Trastuzumab in Combination with Metronomic Cyclophosphamide and Methotrexate in Patients with HER-2 Positive Metastatic Breast Cancer

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2006 Sep 19

PMID 16978400

Citations 37

Authors

Laura Orlando

Anna Cardillo

Raffaella Ghisini

Andrea Rocca

Alessandra Balduzzi

Rosalba Torrisi

Giulia Peruzzotti

Aron Goldhirsch

Elisabetta Pietri

Marco Colleoni

Affiliations

Soon will be listed here.

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).

Methods: Between April 2002 and June 2005, twenty-two patients with metastatic breast cancer with the presence of overexpression or amplification of HER2-/neu, all pre-treated with trastuzumab plus other cytotoxics, were treated with trastuzumab (6 mg/kg every three weeks) in combination with metronomic chemotherapy (MTX 2.5 mg, bid on Day 1 and Day 4 every week) and CTX (50 mg daily) (CM).

Results: The 22 enrolled patients are evaluable: most had an ECOG performance status of 0 (17 pts), and all were pre-treated with chemotherapy for metastatic disease; 14 had progressive disease at study entry, and 11 had progressive disease during the last trastuzumab therapy. Metastatic sites included: lung (5 pts), liver (14 pts), bone (12 pts), lymph nodes (8 pts), central nervous system (CNS) (9 pts). We observed 4 partial remission (PR) (18%, 95% CI 5-40%), 10 stable disease (SD) (46%, 95% CI 24-68%), and 8 PD (36%, CI 17-59%). The clinical benefit (RP plus RC plus SD for > or = 24 weeks) in all pts and in pts with disease resistant to previous trastuzumab therapy were 46% (95% CI, 24-68%) and 27% (95% CI, 6-61%), respectively. Median time to progression was 6 months and median duration of treatment was 5 months (range, 0,7 to 18.4 months and range, 1 to 18 months, respectively). Overall clinical toxicity was generally mild. Grade > or =2 reversible liver toxicity and leukopenia were reported in 5 and 3 pts, respectively.

Conclusion: The combination of trastuzumab and metronomic chemotherapy is effective and minimally toxic in advanced breast cancer patients. The efficacy observed in patients with disease resistant to trastuzumab supports the need of larger trial to confirm a role of this combination to delay acquired trastuzumab resistance.

Citing Articles

A randomized phase II study of metronomic cyclophosphamide and methotrexate (CM) with or without bevacizumab in patients with advanced breast cancer.

Mayer E, Tayob N, Ren S, Savoie J, Spigel D, Burris 3rd H Breast Cancer Res Treat. 2023; 204(1):123-132.

PMID: 38019444 DOI: 10.1007/s10549-023-07167-9.

Multi-task learning for predicting synergistic drug combinations based on auto-encoding multi-relational graphs.

Shan W, Shen C, Luo L, Ding P iScience. 2023; 26(10):108020.

PMID: 37854693 PMC: 10579440. DOI: 10.1016/j.isci.2023.108020.

High-Risk Peritoneal Mesothelioma: Does Metronomic Chemotherapy Have a Role?.

Kammar P, Garach N, Bhatt A, Anam J, Maniar V, Gore A Indian J Surg Oncol. 2023; 14(Suppl 1):181-188.

PMID: 37359939 PMC: 10284749. DOI: 10.1007/s13193-022-01691-8.

Current Research Status of Metronomic Chemotherapy in Combination Treatment of Breast Cancer.

Liu J, He M, Wang Z, Li Q, Xu B Oncol Res Treat. 2022; 45(11):681-692.

PMID: 35988534 PMC: 9677858. DOI: 10.1159/000526481.

High-throughput metabolomics reveals dysregulation of hydrophobic metabolomes in cancer cell lines by Eleusine indica.

Puah P, Lee D, Puah S, Nik Lah N, Ling Y, Fong S Sci Rep. 2022; 12(1):9347.

PMID: 35668092 PMC: 9168358. DOI: 10.1038/s41598-022-13575-6.

