TLE3 as a candidate biomarker of response to taxane therapy

Breast Cancer Research 2009, 11:R17

Swati A Kulkarni¹, David G Hicks², Nancy Watroba¹, Christine Murekeyisoni¹, Helena Hwang³, Thaer Khoury³, Rodney A Beck⁴, Brian Z Ring⁴, Noel Estopinal⁵, Marshall Schreeder⁶, Robert S Seitz⁴, and Douglas T Ross⁴

¹Surgical Onoclogy, Roswell Park Cancer Institute (Buffalo, NY), ²Pathology and Laboratory Medicine, University of Rochester (Rochester, NY), ³Pathology, Rosell Park Cancer Institute (Buffalo, NY), ⁴Applied Genomics, Inc (Huntsville, AL), ⁵Radiation Oncology, Center for Cancer Care (Huntsville, AL), ⁶Medical Oncology, Clearview Cancer Institute (Huntsville, AL).

Abstract

Introduction

The addition of taxanes (T) to chemotherapeutic regimens has not demonstrated a consistent benefit in early stage breast cancer. To date, no clinically relevant biomarkers have been identified that predict T response.

Methods

A dataset of immunohistochemistry (IHC) stains in 411 patients was mined to identify potential markers of response. TLE3 emerged as a candidate marker for T response. To test the association with T sensitivity, an independent 'triple negative' (TN) validation cohort was stained with anti-TLE3 antibody.

Results

TLE3 staining was associated with improved five-year disease free interval (DFI) in the overall cohort (n = 441, P < 0.004), in patients treated with cyclophosphamide (C), methotrexate (M), and 5-fluorouracil (F) (n = 72, P < 0.02), and in those treated with regimens containing doxorubicin (A), and a T (n = 65, P < 0.04). However, no association was shown with outcome in untreated patients (n = 203, P = 0.49) or those treated with a regimen containing A only (n = 66, P = 0.97). In the TN cohort, TLE3 staining was significantly associated with improved five-year DFI in all patients (n = 81, P < 0.015), in patients treated with AC + T (n = 45, P < 0.02), but not in patients treated with AC (n = 17, P = 0.81). TLE3 was independent of tumor size, and nodal status, and grade, by bi-variable analysis in both cohorts.

Conclusions

TLE3 staining is associated with improved DFI in taxane treated patients in two independent cohorts. Since the validation study was performed in a TN cohort, TLE3 is not serving as a surrogate for ER or HER2 expression. TLE3 should be studied in large clinical trial cohorts to establish its role in T chemotherapy selection.

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