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

Smruthy Sivakumar (), Dexter X. Jin, Hanna Tukachinsky, Karthikeyan Murugesan, Kimberly McGregor, Natalie Danziger, Dean Pavlick, Ole Gjoerup, Jeffrey S. Ross, Robert Harmon, Jon Chung, Brennan Decker, Lucas Dennis, Garrett M. Frampton, Luciana Molinero, Steffi Oesterreich, Jeffrey M. Venstrom, Geoffrey R. Oxnard, Priti S. Hegde and Ethan S. Sokol ()
Additional contact information
Smruthy Sivakumar: Foundation Medicine, Inc.
Dexter X. Jin: Foundation Medicine, Inc.
Hanna Tukachinsky: Foundation Medicine, Inc.
Karthikeyan Murugesan: Foundation Medicine, Inc.
Kimberly McGregor: Foundation Medicine, Inc.
Natalie Danziger: Foundation Medicine, Inc.
Dean Pavlick: Foundation Medicine, Inc.
Ole Gjoerup: Foundation Medicine, Inc.
Jeffrey S. Ross: Foundation Medicine, Inc.
Robert Harmon: Foundation Medicine, Inc.
Jon Chung: Foundation Medicine, Inc.
Brennan Decker: Foundation Medicine, Inc.
Lucas Dennis: Foundation Medicine, Inc.
Garrett M. Frampton: Foundation Medicine, Inc.
Luciana Molinero: Genentech, Inc.
Steffi Oesterreich: University of Pittsburgh
Jeffrey M. Venstrom: Foundation Medicine, Inc.
Geoffrey R. Oxnard: Foundation Medicine, Inc.
Priti S. Hegde: Foundation Medicine, Inc.
Ethan S. Sokol: Foundation Medicine, Inc.

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-35245-x

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