Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer

Bradon R. McDonald, Tania Contente-Cuomo, Stephen John Sammut, Ahuva Odenheimer-Bergman, Brenda Ernst, Nieves Perdigones, Suet Feung Chin, Maria Farooq, Rosa Mejia, Patricia A. Cronin, Karen S. Anderson, Heidi E. Kosiorek, Donald W Northfelt, Ann E. McCullough, Bhavika Patel, Jeffrey N. Weitzel, Thomas P. Slavin, Carlos Caldas, Barbara A Pockaj, Muhammed Murtaza

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Longitudinal analysis of circulating tumor DNA (ctDNA) has shown promise for monitoring treatment response. However, most current methods lack adequate sensitivity for residual disease detection during or after completion of treatment in patients with nonmetastatic cancer. To address this gap and to improve sensitivity for minute quantities of residual tumor DNA in plasma, we have developed targeted digital sequencing (TARDIS) for multiplexed analysis of patient-specific cancer mutations. In reference samples, by simultaneously analyzing 8 to 16 known mutations, TARDIS achieved 91 and 53% sensitivity at mutant allele fractions (AFs) of 3 in 104 and 3 in 105, respectively, with 96% specificity, using input DNA equivalent to a single tube of blood. We successfully analyzed up to 115 mutations per patient in 80 plasma samples from 33 women with stage I to III breast cancer. Before treatment, TARDIS detected ctDNA in all patients with 0.11% median AF. After completion of neoadjuvant therapy, ctDNA concentrations were lower in patients who achieved pathological complete response (pathCR) compared to patients with residual disease (median AFs, 0.003 and 0.017%, respectively, P = 0.0057, AUC = 0.83). In addition, patients with pathCR showed a larger decrease in ctDNA concentrations during neoadjuvant therapy. These results demonstrate high accuracy for assessment of molecular response and residual disease during neoadjuvant therapy using ctDNA analysis. TARDIS has achieved up to 100-fold improvement beyond the current limit of ctDNA detection using clinically relevant blood volumes, demonstrating that personalized ctDNA tracking could enable individualized clinical management of patients with cancer treated with curative intent.

Original languageEnglish (US)
Article numbereaax7392
JournalScience translational medicine
Volume11
Issue number504
DOIs
StatePublished - Aug 7 2019

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Neoadjuvant Therapy
Breast Neoplasms
DNA
Neoplasms
Alleles
Mutation
Residual Neoplasm
Blood Volume
Area Under Curve
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

McDonald, B. R., Contente-Cuomo, T., Sammut, S. J., Odenheimer-Bergman, A., Ernst, B., Perdigones, N., ... Murtaza, M. (2019). Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer. Science translational medicine, 11(504), [eaax7392]. https://doi.org/10.1126/scitranslmed.aax7392

Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer. / McDonald, Bradon R.; Contente-Cuomo, Tania; Sammut, Stephen John; Odenheimer-Bergman, Ahuva; Ernst, Brenda; Perdigones, Nieves; Chin, Suet Feung; Farooq, Maria; Mejia, Rosa; Cronin, Patricia A.; Anderson, Karen S.; Kosiorek, Heidi E.; Northfelt, Donald W; McCullough, Ann E.; Patel, Bhavika; Weitzel, Jeffrey N.; Slavin, Thomas P.; Caldas, Carlos; Pockaj, Barbara A; Murtaza, Muhammed.

In: Science translational medicine, Vol. 11, No. 504, eaax7392, 07.08.2019.

Research output: Contribution to journalArticle

McDonald, BR, Contente-Cuomo, T, Sammut, SJ, Odenheimer-Bergman, A, Ernst, B, Perdigones, N, Chin, SF, Farooq, M, Mejia, R, Cronin, PA, Anderson, KS, Kosiorek, HE, Northfelt, DW, McCullough, AE, Patel, B, Weitzel, JN, Slavin, TP, Caldas, C, Pockaj, BA & Murtaza, M 2019, 'Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer', Science translational medicine, vol. 11, no. 504, eaax7392. https://doi.org/10.1126/scitranslmed.aax7392
McDonald, Bradon R. ; Contente-Cuomo, Tania ; Sammut, Stephen John ; Odenheimer-Bergman, Ahuva ; Ernst, Brenda ; Perdigones, Nieves ; Chin, Suet Feung ; Farooq, Maria ; Mejia, Rosa ; Cronin, Patricia A. ; Anderson, Karen S. ; Kosiorek, Heidi E. ; Northfelt, Donald W ; McCullough, Ann E. ; Patel, Bhavika ; Weitzel, Jeffrey N. ; Slavin, Thomas P. ; Caldas, Carlos ; Pockaj, Barbara A ; Murtaza, Muhammed. / Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer. In: Science translational medicine. 2019 ; Vol. 11, No. 504.
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abstract = "Longitudinal analysis of circulating tumor DNA (ctDNA) has shown promise for monitoring treatment response. However, most current methods lack adequate sensitivity for residual disease detection during or after completion of treatment in patients with nonmetastatic cancer. To address this gap and to improve sensitivity for minute quantities of residual tumor DNA in plasma, we have developed targeted digital sequencing (TARDIS) for multiplexed analysis of patient-specific cancer mutations. In reference samples, by simultaneously analyzing 8 to 16 known mutations, TARDIS achieved 91 and 53{\%} sensitivity at mutant allele fractions (AFs) of 3 in 104 and 3 in 105, respectively, with 96{\%} specificity, using input DNA equivalent to a single tube of blood. We successfully analyzed up to 115 mutations per patient in 80 plasma samples from 33 women with stage I to III breast cancer. Before treatment, TARDIS detected ctDNA in all patients with 0.11{\%} median AF. After completion of neoadjuvant therapy, ctDNA concentrations were lower in patients who achieved pathological complete response (pathCR) compared to patients with residual disease (median AFs, 0.003 and 0.017{\%}, respectively, P = 0.0057, AUC = 0.83). In addition, patients with pathCR showed a larger decrease in ctDNA concentrations during neoadjuvant therapy. These results demonstrate high accuracy for assessment of molecular response and residual disease during neoadjuvant therapy using ctDNA analysis. TARDIS has achieved up to 100-fold improvement beyond the current limit of ctDNA detection using clinically relevant blood volumes, demonstrating that personalized ctDNA tracking could enable individualized clinical management of patients with cancer treated with curative intent.",
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AU - Ernst, Brenda

AU - Perdigones, Nieves

AU - Chin, Suet Feung

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AU - Mejia, Rosa

AU - Cronin, Patricia A.

AU - Anderson, Karen S.

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AU - Northfelt, Donald W

AU - McCullough, Ann E.

AU - Patel, Bhavika

AU - Weitzel, Jeffrey N.

AU - Slavin, Thomas P.

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AU - Murtaza, Muhammed

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