Searching for Positives in Triple-Negative Breast Cancer

Cheryl Zigrand
Published Online: March 18, 2014
Lisa A. Carey, MD

Lisa A. Carey, MD

Treatments for triple-negative breast cancer (TNBC) have made significantly less progress in comparison with other subtypes. Patients with TNBC have poor prognosis, and the primary therapeutic approach for this breast cancer subtype is still chemotherapy, which is often inadequate for many patients, according to Lisa A. Carey, MD, division chief of Hematology and Oncology, University of North Carolina, Durham.

Defining Subsets and Targets

“The majority of breast cancer has markers that can identify targetable subtypes such as the estrogen receptor (ER), the progesterone receptor, and human epidermal growth factor receptor 2 (HER2),” said Brian Lehmann, PhD, assistant professor, Department of Biochemistry, Vanderbilt University, Nashville, Tennessee. “Clinicians can use tests to identify these populations of breast cancers, and order targeted therapies for them. The absence of these markers renders TNBC a disease of exclusion, and it comes as no surprise that it is a heterogeneous collection of biologically distinct cancers.”

Although in its early stages, research into the potential subsets that comprise TNBC is making progress. Lehmann said, “Our recent work has given some insight into this heterogeneous disease by examining the similarities of global transcriptional profiles from just triple-negative breast cancers. These studies indicate that there are at least six distinct subsets based on transcriptional profiles and that cell-line models differentially respond to chemotherapeutics and targeted therapies. These subtypes include two basal-like subtypes (BL1 and BL2), an immunomodulatory subtype (IM), two mesenchymal subtypes (M and MSL), and a luminal androgen receptor (LAR) subtype.” Defining these transcriptional profiles may be useful in biomarker selection, drug discovery, and clinical trial design, all with the goal of matching patients with TNBC with appropriate targeted therapies.1 Lehmann added, “We are trying to refine these subtypes and look for genomic aberrations that are shared within these subtypes that may be targetable.”

One targeted therapy being investigated is glembatumumab vedotin (CDX-011), an antibody-drug conjugate that targets glycoprotein NMB (GPNMB). GPNMB is a protein overexpressed by multiple tumor types, including breast cancer and melanoma. A randomized, multicenter pivotal study of CDX-011 in patients with metastatic, GPNMB over-expressing TNBC (The METRIC Study) is currently enrolling participants. The study’s purpose is to determine the efficacy and safety of CDX-011 in this patient population. Primary endpoints include overall response rate and progression-free survival. Eligible patients will be randomly assigned to receive treatment with CDX-011 or with capecitabine. Final data collection date for primary outcomes is scheduled for September 2015 (NCT01997333).

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