scholarly journals VERU-111: An Oral Tubulin Inhibitor That Suppresses Taxane-Sensitive and Taxane-Resistant Breast Cancer

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1035-A1035
Author(s):  
Shanshan Deng ◽  
Raisa I Krutilina ◽  
Deanna Parke ◽  
Hao Chen ◽  
Duane D Miller ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Advanced Breast Cancer ◽  
Cell Lines ◽  
Advanced Breast ◽  
Study Endpoint ◽  
Axillary Lymph ◽  
Dependent Manner ◽  
Tubulin Inhibitor ◽  
Orally Bioavailable

Abstract Triple negative breast cancer (TNBC) patients have poorer overall prognosis relative to patients diagnosed with other molecular subtypes due to rapid onset of drug resistance to conventional chemotherapies and increased risk of visceral metastases. The microtubule inhibitor paclitaxel (Taxol, a taxane) is a frontline therapy for advanced breast cancer. We evaluated in TNBC models the preclinical safety and efficacy of a novel, potent, and orally bioavailable tubulin inhibitor, VERU-111, a tubulin inhibitor targeting the colchicine binding site. VERU-111 showed potent anti-proliferative and anti-migratory activity against several taxane-sensitive and taxane-resistant TNBC breast cancer cell lines. Based on these observations, taxane-resistant HER2+ cell lines were generated, and were also found to be responsive to VERU-111 treatment. In vivo, orally administered VERU-111 inhibited MDA-MB-231 tumor growth in a dose-dependent manner with antitumor potency similar to paclitaxel, and repressed metastases originating from the mammary fat pad or following tail vein injection. In contrast, in a MDA-MB-231 paclitaxel-resistant (TxR) subline, tumor growth was refractory to paclitaxel whereas VERU-111 significantly inhibited primary tumor growth and reduced lung and liver metastases. VERU-111 was then tested in a luciferase-labeled, multidrug resistant patient-derived xenograft (PDX) TNBC model. VERU-111 significantly inhibited HCI-10 PDX tumor growth and suppressed the expansion of axillary lymph node metastases present prior to initiation of therapy while suppressing lung, liver, bone and kidney metastases at study endpoint. Moreover, in contrast to paclitaxel, VERU-111 therapy did not cause a significant decrease in mouse body weight during treatment. Evaluation of efficacy of VERU-111 in taxane-sensitive and -resistant HER2+ xenograft models is in progress. Overall, we conclude that VERU-111 is a new generation orally bioavailable tubulin inhibitor that potently inhibits the growth of taxane-sensitive and taxane-resistant breast cancers with reduced adverse side effects relative to paclitaxel. Importantly, VERU-111 is well-tolerated in patients as evaluated in phase I/II clinical trials for advanced prostate cancer patients (NCT03752099). We propose that VERU-111 will be an effective second line therapy for patients with advanced breast cancer who progress on taxane-based therapeutic regimens.

Concurrent chemoradiotherapy (CRT) following neoadjuvant chemotherapy (NACT) in locally advanced breast cancer (LABC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 11063-11063
Author(s):  
A. Alvarado-Miranda ◽  
R. Morales-Barrera ◽  
O. Arrieta ◽  
J. Zinser-Sierra ◽  
A. Gamboa-Vignole ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multivariate Analysis ◽  
Advanced Breast Cancer ◽  
Concurrent Chemoradiotherapy ◽  
Locally Advanced Breast Cancer ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Advanced Breast ◽  
Axillary Lymph ◽  
Main Determinant

