, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, Viatris; Financial Interests, Personal, Research Grant: Amgen, AstraZeneca, Daiichi Sankyo, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Italfarmaco, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Seagen, Takeda, Viatris; Financial Interests, Personal, Speaker, Consultant, Advisor: Eisai ; Financial Interests, Personal, Research Funding: Roche. All other authors have declared no conflicts of interest.