42 Tissue and Liquid Biopsy–Based Comprehensive Genomic Profiling Reveal Mechanisms of Therapy Resistance and Rare Targetable Alterations in Breast Cancer

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Miami Breast Cancer Conference® Abstracts Supplement, 39th Annual Miami Breast Cancer Conference® - Abstracts, Volume 36, Issue suppl 3
Pages: 17

Background

Pathological and genomic profiling aid in the selection of targeted treatments for patients with breast cancer. However, tumors often evolve and evade therapeutic interventions. Here we examine patients profiled with tissue and liquid biopsy, to characterize the genomic landscape and identify potential vulnerabilities in the relapsed setting.


Patients and Methods

Comprehensive genomic profiling (CGP) was carried out on 29,704 patients with breast cancer profiled with tissue biopsy, 3339 with liquid biopsy (targeting up to 70 genes), and 712 patients profiled on both platforms during routine clinical care. Additionally, CGP profiles from 1430 patients tested on the most recent liquid biopsy assay (FoundationOne Liquid CDx) targeting 324 genes were also examined.


Results

Potentially actionable driver alterations were observed in both cohorts, including PIK3CA (34.0% tissue biopsy vs 33.3% liquid biopsy) and BRCA1/2 (7.1% vs 7.4%). In an analysis limited to the recent liquid biopsy assay, similar results were seen (PIK3CA 30.2% vs BRCA1/2 7.9%). Among 712 patients with paired tissue/liquid biopsies, presumably tumor-initiating truncal alterations were frequently shared. When sufficient circulating tumor DNA was present (≥10% tumor fraction), positive percent agreement was high, especially for PIK3CA (93.4%), BRCA (95.0%), and TP53 (92.8%). Acquired liquid biopsy alterations were detected in a majority of patients, with the highest frequency in estrogen receptor–positive disease (60%) and in patients with longer biopsy intervals (71% for biopsies taken >3 years apart). In addition to well-characterized resistance mutations (ESR1, NF1, RB1, and ERBB2), a diversity of potentially actionable alterations were identified in follow-up liquid biopsies, including activating mutations in PIK3CA, HRAS, NRAS, KRAS, FGFR1/2/3, and BRAF. Rare, acquired fusions included FGFR1/2 fusions in multiple patients with estrogen receptor–positive/HER2–negative disease, an ERBB2 fusion in a patient with HER2-positive disease, and an acquired RET fusion. Acquired mutations were primarily identified at a low clonal fraction and were often polyclonal, suggesting convergent evolutionary mechanisms to evade therapeutic pressure.


Conclusions

Liquid biopsy profiling provides evidence for therapeutic and selection-driven evolution, with a high frequency of shared driver alterations and a diverse set of in-pathway subclonal acquired alterations. Potentially actionable baseline and acquired alterations identified in liquid biopsies may provide insights into additional treatment options, potentially through combinatorial strategies.

Author Affiliations:

Ethan Sokol,1 Smruthy Sivakumar,2 Dexter X. Jin,2 Hanna Tukachinsky,2 Karthikeyan Murugesan,2 Dean Pavlick,2 Jeffrey S. Ross,2 Garrett M. Frampton,2 Geoffrey R. Oxnard,2 Priti S. Hegde2

1Senior Scientist, Foundation Medicine, Cambridge, MA

2Foundation Medicine, Cambridge, MA