Circulating tumor DNA reveals complex biological features with clinical relevance in metastatic breast cancer

Aleix Prat (), Fara Brasó-Maristany, Olga Martínez-Sáez, Esther Sanfeliu, Youli Xia, Meritxell Bellet, Patricia Galván, Débora Martínez, Tomás Pascual, Mercedes Marín-Aguilera, Anna Rodríguez, Nuria Chic, Barbara Adamo, Laia Paré, Maria Vidal, Mireia Margelí, Ester Ballana, Marina Gómez-Rey, Mafalda Oliveira, Eudald Felip, Judit Matito, Rodrigo Sánchez-Bayona, Anna Suñol, Cristina Saura, Eva Ciruelos, Pablo Tolosa, Montserrat Muñoz, Blanca González-Farré, Patricia Villagrasa, Joel S. Parker, Charles M. Perou and Ana Vivancos
Additional contact information
Aleix Prat: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Fara Brasó-Maristany: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Olga Martínez-Sáez: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Esther Sanfeliu: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Youli Xia: Reveal Genomics
Meritxell Bellet: SOLTI cooperative group
Patricia Galván: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Débora Martínez: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Tomás Pascual: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Mercedes Marín-Aguilera: Reveal Genomics
Anna Rodríguez: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Nuria Chic: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Barbara Adamo: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Laia Paré: Reveal Genomics
Maria Vidal: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Mireia Margelí: Hospital Germans Trias i Pujol
Ester Ballana: Hospital Germans Trias i Pujol
Marina Gómez-Rey: Vall d´Hebron Institute of Oncology (VHIO)
Mafalda Oliveira: SOLTI cooperative group
Eudald Felip: Hospital Germans Trias i Pujol
Judit Matito: Vall d´Hebron Institute of Oncology (VHIO)
Rodrigo Sánchez-Bayona: Hospital Universitario 12 de Octubre
Anna Suñol: Autonomous University of Barcelona
Cristina Saura: SOLTI cooperative group
Eva Ciruelos: Hospital Universitario 12 de Octubre
Pablo Tolosa: Hospital Universitario 12 de Octubre
Montserrat Muñoz: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Blanca González-Farré: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Patricia Villagrasa: Reveal Genomics
Joel S. Parker: University of North Carolina
Charles M. Perou: University of North Carolina
Ana Vivancos: Vall d´Hebron Institute of Oncology (VHIO)

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Liquid biopsy has proven valuable in identifying individual genetic alterations; however, the ability of plasma ctDNA to capture complex tumor phenotypes with clinical value is unknown. To address this question, we have performed 0.5X shallow whole-genome sequencing in plasma from 459 patients with metastatic breast cancer, including 245 patients treated with endocrine therapy and a CDK4/6 inhibitor (ET + CDK4/6i) from 2 independent cohorts. We demonstrate that machine learning multi-gene signatures, obtained from ctDNA, identify complex biological features, including measures of tumor proliferation and estrogen receptor signaling, similar to what is accomplished using direct tumor tissue DNA or RNA profiling. More importantly, 4 DNA-based subtypes, and a ctDNA-based genomic signature tracking retinoblastoma loss-of-heterozygosity, are significantly associated with poor response and survival outcome following ET + CDK4/6i, independently of plasma tumor fraction. Our approach opens opportunities for the discovery of additional multi-feature genomic predictors coming from ctDNA in breast cancer and other cancer-types.

Date: 2023
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DOI: 10.1038/s41467-023-36801-9

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