Phase II studies of two different schedules of dasatinib in bone metastasis predominant metastatic breast cancer: SWOG S0622

Abstract

Purpose Bone metastases from breast cancer are common, causing significant morbidity. Preclinical data of dasatinib, an oral small molecule inhibitor of multiple oncogenic tyrosine kinases, suggested efficacy in tumor control and palliation of bone metastases in metastatic breast cancer (MBC). This clinical trial aimed to determine whether treatment with either of 2 dose schedules of dasatinib results in a progression free survival (PFS) > 50% at 24 weeks in bone metastasis-predominant MBC, to evaluate the toxicity of the 2 dosing regimens, and explore whether treatment results in decreased serum bone turnover markers and patient reported “worst pain”. Methods Subjects with bone metastasis-predominant MBC were randomly assigned to either 100 mg of dasatinib once daily, or 70 mg twice daily, with treatment continued until time of disease progression or intolerable toxicity. Planned accrual was 40 patients in each arm. The primary trial endpoint was PFS, defined as time from registration to progression or death due to any cause. Results Median PFS for all eligible patients (79) was 12.6 weeks (95% CI 9.1 – 16.7). Neither cohort met the threshold for further clinical interest. There were no significant differences in PFS by randomized treatment arm (p=0.85). Toxicity was similar in both cohorts, with no clear trend in serum biomarkers of bone turnover or patient-reported pain. Conclusions Dasatinib was ineffective in controlling bone-predominant MBC in a patient population unselected by molecular markers. Further study of dasatinib in breast cancer should not be pursued unless performed in molecularly determined patient subsets, or rational combinations.

Growth inhibitory effect of the Src inhibitor dasatinib in combination with anticancer agents on uterine cervical adenocarcinoma cells

“…Patients in the advanced stage in various solid tumors show resistance to treatment, and a number of studies have investigated novel antitumor agents, with a particular focus on molecularly targeted drugs. In recent years, Src inhibitors have been studied extensively ( 8 – 17 ).…”

“…Clinical trials have revealed no effect of dasatinib alone on breast, pancreatic, colorectal and ovarian tumor progression, overall survival or progression-free survival ( 8 , 12 , 13 , 15 ). This may be due to the activation of other signaling molecules, such as the Src family kinases Janus kinase and FGR ( 14 ).…”

“…It was originally approved as a drug for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia ( 4 , 5 ). Clinical trials have been conducted using dasatinib in combination with anticancer drugs for the treatment of breast, colon, prostate and other cancers ( 8 – 17 ). Single-agent dasatinib has not exhibited any clinical activity in breast, pancreatic, colorectal and ovarian carcinoma ( 8 , 12 , 13 , 15 ).…”

“…Clinical trials have been conducted using dasatinib in combination with anticancer drugs for the treatment of breast, colon, prostate and other cancers ( 8 – 17 ). Single-agent dasatinib has not exhibited any clinical activity in breast, pancreatic, colorectal and ovarian carcinoma ( 8 , 12 , 13 , 15 ). However, combination therapy with dasatinib and anticancer drugs has been demonstrated to be clinically effective in the treatment of breast, prostate, ovarian and pancreatic cancers ( 9 – 11 , 14 , 16 , 17 ).…”

Breast cancer bone metastases are attenuated in a Tgif1-deficient bone microenvironment

“…This results in the release of matrix-derived growth factors, such as transforming growth factor-β1 (TGF-β1), which further stimulate tumor growth [6,7]. Although novel therapeutic options and targets are emerging (e.g., tyrosine kinase inhibitors, microRNAs [8][9][10][11]), the disease remains incurable once osteolytic lesions have developed.…”