11063 Background: Despite broad advances in the treatment of LABC, 30 to 40% of patients responding to NACT develop locoregional relapse. We performed a retrospective analysis of the experience obtained so far in patients with LABC who were treated with CRT after NACT in terms of pathologic complete response (pCR), relapse-free survival (RFS) and overall survival (OS) at our institution. Methods: One hundred and twelve patients with LABC (Stage IIB-IIIB) were treated between January 2000 and December 2003 with NACT with 5FU 500mg/m2, doxorubicin 50 mg/m2 and cyclophosphamide 500mg/m2 (FAC) or doxorubicin 50 mg/m2 and cyclophosphamide 500mg/m2 (AC) administered i.v. in four 21-day cycles. CRT with 60 Gy whole-breast irradiation and concurrent weekly mitomycin 5mg, 5FU 500mg and dexamethasone 16 mg or cisplatin 30 mg, gemcitabine 100 mg and dexamethasone 16 mg. Subsequently they underwent surgery and 6 to 8 weeks later received 2 additional courses of FAC, AC or paclitaxel 90mg weekly for 12 weeks and in estrogen receptor (ER) positive patients hormone therapy. Results: Median tumor size 5 cm; stages IIB, IIIA and IIIB were 21.4%, 42.9% and 35.7% respectively. pCR was 42% (CI 95% 33.2 - 50.5) in breast and 29.5% (CI 95% 21.4 - 37.5) in breast and axillary lymph nodes. Multivariate analysis showed the main determinant of pCR was negative ER (P 0.016). Median RFS has not been reached. The 5 year RFS is 76.9% (CI 95% 68.2 - 84.7). No relationship between pCR and RFS was found. Multivariate analysis showed the main determinant of RFS was the clinical stage (p=0.03). Only one patient had local recurrence. The 5 year OS is 84.2% (CI 95% 75 - 93.2). Toxicity during CRT: grade 1–2 neutropenia 32.2%, grade 1–2 anemia 5.2%, grade 3 radioepithelitis 22.4% Conclusions: This modality has good locoregional control for locally advanced breast cancer with an acceptable toxicity profile. Futher investigation of concurrent chemoradiotherapy should be explored in LABC. No significant financial relationships to disclose.

scholarly journals Rapid Stereology Based Quantitative Immunohistochemistry of Dendritic Cells in Lymph Nodes: A Methodological Study

2001 ◽  
Vol 22 (3) ◽  
pp. 143-149 ◽  
Author(s):  
Yvette van Hensbergen ◽  
Sylvia A. Luykx‐de Bakker ◽  
Daniëlle A. M. Heideman ◽  
Gerrit A. Meijer ◽  
Herbert M. Pinedo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dendritic Cells ◽  
Lymph Nodes ◽  
Advanced Breast Cancer ◽  
Sample Size ◽  
Locally Advanced Breast Cancer ◽  
Locally Advanced ◽  
Advanced Breast ◽  
Axillary Lymph ◽  
Quantitative Immunohistochemistry

This study was done to arrive at a fast and reliable protocol for assessment of fractional volumes of immunohistochemically stained dendritic cells in lymph nodes. Twenty axillary lymph nodes of patients with locally advanced breast cancer were immuno‐histochemically stained with an S100 antibody. Fractional volumes of dendritic cells were assessed by stereology based quantitative immunohistochemistry using an interactive video overlay system including an automated microscope. The gold standard percentage of dendritic cells was the fractional volume of S100 stained cells in 500 fields systematically spread over the whole lymph node. Then, in a computer simulation, different sample sizes (1–200 fields of vision) were tested and the coefficient of variation (CV) for each sample size was calculated. The CV dropped with increasing sample size. A sample size of 100 fields of vision appeared to be optimal. Intra‐ and interobserver reproducibility appeared to be good (correlation coefficients of 0.95 and 0.86, respectively) when re‐analyzing the cases with the established protocol. In conclusion, a fast and reliable assessment of the fractional volume of dendritic cells in lymph nodes is possible with semi‐automated quantitative immuno‐histochemistry. This method will form the base for further clinical studies into the immunological response in lymph nodes of patients with locally advanced breast cancer.

scholarly journals HER2 Nuclear Translocation and Decreased T-DM1 Efficacy in HER2 Positive Advanced Breast Cancer Treated with Dual HER2 Blockade. The SePHER Study.

