Next-Generation Sequencing of Tissue and Circulating Tumor DNA: The UC San Diego Moores Center for Personalized Cancer Therapy Experience with Breast Malignancies.

Rebecca Shatsky,Nam Q Bui,Barbara A Parker,Richard B Schwab,Teresa Helsten,Sarah G Boles,Razelle Kurzrock

doi:10.1158/1535-7163.mct-17-1038

Rebecca Shatsky, Nam Q Bui + Show 5 more

Open Access

https://doi.org/10.1158/1535-7163.mct-17-1038

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Abstract

Clinical-grade next-generation sequencing (NGS) of tissue- and blood-derived circulating tumor DNA (ctDNA) allows assessment of multiple genomic alterations in patients with cancer. We analyzed ctDNA (54-70 genes) in 62 patients with advanced breast cancer (median = five prior therapies); 38 also had tissue NGS (236-315 genes). Overall, 42 of 62 patients (68%) had detectable (characterized) ctDNA alterations (variants of unknown significance excluded), and 37 of 38 (97%) had tissue alterations. The median (range) number of characterized alterations in ctDNA was 1 (0-7), and in tissue, 4 (0-17). The most common alterations in ctDNA were in TP53 (37% of patients) and PIK3CA (23%), and for tissue, TP53 (37%) and PIK3CA (24%); EGFR amplification was seen in ctDNA (11%), but not in tissue. Concordance between ctDNA and tissue appeared higher if <6 months separated the sample acquisition, although small sample size precluded statistical validation. Overall, 32 of 67 tissue alterations (48%) were also detected in ctDNA; 35 of 72 ctDNA alterations (48%) were also in tissue. Excluding estrogen receptor and ERBB2, 41 of 62 patients (66%) had potentially actionable alterations in ctDNA, and 36 of 38 (95%), in tissue (with potential actionability based on either preclinical or clinical evidence). If ≥1 genomic alteration had ctDNA ≥5%, survival was shorter than if ctDNA was <5% (median, 6.7 vs. 17.9 months; P = 0.01). In conclusion, tissue and ctDNA NGS reveal potentially actionable alterations in most patients. The genomic results of ctDNA and tissue NGS overlap, but there are differences, perhaps reflecting temporal spacing and tumor heterogeneity. ctDNA quantification also provides prognostic information.

Highlights

The field of breast oncology was one of the first to exploit "targeted" therapy using characteristics from a patient's own tumor to direct patient care
Patient characteristics From November 2013 to March 2016, 62 patients with metastatic or locally advanced/unresectable breast cancer had circulating tumor DNA (ctDNA) next-generation sequencing (NGS) performed and available for review; 38 of these patients (61%) had tumor biopsies from either primary breast tumors or various metastatic sites sent for tissue NGS
Patients had a median of one characterized alteration detected by ctDNA NGS and a median of four detected by tissue NGS

Summary

Introduction

The field of breast oncology was one of the first to exploit "targeted" therapy using characteristics from a patient's own tumor to direct patient care. This practice began with the use of anti-estrogen approaches with oophorectomy in the 1950's and 60's (1) and expanded rapidly with the use of agents to target hormone receptor–positive tumors in the 1980's (2). Targeted therapy in breast cancer has continued to grow as new therapeutic agents have been identified targeting tumors expressing hormone receptors (progestational agents, selective estrogen receptor (ER) modulators, aromatase inhibitors, selective ER degraders, and CDK4/6 inhibitors) and tumors with.

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