Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer

Orlando, Laura; Cardillo, Anna; Ghisini, R.; Rocca, Andrea; Balduzzi, Alessandra; Torrisi, Rosalba; Peruzzotti, G.; Goldhirsch, Aron; Pietri, Elisabetta; Colleoni, Marco

doi:10.1186/1471-2407-6-225

Cited by 108 publications

(56 citation statements)

References 23 publications

(24 reference statements)

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“…In agreement to our findings, other promising results using MCT were obtained in patients with metastatic breast cancer treated with Cy plus Methotrexate (Mtx) [28], Cy plus Mtx and Thalidomide [29], Cy plus Mtx and Trastuzumab in Her2/neu+ patients [30]; besides, it was recently demonstrated that MCT with capecitabine displayed good therapeutic activity in advanced breast cancer [31]. Also, in patients with colorectal cancer at high risk of recurrence, adjuvant postoperative MCT using Irinotecan plus Uracil and Tegafur improved overall survival rates [32].…”

Section: Discussionsupporting

confidence: 78%

Safety and Therapeutic Effect of Metronomic Chemotherapy with Cyclophosphamide and Celecoxib in Advanced Breast Cancer Patients

et al. 2013

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Section: Discussionsupporting

confidence: 78%

Safety and Therapeutic Effect of Metronomic Chemotherapy with Cyclophosphamide and Celecoxib in Advanced Breast Cancer Patients

et al. 2013

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“…The novelty of our study combines metronomic chemotherapy with an anti-angiogenic agent in the clinical setting. There are few published clinical trials using such a combination, mostly phase I-II or abstracts [32][33][34][35][36][37][38][39]. In contrast to our study which showed benefit of docetaxel with thalidomide in solid tumors, Colleoni found that the addition of thalidomide to metronomic chemotherapy in advanced breast cancer patients did not improve the response rate compared to chemotherapy alone [40].…”

Section: Discussioncontrasting

confidence: 54%

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

et al. 2008

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Summary Purpose: Pre-clinical models have demonstrated the benefit of metronomic schedules of cytotoxic chemotherapy combined with anti-angiogenic compounds. This trial was undertaken to determine the toxicity of a low dose regimen using docetaxel and thalidomide. Patients and Methods: Patients with advanced solid tumors were enrolled. Thalidomide 100mg twice daily was given with escalating doses of docetaxel from 10 to 30mg/m 2 /week. One cycle consisted of 12 consecutive weeks of therapy. The maximal tolerated dose (MTD) was defined as the dose of thalidomide along with docetaxel that caused ≤grade 1 non-hematologic or ≤grade 2 hematologic toxicity for cycle one. Results: Twenty-six patients were enrolled. Doselimiting toxicities (DLTs) were bradycardia, fatigue, fever, hyperbilirubinemia, leukopenia, myocardial infarction, and neutropenia. Prolonged freedom from disease progression was observed in 44.4% of the evaluable patients. Conclusions: This anti-angiogenic regimen was well tolerated and demonstrated clinical benefit. The recommended phase II dosing schedule is thalidomide 100mg twice daily with docetaxel 25mg/m 2 /week.

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“…The goal of low-dose chemotherapy is to lessen the side effects of treatment and inhibit tumor growth, possibly through an antiangiogenic effect (20,34). In these studies, however, we exploited a new opportunity to use similarly low, clinically achievable levels of MTX (,10 mmol/L) to enhance the radiosensitivity of breast cancer cells to 111 In-NLS-trastuzumab.…”

Section: Discussionmentioning

confidence: 99%

“…Trastuzumab is commonly combined with taxane-or platinum-based chemotherapy regimes (27), but it was recently demonstrated that significant clinical benefit could be achieved in patients refractory to trastuzumab by combining the drug with oral low doses of cyclophosphamide and MTX (34). The goal of low-dose chemotherapy is to lessen the side effects of treatment and inhibit tumor growth, possibly through an antiangiogenic effect (20,34).…”

Section: Discussionmentioning

confidence: 99%

Trastuzumab-Resistant Breast Cancer Cells Remain Sensitive to the Auger Electron–Emitting Radiotherapeutic Agent ¹¹¹In-NLS-Trastuzumab and Are Radiosensitized by Methotrexate

