Exemestane for Breast-Cancer Prevention in Postmenopausal Women

SUMMARY: Breast cancer is the second most common cause of death in the United States. Presently two Selective Estrogen Receptor Modulators (SERM’s), tamoxifen and raloxifene are approved by the FDA, for the primary prevention of breast cancer. Tamoxifen has been associated with increased risk of venous thromboembolism and endometrial cancers. Raloxifene can also be associated with venous thromboembolism but has not been associated with endometrial cancers. Exemestane is an irreversible, steroidal aromatase inactivator. This agent was evaluated in a randomized, placebo controlled, double blind study, to reduce the risk of invasive breast cancer in postmenopausal women, considered to be at moderately increased risk of developing breast cancer. Risk factors included age over 60 years, Gail five year risk score greater than 1.66% and prior atypical ductal/ lobular hyperplasia, LCIS, or DCIS with mastectomy. At a median follow up of 3 years, exemestane reduced the relative incidence of invasive breast cancers by 65% compared to placebo and this benefit was accomplished without serious toxicities and with minimal changes in quality of life. This is the first aromatase inhibitor/inactivator to demonstrate proven efficacy in breast cancer prevention, in a randomized clinical trial. N Engl J Med 2011; 364:2381-2391

Breast Cancer Prevention

Exemestane is an aromatase inactivator presently approved by the FDA for the treatment of breast cancer. This drug was studied in a large randomized clinical trial for the prevention of breast cancer. The results of this study were published in the June 23 issue of the NEJM. Exemestane reduced the relative incidence of invasive breast cancer by 65%, in postmenopausal women with moderate risk of developing breast cancer. The benefit with this drug was accomplished without any significant serious toxicities.

Breast Cancer is the second most common cause of cancer death in the United States. This new addition will be additional ammunition, in the fight against breast cancer

BRAF Mutations in Hairy-Cell Leukemia

SUMMARY: Hairy cell leukemia (HCL) is a relatively indolent disorder with characteristic immunophenotypic findings. In spite of the lack of clear understanding of the molecular biology of HCL, treatment with purine nucleoside analogs has resulted in long term remissions and cure. To under the genetic abnormalities in patients with HCL, Tiacci and colleagues evaluated the peripheral blood of 48 patients with HCL. They noted that all 48 patients had BRAF V600E mutation. This is the same mutation that has been noted in approximately 50% of the patients with melanoma. They further tested the peripheral blood of 5 patients in vitro with BRAF inhibitor vemurafenib. This drug indeed demonstrated efficacy by markedly decreasing phosphorylated ERK and MEK. This interesting finding may help us better understand the pathogenesis of HCL and targeted therapy with BRAF inhibitors may change the way we treat patients with HCL. N Engl J Med 2011; 364:2305-2315

Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600E BRAF-mutated melanoma

SUMMARY: The Mitogen- Activated Protein kinase pathway (MAP kinase pathway) is a key signaling pathway which enables the cell to respond external stimuli. There are a number of MAP kinase pathways which share different proteins at each step. The MAP kinase pathway plays a dual role regulating cytokine production and participating in cytokine dependent signaling cascade. The MAP kinase pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAS family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6%-8% of all malignancies. The most common BRAF mutations in melanoma is at the V600E site and is detected in approximately 50% of melanomas. Vemurafenib is a novel oral  inhibitor of mutated BRAF. Based on the impressive phase I and phase II data, BRIM 3, a randomized, open-label, multicenter, phase III trial was conducted, in treatment naïve patients with unresectable Stage IIIC or Stage IV melanoma with V600E BRAF mutation. Patients in this trial received either Vemurafenib or Dacarbazine. The primary end points were progression- free survival and overall survival . There was a statistically significant improvement both in  progression free survival and overall survival in the Vemurafenib group compared to those in the Dacarbazine group.This is a major advance in the field of personalized medicine and molecular targeted therapy. J Clin Oncol 29: 2011 (suppl; abstr LBA4)

Improving Survival in Metastatic Melanoma

Approximately 50% of the patients with melanoma have an activating BRAF mutation, V600E.  Vemurafenib is an oral BRAF kinase inhibitor. In a randomized phase III study involving treatment naive patients with unresectable stage III or stage IV melanoma patients with BRAF mutation V600E, Vemurafenib significantly improved progression free survival (PFS) and overall survival (OS) compared to Dacarbazine (DTIC). This is a major advance in the field of personalized medicine and molecular targeted therapy.  This information was presented at the 2011 ASCO meeting.