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?
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.
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.
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.
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).
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).
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.
ClinicalTrials.gov Identifier: NCT02101385
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Radovich M, Jiang G, Hancock BA, et al. 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. JAMA Oncol. Published online July 09, 2020. doi:10.1001/jamaoncol.2020.2295
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