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Report for Clinical Trial NCT03168074

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Phase II Window-of-opportunity Study of Single Agent Lenvatinib in Estrogen Receptor Positive Early Stage Breast Cancer

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.

NCT03168074 Breast Cancer
MeSH: Breast Neoplasms
HPO: Breast carcinoma Neoplasm of the breast

1 Interventions

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: Drug

lenvatinib


Primary Outcomes

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 lenvatinib

Description: 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 lenvatinib

Description: 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 lenvatinib

Description: 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 lenvatinib

Description: 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 lenvatinib

Description: 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 lenvatinib

Secondary Outcomes

Description: 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 lenvatinib

Description: 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 lenvatinib

Description: 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 lenvatinib

Description: : 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 lenvatinib

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 T47D

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 ---



HPO Nodes


HPO:
Breast carcinoma
Genes 95
TP53 PPM1D CTNNB1 TP53 COL14A1 AKT1 AKT1 OPCML MDM2 BRCA1 SLC22A18 POLE BRCA2 BRCA1 SDHC NTHL1 PTEN XRCC3 MSH6 IDH1 RAD51C RAD51C CASP8 RB1CC1 PIK3CA PALLD KRAS PIK3CA CHEK2 BRIP1 MRE11 NTHL1 ATM TP53 RAD51D STK11 PRKN ESR1 PIK3CA KLLN MSH2 SDHD KRAS SEC23B HMMR PTEN POLD1 PIK3CA IDH2 BRCA1 PALB2 BRIP1 TP53 RAD51 RNF43 BARD1 BARD1 AAGAB AKT1 SMAD4 RAD50 STK11 CHEK2 RAD54L NBN CDKN2A SEC23B CDH1 WRN NQO2 PALB2 ATR PALB2 TWIST1 SDHB MSH2 BRCA2 BRCA1 RAD51 CHEK2 MLH1 BRCA1 FGFR2 TP53 PHB BRCA2 CDH1 PTEN BRCA2 CHEK2 CDKN2A APC MLH1 AKT1 APC
Neoplasm of the breast
Genes 123
PPM1D CTNNB1 PTEN MGMT AKT1 BRCA1 SLC22A18 BRCA1 SDHC NTHL1 XRCC3 APC IDH1 LMNA RAD51C CDKN2B PIK3CA PALLD CHEK2 NTHL1 ATM RAD51D ESR1 GNAS APC PIK3CA RASGRP1 SDHD PRKCD KRAS BAP1 IDH2 PALB2 FAS RAD51 RNF43 PRLR AKT1 CHEK2 CDKN2A CDH1 CDK4 RELA BRCA2 BRCA1 TERF2IP CHEK2 MLH1 BRCA1 PRKAR1A POT1 BRCA2 CDH1 TERT APC MLH1 AKT1 TP53 CASP10 TP53 COL14A1 AKT1 OPCML MDM2 POLE BRCA2 PTEN MSH6 RAD51C CASP8 RB1CC1 KRAS ACD PIK3CA BRIP1 MRE11 TP53 STK11 PRKN KLLN MSH2 SEC23B HMMR PTEN POLD1 PIK3CA BRCA1 MITF FAS BRIP1 TP53 BARD1 BARD1 AAGAB SMAD4 RAD50 STK11 RAD54L NBN C11ORF95 SEC23B WRN PTEN NQO2 PTEN PALB2 ATR PALB2 CDKN2A TWIST1 SDHB MSH2 MC1R FASLG RAD51 FGFR2 TP53 PHB PTEN BRCA2 CHEK2 CDKN2A APC