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Brief Report
July 9, 2020

Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer: Preplanned Secondary Analysis of the BRE12-158 Randomized Clinical Trial

Author Affiliations
  • 1Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis
  • 2Medical College of Wisconsin, Milwaukee
  • 3University of Chicago, Chicago, Illinois
  • 4University of Alabama at Birmingham, Birmingham
  • 5Georgetown University, Washington, DC
  • 6Memorial Healthcare System, Hollywood, Florida
  • 7Winship Cancer Institute of Emory University, Atlanta, Georgia
  • 8Community Regional Cancer Care, Indianapolis, Indiana
  • 9University of Florida, Gainesville
  • 10Sylvester Comprehensive Cancer Center, Deerfield Beach, Florida
  • 11Advocate Aurora Health Care, Milwaukee, Wisconsin
  • 12Erlanger Health System, Chattanooga, Tennessee
  • 13Foundation Medicine Inc, Cambridge, Massachusetts
  • 14University of California at Davis, Davis
  • 15Purdue University School of Mechanical Engineering, West Lafayette, Indiana
JAMA Oncol. Published online July 9, 2020. doi:10.1001/jamaoncol.2020.2295
Key Points

Question  Is the presence of circulating tumor DNA and circulating tumor cells after surgery associated with inferior outcomes for patients with early-stage triple-negative breast cancer?

Findings  This large preplanned secondary analysis of 196 female patients from a recently completed randomized clinical trial found that the presence of circulating tumor DNA and circulating tumor cells after neoadjuvant chemotherapy in patients with early-stage triple-negative breast cancer was associated with significantly inferior distant disease–free survival, disease-free survival, and overall survival.

Meaning  Detection of circulating tumor DNA and circulating tumor cells after neoadjuvant chemotherapy in patients with early-stage triple-negative breast cancer is independently associated with disease recurrence, above and beyond standard clinical parameters, and represents an important novel stratification factor for future postneoadjuvant trials.

Abstract

Importance  A significant proportion of patients with early-stage triple-negative breast cancer (TNBC) are treated with neoadjuvant chemotherapy. Sequencing of circulating tumor DNA (ctDNA) after surgery, along with enumeration of circulating tumor cells (CTCs), may be used to detect minimal residual disease and assess which patients may experience disease recurrence.

Objective  To determine whether the presence of ctDNA and CTCs after neoadjuvant chemotherapy in patients with early-stage TNBC is independently associated with recurrence and clinical outcomes.

Design, Setting, and Participants  A preplanned secondary analysis was conducted from March 26, 2014, to December 18, 2018, using data from 196 female patients in BRE12-158, a phase 2 multicenter randomized clinical trial that randomized patients with early-stage TNBC who had residual disease after neoadjuvant chemotherapy to receive postneoadjuvant genomically directed therapy vs treatment of physician choice. Patients had blood samples collected for ctDNA and CTCs at time of treatment assignment; ctDNA analysis with survival was performed for 142 patients, and CTC analysis with survival was performed for 123 patients. Median clinical follow-up was 17.2 months (range, 0.3-58.3 months).

Interventions  Circulating tumor DNA was sequenced using the FoundationACT or FoundationOneLiquid Assay, and CTCs were enumerated using an epithelial cell adhesion molecule–based, positive-selection microfluidic device.

Main Outcomes and Measures  Primary outcomes were distant disease–free survival (DDFS), disease-free survival (DFS), and overall survival (OS).

Results  Among 196 female patients (mean [SD] age, 49.6 [11.1] years), detection of ctDNA was significantly associated with inferior DDFS (median DDFS, 32.5 months vs not reached; hazard ratio [HR], 2.99; 95% CI, 1.38-6.48; P = .006). At 24 months, DDFS probability was 56% for ctDNA-positive patients compared with 81% for ctDNA-negative patients. Detection of ctDNA was similarly associated with inferior DFS (HR, 2.67; 95% CI, 1.28-5.57; P = .009) and inferior OS (HR, 4.16; 95% CI,1.66-10.42; P = .002). The combination of ctDNA and CTCs provided additional information for increased sensitivity and discriminatory capacity. Patients who were ctDNA positive and CTC positive had significantly inferior DDFS compared with those who were ctDNA negative and CTC negative (median DDFS, 32.5 months vs not reached; HR, 5.29; 95% CI, 1.50-18.62; P = .009). At 24 months, DDFS probability was 52% for patients who were ctDNA positive and CTC positive compared with 89% for those who were ctDNA negative and CTC negative. Similar trends were observed for DFS (HR, 3.15; 95% CI, 1.07-9.27; P = .04) and OS (HR, 8.60; 95% CI, 1.78-41.47; P = .007).

Conclusions and Relevance  In this preplanned secondary analysis of a randomized clinical trial, detection of ctDNA and CTCs in patients with early-stage TNBC after neoadjuvant chemotherapy was independently associated with disease recurrence, which represents an important stratification factor for future postneoadjuvant trials.

Trial Registration  ClinicalTrials.gov Identifier: NCT02101385

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