The use of serial circulating tumor DNA to detect resistance alterations in progressive metastatic breast cancer

Saya Jacob; Andrew A. Davis; Lorenzo Gerratana; Marko Velimirovic; Ami N. Shah; Firas Wehbe; Neelima Katam; Qiang Zhang; Lisa Flaum; Kalliopi P. Siziopikou; Leonidas C. Platanias; William J. Gradishar; Amir Behdad; Aditya Bardia; Massimo Cristofanilli

doi:10.1158/1078-0432.CCR-20-1566

The use of serial circulating tumor DNA to detect resistance alterations in progressive metastatic breast cancer

Saya Jacob, Andrew A. Davis, Lorenzo Gerratana, Marko Velimirovic, Ami N. Shah, Firas Wehbe, Neelima Katam, Qiang Zhang, Lisa Flaum, Kalliopi P. Siziopikou, Leonidas C. Platanias, William J. Gradishar, Amir Behdad, Aditya Bardia, Massimo Cristofanilli^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

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 HER2^þ, 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.

Original language	English (US)
Pages (from-to)	1361-1370
Number of pages	10
Journal	Clinical Cancer Research
Volume	27
Issue number	5
DOIs	https://doi.org/10.1158/1078-0432.CCR-20-1566
State	Published - Mar 1 2021

Funding

A.A. Davis reports other from Menarini Silicon Biosystems outside the submitted work. A.N. Shah reports personal fees from Abbvie, Daiichi Sankyo, and Taiho, as well as nonfinancial support from Pfizer outside the submitted work. K.P. Siziopikou reports other from Merck and Lilly outside the submitted work. A. Behdad reports honorarium from Foundation Medicine in China and Bayer that are not relevant to this work. A. Bardia reports grants and personal fees from Novartis, Pfizer, Genentech, Merck, Radius Health, Immunomedics (Gilead), Taiho, Sanofi, and Diiachi Pharma/ AstraZeneca, as well as personal fees from Puma, Biothernostics, Phillips, Eli Lilly, and Foundation Medicine during the conduct of the study. M. Cristofanilli reports personal fees from Lilly, Pfizer, Foundation Medicine, Sermonix, G1 Therapeutics, Novartis, Menarini, and Amarex, as well as grants and personal fees from CytoDyn outside the submitted work. No disclosures were reported by the other authors. M. Cristofanilli acknowledges financial support from the Lynn Sage Cancer Research Foundation.

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General Medicine

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10.1158/1078-0432.CCR-20-1566

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Jacob, S., Davis, A. A., Gerratana, L., Velimirovic, M., Shah, A. N., Wehbe, F., Katam, N., Zhang, Q., Flaum, L., Siziopikou, K. P., Platanias, L. C., Gradishar, W. J., Behdad, A., Bardia, A., & Cristofanilli, M. (2021). The use of serial circulating tumor DNA to detect resistance alterations in progressive metastatic breast cancer. Clinical Cancer Research, 27(5), 1361-1370. https://doi.org/10.1158/1078-0432.CCR-20-1566

@article{2172c1055eb9452bbb7430a5a7aec1c8,

title = "The use of serial circulating tumor DNA to detect resistance alterations in progressive metastatic breast cancer",

abstract = "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 HER2{\th}, 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.",

author = "Saya Jacob and Davis, {Andrew A.} and Lorenzo Gerratana and Marko Velimirovic and Shah, {Ami N.} and Firas Wehbe and Neelima Katam and Qiang Zhang and Lisa Flaum and Siziopikou, {Kalliopi P.} and Platanias, {Leonidas C.} and Gradishar, {William J.} and Amir Behdad and Aditya Bardia and Massimo Cristofanilli",

note = "Funding Information: A.A. Davis reports other from Menarini Silicon Biosystems outside the submitted work. A.N. Shah reports personal fees from Abbvie, Daiichi Sankyo, and Taiho, as well as nonfinancial support from Pfizer outside the submitted work. K.P. Siziopikou reports other from Merck and Lilly outside the submitted work. A. Behdad reports honorarium from Foundation Medicine in China and Bayer that are not relevant to this work. A. Bardia reports grants and personal fees from Novartis, Pfizer, Genentech, Merck, Radius Health, Immunomedics (Gilead), Taiho, Sanofi, and Diiachi Pharma/ AstraZeneca, as well as personal fees from Puma, Biothernostics, Phillips, Eli Lilly, and Foundation Medicine during the conduct of the study. M. Cristofanilli reports personal fees from Lilly, Pfizer, Foundation Medicine, Sermonix, G1 Therapeutics, Novartis, Menarini, and Amarex, as well as grants and personal fees from CytoDyn outside the submitted work. No disclosures were reported by the other authors. Funding Information: M. Cristofanilli acknowledges financial support from the Lynn Sage Cancer Research Foundation. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2021",

month = mar,

day = "1",

doi = "10.1158/1078-0432.CCR-20-1566",

language = "English (US)",

volume = "27",

pages = "1361--1370",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "5",

}

Jacob, S, Davis, AA, Gerratana, L, Velimirovic, M, Shah, AN, Wehbe, F, Katam, N, Zhang, Q , Flaum, L , Siziopikou, KP , Platanias, LC , Gradishar, WJ, Behdad, A, Bardia, A & Cristofanilli, M 2021, 'The use of serial circulating tumor DNA to detect resistance alterations in progressive metastatic breast cancer', Clinical Cancer Research, vol. 27, no. 5, pp. 1361-1370. https://doi.org/10.1158/1078-0432.CCR-20-1566

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 - Funding Information: A.A. Davis reports other from Menarini Silicon Biosystems outside the submitted work. A.N. Shah reports personal fees from Abbvie, Daiichi Sankyo, and Taiho, as well as nonfinancial support from Pfizer outside the submitted work. K.P. Siziopikou reports other from Merck and Lilly outside the submitted work. A. Behdad reports honorarium from Foundation Medicine in China and Bayer that are not relevant to this work. A. Bardia reports grants and personal fees from Novartis, Pfizer, Genentech, Merck, Radius Health, Immunomedics (Gilead), Taiho, Sanofi, and Diiachi Pharma/ AstraZeneca, as well as personal fees from Puma, Biothernostics, Phillips, Eli Lilly, and Foundation Medicine during the conduct of the study. M. Cristofanilli reports personal fees from Lilly, Pfizer, Foundation Medicine, Sermonix, G1 Therapeutics, Novartis, Menarini, and Amarex, as well as grants and personal fees from CytoDyn outside the submitted work. No disclosures were reported by the other authors. Funding Information: M. Cristofanilli acknowledges financial support from the Lynn Sage Cancer Research Foundation. 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.

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The use of serial circulating tumor DNA to detect resistance alterations in progressive metastatic breast cancer

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