Updated: Dec 6, 2018
Several pre-clinical and some clinical studies have revealed that bone marrow stem cells and the surrounding microenvironment are key components in breast cancer metastases. There are now many studies demonstrating that copper depletion in-vitro decreases angiogenesis was well as cell proliferation, growth, and motility. (Please refer to the references from the link below.) Researchers from Weill Cornell Medicine have now published the results of their Phase II clinical study of copper depletion in patients with stage II TNBC and stage III and IV of all molecular subtypes in Clinical Cancer Research. The results are promising.
The primary tumor secretes several substances that prepares the microenvironment for metastases including lysyl oxidase (LOX), superoxide dismutase-1, and vascular adhesion protein-1. LOX is a copper-dependent amine oxidase that acts at premetastatic sites to allow for tumor survival and growth. Oral tetrathiomolybdate, most notably used as a copper chelator in patients with Wilson's disease, blocks copper chaperones and copper-dependent enzymes such as LOX.
The researchers have performed many laboratory and clinical studies on tetrathiomolybdate and recently examined the effects on 75 patients (48% of whom had stage II-IV TNBC) over the course of 6.3 years. Tetrathiomolybdate by GMP was purchased from Sigma Aldrich Chemical Company. It was stored under argon and routinely stability tested and dispensed in gelatin capsules by pharmacists. Patients received an induction dose of 180 mg in 4 divided doses until ceruloplasmin (Cp) reached the target range of 5-17 mg/dL. Patients were examined and evaluated every 4 weeks. When Cp reached the target range, patients were switched to a maintenance dose of 100 mg daily (divided). Doses were reduced in 20 mg increments to reduce toxicity. Proton pump inhibitors significantly increased the absorption of tetrathiomolybdate. Twenty four patients dropped out: recurrent disease (12 patients), toxicity (3 patients), and other reasons (9 patients).
Endothelial progenitor cells from the bone marrow were assessed for changes in VEGFR2 and secondary end-points of safety, event-free survival, VEGFR1 changes in hematopoietic progenitor cells, cytokines, and plasma angiogenic factors levels were examined as well. Side-effects were not insignificant but patients were monitored very closely. Among many of the usual side effects from medications, hematologic side-effects were common. Serious neutropenia (low neutrophil counts) and leukopenia (low leukocyte counts) were observed 47 and 23 times respectively per 28 day cycle of the study. One patient was admitted for febrile neutropenia.
Event free survival (EFS) and overall survival (OS) for patients with stage II-IV disease was 72% and 84%, respectively, over the course of 6.3 years. For patients with stage II-III disease, at 2 years, EFS was 91% and OS 96%. For patients with stage IV disease, 67% demonstrated no evidence of disease (NED) and OS was 93%. Looking at just stage II & III TNBC patients, 2 year EFS was 90%. 69% of stage IV NED TNBC patients had no recurrence after 2 years. There was no significant difference between the non-TNBC (<10% receptor postive group) and TNBC groups (p=0.814). The majority of the patients in this study were stage III (55%) and stage IV NED (40%). Recurrences were rare after 2 years from entering the study.
LOX and other protein activity related to tumor micro-environment (as mentioned above) were also found to be reduced. Overall, the data is very promising but larger randomized trials need to be performed with a controlled group and more detailed baseline characteristics.
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