2020 ◽  
Author(s):  
Giulia Bon ◽  
Laura Pizzuti ◽  
Valentina Laquintana ◽  
Rossella Loria ◽  
Manuela Porru ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Nuclear Translocation ◽  
Cancer Cell Lines ◽  
Advanced Breast ◽  
Breast Cancer Cell Lines ◽  
Second Line

Abstract Background: ErbB2-targeting agents have dramatically changed the therapeutic landscape of ErbB2+ advanced breast cancer (ABC). However, their optimal sequence of administration deserves further investigation.Methods: The biology of ErbB2 was investigated through sequential treatments in vitro, in ErbB2+ breast cancer cell lines resistant to trastuzumab, pertuzumab, and their combination. We analyzed data from 555 ErbB2+ ABC patients treated with trastuzumab emtansine (T-DM1) and explored the efficacy of T-DM1 in the 371 patients who received it in second-line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.Results: We show here lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Reduced T-DM1 efficacy is associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. Membrane-HER2 downregulation was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p=0.0006 and 0.03 for OS and PFS2, respectively). Conclusions: Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 to cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.

scholarly journals A clinical study of outcome of neoadjuvant chemotherapy in 30 cases of locally advanced breast carcinoma

2019 ◽  
Vol 6 (12) ◽  
pp. 4383
Author(s):  
Shwetal Ravindrabhai Sonvane ◽  
Mukesh Pancholi ◽  
Akhil Sharma
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Neoadjuvant Chemotherapy ◽  
Advanced Breast Cancer ◽  
Clinical Response ◽  
Locally Advanced Breast Cancer ◽  
Locally Advanced ◽  
Advanced Breast ◽  
Axillary Lymph ◽  
Management Problem

Background: Locally advanced breast cancer presents with a difficult management problem. It remains a challenge to achieve local and distant control of locally advanced breast cancer. Over the last decade preoperative/ neoadjuvant chemotherapy has emerged as the standard of care for these patients. Successful reduction in the size of the tumor is associated with increased rate of operability. The objective of this study is to observe the response of neoadjuvant chemotherapy in locally advanced breast carcinoma in form of outcome and complications. The outcome is measured as down staging or downgrading of tumor, results of surgery and its complications, disease free survival and recurrence.Methods: This is the observational prospective study of consecutive 30 cases of locally advanced breast cancer admitted in department of general surgery during a period from May 2017 to August 2018 at new civil hospital, Surat. Neo adjuvant chemotherapy were given every three weekly and the response of therapy calculated in form of reduction in the size of tumor or getting the margin free from skin or pectoral muscles or reduction in the axillary lymph node mass.Results: In this study about 93% of cases responded to neoadjuvant chemotherapy with 10% of cases shows complete clinical response where tumor becomes completely free from skin or pectoral muscles or negative axillary lymph nodes.Conclusions: With the evidence from the literature and study conducted earlier, our observations of clinical response of neoadjuvant chemotherapy in patients with locally advanced breast cancer had corroborative evidence.

scholarly journals Clinical efficacy of neoadjuvant FAC chemotherapy in locally advanced breast cancer patients

2003 ◽  
Vol 11 (3) ◽  
pp. 148-148
Author(s):  
Zdravko Zdrale ◽  
Snezana Susnjar ◽  
Ljiljana Stamatovic ◽  
Miodrag Matijasevic ◽  
Zora Neskovic-Konstantinovic
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Surgical Treatment ◽  
Advanced Breast Cancer ◽  
Locally Advanced Breast Cancer ◽  
Locally Advanced ◽  
Advanced Breast ◽  
Lymph Node Status ◽  
Axillary Lymph ◽  
Fac Chemotherapy

