Clinical Overview of Sorafenib in Breast Cancer
Clinical Overview of Sorafenib in Breast Cancer
Breast carcinoma remains the most common malignancy of women around the world, and despite the advances in the early diagnosis and adjuvant treatment of this disease, many women still relapse with metastatic breast cancer. There is therefore an urgent need for the development and testing of novel agents targeting pathways thought to be involved in the pathogenesis of breast cancer. Aberrant activation of the Ras/Raf/MAPK/ERK kinase/extracellular signal-regulated kinase cascade and the VEGF pathway are commonly observed in breast cancer cells leading to malignant cell proliferation, cell growth, prevention of apoptosis, tumor invasion and neo-angiogenesis. Sorafenib is an oral multikinase inhibitor that inhibits tumor growth and proliferation by interfering with several receptor tyrosine kinases involved in the pathogenesis and perpetuation of malignant breast cancer cells. This article reviews previous experiences and current and future development strategies of sorafenib in breast cancer.
Breast carcinoma remains the most common malignancy of women around the world, and despite the advances in the early diagnosis and adjuvant treatment of this disease, many women still relapse with metastatic breast cancer (MBC). There is therefore an urgent need for the development and testing of novel agents targeting pathways thought to be involved in the pathogenesis of breast cancer. Among them, the Ras/Raf/MAPK signaling pathway, the PI3K/mTOR pathway and the VEGF pathway are often abnormally activated in breast cancer. These pathways mediate responses to growth signals and angiogenic factors.
Aberrant activation of the Ras/Raf/MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) cascade is commonly observed in cancer cells, leading to malignant cell proliferation, cell growth, prevention of apoptosis, tumor invasion and neo-angiogenesis. Thus, drugs able to target these pathways can arrest cell growth and induce cell apoptosis. It is also believed that for a tumor to be able to grow, invade and metastasize, it needs to create and grow new blood vessels. To do so, tumors would overexpress the pro-angiogenic VEGF and its receptors. This angiogenic pathway can be interrupted by different drugs, such as the recombinant, humanized monoclonal antibody bevacizumab. Clinical trials combining bevacizumab and chemotherapy have demonstrated improved outcomes of patients with MBC. In addition, PDGF is another angiogenic growth factor overexpressed in stromal and malignant cells of breast tumors that contributes to their progression. A drug capable of interfering with all these different aberrant signaling pathways can have a significant impact on the treatment of early- and advanced-stage breast cancer.
Sorafenib tosylate (Nexavar®; Bayer Healthcare Pharmaceuticals, NJ, USA and Onyx Pharmaceuticals, Inc., CA, USA) is an oral multikinase inhibitor that inhibits tumor growth and proliferation by interfering with several receptor tyrosine kinases on the tumor cells and cells of the tumor vasculature, including the VEGF receptors 1, 2 and 3, PDGF receptors α and β, RET, Flt3 and c-KIT. Additionally, sorafenib is a RAF kinase and MAPK pathway inhibitor. The tolerance and efficacy of sorafenib have been evaluated through preclinical in vivo models in combination with several chemotherapeutic agents, including capecitabine, paclitaxel, doxorubicin, irinotecan, gemcitabine and carboplatin/cisplatin, as well as with other targeted agents, such as gefitinib and bevacizumab among others, and with hormonal therapies. Sorafenib has been evaluated in more than 35,000 patients in a variety of clinical trials, and it is approved for the treatment of metastatic renal cell carcinoma and advanced hepatocellular carcinoma. It has also been tested, either as single agent or in combination with chemotherapy, in a variety of solid tumors, including breast, thyroid, colorectal, gastric, ovarian, melanoma, sarcoma, lung, head-and-neck and pancreatic cancer. Commonly reported adverse events (AEs; dose limiting or grade 3–4) observed when sorafenib is combined with standard chemotherapy include hand–foot syndrome skin reaction, rash, fatigue, neutropenia and thrombocytopenia. This article will review previous experiences, current and future development strategies of sorafenib in breast cancer. There are over 35 clinical trials completed or ongoing using sorafenib or sunitinib, another oral small molecule that targets some of the same tyrosine kinases as sorafenib, as single agents or in combination with chemotherapy, for the treatment of early-stage breast cancer and MBC.
