Despite advances in breast cancer prevention, diagnosis, and therapy, 5-10% of patients with
breast cancer have metastatic disease at initial presentation, and approximately 30% of
patients with breast cancer develop metastatic disease during the course of disease.
Metastatic cascade is a multistep process that enables the migration of tumor cells from the
primary site to a distant location, where they can potentially establish a new cancer growth.
To execute the metastatic cascade, epithelial cancer cells must detach from the primary
tumor, pass through the peripheral circulation, extravasate at the distant site and create a
new tumor.
Experimental and clinical data suggest a close relationship between activation of EMT program
and generation of CTCs. EMT is associated with a set of molecular changes in epithelial
cancer cells that results in increased motility and the induction of proteases that are
involved in degradation of the extracellular matrix facilitating thus invasion and
intravasation into the bloodstream. EMT has also been linked to the stem cell phenotype and
resistance to apoptotic signals, facilitating EMT-derived CTCs to survive in foreign
environments. Cancer stem cell phenotype is closely related to ALDH expression. Several
studies showed that CTCs with EMT phenotype is associated with inferior outcome in primary as
well as in metastatic setting.
In a biomarker study in primary breast cancer, CTC_EMT were detected in 77 (18.0%) of
patients. Patients without detectable CTC_EMT in the peripheral blood had significantly
superior DFS compared to patients with detectable CTC_EMT (HR = 0.42, 95%CI 0.22 - 0.78, p =
0.0003). Prognostic value of CTC_EMT was demonstrated in all subgroups of patients, most
pronounced in hormone receptor positive, HER2 negative subgroup. In multivariate analysis,
presence of CTC_EMT, axillary nodal involvement and hormone receptor status were
independently associated with DFS. Presence of CTC_EMT could lead to better identification of
patients with increased risk of recurrence, especially in hormone receptor positive, HER-2
negative primary breast cancer patients.
Disulfiram (DSF) in combination with copper (Cu) has been reported to override drug
resistance in cancer cells, and DSF combined with chemotherapy based on the microtubule
inhibitor vinorelbine appears to prolong survival in non-small cell lung cancer patients.
Based on aforementioned data, it is suggested that there is strong rationale to inhibit ALDH
in MBC. Inactivation of ALDH by disulfiram/copper will be lead to increase of objective
response rate in patients with refractory MBC.
Inclusion Criteria:1) Female patients with histologically confirmed carcinoma of the
breast.
2) CTC_EMT positivity in the peripheral blood. 3) Patients with locally recurrent or
metastatic disease hormone receptor positive, HER2 negative, who have received at least two
(and not more than five) prior chemotherapeutic regimens for breast cancer, at least two of
which were administered for treatment of locally recurrent and/or metastatic disease.
4) Prior therapy must be documented by the following criteria prior to entry onto study:
- Regimens must have included an anthracycline (e.g., doxorubicin, epirubicin) and a
taxane (e.g., paclitaxel, docetaxel) in any combination or order. Treatment with any
of these agents is not required if they are contraindicated for a certain patient.
- One or two of these regimens may have been administered as adjuvant and/or neoadjuvant
therapy, but at least 2 must have been given for relapsed or metastatic disease.
- Patients must have proved refractory to the most recent chemotherapy, documented by
progression on or within six (6) months of therapy.
5) Patients may have additionally been treated with anti-hormonal therapy. 6)
Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or
lower, except for stable sensory neuropathy <= Grade 2 and alopecia.
7) Age >= 18 years. 8) Eastern Cooperative Oncology Group (ECOG) Performance Status of
0 to 2. 9) Life expectancy of >= 3 months. 10) Adequate renal function as evidenced by
calculated creatinine clearance >= 40 mL/min per the Cockcroft and Gault formula.
11) Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) >=
1.5 x 10^9/L, hemoglobin >= 9.0 g/dL (a hemoglobin <10.0 g/dL is acceptable if it is
corrected by growth factor or transfusion), and platelet count >= 100 x 10^9/L.
12) Adequate liver function as evidenced by bilirubin <= 1.5 times the upper limits of
normal (ULN) and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate
aminotransferase (AST) <= 3 x ULN (in the case of liver metastases <= 5 x ULN), unless
there are bone metastases, in which case liver specific alkaline phosphatase must be
separated from the total and used to assess the liver function instead of the total
alkaline phosphatase. In case alkaline phosphatase is >3 x ULN (in absence of liver
metastases) or > 5 x ULN (in presence of liver metastases) AND patient is known to
have bone metastases, the liver specific alkaline phosphatase must be separated from
the total and used to assess the liver function instead of the total alkaline
phosphatase.
13) Patients willing and able to comply with the study protocol for the duration of
the study.
14) Written informed consent prior to any study-specific screening procedures with
theunderstanding that the patient may withdraw consent at any time without prejudice.
Exclusion Criteria:
1. Patients who have received any of the following treatments within the specified period
before study treatment start: chemotherapy, radiation, trastuzumab or hormonal therapy
within three weeks, any investigational drug within four weeks, radiation therapy
encompassing > 30% of marrow.
2. Addiction to alcohol or drugs.
3. Need for metronidazole, warfarin and/or theophylline medication, the metabolism of
which is likely influenced by disulfiram and copper, see Table 4.
4. Patients who are taking medications metabolized by cytochrome P450 2E1, including
chlorzoxazone or halothane and its derivatives, see Table 4.
5. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring
active treatment, including the use of oxygen.
6. Patients with brain or subdural metastases are not eligible, unless they have
completed local therapy and have discontinued the use of corticosteroids for this
indication for at least 4 weeks before starting treatment in this study. Any signs
(e.g., radiologic) and/or symptoms of brain metastases must be stable for at least 4
weeks before starting study treatment; radiographic stability should be determined by
comparing a contrast-enhanced computed tomography or magnetic resonance imaging brain
scan performed during screening to a prior scan performed at least 4 weeks earlier.
7. Patients with meningeal carcinomatosis.
8. Women who are pregnant or breast-feeding; women of childbearing potential with either
a positive pregnancy test at screening or no pregnancy test; women of childbearing
potential unless (1) surgically sterile or (2) using adequate measures of
contraception in the opinion of the Investigator. Perimenopausal women must be
amenorrheic for at least 12 months to be considered of non-childbearing potential.
9. Severe/uncontrolled intercurrent illness/infection.
10. Patients with organ allografts requiring immunosuppression.
11. Patients with known positive HIV status.
12. Hemochromatosis.
13. Patients who have had a prior malignancy, other than previous breast cancer, carcinoma
in situ of the cervix, or non-melanoma skin cancer, unless the prior malignancy was
diagnosed and definitively treated >= 5 years previously with no subsequent evidence
of recurrence.
14. Patients with pre-existing neuropathy > Grade 2.
15. Patients with other significant disease or disorders that, in the Investigator's
opinion, would exclude the patient from the study.
