Kinetics of Circulating Tumor Cells and Survival Outcomes after Stereotactic Radiotherapy/Radiosurgery for Brain Metastases of Breast Cancer

Purpose Epigenetic alterations measured in blood may help guide breast cancer treatment. The multisite prospective study TBCRC 005 was conducted to examine the ability of a novel panel of cell-free DNA methylation markers to predict survival outcomes in metastatic breast cancer (MBC) using a new quantitative multiplex assay (cMethDNA). Patients and Methods Ten genes were tested in duplicate serum samples from 141 women at baseline, at week 4, and at first restaging. A cumulative methylation index (CMI) was generated on the basis of six of the 10 genes tested. Methylation cut points were selected to maximize the log-rank statistic, and cross-validation was used to obtain unbiased point estimates. Logistic regression or Cox proportional hazard models were used to test associations between the CMI and progression-free survival (PFS), overall survival (OS), and disease status at first restaging. The added value of the CMI in predicting survival outcomes was evaluated and compared with circulating tumor cells (CellSearch). Results Median PFS and OS were significantly shorter in women with a high CMI (PFS, 2.1 months; OS, 12.3 months) versus a low CMI (PFS, 5.8 months; OS, 21.7 months). In multivariable models, among women with MBC, a high versus low CMI at week 4 was independently associated with worse PFS (hazard ratio, 1.79; 95% CI, 1.23 to 2.60; P = .002) and OS (hazard ratio, 1.75; 95% CI, 1.21 to 2.54; P = .003). An increase in the CMI from baseline to week 4 was associated with worse PFS ( P < .001) and progressive disease at first restaging ( P < .001). Week 4 CMI was a strong predictor of PFS, even in the presence of circulating tumor cells ( P = .004). Conclusion Methylation of this gene panel is a strong predictor of survival outcomes in MBC and may have clinical usefulness in risk stratification and disease monitoring.

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Initial Findings of Analysis of Circulating Tumor Cells in Patients with Brain Metastases of Breast Cancer

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2018.07.730 ◽

2018 ◽

Vol 102 (3) ◽

pp. e207-e208

Author(s):

D.G. Castro ◽

C. Pellizzon ◽

G.R.M. Gondim ◽

M.L.G. Silva ◽

M.J. Chen ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Tumor Cells ◽

Circulating Tumor Cells

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Molecular characterization of breast cancer brain metastases and circulating tumor cells

Annals of Oncology ◽

10.1093/annonc/mdv116.10 ◽

2015 ◽

Vol 26 ◽

pp. iii10

Author(s):

H. Wikman ◽

I. Hohensee ◽

C. Riebensahm ◽

I. Witzel ◽

J. Matschke ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Tumor Cells ◽

Molecular Characterization ◽

Circulating Tumor Cells ◽

Breast Cancer Brain Metastases

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Heterogeneity of HER2 expression in circulating tumor cells of patients with breast cancer brain metastases and impact on brain disease control.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2029 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2029-2029

Author(s):

Douglas Guedes Castro ◽

Antonio Cassio Assis Pellizzon ◽

Alexcia Camila Braun ◽

Michael Jenwei Chen ◽

Maria Leticia Gobo Silva ◽

...

Keyword(s):

Breast Cancer ◽

Multivariate Analysis ◽

Brain Metastases ◽

Disease Control ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Her2 Expression ◽

Brain Failure ◽

Breast Cancer Brain Metastases ◽

Distant Brain Failure

2029 Background: The HER2 expression switching in circulating tumor cells (CTC) of breast cancer is dynamic and may have prognostic and predictive clinical implications. This study aims to analyse the association between expression of HER2 in CTC of patients with breast cancer brain metastases (BCBM) and brain disease control. Methods: Exploratory analysis of a prospective assessment (NCT02941536) of CTC before (CTC1) and 4–5 weeks after (CTC2) stereotactic radiotherapy/radiosurgery (SRT). CTC were isolated and quantified by a method of isolation by size of tumors and analyzed by immunocytochemistry to evaluate the expression of HER2. Distant brain failure-free survival (DBFFS), the primary endpoint, and overall survival (OS) were estimated by Kaplan-Meier estimator. Log-rank tests were applied in order to compare the survival curves. For multivariate analysis of prognostic factors that affected DBFFS and OS, the Cox proportional model was adjusted. Results: The median age at SRT was 54 (34-70), the diagnosis-specific graded prognostic assessment (DS-GPA) was 1–2 in 17.5% and 2.5–4 in 82.5% and the primary immunophenotype (PIP) was HER2-enriched in 51%, luminal B (LB) in 31% and triple negative (TN) in 18% of the total of 39 patients. CTC were detected in all 39 patients before SRT and the median CTC1 was 2 CTC/mL. After SRT, CTC were detected in 34 of 35 patients (4 deaths between CTC1 and CTC2) and the median CTC2 was 2.33 CTC/mL. HER2 was expressed in CTC1 and/or CTC2 in 9 patients, of which only 2 patients had PIP HER2-enriched. After a median follow-up of 16.6 months, there were 15 patients with distant brain failure and 16 deaths. The median DBFFS and OS were 15.3 and 19.5 months, respectively. Median DBFFS was 7 months in patients with PIP TN and was not reached in PIP LB and HER2-enriched (p = 0.036); 14 months in patients with DS-GPA 1-2 and 7 months with DS-GPA 2.5-4 (p = 0.017); 10 months in patients without HER2 expressed in CTC and not reached in patients with HER2 expressed in CTC (p = 0.012). Median OS was 4.8 months in patients with PIP TN and was not reached in PIP LB and HER2-enriched (p = 0.0026); 19.54 months in patients with DS-GPA 1-2 and 7.6 months with DS-GPA 2.5-4 (p = 0.00088); 17 months in patients without HER2 expressed in CTC and not reached in patients with HER2 expressed in CTC (p = 0.104). On multivariate analysis, DBFFS was superior in patients with PIP HER2-enriched (HR 0.128, 95% CI 0.025–0.534; p = 0.013) and OS was superior in patients with PIP HER2-enriched (HR 0.073, 95% CI 0.018-0.288; p < 0.0001) and LB (HR 0.224, 95% CI 0.062–0.816; p = 0.023). The status of expression of HER2 in CTC was not included in Cox model for DBFFS due to lack of events in patients with HER2 expressed in CTC. Conclusions: The expression of HER2 in CTC was associated with a longer DBFFS and the switching of HER2 expression between PIP and CTC may have impact on prognosis and treatment selection of BCBM.

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