References

Kerbel R, Viloria-Petit A, Klement G, Rak J . 'Accidental' anti-angiogenic drugs. anti-oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples. Eur J Cancer. 2000; 36(10):1248-57. DOI: 10.1016/s0959-8049(00)00092-7. View

du Manoir J, Francia G, Man S, Mossoba M, Medin J, Viloria-Petit A . Strategies for delaying or treating in vivo acquired resistance to trastuzumab in human breast cancer xenografts. Clin Cancer Res. 2006; 12(3 Pt 1):904-16. DOI: 10.1158/1078-0432.CCR-05-1109. View

Burstein H, Kuter I, Campos S, Gelman R, Tribou L, Parker L . Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2001; 19(10):2722-30. DOI: 10.1200/JCO.2001.19.10.2722. View

Laughner E, Taghavi P, Chiles K, Mahon P, Semenza G . HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001; 21(12):3995-4004. PMC: 87062. DOI: 10.1128/MCB.21.12.3995-4004.2001. View

Colleoni M, Rocca A, Sandri M, Zorzino L, Masci G, Nole F . Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002; 13(1):73-80. DOI: 10.1093/annonc/mdf013. View

Izumi Y, Xu L, Tomaso E, Fukumura D, Jain R . Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature. 2002; 416(6878):279-80. DOI: 10.1038/416279b. View

Esteva F, Valero V, Booser D, Guerra L, Murray J, Pusztai L . Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002; 20(7):1800-8. DOI: 10.1200/JCO.2002.07.058. View

Yen L, Benlimame N, Xiao D, Wang T, Moustafa A, Esumi H . Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers. Mol Biol Cell. 2002; 13(11):4029-44. PMC: 133612. DOI: 10.1091/mbc.e02-02-0084. View

Koukourakis M, Simopoulos C, Polychronidis A, Perente S, Botaitis S, Giatromanolaki A . The effect of trastuzumab/docatexel combination on breast cancer angiogenesis: dichotomus effect predictable by the HIFI alpha/VEGF pre-treatment status?. Anticancer Res. 2003; 23(2C):1673-80. View

10.

Fountzilas G, Razis E, Tsavdaridis D, Karina M, Labropoulos S, Christodoulou C . Continuation of trastuzumab beyond disease progression is feasible and safe in patients with metastatic breast cancer: a retrospective analysis of 80 cases by the hellenic cooperative oncology group. Clin Breast Cancer. 2003; 4(2):120-5. DOI: 10.3816/cbc.2003.n.017. View

11.

Klos K, Zhou X, Lee S, Zhang L, Yang W, Nagata Y . Combined trastuzumab and paclitaxel treatment better inhibits ErbB-2-mediated angiogenesis in breast carcinoma through a more effective inhibition of Akt than either treatment alone. Cancer. 2003; 98(7):1377-85. DOI: 10.1002/cncr.11656. View

12.

Tripathy D, Slamon D, Cobleigh M, Arnold A, Saleh M, Mortimer J . Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol. 2004; 22(6):1063-70. DOI: 10.1200/JCO.2004.06.557. View

13.

Gelmon K, Mackey J, Verma S, Gertler S, Bangemann N, Klimo P . Use of trastuzumab beyond disease progression: observations from a retrospective review of case histories. Clin Breast Cancer. 2004; 5(1):52-8. DOI: 10.3816/cbc.2004.n.010. View

14.

Bargmann C, Hung M, Weinberg R . The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature. 1986; 319(6050):226-30. DOI: 10.1038/319226a0. View

15.

Yamamoto T, Ikawa S, Akiyama T, Semba K, Nomura N, Miyajima N . Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. Nature. 1986; 319(6050):230-4. DOI: 10.1038/319230a0. View

16.

ROSNER D, Nemoto T, Lane W . Chemotherapy induces regression of brain metastases in breast carcinoma. Cancer. 1986; 58(4):832-9. DOI: 10.1002/1097-0142(19860815)58:4<832::aid-cncr2820580404>3.0.co;2-w. View

17.

Slamon D, Clark G, Wong S, Levin W, Ullrich A, McGuire W . Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235(4785):177-82. DOI: 10.1126/science.3798106. View

18.

Hanahan D, Folkman J . Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996; 86(3):353-64. DOI: 10.1016/s0092-8674(00)80108-7. View

19.

Baselga J, Seidman A, Rosen P, Norton L . HER2 overexpression and paclitaxel sensitivity in breast cancer: therapeutic implications. Oncology (Williston Park). 1997; 11(3 Suppl 2):43-8. View

20.

Petit A, Rak J, Hung M, Rockwell P, Goldstein N, Fendly B . Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy.... Am J Pathol. 1997; 151(6):1523-30. PMC: 1858348. View