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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Radovich reported serving as an advisor for LifeOmic; and having stock ownership in LifeOmic, Macrogenics, Immunomedics, Arqule, and Tyme Technologies outside the submitted work. Dr Falkson reported receiving grants from TBCRC during the conduct of the study. Dr Lynce reported receiving grants from Indiana University during the conduct of the study; and grants from Inivata, Tesaro, Regeneron, Immunomedics, Calithera, and Chugai; grants and personal fees from Pfizer; receiving grants from and serving as a consultant/advisor for BMS; serving as a consultant/advisor for AstraZeneca; and receiving personal fees from ASCO, outside the submitted work. Dr Isaacs reported receiving grants from the National Cancer Institute during the conduct of the study; and personal fees from Genentech, Pfizer, Novartis, AstraZeneca, PUMA, and Seattle Genetics; and grants from Tesaro outside the submitted work. Dr Paplomata reported receiving grants from Hoosier Cancer Research Network during the conduct of the study; and grants and personal fees from Novartis; grants and meals from Genentech and Merck; personal fees from Pfizer, R-Pharm, and Mylan; meals from Tesaro and Amgen; grants from Corcept, Seattle Genetics, and Cascadian outside the submitted work. Dr Mahtani reported receiving personal fees for serving as a consultant/advisor for Agendia, Biotheranostics, Daiichi, Eisai, Genentech, Pfizer, Lilly, Novartis, Seattle Genetics, and Puma outside the submitted work; and reported research support from Genentech to her institution. Dr Thompson reported serving as a consultant/advisor for Syapse, UpToDate, and Doximity; and personal fees from VIA Oncology, Adaptive, GSK, Takeda, and Celgene outside the submitted work. Mr Pavlick reported receiving personal fees from Foundation Medicine and F. Hoffmann-La Roche AG outside the submitted work. Dr Albacker reported receiving personal fees from Foundation Medicine Inc and Roche Holding AG outside the submitted work. Dr Gregg reported receiving personal fees from Foundation Medicine, AstraZeneca, BMS, Novartis, and Roche; and grants from AstraZeneca outside the submitted work. Dr Chen reported being currently employed at Foundation Medicine Inc. Dr Ballinger reported receiving personal fees from Novartis and Medscape outside the submitted work. Dr Chang reported receiving grants from Tom Hurvisand the McKinley Educational Foundation; and personal fees from Savran Technologies Inc during the conduct of the study; stock ownership from Savran Technologies Inc outside the submitted work; and having a patent to 10,335,790 issued, a patent to 10,207,267 issued, a patent to EP2694965B1 issued, a patent to 9,494,557 issued, and a patent to 9,500,625 issued. Mr Zhong reported receiving personal fees from Savran Technologies Inc during the conduct of the study. Dr Savran reported receiving grants from McKinley Educational Foundation and Tom Hurvis during the conduct of the study; stock ownership from Savran Technologies Inc outside the submitted work; and having a patent to 10,335,790 issued, a patent to 10,207,267 issued, a patent to EP2694965B1 issued, a patent to 9,494,557 issued, and a patent to 9,500,625 issued. No other disclosures were reported.

Figures

Figure 1.. Survival of Study Patients With vs Without Circulating Tumor DNA (ctDNA)

A, Distant disease–free survival (DDFS) (median, 32.5 months vs not reached; hazard ratio [HR], 2.99; 95% CI, 1.38-6.48; P = .006). B, Disease-free survival (DFS) (median, 22.8 months vs not reached; HR, 2.67; 95% CI, 1.28-5.57; P = .009). C, Overall survival (OS) (median, not reached vs not reached; HR, 4.16; 95% CI, 1.66-10.42; P = .002).

Figure 2.. Survival of Study Patients With vs Without Circulating Tumor DNA (ctDNA) and Circulating Tumor Cells (CTCs)

A, Distant disease–free survival (DDFS) (median, 32.5 months vs not reached; hazard ratio [HR], 5.29; 95% CI, 1.50-18.62; P = .009). B, Disease-free survival (DFS) (median, 20.8 months vs not reached; HR, 3.15; 95% CI, 1.07-9.27; P = .04). C, Overall survival (OS) (median, not reached vs not reached; HR, 8.60; 95% CI, 1.78-41.47; P = .007).