Triple-Negative Breast Cancer

As knowledge increases about the processes underlying cancer, it is becoming feasible to design “targeted therapies” directed toward specific pathways that are critical to the genesis or maintenance of the malignant phenotype. Poly(ADP-ribose) polymerase (PARP) inhibitors are an example of this new framework. DNA damage repair is a complex and multifaceted process that is critical to cell survival. Members of the PARP family are central to specific DNA damage repair pathways, particularly the base excision repair (BER) pathway. PARP inhibition, with subsequent impairment of the BER mechanism, may enhance the cytotoxicity of agents that generate single-strand breaks in DNA, such as radiation and certain chemotherapy drugs. In addition, PARP inhibitors may induce death through “synthetic lethality” if the DNA repair mechanisms that rescue BER-deficient cells are themselves impaired. This mechanism is thought to underlie the impressive results of PARP inhibition in BRCA-associated breast and ovarian cancer, and may also account for the reported benefit of this approach in “triple-negative” breast cancer. This review will examine the current understanding of PARP inhibition as a treatment for breast cancer, ongoing clinical trials, and future directions for this new approach.

ORLANDO-Oncologists can expect to hear more about inhibitors of the enzyme poly (ADP-ribose) polymerase-1, or PARP. An experimental agent in this class, BSI-201, prolonged event-free and overall survival in patients with triple-negative breast cancer when used together with gemcitabine (Gemzar) and carboplatin, according to early study results.

Two new studies reported at this year’s ASCO meeting demonstrated the effect of a new class of targeted therapy called poly (ADP-ribose) polymerase (PARP) inhibitors on traditionally difficult-to-treat breast cancers-so-called “triple-negative” breast cancer and BRCA1/2-deficient breast cancers.

Patients with operable triple-negative breast cancer are at increased risk for recurrence if their tumor has higher levels of a protein-encoding gene implicated in migration, proliferation, and other cellular processes, reported Joseph A. Sparano, MD, from the Eastern Cooperative Oncology Group.

In 2008, it is estimated that over 1 million women worldwide will be diagnosed with breast cancer, of which 172,695 will be classified as “triple-negative.”[1] The triple-negative phenotype encompasses a breast tumor subtype that is clinically negative for expression of the estrogen and progesterone receptors (ER and PR) and lacks overexpression of the HER2 protein, with unique prognostic and therapeutic implications.

Two years after her first mammogram the patient, EC, noticed swelling and skin changes in one breast. A bone scan, chest and abdomen CT, and PET scan were negative for metastatic spread, staging the cancer at IIIB.

Novel agents are adding to the wide choices of standard chemotherapies already available. This review offers an approach to the selection of individualized and rational therapies for patients with metastatic breast cancer.

This article reviews recent findings from clinical trials of epothilones and discusses future directions for the use of these agents in cancer therapy, with a focus on the two most-studied epothilones to date: ixabepilone and patupilone.

The combination of capecitabine (Xeloda) and ixabepilone (Ixempra) appears to be robust in patients with the so-called triple-negative breast cancer phenotype