Costantini

Bateman²,

McLarty³

et al. 2008

J Nucl Med

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Our goals in this study were to determine whether 111 In-trastuzumab coupled to peptides harboring nuclear localizing sequences (NLSs) could kill trastuzumab-resistant breast cancer cell lines through the emission of Auger electrons and whether the combination of radiosensitization with methotrexate (MTX) would augment the cytotoxicity of this radiopharmaceutical. Methods: Trastuzumab was derivatized with sulfosuccinimidyl-4-(Nmaleimidomethyl)cyclohexane-1-carboxylate for reaction with NLS peptides and then conjugated with diethylenetriaminepentaacetic acid for labeling with 111 In. HER2 expression was determined by Western blot and by radioligand binding assay using 111 In-trastuzumab in a panel of breast cancer cell lines, including SK-BR-3, MDA-MB-231 and its HER2-transfected subclone (231-H2N), and 2 trastuzumab-resistant variants (TrR1 and TrR2). Nuclear importation of 111 In-NLS-trastuzumab and 111 Intrastuzumab in breast cancer cells was measured by subcellular fractionation, and the clonogenic survival of these cells was determined after incubation with 111 In-NLS-trastuzumab, 111 Intrastuzumab, or trastuzumab (combined with or without MTX). Survival curves were analyzed according to the dose-response model, and the radiation-enhancement ratio was calculated from the survival curve parameters. Results: The expression of HER2 was highest in SK-BR-3 cells (12.6 · 10 5 receptors/cell), compared with 231-H2N and TrR1 cells (6.1 · 10 5 and 5.1 · 10 5 receptors/cell, respectively), and lowest in MDA-MB-231 and TrR2 cells (0.4 · 10 5 and 0.6 · 10 5 receptors/cell, respectively). NLS peptides increased the nuclear uptake of 111 In-trastuzumab in MDA-MB-231, 231-H2N, TrR1, and TrR2 cells from 0.1% 6 0.01%, 2.5% 6 0.2%, 2.8% 6 0.7%, and 0.5% 6 0.1% to 0.5% 6 0.1%, 4.6% 6 0.1%, 5.2% 6 0.6%, and 1.5% 6 0.2%, respectively. The cytotoxicity of 111 In-NLS-trastuzumab on breast cancer cells was directly correlated with the HER2 expression densities of the cells. On a molar concentration basis, the effective concentration required to kill 50% of 231-H2N and TrR1 cells for 111 In-NLS-trastuzumab was 9-to 12-fold lower than for 111 Intrastuzumab and 16-to 77-fold lower than for trastuzumab.MDA-MB-231 and TrR2 cells were less sensitive to 111 In-NLStrastuzumab or 111 In-trastuzumab, and both cell lines were completely insensitive to trastuzumab. The radiation-enhancement ratio induced by MTX for 231-H2N and TrR1 cells after exposure to 111 In-NLS-trastuzumab was 1.42 and 1.68, respectively. Conclusion: Targeted Auger electron radioimmunotherapy with 111 In-NLS-trastuzumab can overcome resistance to trastuzumab, and MTX can potently enhance the sensitivity of HER2-overexpressing breast cancer cells to the lethal Auger electrons emitted by this radiopharmaceutical.

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Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer

Abstract: Background: HER2/neu overexpression is linked to promotion of angiogenesis in breast cancer. We therefore tested the activity of the combination of Trastuzumab with metronomic, low dose chemotherapy with cyclophosphamide (CTX) and methotrexate (MTX) in metastatic breast cancer (MBC).

Cited by 108 publications

References 23 publications

Safety and Therapeutic Effect of Metronomic Chemotherapy with Cyclophosphamide and Celecoxib in Advanced Breast Cancer Patients

Safety and Therapeutic Effect of Metronomic Chemotherapy with Cyclophosphamide and Celecoxib in Advanced Breast Cancer Patients

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

Trastuzumab-Resistant Breast Cancer Cells Remain Sensitive to the Auger Electron–Emitting Radiotherapeutic Agent ¹¹¹In-NLS-Trastuzumab and Are Radiosensitized by Methotrexate

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Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer

Abstract: Background: HER2/neu overexpression is linked to promotion of angiogenesis in breast cancer. We therefore tested the activity of the combination of Trastuzumab with metronomic, low dose chemotherapy with cyclophosphamide (CTX) and methotrexate (MTX) in metastatic breast cancer (MBC).

Cited by 108 publications

References 23 publications

Safety and Therapeutic Effect of Metronomic Chemotherapy with Cyclophosphamide and Celecoxib in Advanced Breast Cancer Patients

Safety and Therapeutic Effect of Metronomic Chemotherapy with Cyclophosphamide and Celecoxib in Advanced Breast Cancer Patients

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

Trastuzumab-Resistant Breast Cancer Cells Remain Sensitive to the Auger Electron–Emitting Radiotherapeutic Agent 111In-NLS-Trastuzumab and Are Radiosensitized by Methotrexate

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Trastuzumab-Resistant Breast Cancer Cells Remain Sensitive to the Auger Electron–Emitting Radiotherapeutic Agent ¹¹¹In-NLS-Trastuzumab and Are Radiosensitized by Methotrexate