Targeted Therapies for the Treatment of Metastatic Breast Cancer

Abstract

In the United States, 13% of women are diagnosed with invasive breast cancer in their lifetime and 6% of breast cancer patients have metastatic disease at initial diagnosis. Moreover, nearly 30% of women with early stage breast cancer will develop metastatic disease. About 42,000 deaths from breast cancer occur annually, largely due to metastatic breast cancer (MBC). The prognosis of MBC is poor and the five-year survival rate is about 27%. Metastatic breast cancer is characterized with high heterogeneity. It consists of many different molecular subtypes, which include hormone receptor positive (HR+), epidermal growth factor receptor type 2 positive (HER2+) and triple negative breast cancer (TNBC). In addition to molecular heterogeneity, individuals often reveal various inherited genetic alterations, such as germline mutations in BRCA 1 or 2, PALB2, CHEK2, and others which may influence the outcome of therapies. Tumor molecular features may also change as drug resistance emerges during the course of disease. All of these make the treatment of MBC and the evaluation of new therapies a complex process. However, in recent years, a better understanding of molecular features and genetic heterogeneity have contributed to the development of new targeted therapies such as HER2 inhibitors, CDK4/6 inhibitors, PI3K inhibitors and PARP inhibitors, as well as combined strategies including hormone therapy with CDK4/6 inhibitors for HR+ disease and HER2 inhibitors with chemotherapy for HER+. Despite the efficacy of these new therapies, drug resistance remains a major issue in the management of MBC. Therefore, development of new targeted strategies will always be necessary for treating MBC. The purpose of my work was to investigate how new therapeutic drugs or combinations, advance the knowledge and guide clinical practice in treating MBC. I have advanced my understanding of the process of clinical research through analysis and interpretation of two Phase II clinical trials of targeted therapies in breast cancer. Overexpression of MET, RET and VEGFR are prominent in subsets of metastatic breast cancer, which implicate tumor proliferation, angiogenesis, progression and survival. Cabozantinib targeting these receptor tyrosine kinases (RTKs) poses a promising therapeutic strategy for improving breast cancer treatment. However, clinical experience with Cabozantinib is very limited in metastatic breast cancer. In addition, bone lesions are a prominent challenge for treatment of MBC. Nearly 75% of patients with HR+ MBC develop bone metastasis and many have bone-only disease, which has been difficult to evaluate for response. Cabozantinib has been noted to contribute to an improved bone scan response in metastatic prostate cancer patients, but this observation has not been translated into a survival benefit in a randomized clinical trial. Therefore, my first study was to assess the efficacy of cabozantinib in patients of HR+ breast cancer with bone metastases using bone scan response as a primary endpoint and evaluating whether bone scan response was correlated with other important clinical endpoints, such as overall survival and progression free survival. PARP inhibitors, which block an important initial step in the repair of DNA, offer a very promising therapeutic strategy for metastatic breast cancer, particularly for BRCA1/2 deficient tumors. These inhibitors are known to potentiate the cytotoxic effects of DNA-damaging chemotherapies, such as temozolomide, an alkylating agent. Veliparib (ABT888) as a novel oral PARP inhibitor, has modest activity as a monotherapy in breast cancer because of low trapping efficiency; however, it demonstrated potential in the combination setting due to less toxicity profile, compared to other PARP inhibitors. Combination of veliparib (a PARP inhibitor) and temozolomide has demonstrated substantial activity against breast cancer in preclinical models and in patients with other solid tumors. Thus, my second study evaluated this novel, oral combination therapy in breast cancer patients with or without germline BRCA mutations.