TY - JOUR
T1 - The use of serial circulating tumor DNA to detect resistance alterations in progressive metastatic breast cancer
AU - Jacob, Saya
AU - Davis, Andrew A.
AU - Gerratana, Lorenzo
AU - Velimirovic, Marko
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 - Bardia, Aditya
AU - Cristofanilli, Massimo
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Purpose: Circulating tumor DNA (ctDNA) is a promising tool for noninvasive longitudinal monitoring of genomic alterations. We analyzed serial ctDNA to characterize genomic evolution in progressive metastatic breast cancer. Experimental Design: This was a retrospective cohort between 2015 and 2019 obtained under an Institutional Review Board-approved protocol at Northwestern University (Chicago, IL). ctDNA samples were analyzed with Guardant360 next-generation sequencing (NGS) assay. A total of 86 patients had at least two serial ctDNA collections with the second drawn at first post-NGS progression (PN1) by imaging and clinical assessment. A total of 27 participants had ctDNA drawn at second post-NGS clinical progression (PN2). We analyzed alterations, mutant allele frequency (MAF), number of alterations (NOA), and sites of disease on imaging in close proximity to ctDNA evaluation. Matched pairs' variations in MAF, NOA, and alterations at progression were tested through Wilcoxon test. We identified an independent control cohort at Massachusetts General Hospital (Boston, MA) of 63 patients with serial ctDNA sampling and no evidence of progression. Results: We identified 44 hormone receptor-positive, 20 HER2þ, and 22 triple-negative breast cancer cases. The significant alterations observed between baseline and PN1 were TP53 (P < 0.0075), PIK3CA (P < 0.0126), AR (P < 0.0126), FGFR1 (P < 0.0455), and ESR1 (P < 0.0143). Paired analyses revealed increased MAF and NOA from baseline to PN1 (P ¼ 0.0026, and P < 0.0001, respectively). When compared with controls without progression, patients with ctDNA collection at times of progression were associated with increased MAF and NOA (P ¼ 0.0042 and P < 0.0001, respectively). Conclusions: Serial ctDNA testing identified resistance alterations and increased NOA and MAF were associated with disease progression. Prospective longitudinal ctDNA evaluation could potentially monitor tumor genomic evolution.
AB - Purpose: Circulating tumor DNA (ctDNA) is a promising tool for noninvasive longitudinal monitoring of genomic alterations. We analyzed serial ctDNA to characterize genomic evolution in progressive metastatic breast cancer. Experimental Design: This was a retrospective cohort between 2015 and 2019 obtained under an Institutional Review Board-approved protocol at Northwestern University (Chicago, IL). ctDNA samples were analyzed with Guardant360 next-generation sequencing (NGS) assay. A total of 86 patients had at least two serial ctDNA collections with the second drawn at first post-NGS progression (PN1) by imaging and clinical assessment. A total of 27 participants had ctDNA drawn at second post-NGS clinical progression (PN2). We analyzed alterations, mutant allele frequency (MAF), number of alterations (NOA), and sites of disease on imaging in close proximity to ctDNA evaluation. Matched pairs' variations in MAF, NOA, and alterations at progression were tested through Wilcoxon test. We identified an independent control cohort at Massachusetts General Hospital (Boston, MA) of 63 patients with serial ctDNA sampling and no evidence of progression. Results: We identified 44 hormone receptor-positive, 20 HER2þ, and 22 triple-negative breast cancer cases. The significant alterations observed between baseline and PN1 were TP53 (P < 0.0075), PIK3CA (P < 0.0126), AR (P < 0.0126), FGFR1 (P < 0.0455), and ESR1 (P < 0.0143). Paired analyses revealed increased MAF and NOA from baseline to PN1 (P ¼ 0.0026, and P < 0.0001, respectively). When compared with controls without progression, patients with ctDNA collection at times of progression were associated with increased MAF and NOA (P ¼ 0.0042 and P < 0.0001, respectively). Conclusions: Serial ctDNA testing identified resistance alterations and increased NOA and MAF were associated with disease progression. Prospective longitudinal ctDNA evaluation could potentially monitor tumor genomic evolution.
UR - http://www.scopus.com/inward/record.url?scp=85102505306&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-1566
DO - 10.1158/1078-0432.CCR-20-1566
M3 - Article
C2 - 33323406
AN - SCOPUS:85102505306
SN - 1078-0432
VL - 27
SP - 1361
EP - 1370
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -