Dataset Information

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

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.

SUBMITTER: McDonald BR

PROVIDER: S-EPMC7236617 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

McDonald Bradon R BR Contente-Cuomo Tania T Sammut Stephen-John SJ Odenheimer-Bergman Ahuva A Ernst Brenda B Perdigones Nieves N Chin Suet-Feung SF Farooq Maria M Mejia Rosa R Cronin Patricia A PA Anderson Karen S KS Kosiorek Heidi E HE Northfelt Donald W DW McCullough Ann E AE Patel Bhavika K BK Weitzel Jeffrey N JN Slavin Thomas P TP Caldas Carlos C Pockaj Barbara A BA Murtaza Muhammed M

Science translational medicine 20190801 504

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 ref ...[more]

PMID: 31391323

Similar Datasets

Project description:Patients with breast cancer (BC) undergoing neoadjuvant chemotherapy (NACT) may experience metastatic relapse despite achieving a pathologic complete response. We analyzed patients with BC before and after NACT for disseminated tumor cells (DTCs) in the bone marrow(BM); comprehensively characterized circulating tumor cells (CTCs), including stem cell-like CTCs (slCTCs), in blood to prove the effectiveness of treatment on these cells; and correlated these findings with response to therapy, progression-free survival (PFS), and overall survival (OS).CTCs (n?=?135) and slCTCs (n?=?91) before and after NACT were analyzed using the AdnaTest BreastCancer, AdnaTest TumorStemCell, and epithelial-mesenchymal transition (QIAGEN Hannover GmbH Germany). The expression of estrogen receptor, progesterone receptor, and the resistance marker excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), nuclease were studied in separate single-plex reverse transcription polymerase chain reaction experiments. DTCs were evaluated in 142 patients before and 165 patients after NACT using the pan-cytokeratin antibody A45-B/B3 for immunocytochemistry.The positivity rates for DTCs, CTCs, and slCTCs were 27 %, 24 %, and 51 % before and 20 %, 8 %, and 20 % after NACT, respectively. Interestingly, 72 % of CTCs present after therapy were positive for ERCC1, and CTCs before (p?=?0.005) and after NACT (p?=?0.05) were significantly associated with the presence of slCTCs. Whereas no significant associations with clinical parameters were found for CTCs and slCTCs, DTCs were significantly associated with nodal status (p?=?0.03) and histology (0.046) before NACT and with the immunohistochemical subtype (p?=?0.02) after NACT. Univariable Cox regression analysis revealed that age (p?=?0.0065), tumor size before NACT (p?=?0.0473), nodal status after NACT (p?=?0.0137), and response to NACT (p?=?0.0136) were significantly correlated with PFS, whereas age (p?=?0.0162) and nodal status after NACT (p?=?0.0243) were significantly associated with OS. No significant correlations were found for DTCs or any CTCs before and after therapy with regard to PFS and OS.Although CTCs were eradicated more effectively than DTCs, CTCs detected after treatment seemed to be associated with tumor cells showing tumor stem cell characteristics as well as with resistant tumor cell populations that might indicate a worse outcome in the future. Thus, these patients might benefit from additional second-line treatment protocols including bisphosphonates for the eradication of DTCs.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets