Abstract
Circulating tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). The CTC-endocrine therapy index (CTC-ETI), consisting of CTC-ER (estrogen receptor), BCL2, human epidermal growth factor receptor (HER2), and Ki67 expression, might predict resistance to endocrine therapy (ET) in patients with ER-positive MBC. One hundred twenty-one patients with ER-positive/HER2-negative MBC initiating a new ET after ≥1 lines of ET were enrolled in a prospective, multi-institutional clinical trial. CTC-ETI and clinical/imaging follow-up were performed at baseline and serial time points. Progression-free survival (PFS) and rapid progression (RP; determined at the 3-month time point) were primary endpoints. Associations with clinical outcomes used logrank and Fisher’s exact tests. At baseline, 36% (38/107) of patients had ≥5 CTC/7.5 ml whole blood (WB). Patients with ≥5 vs. <5 CTC/7.5 ml WB had significantly worse PFS (median 3.3 vs. 5.9 months, P = 0.03). Elevated CTC at 1 month was associated with even worse PFS (1.9 vs. 5.0 months from the 1-month sample, P < 0.001). Low, intermediate, and high CTC-ETI were observed in 71 (66%), 8 (8%), and 28 (26%) patients, with median PFS of 6.9, 8.5, and 2.8 months, respectively (P = 0.008). Patients with high vs. low CTC and CTC-ETI more frequently experienced RP (CTC: 66% vs. 41%; P = 0.03; CTC-ETI: 79% vs. 40%; P = 0.002). In conclusion, CTC enumeration and the CTC-ETI assay are prognostic at baseline and follow-up in patients with ER-positive/HER2-negative MBC starting new ET. CTC at first follow-up might identify a group of patients with ER-positive MBC that could forego ET, but CTC-ETI did not contribute further.
Highlights
Hormone receptor (HR) status has been used to guide endocrine therapy (ET) of patients with metastatic breast cancer (MBC).Patients with estrogen (ER) and progesterone (PgR) receptornegative MBC have almost no chance of benefit from ET, and are treated with more toxic, but more likely beneficial, chemotherapy[1]
We have previously developed an analytically validated assay, designated the circulating tumor cells (CTC)-endocrine therapy index (CTC-ETI), which is based on CTC enumeration, as well as semiquantitative analyses of CTC expression of four different markers associated with ET benefit [ER, B-cell lymphoma 2 (BCL2)] or resistance [human epidermal growth factor receptor (HER2) and Ki67]6
Multi-institutional, and multi-national phase 2 trial, we investigated the prognostic effect of a phenotypically based CTC assay, the CTC-ETI, in patients with ER-positive, HER2negative MBC starting second-line or later ET6
Summary
Hormone receptor (HR) status has been used to guide endocrine therapy (ET) of patients with metastatic breast cancer (MBC).Patients with estrogen (ER) and progesterone (PgR) receptornegative MBC have almost no chance of benefit from ET, and are treated with more toxic, but more likely beneficial, chemotherapy[1]. There is no validated method to identify which HR-positive patients are unlikely to respond to ET and would be better treated with other therapies, such as combination ET and other targeted treatments or with chemotherapy. Serial biopsies are impractical, costly, and invasive for patients In this regard, use of circulating tumor biomarkers, designated as “liquid biopsies” might provide a more convenient and practical surrogate for tissue biopsies[3]. We have previously developed an analytically validated assay, designated the CTC-endocrine therapy index (CTC-ETI), which is based on CTC enumeration, as well as semiquantitative analyses of CTC expression of four different markers associated with ET benefit [ER, B-cell lymphoma 2 (BCL2)] or resistance [human epidermal growth factor receptor (HER2) and Ki67]6. We further hypothesized that CTC-ETI could identify a subset of patients with ER-positive, HER2-negative MBC who might have ET-refractory disease and would be better treated with chemotherapy
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