The Investigators hypothesize that single agent lenvatinib has biological activity in estrogen receptor positive breast cancer, and that the effects are more pronounced in patients with positive RET expression in the tumor.
Name: lenvatinib
Description: Eligible patients will be treated with approximately 2 weeks of single agent lenvatinib (range 10-28 days, depending on the date of breast cancer surgery; last dose of lenvatinib to be administered no later than 48 hours before surgery in patients who are planned to receive ≤14 days lenvatinib, and no later than 120 hours before surgery in patients who are planned to receive 15-28 days lenvatinib).Tissue sections from the pre-treatment and post-treatment tumor will be collected for biomarker analysis. Pre- and post-treatment ultrasound will be used to document the size of the target lesions.Type: Druglenvatinib
Description: To evaluate Ki67 changes. The Ki-67 protein is a cellular marker for proliferation. It is strictly associated with cell proliferation. Ki67 has been shown to be a surrogate marker of biological activity and treatment response in estrogen receptor positive breast cancer treated with endocrine therapy.
Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design Time: after 10-28 days of single agent lenvatinibDescription: To evaluate histological response such as the improvement in the appearance of microscopic tissue specimens after treatment with lenvatinib. The improved appearance of biopsy specimens after treatment often suggests the patient's prognosis will improve as well.
Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design Time: after 10-28 days of single agent lenvatinibDescription: To evaluate apoptosis. Apoptosis is the death of cells which occurs as a normal and controlled part of an organism's growth or development. The presence of apoptosis indicates anti-cancer effects.
Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design Time: after 10-28 days of single agent lenvatinibDescription: To evaluate RET. RET is an estrogen response gene. RET is associated with resistance to tamoxifen and aromatase inhibitors, and increased RET expression has been demonstrated in hormone resistant cell lines and primary tumors.
Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design Time: after 10-28 days of single agent lenvatinibDescription: To evaluate downstream targets such as AKT. AKT /protein kinase B (PKB) is a cardinal node in diverse signaling cascades important in both normal cellular physiology and various disease states. AKT signaling regulates cell proliferation and survival, cell growth (size), glucose metabolism, cell motility and angiogenesis. Aberrant regulation of these processes results in cellular perturbations considered hallmarks of cancer, and numerous studies testify to the frequent hyperactivation of AKT signaling in many human cancer.
Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design Time: after 10-28 days of single agent lenvatinibDescription: To evaluate downstream targets such as ERK. ERK is Extracellular signal-regulated kinase. Deregulation of ERK signalling pathway is linked to many other aspects of the tumour phenotype.
Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design Time: after 10-28 days of single agent lenvatinibDescription: to obtain the percentage change in primary breast tumor dimension measured by ultrasound
Measure: Changes in the primary tumor dimensions Time: after 10-28 days of single agent lenvatinibDescription: to obtain the proportion of subjects with tumor reduction of at least 10%
Measure: The proportion of subjects with tumor reduction Time: after 10-28 days of single agent lenvatinibDescription: To compare clinical response of lenvatinib in RET negative versus RET positive, ER positive breast cancers
Measure: Comparison of the clinical response of lenvatinib in RET negative versus RET positive, ER positive breast cancers Time: after 10-28 days of single agent lenvatinibDescription: : Comparison of the number of patients with Ki67 changes, histological response, apoptosis, RET and downstream targets such as AKT and ERK, between RET negative versus RET positive, ER positive breast cancers.
Measure: Comparison in the overall average changes in biological effects of lenvatinib between RET negative and RET positive, ER positive breast cancers. Time: after 10-28 days of single agent lenvatinibSingle Group Assignment
There is one SNP
The investigators tested 9 ER+ breast cancer cell lines for RET expression using Western blot, and identified 4 with high expression (BT474, MB361, HCC1419, UACC812), 2 with normal expression (MCF7, CAMA1), and 3 with low expression (T47D, ZR-75-1, BT483). --- T47D ---
To evaluate the effects of combining lenvatinib with endocrine therapy in ER+ breast cancer cell lines with different RET expression, the investigators performed experiments using 6 cell lines, including 2 with high RET expression (BT474, MB361), 2 with normal RET expression (MCF7, CAMA1), and 2 with low RET expression (T47D, ZR-75-1). --- T47D ---
Lenvatinib was at least additive with tamoxifen in all 6 ER positive breast cancer cell lines tested, with the combination resulting in ≥50% cell kill compared to single agent tamoxifen in BT474, CAMA1, and T47D cell lines. --- T47D ---