A Phase II Study of Copper-Depletion Using Tetrathiomolybdate (TM) in Patients (pts) with Breast Cancer (BC) at High Risk for Recurrence: Updated Results with Linda Vadhat, MD, MBA
Background: The tumor microenvironment (TME) plays a critical role in the spread of tumors. Bone marrow derived VEGFR2+ endothelial progenitor cells (EPCs), copper-dependent lysyl oxidase (LOX) and collagen remodeling are key components in tumor progression. We hypothesized TM-associated copper depletion inhibits tumor metastases by reducing the number of EPCs and other copper-dependent (CD) processes in the pre-metastatic niche TME. These results are an update with longer follow-up.
Methods: Phase II study of BC pts at high risk for recurrence, defined as node+ triple-negative (TNBC), stage 3 and 4 with no evidence of disease (NED) were enrolled on a trial of CD with TM. Ceruloplasmin (Cp) levels were maintained between 8-16 mg/dl for two years with an extension phase or until relapse. The primary endpoint was a change in EPCs measured by flow cytometry before and during treatment. Secondary endpoints included tolerability, safety, PFS, and LOXL-2 levels. Exploratory endpoints included biomarkers of collagen remodeling, ATOX1 expression in the primary tumor, and ctDNA. 16 pts continue on study for greater than 6 years, 14 are stage 4 NED and 2 with stage 3 or 4 NED (unclear at presentation).
Results: 75 pts received 3478 cycles of TM on primary and extension study. The median age is 51 years (range 29-66). Forty-five pts have stage 2/3 BC and 30 with stage 4 NED. TNBC pts were 48% and 40% of pts are stage 4 NED. Median Cp level decreased from 28 to 16 (p<0.0001) after one cycle. Copper depletion was most efficient in TNBC where Cp levels dropped from 23.5 to 13 after one cycle. TM was well tolerated with grade 3/4 toxicities including: reversible neutropenia (1.7%), febrile neutropenia (0.03%), fatigue (0.2%). Five-year analysis showed a decrease in EPC’s (p=0.004) and LOXL-2 (p<0.001). At a median follow-up of 9.4 years, the EFS for 75 pts is 71.4%. PFS for 36 pts with TNBC is 71.7%. EFS for stage 2/3 TNBC is 88% and for stage IV TNBC is 59.3.%. ATOX1, ctDNA dat analysis are ongoing.
Conclusions: TM is safe, well-tolerated, and appears to affect multiple components of the TME creating an inhospitable environment for tumor progression especially in high-risk patients such as TNBC. Randomized trials in patients at high risk for relapse TNBC are currently being planned.
Background: The tumor microenvironment (TME) plays a critical role in the spread of tumors. Bone marrow derived VEGFR2+ endothelial progenitor cells (EPCs), copper-dependent lysyl oxidase (LOX) and collagen remodeling are key components in tumor progression. We hypothesized TM-associated copper depletion inhibits tumor metastases by reducing the number of EPCs and other copper-dependent (CD) processes in the pre-metastatic niche TME. These results are an update with longer follow-up.
Methods: Phase II study of BC pts at high risk for recurrence, defined as node+ triple-negative (TNBC), stage 3 and 4 with no evidence of disease (NED) were enrolled on a trial of CD with TM. Ceruloplasmin (Cp) levels were maintained between 8-16 mg/dl for two years with an extension phase or until relapse. The primary endpoint was a change in EPCs measured by flow cytometry before and during treatment. Secondary endpoints included tolerability, safety, PFS, and LOXL-2 levels. Exploratory endpoints included biomarkers of collagen remodeling, ATOX1 expression in the primary tumor, and ctDNA. 16 pts continue on study for greater than 6 years, 14 are stage 4 NED and 2 with stage 3 or 4 NED (unclear at presentation).
Results: 75 pts received 3478 cycles of TM on primary and extension study. The median age is 51 years (range 29-66). Forty-five pts have stage 2/3 BC and 30 with stage 4 NED. TNBC pts were 48% and 40% of pts are stage 4 NED. Median Cp level decreased from 28 to 16 (p<0.0001) after one cycle. Copper depletion was most efficient in TNBC where Cp levels dropped from 23.5 to 13 after one cycle. TM was well tolerated with grade 3/4 toxicities including: reversible neutropenia (1.7%), febrile neutropenia (0.03%), fatigue (0.2%). Five-year analysis showed a decrease in EPC’s (p=0.004) and LOXL-2 (p<0.001). At a median follow-up of 9.4 years, the EFS for 75 pts is 71.4%. PFS for 36 pts with TNBC is 71.7%. EFS for stage 2/3 TNBC is 88% and for stage IV TNBC is 59.3.%. ATOX1, ctDNA dat analysis are ongoing.
Conclusions: TM is safe, well-tolerated, and appears to affect multiple components of the TME creating an inhospitable environment for tumor progression especially in high-risk patients such as TNBC. Randomized trials in patients at high risk for relapse TNBC are currently being planned.
Background: The tumor microenvironment (TME) plays a critical role in the spread of tumors. Bone marrow derived VEGFR2+ endothelial progenitor cells (EPCs), copper-dependent lysyl oxidase (LOX) and collagen remodeling are key components in tumor progression. We hypothesized TM-associated copper depletion inhibits tumor metastases by reducing the number of EPCs and other copper-dependent (CD) processes in the pre-metastatic niche TME. These results are an update with longer follow-up.
Methods: Phase II study of BC pts at high risk for recurrence, defined as node+ triple-negative (TNBC), stage 3 and 4 with no evidence of disease (NED) were enrolled on a trial of CD with TM. Ceruloplasmin (Cp) levels were maintained between 8-16 mg/dl for two years with an extension phase or until relapse. The primary endpoint was a change in EPCs measured by flow cytometry before and during treatment. Secondary endpoints included tolerability, safety, PFS, and LOXL-2 levels. Exploratory endpoints included biomarkers of collagen remodeling, ATOX1 expression in the primary tumor, and ctDNA. 16 pts continue on study for greater than 6 years, 14 are stage 4 NED and 2 with stage 3 or 4 NED (unclear at presentation).
Results: 75 pts received 3478 cycles of TM on primary and extension study. The median age is 51 years (range 29-66). Forty-five pts have stage 2/3 BC and 30 with stage 4 NED. TNBC pts were 48% and 40% of pts are stage 4 NED. Median Cp level decreased from 28 to 16 (p<0.0001) after one cycle. Copper depletion was most efficient in TNBC where Cp levels dropped from 23.5 to 13 after one cycle. TM was well tolerated with grade 3/4 toxicities including: reversible neutropenia (1.7%), febrile neutropenia (0.03%), fatigue (0.2%). Five-year analysis showed a decrease in EPC’s (p=0.004) and LOXL-2 (p<0.001). At a median follow-up of 9.4 years, the EFS for 75 pts is 71.4%. PFS for 36 pts with TNBC is 71.7%. EFS for stage 2/3 TNBC is 88% and for stage IV TNBC is 59.3.%. ATOX1, ctDNA dat analysis are ongoing.
Conclusions: TM is safe, well-tolerated, and appears to affect multiple components of the TME creating an inhospitable environment for tumor progression especially in high-risk patients such as TNBC. Randomized trials in patients at high risk for relapse TNBC are currently being planned.