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1
Department of Medicine, Kansas City School of Medicine, University of Missouri, Kansas City, MO 64110, USA. imperialr@umkc.edu.
2
Department of Medicine, Kansas City School of Medicine, University of Missouri, Kansas City, MO 64110, USA. nazerm@umkc.edu.
3
Department of Medicine, Kansas City School of Medicine, University of Missouri, Kansas City, MO 64110, USA. ahmedza@umkc.edu.
4
Division of Hematology/Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA. Audrey_E_Kam@rush.edu.
5
Department of Medicine, Kansas City School of Medicine, University of Missouri, Kansas City, MO 64110, USA. tpluard@saint-lukes.org.
6
Division of Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA. tpluard@saint-lukes.org.
7
Department of Medicine, Kansas City School of Medicine, University of Missouri, Kansas City, MO 64110, USA. bahajw@umkc.edu.
8
Division of Hematology/Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA. Mia_Levy@rush.edu.
9
Rush Precision Oncology Program, Rush University Medical Center, Chicago, IL 60612, USA. Mia_Levy@rush.edu.
10
Division of Hematology/Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA. Timothy_Kuzel@rush.edu.
11
Rush Precision Oncology Program, Rush University Medical Center, Chicago, IL 60612, USA. Timothy_Kuzel@rush.edu.
12
Division of Surgical Oncology, Rush University Medical Center, Chicago, IL 60612, USA. Dana_M_Hayden@rush.edu.
13
Division of Surgical Oncology, Rush University Medical Center, Chicago, IL 60612, USA. Sam_G_Pappas@rush.edu.
14
Department of Medicine, Kansas City School of Medicine, University of Missouri, Kansas City, MO 64110, USA. jsubramanian@saint-lukes.org.
15
Division of Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA. jsubramanian@saint-lukes.org.
16
Division of Hematology/Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA. ashiq_masood@rush.edu.
17
Rush Precision Oncology Program, Rush University Medical Center, Chicago, IL 60612, USA. ashiq_masood@rush.edu.
1
Department of Medicine, Kansas City School of Medicine, University of Missouri, Kansas City, MO 64110, USA. imperialr@umkc.edu.
2
Department of Medicine, Kansas City School of Medicine, University of Missouri, Kansas City, MO 64110, USA. nazerm@umkc.edu.
3
Department of Medicine, Kansas City School of Medicine, University of Missouri, Kansas City, MO 64110, USA. ahmedza@umkc.edu.
4
Division of Hematology/Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA. Audrey_E_Kam@rush.edu.
5
Department of Medicine, Kansas City School of Medicine, University of Missouri, Kansas City, MO 64110, USA. tpluard@saint-lukes.org.
6
Division of Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA. tpluard@saint-lukes.org.
7
Department of Medicine, Kansas City School of Medicine, University of Missouri, Kansas City, MO 64110, USA. bahajw@umkc.edu.
8
Division of Hematology/Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA. Mia_Levy@rush.edu.
9
Rush Precision Oncology Program, Rush University Medical Center, Chicago, IL 60612, USA. Mia_Levy@rush.edu.
10
Division of Hematology/Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA. Timothy_Kuzel@rush.edu.
11
Rush Precision Oncology Program, Rush University Medical Center, Chicago, IL 60612, USA. Timothy_Kuzel@rush.edu.
12
Division of Surgical Oncology, Rush University Medical Center, Chicago, IL 60612, USA. Dana_M_Hayden@rush.edu.
13
Division of Surgical Oncology, Rush University Medical Center, Chicago, IL 60612, USA. Sam_G_Pappas@rush.edu.
14
Department of Medicine, Kansas City School of Medicine, University of Missouri, Kansas City, MO 64110, USA. jsubramanian@saint-lukes.org.
15
Division of Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA. jsubramanian@saint-lukes.org.
16
Division of Hematology/Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA. ashiq_masood@rush.edu.
17
Rush Precision Oncology Program, Rush University Medical Center, Chicago, IL 60612, USA. ashiq_masood@rush.edu.
Tumor heterogeneity, especially intratumoral heterogeneity, is a primary reason for treatment failure. A single biopsy may not reflect the complete genomic architecture of the tumor needed to make therapeutic decisions. Circulating tumor DNA (ctDNA) is believed to overcome these limitations. We analyzed concordance between ctDNA and whole-exome sequencing/whole-genome sequencing (WES/WGS) of tumor samples from patients with breast (
n
= 12), gastrointestinal (
n
= 20), lung (
n
= 19), and other tumor types (
n
= 13). Correlation in the driver, hotspot, and actionable alterations was studied. Three cases in which more-in-depth genomic analysis was required have been presented. A total 58% (37/64) of patients had at least one concordant mutation. Patients who had received systemic therapy before tissue next-generation sequencing (NGS) and ctDNA analysis showed high concordance (78% (21/27) vs. 43% (12/28)
p
= 0.01, respectively). Obtaining both NGS and ctDNA increased actionable alterations from 28% (18/64) to 52% (33/64) in our patients. Twenty-one patients had mutually exclusive actionable alterations seen only in either tissue NGS or ctDNA samples. Somatic hotspot mutation analysis showed significant discordance between tissue NGS and ctDNA analysis, denoting significant tumor heterogeneity in these malignancies. Increased tissue tumor mutation burden (TMB) positively correlated with the number of ctDNA mutations in patients who had received systemic therapy, but not in treatment-naïve patients. Prior systemic therapy and TMB may affect concordance and should be taken into consideration in future studies. Incorporating driver, actionable, and hotspot analysis may help to further refine the correlation between these two platforms. Tissue NGS and ctDNA are complimentary, and if done in conjunction, may increase the detection rate of actionable alterations and potentially therapeutic targets.
Ashiq Masood, MD Advisory board and speaker Bureau Bristol-Myers Squibb; Speakers Bureau—Boehringer Ingelheim; Honorariurm—Biocept; Janakiraman Subramanian, MD Advisory board—Astra Zeneca, Pfizer, Boehringer Ingelheim, Alexion, Paradigm, Bristol-Myers Squibb; Speakers Bureau—Astra Zeneca, Boehringer Ingelheim, Lilly; Research Support—Biocept and Paradigm; All other authors declare no conflict of interest.
Patient example clinical course. (
a
) Patient A had progression of squamous cell bladder carcinoma, with a new lesion caudal to the bladder identified by positron emission tomography (PET) scan while on standard of care chemotherapy. Tissue next generation sequencing (tissue NGS) identified
HER-2
amplification on manual review. Patient started on Opdivo with significant response and reduction of
HER-2
amplification to undetectable levels. (
b
) Patient B had progression of cholangiocarcinoma on standard of care chemotherapy. No targetable alterations were seen on initial tissue NGS. Follow up ctDNA identified
BRAF
G469V as a possible targetable alteration. The initial tissue NGS was manually reviewed and
BRAF
G469V was also present. Patient B was started on dabrafenib and trametinib but unfortunately progressed. (
c
) Patient C had progression of colon cancer following subtotal proctocolectomy and standard-of-care chemotherapy. Multiple targetable alterations were identified including members of the RTK/RAS/MAPK pathway. Patient C was started on pembrolizumab with a dramatic response.