Background: FAC chemotherapy (CT) regimen is a well-established standard in the neo-adjuvant or primary chemotherapy for locally advanced breast cancer (LABC) treatment. Its main goal is to achieve locoregional tumor shrinkage allowing for the radical surgical treatment with curative intent. Concerning that prognosis of these patients depends on the response to initial neo-adjuvant therapy, we have analyzed clinical response to standard FAC CT in a group of routinely treated unrespectable LABC patients. Methods: During the three-year period, 50 pre- and postmenopausal patients without any cardiac risk factors, aged from 38-61 years, were treated with 3 to 4 cycles of neo-adjuvant FAC CT (500-50-500 mg/m 2 /21d). The initial diagnosis of LABC was based on tumor, nodal and/or skin characteristics: in 25 patients tumor was classified as T3-T4, N2 category was registered in 28 patients while skin lymphagiosis was found in 22 patients. Pathological diagnosis was confirmed either by skin, tumor and/or lymph node biopsy, or by tumorectomy (in 45 and 5 patients, respectively). Steroid receptor status was determined by biochemical DCC method in 35, or by immunohistochemistry in 7 patients. Results: Axillary lymph node status was evaluable in 47/50, and T status in 48/50 patients. Objective nodal response was achieved in 41/47 patients (12 CR and 29 PR, respectively), inflammatory skin features responded in 17/22 patients (2CR and 15PR, respectively). Overall objective response was achieved in 41/48 (82%) patients (9 CR, 32 PR), while 5 patients were classified as SD, and 2 consecutive patients as PD, with 2 non-evaluable patients. As far as toxicity was concerned, no acute cardiac damage was noted, emesis was successfully prevented with standard anti-emetics, and grade 3 to 4 alopecia developed in most of patients. Hematological tolerance was also good. Conclusion: Our results confirmed the high response rate to standard neoadjuvant FAC CT in unresectable LABC patients, in whom downstaging was achieved in majority, allowing for radical surgical treatment.

scholarly journals Efficacy of Combination Neoadjuvant Chemotherapy and Regional Inductive Moderate Hyperthermia in the Treatment of Patients With Locally Advanced Breast Cancer

2020 ◽  
Vol 19 ◽  
pp. 153303382096359
Author(s):  
Anton Loboda ◽  
Ivan Smolanka Sr ◽  
Valerii E. Orel ◽  
Liubov Syvak ◽  
Tetiana Golovko ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Advanced Breast Cancer ◽  
Locally Advanced Breast Cancer ◽  
Objective Response ◽  
Locally Advanced ◽  
Advanced Breast ◽  
Control Group ◽  
Axillary Lymph ◽  
Experimental Group

Purpose: To evaluate the efficacy of neoadjuvant chemotherapy in combination with regional inductive moderate hyperthermia for patients with locally advanced breast cancer. Patients and Methods: 200 patients with stage IIB-IIIA breast cancer received neoadjuvant chemotherapy (control group, n = 97) or chemotherapy combined with hyperthermia (experimental group, n = 103). Inductive hyperthermia was set at 27.12 ± 0.16 MHz and the 50 W output power. Results: Thermal and color Doppler ultrasound imaging demonstrated that hyperthermia increased the surface temperature on the breasts to < 4°С while the mean values for systolic blood flow were 3.5 times as high as those prior to treatment. Assessment of tumor size and response found a (31.24 ± 3.85)% reduction in the size of the primary tumor in patients receiving chemotherapy + hyperthermia, while chemotherapy alone showed a (22.95 ± 3.61)% decrease on average (p = 0.034). The rate of objective response increased by 15.9% in the experimental group (р = 0.034) compared with the control group. The patients in the experimental group also had axillary lymph node regression of 14.17% greater than in the control group (p = 0.011). Moreover, the combination treatment allowed to increase the proportion of women eligible for breast-conserving and reconstructive surgery by 13.63% in the experimental group. The viable tumor volume was lower in patients receiving neoadjuvant chemotherapy + hyperthermia (24.4 ± 0.2)% compared with those given chemotherapy alone (30.4 ± 0.25)%. The 10-year overall survival rates were higher (log-rank: p = 0.009) in breast cancer patients who underwent chemotherapy combined with hyperthermia than in patients receiving chemotherapy only. Conclusion: The combination neoadjuvant chemotherapy and the technology of regional inductive moderate hyperthermia improved the efficacy of treatment for patients with locally advanced breast cancer staged IIB-IIIA.

Sign in / Sign up

Export Citation Format

Share Document