Abstract and Introduction
Abstract
Breast carcinoma remains the most common malignancy of women around the world, and despite the advances in the early diagnosis and adjuvant treatment of this disease, many women still relapse with metastatic breast cancer. There is therefore an urgent need for the development and testing of novel agents targeting pathways thought to be involved in the pathogenesis of breast cancer. Aberrant activation of the Ras/Raf/MAPK/ERK kinase/extracellular signal-regulated kinase cascade and the VEGF pathway are commonly observed in breast cancer cells leading to malignant cell proliferation, cell growth, prevention of apoptosis, tumor invasion and neo-angiogenesis. Sorafenib is an oral multikinase inhibitor that inhibits tumor growth and proliferation by interfering with several receptor tyrosine kinases involved in the pathogenesis and perpetuation of malignant breast cancer cells. This article reviews previous experiences and current and future development strategies of sorafenib in breast cancer.
Introduction
Breast carcinoma remains the most common malignancy of women around the world, and despite the advances in the early diagnosis and adjuvant treatment of this disease, many women still relapse with metastatic breast cancer (MBC). There is therefore an urgent need for the development and testing of novel agents targeting pathways thought to be involved in the pathogenesis of breast cancer. Among them, the Ras/Raf/MAPK signaling pathway, the PI3K/mTOR pathway and the VEGF pathway are often abnormally activated in breast cancer. These pathways mediate responses to growth signals and angiogenic factors.
Aberrant activation of the Ras/Raf/MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) cascade is commonly observed in cancer cells, leading to malignant cell proliferation, cell growth, prevention of apoptosis, tumor invasion and neo-angiogenesis. Thus, drugs able to target these pathways can arrest cell growth and induce cell apoptosis. It is also believed that for a tumor to be able to grow, invade and metastasize, it needs to create and grow new blood vessels. To do so, tumors would overexpress the pro-angiogenic VEGF and its receptors. This angiogenic pathway can be interrupted by different drugs, such as the recombinant, humanized monoclonal antibody bevacizumab. Clinical trials combining bevacizumab and chemotherapy have demonstrated improved outcomes of patients with MBC. In addition, PDGF is another angiogenic growth factor overexpressed in stromal and malignant cells of breast tumors that contributes to their progression. A drug capable of interfering with all these different aberrant signaling pathways can have a significant impact on the treatment of early- and advanced-stage breast cancer.
Sorafenib tosylate (Nexavar®; Bayer Healthcare Pharmaceuticals, NJ, USA and Onyx Pharmaceuticals, Inc., CA, USA) is an oral multikinase inhibitor that inhibits tumor growth and proliferation by interfering with several receptor tyrosine kinases on the tumor cells and cells of the tumor vasculature, including the VEGF receptors 1, 2 and 3, PDGF receptors α and β, RET, Flt3 and c-KIT. Additionally, sorafenib is a RAF kinase and MAPK pathway inhibitor. The tolerance and efficacy of sorafenib have been evaluated through preclinical in vivo models in combination with several chemotherapeutic agents, including capecitabine, paclitaxel, doxorubicin, irinotecan, gemcitabine and carboplatin/cisplatin, as well as with other targeted agents, such as gefitinib and bevacizumab among others, and with hormonal therapies. Sorafenib has been evaluated in more than 35,000 patients in a variety of clinical trials, and it is approved for the treatment of metastatic renal cell carcinoma and advanced hepatocellular carcinoma. It has also been tested, either as single agent or in combination with chemotherapy, in a variety of solid tumors, including breast, thyroid, colorectal, gastric, ovarian, melanoma, sarcoma, lung, head-and-neck and pancreatic cancer. Commonly reported adverse events (AEs; dose limiting or grade 3–4) observed when sorafenib is combined with standard chemotherapy include hand–foot syndrome skin reaction, rash, fatigue, neutropenia and thrombocytopenia. This article will review previous experiences, current and future development strategies of sorafenib in breast cancer. There are over 35 clinical trials completed or ongoing using sorafenib or sunitinib, another oral small molecule that targets some of the same tyrosine kinases as sorafenib, as single agents or in combination with chemotherapy, for the treatment of early-stage breast cancer and MBC.
