TY - JOUR
T1 - Landscape of circulating tumour DNA in metastatic breast cancer
AU - Davis, Andrew A.
AU - Jacob, Saya
AU - Gerratana, Lorenzo
AU - Shah, Ami N.
AU - Wehbe, Firas
AU - Katam, Neelima
AU - Zhang, Qiang
AU - Flaum, Lisa
AU - Siziopikou, Kalliopi P.
AU - Platanias, Leonidas C.
AU - Gradishar, William J.
AU - Behdad, Amir
AU - Cristofanilli, Massimo
N1 - Funding Information:
Lynn Sage Cancer Research Foundation, OncoSET Precision Medicine Program, and REDCap support was funded in part by a Clinical and Translational Science Award (CTSA) grant from the National Institutes of Health UL1TR001422. The funding sources had no role in the study design, data collection, data analysis, interpretation, or writing of the manuscript.
Funding Information:
Andrew A. Davis reports receiving travel support from Menarini Silicon Biosystems, outside the submitted work; Lorenzo Gerratana reports non-financial support from Menarini Silicon Biosystems, personal fees from Lilly, outside the submitted work; Ami N. Shah reports personal fees from Abbvie, personal fees from Taiho, personal fees from Daiichi-Sankyo, outside the submitted work; Amir Behdad reports personal fees from Pfizer, personal fees from Foundation Medicine, personal fees from Bayer, outside the submitted work. Massimo Cristofanilli reports personal fees from Foundation Medicine, personal fees from Lilly, grants and personal fees from Pfizer, personal fees from Cytodyn, personal fees from Sermonix, grants and personal fees from G1Therapeutics, outside the submitted work.
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/8
Y1 - 2020/8
N2 - Background: We describe the genomic landscape of circulating tumour DNA (ctDNA) across pathological subtypes of metastatic breast cancer. Methods: 255 clinically annotated patients with ctDNA testing by Guardant360 were stratified into HR+, HER2+, and TNBC cohorts. Frequency and heterogeneity of alterations were reported. Paired ctDNA and tissue sequencing were compared for a subset of patients. The association of ctDNA and metastatic sites of disease on imaging was also assessed. Findings: 89% of patients had at least one ctDNA alteration detected. The most common single nucleotide variants (SNVs) for HR+ patients were PIK3CA, ESR1, and TP53. For HER2+, these were TP53, PIK3CA, and ERBB2 with ERBB2 as the most frequent copy number variant (CNV). For TNBC, the most common SNVs were TP53 and PIK3CA, and the most frequent CNVs were MYC, CCNE1, and PIK3CA. TNBC patients had a significantly higher mutant allele frequency (MAF) of the highest variant compared to HR+ or HER2+ patients (P<0.05). Overall, alterations in PIK3CA, ESR1, and ERBB2 were observed in 39.6%, 16.5%, and 21.6% of patients, respectively. Agreement between blood and tissue was 79–91%. MAF and number of alterations were significantly associated with number of metastatic sites on imaging (P<0.0001). Interpretation: These data demonstrate the genetic heterogeneity of metastatic breast cancer in blood, the high prevalence of clinically actionable alterations, and the potential to utilise ctDNA as a surrogate for tumour burden on imaging. Funding: Lynn Sage Cancer Research Foundation, OncoSET Precision Medicine Program, and REDCap support was funded by the National Institutes of Health UL1TR001422.
AB - Background: We describe the genomic landscape of circulating tumour DNA (ctDNA) across pathological subtypes of metastatic breast cancer. Methods: 255 clinically annotated patients with ctDNA testing by Guardant360 were stratified into HR+, HER2+, and TNBC cohorts. Frequency and heterogeneity of alterations were reported. Paired ctDNA and tissue sequencing were compared for a subset of patients. The association of ctDNA and metastatic sites of disease on imaging was also assessed. Findings: 89% of patients had at least one ctDNA alteration detected. The most common single nucleotide variants (SNVs) for HR+ patients were PIK3CA, ESR1, and TP53. For HER2+, these were TP53, PIK3CA, and ERBB2 with ERBB2 as the most frequent copy number variant (CNV). For TNBC, the most common SNVs were TP53 and PIK3CA, and the most frequent CNVs were MYC, CCNE1, and PIK3CA. TNBC patients had a significantly higher mutant allele frequency (MAF) of the highest variant compared to HR+ or HER2+ patients (P<0.05). Overall, alterations in PIK3CA, ESR1, and ERBB2 were observed in 39.6%, 16.5%, and 21.6% of patients, respectively. Agreement between blood and tissue was 79–91%. MAF and number of alterations were significantly associated with number of metastatic sites on imaging (P<0.0001). Interpretation: These data demonstrate the genetic heterogeneity of metastatic breast cancer in blood, the high prevalence of clinically actionable alterations, and the potential to utilise ctDNA as a surrogate for tumour burden on imaging. Funding: Lynn Sage Cancer Research Foundation, OncoSET Precision Medicine Program, and REDCap support was funded by the National Institutes of Health UL1TR001422.
KW - Circulating tumour DNA
KW - Genomics
KW - Metastatic breast cancer
KW - Next-generation sequencing
KW - cell-free DNA
UR - http://www.scopus.com/inward/record.url?scp=85088258641&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85088258641&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2020.102914
DO - 10.1016/j.ebiom.2020.102914
M3 - Article
C2 - 32707446
AN - SCOPUS:85088258641
SN - 2352-3964
VL - 58
JO - EBioMedicine
JF - EBioMedicine
M1 - 102914
ER -
