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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 PARTICIPANTSA 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 RELEVANCEIn 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 pos...

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PURPOSE Patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence with prior data suggesting improved outcomes with capecitabine. Targeted agents have demonstrated activity across multiple cancer types. BRE12-158 was a phase II, multicenter trial that randomly allocated patients with TNBC with residual disease after NAC to genomically directed therapy versus treatment of physician choice (TPC). PATIENTS AND METHODS From March 2014 to December 2018, 193 patients were enrolled. Residual tumors were sequenced using a next-generation sequencing test. A molecular tumor board adjudicated all results. Patients were randomly allocated to four cycles of genomically directed therapy (arm A) versus TPC (arm B). Patients without a target were assigned to arm B. Primary end point was 2-year disease-free survival (DFS) among randomly assigned patients. Secondary/exploratory end points included distant disease-free survival, overall survival, toxicity assessment, time-based evolution of therapy, and drug-specific outcomes. RESULTS One hundred ninety-three patients were randomly allocated or were assigned to arm B. The estimated 2-year DFS for the randomized population only was 56.6% (95% CI, 0.45 to 0.70) for arm A versus 62.4% (95% CI, 0.52 to 0.75) for arm B. No difference was seen in DFS, distant disease-free survival, or overall survival for the entire or randomized populations. There was increased uptake of capecitabine for TPC over time. Patients randomly allocated later had less distant recurrences. Circulating tumor DNA status remained a significant predictor of outcome with some patients demonstrating clearance with postneoadjuvant therapy. CONCLUSION Genomically directed therapy was not superior to TPC for patients with residual TNBC after NAC. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes. Circulating tumor DNA should be considered a standard covariate for trials in this setting.

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images in clinical medicineT h e n e w e ng l a n d j o u r na l o f m e dic i n e n engl j med 365;10 nejm.org september 8, 2011 e20 A fter undergoing breast lumpectomy and biopsy of the sentinel lymph nodes, a 42-year-old woman with triple-negative invasive ductal carcinoma began adjuvant chemotherapy with doxorubicin, cyclophosphamide, and paclitaxel. After the second cycle of doxorubicin and cyclophosphamide, asymptomatic hyperpigmented macules and patches were noted on the patient's tongue (Panel A). There was no hyperpigmentation of the palms, soles, dermal creases, or nails, and the remainder of the physical examination was normal. Dermal hyperpigmentation is a well-known adverse effect of a number of chemotherapeutic agents and has been reported to occur in association with both doxorubicin and cyclophosphamide. The condition may be local or generalized and may affect skin, mucous membranes, nails, or hair. The underlying mechanism remains uncertain. In this patient, the tongue lesions started to fade after the completion of therapy and disappeared almost completely within 12 weeks (Panel B).

The combination of capecitabine and docetaxel is active and well tolerated in mPC patients pretreated with gemcitabine-based therapy.

Background: A significant proportion of patients with early-stage TNBC are treated with neoadjuvant chemotherapy (NAC). Sequencing of ctDNA after surgery can be used to detect minimal residual disease and predict which patients may experience clinical recurrence. Methods: BRE12-158 is a recently completed Phase II clinical trial which randomized early-stage TNBC patients with residual disease after NAC to post-neoadjuvant genomically-directed therapy vs treatment of physician choice. 151 patients had a plasma sample collected at the time of treatment assignment (after surgery and radiation). ctDNA was successfully sequenced in 150 patients. 148 of the 150 sequenced patients had clinical follow-up. Sequencing was performed by Foundation Medicine using the FoundationOne Liquid assay which profiles for 70 commonly mutated oncogenes. Presence of mutated ctDNA was associated with distant disease free survival (DDFS) and overall survival (OS) in univariate analysis using the Log-Rank test, and in multi-variate analysis using Cox proportional hazards model. Results: Mutated ctDNA was detected in 94 of 148 sequenced patients (64%). TP53 was the most commonly mutated gene consistent with prior genomic studies of TNBC. At 16.7 months of median follow-up, detection of ctDNA was significantly associated with an inferior DDFS (median DDFS 32.5 months vs. Not Reached, p=0.0030). At 24 months, the DDFS probability was 53% in ctDNA-positive patients as compared to 81% in ctDNA-negative patients. In multi-variate analysis, when considering significant covariates, including: residual cancer burden (RCB); number of positive lymph nodes; tumor size; stage; grade; age; and race; detection of ctDNA remained independently associated with inferior DDFS (HR=3.1, CI: 1.4-6.8, p=0.0048). Similarly, detection of ctDNA was associated with inferior OS in univariate (p=0.021) and multi-variate analysis (HR=2.7, CI:1.1-6.2, p=0.022). Lastly, we observed a correlation between higher maximum somatic allele frequency and a shorter DDFS interval in multivariate analysis (HR=4.7, CI: 1.04-21.1, p=0.044) and shorter OS (HR=4.9, CI:1.06-22.4, p=0.041), suggesting that the quantitative degree of ctDNA burden is associated with clinical outcome. Conclusions: Detection of ctDNA in early-stage TNBC after neoadjuvant chemotherapy is an independent predictor of disease recurrence, and represents an important novel stratification factor for future post-neoadjuvant trials. Citation Format: Milan Radovich, Guanglong Jiang, Christopher Chitambar, Rita Nanda, Carla Falkson, Filipa C. Lynce, Christopher Gallagher, Claudine Isaacs, Marcelo Blaya, Elisavet Paplomata, Radhika Walling, Karen Daily, Reshma Mahtani, Michael A. Thompson, Robert Graham, Maureen E. Cooper, Dean C. Pavlick, Lee Albacker, Jeff Gregg, Casey L. Bales, Bradley A. Hancock, Erica Cantor, Fei Shen, Anna Maria V. Storniolo, Sunil Badve, Tarah Ballinger, Kathy D. Miller, Bryan P. Schneider. Detection of circulating tumor DNA (ctDNA) after neoadjuvant chemotherapy is significantly associated with disease recurrence in early-stage triple-negative breast cancer (TNBC): Preplanned correlative results from clinical trial BRE12-158 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS5-02.