TY - JOUR
T1 - Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer
AU - McDonald, Bradon R.
AU - Contente-Cuomo, Tania
AU - Sammut, Stephen John
AU - Odenheimer-Bergman, Ahuva
AU - Ernst, Brenda
AU - Perdigones, Nieves
AU - Chin, Suet Feung
AU - Farooq, Maria
AU - Mejia, Rosa
AU - Cronin, Patricia A.
AU - Anderson, Karen S.
AU - Kosiorek, Heidi E.
AU - Northfelt, Donald W.
AU - McCullough, Ann E.
AU - Patel, Bhavika K.
AU - Weitzel, Jeffrey N.
AU - Slavin, Thomas P.
AU - Caldas, Carlos
AU - Pockaj, Barbara A.
AU - Murtaza, Muhammed
N1 - Publisher Copyright:
© 2019 The Authors.
PY - 2019/8/7
Y1 - 2019/8/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85070599463&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070599463&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aax7392
DO - 10.1126/scitranslmed.aax7392
M3 - Article
C2 - 31391323
AN - SCOPUS:85070599463
SN - 1946-6234
VL - 11
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 504
M1 - eaax7392
ER -