Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection
AuthorsCani, A. K.
Dolce, E. M.
Darga, E. P.
Liu, C. J.
Carr, T. H.
Harrington, E. A.
Barrett, J. C.
Armstrong, Anne C
Im, S. A.
Patel, M. R.
Tomlins, S. A.
Udager, A. M.
Hayes, D. F.
AffiliationDivision of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
MetadataShow full item record
AbstractNearly 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.
CitationCani 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.
- Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.
- Authors: Paoletti C, Schiavon G, Dolce EM, Darga EP, Carr TH, Geradts J, Hoch M, Klinowska T, Lindemann J, Marshall G, Morgan S, Patel P, Rowlands V, Sathiyayogan N, Aung K, Hamilton E, Patel M, Armstrong A, Jhaveri K, Im SA, Iqbal N, Butt F, Dive C, Harrington EA, Barrett JC, Baird R, Hayes DF
- Issue date: 2018 Dec 1
- <i>ESR1</i> Methylation: A Liquid Biopsy-Based Epigenetic Assay for the Follow-up of Patients with Metastatic Breast Cancer Receiving Endocrine Treatment.
- Authors: Mastoraki S, Strati A, Tzanikou E, Chimonidou M, Politaki E, Voutsina A, Psyrri A, Georgoulias V, Lianidou E
- Issue date: 2018 Mar 15
- Hybrid capture-based genomic profiling of circulating tumor DNA from patients with estrogen receptor-positive metastatic breast cancer.
- Authors: Chung JH, Pavlick D, Hartmaier R, Schrock AB, Young L, Forcier B, Ye P, Levin MK, Goldberg M, Burris H, Gay LM, Hoffman AD, Stephens PJ, Frampton GM, Lipson DM, Nguyen DM, Ganesan S, Park BH, Vahdat LT, Leyland-Jones B, Mughal TI, Pusztai L, O'Shaughnessy J, Miller VA, Ross JS, Ali SM
- Issue date: 2017 Nov 1
- Association of a novel circulating tumor DNA next-generating sequencing platform with circulating tumor cells (CTCs) and CTC clusters in metastatic breast cancer.
- Authors: Davis AA, Zhang Q, Gerratana L, Shah AN, Zhan Y, Qiang W, Finkelman BS, Flaum L, Behdad A, Gradishar WJ, Platanias LC, Cristofanilli M
- Issue date: 2019 Dec 4
- Circulating tumour DNA in metastatic breast cancer to guide clinical trial enrolment and precision oncology: A cohort study.
- Authors: Zivanovic Bujak A, Weng CF, Silva MJ, Yeung M, Lo L, Ftouni S, Litchfield C, Ko YA, Kuykhoven K, Van Geelen C, Chandrashekar S, Dawson MA, Loi S, Wong SQ, Dawson SJ
- Issue date: 2020 Oct