Journal Article

Tissue and liquid biopsy profiling reveal convergent tumor evolution and therapy evasion in breast cancer

Tukachinsky, Hanna, Hegde, Priti S., Molinero, Luciana, Oxnard, Geoffrey R., Gjoerup, Ole, Venstrom, Jeffrey M., Danziger, Natalie, Decker, Brennan, Pavlick, Dean, Oesterreich, Steffi, Dennis, Lucas, Frampton, Garrett M., Sokol, Ethan S., Ross, Jeffrey S., Chung, Jon, Jin, Dexter X., Sivakumar, Smruthy, McGregor, Kimberly, Harmon, Robert, Murugesan, Karthikeyan

2022

Overview

Pathological and genomic profiling have transformed breast cancer care by matching patients to targeted treatments. However, tumors evolve and evade therapeutic interventions often through the acquisition of genomic mutations. Here we examine patients profiled with tissue (TBx) and liquid biopsy (LBx) as part of routine clinical care, to characterize the tumor evolutionary landscape and identify potential vulnerabilities in the relapsed setting. Real-world evidence demonstrates that LBx is utilized later in care and identifies associations with intervening therapy. While driver events are frequently shared, acquired LBx alterations are detected in a majority of patients, with the highest frequency in ER+ disease and in patients with longer biopsy intervals. Acquired mutations are often polyclonal and present at lower allelic fractions, suggesting multi-clonal convergent evolution. In addition to well-characterized resistance mutations (e.g., ESR1 , NF1 , RB1 , ERBB2) , we observe a diversity of rarer but potentially targetable mutations (e.g., PIK3CA, HRAS / NRAS / KRAS , FGFR1/2/3 , BRAF ) and fusions (e.g., FGFR1/2 , ERBB2 , RET ), as well as BRCA1/2 reversions through a variety of mechanisms, including splice alterations and structural deletions. This study provides insights on treatment and selection-driven tumor evolution and identifies potential combinatorial treatment options in advanced breast cancer. Liquid biopsies could be valuable tools to monitor breast cancer progression and evolution. Here, the authors investigate genomic profiling of tissue and liquid biopsies in a large cohort of patients with breast cancer during the course of therapy to characterise tumour evolution and acquired mutations.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/23 / 631/67/1347 / 631/67/69 / Biomarkers, Tumor - genetics / Biopsy / BRCA1 protein / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - therapy / Cancer therapies / Combinatorial analysis / Convergence / ErbB-2 protein / ESR1 protein / Evolution / Female / Fibroblast growth factor receptor 1 / Fractions / Genomics / Health services / Humanities and Social Sciences / Humans / Liquid Biopsy / multidisciplinary / Mutation / Patients / Science / Science (multidisciplinary) / Therapeutic applications / Therapy / Tumors