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Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection
Cani, A. K. Dolce, E. M. Darga, E. P. Hu, K. Liu, C. J. Pierce, Jackie Bradbury, Karen Kilgour, Elaine Aung, K. Schiavon, G.
Cani, A. K.
Dolce, E. M.
Darga, E. P.
Hu, K.
Liu, C. J.
Pierce, Jackie
Bradbury, Karen
Kilgour, Elaine
Aung, K.
Schiavon, G.
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Abstract
Nearly all estrogen receptor (ER)-positive (POS) metastatic breast cancers become refractory to endocrine (ET) and other therapies, leading to lethal disease presumably due to evolving genomic alterations. Timely monitoring of the molecular events associated with response/progression by serial tissue biopsies is logistically difficult. Use of liquid biopsies, including circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) might provide highly informative, yet easily obtainable, evidence for better precision oncology care. Although ctDNA profiling has been well investigated, the CTC precision oncology genomic landscape and the advantages it may offer over ctDNA in ER-POS breast cancer remain largely unexplored. Whole blood (WB) specimens were collected at serial time points from patients with advanced ER-POS/HER2-negative (NEG) advanced breast cancer in a phase I trial of AZD9496, an oral selective ER degrader (SERD) ET. Individual CTC were isolated from WB using tandem CellSearch® /DEPArray™ technologies and genomically profiled by targeted single-cell DNA next-generation sequencing (scNGS). High-quality CTC (n=123) from 12 patients profiled by scNGS showed 100% concordance with ctDNA detection of driver estrogen receptor α (ESR1) mutations. We developed a novel CTC-based framework for precision medicine actionability reporting (MI-CTCseq) that incorporates novel features, such as clonal predominance and zygosity of targetable alterations, both unambiguously identifiable in CTC compared to ctDNA. Thus, we nominated opportunities for targeted therapies in 73% of patients, directed at alterations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 2 (FGFR2) and KIT proto-oncogene, receptor tyrosine kinase (KIT). Intra-patient, inter-CTC genomic heterogeneity was observed, at times between timepoints, in subclonal alterations. Our analysis suggests that serial monitoring of the CTC genome is feasible and should enable real-time tracking of tumor evolution during progression, permitting more combination precision medicine interventions.
Authors
Cani, A. K.
Dolce, E. M.
Darga, E. P.
Hu, K.
Liu, C. J.
Pierce, Jackie
Bradbury, Karen
Kilgour, Elaine
Aung, K.
Schiavon, G.
Carroll, D.
Carr, T. H.
Klinowska, T.
Lindemann, J.
Marshall, G.
Rowlands, V.
Harrington, E. A.
Barrett, J. C.
Sathiyayogan, N.
Morrow, C.
Sero, V.
Armstrong, Anne C
Baird, R.
Hamilton, E.
Im, S. A.
Jhaveri, K.
Patel, M. R.
Dive, Caroline
Tomlins, S. A.
Udager, A. M.
Hayes, D. F.
Paoletti, C.
Dolce, E. M.
Darga, E. P.
Hu, K.
Liu, C. J.
Pierce, Jackie
Bradbury, Karen
Kilgour, Elaine
Aung, K.
Schiavon, G.
Carroll, D.
Carr, T. H.
Klinowska, T.
Lindemann, J.
Marshall, G.
Rowlands, V.
Harrington, E. A.
Barrett, J. C.
Sathiyayogan, N.
Morrow, C.
Sero, V.
Armstrong, Anne C
Baird, R.
Hamilton, E.
Im, S. A.
Jhaveri, K.
Patel, M. R.
Dive, Caroline
Tomlins, S. A.
Udager, A. M.
Hayes, D. F.
Paoletti, C.
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Date
2021
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Article
Citation
Cani AK, Dolce EM, Darga EP, Hu K, Liu C, Pierce J, et al. Serial monitoring of genomic alterations in circulating tumor cells of ER‐positive/HER2‐negative advanced breast cancer: feasibility of precision oncology biomarker detection Molecular Oncology. Wiley; 2021.