ANTIBODY-DRUG CONJUGATES FOR THE TREATMENT OF BREAST CANCER.

Background: Trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1) are anti-HER2 antibody-drug conjugates (ADCs) which have shown robust efficacy for treating breast cancer. For both ADCs, however, we lack effective biomarkers to predict outcomes from pre-treatment samples. Methods: To unveil predictive biomarkers for ADCs, we first evaluated 5-year outcomes in a prospective trial (ATEMPT) testing adjuvant T-DM1 in patients with stage I HER2+ breast cancer, and reviewed real-world outcomes with T-DXd for patients with metatatic breast cancer at two academic institutions. Moreover, we conducted a multi-omic assessment of HER2 and extensive translational analyses to predict outcomes with T-DM1 in ATEMPT and T-DXd in the real world. Results: Among 383 patients with stage I HER2+ breast cancer receiving adjuvant T-DM1, the 5-year iDFS was 97.0% (95% CI, 95.2 to 98.7). For those patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes differed according to HER2DX risk score, with significantly better RFI and iDFS among patients with HER2DX low-risk versus high-risk tumors. We also evaluated real-world outcomes among 191 patients with metastatic breast cancer. Herein, we demonstrate that T-DXd is associated with relevant real-world activity, with a time-to-next treatment of 9.1 months (range: 7.6 – 10.4) and an overall survival of 22.2 months (range: 17.1 – 25.2). The quantitative proteomic (High Sensitivity-HER2, Reverse Phase Protein Array), transcriptomic (HER2DX) and circulating tumor DNA (DNADX) assessment of HER2 on pre-T-DXd samples enabled a refined prediction of T-DXd efficacy, including in subgroup analyses of HER2-positive and HER2-negative breast cancer. Conclusion: a multi-omic characterization of HER2 expression in pre-treatment tumor samples showed promise in predicting the efficacy of T-DM1 in an adjuvant trial and T-DXd in the real world. Further validation of the biomarkers included in this study is planned within three ongoing phase 2 clinical trials, and may lead in the future to a refined use of anti-HER2 ADCs in clinical practice.

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2024

Author dc:creator

• TARANTINO, PAOLO

Contributors dc:contributor

• tutor: G. Curigliano ; co-tutor: S. Tolaney ; revisori: P. Lorusso
• F. Andre' ; coordinatore: M. Del Fabbro
• P. Tarantino
• CURIGLIANO, GIUSEPPE
• DEL FABBRO, MASSIMO

• Settore MED/50 - Scienze Tecniche Mediche Applicate

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

http://dx.doi.org/10.13130/tarantino-paolo_phd2024-12-19
10.13130/tarantino-paolo_phd2024-12-19

OAI identifier oai:identifier

oai:air.unimi.it:2434/1119775