Dr Vahdat on the Role of Copper Depletion in Reducing Metastatic Disease Risk in TNBC

Linda Vahdat, MD, MBA, professor of medicine, Geisel School of Medicine at Dartmouth, section chief, Medical Oncology, interim section chief, Hematology, Dartmouth Cancer Center, discusses the role of copper depletion with the copper chelating agent tetrathiomolybdate in potentially decreasing the risk of developing metastatic disease in patients with triple-negative breast cancer (TNBC).

A phase 2 trial (NCT00195091) evaluated tetrathiomolybdate in patients with breast cancer at high risk of recurrence, and findings published in 

 found that that when copper was depleted, patients’ levels of bone marrow–derived progenitor cells were reduced, potentially reducing their chance of relapse.

23rd Annual International Congress on the Future of Breast Cancer® East

, Vahdat spoke about findings from the trial that demonstrated that patients with no evidence of disease (NED) stage IV TNBC who underwent copper depletion therapy exhibited an event-free survival (EFS) rate of 59.3% at a median follow-up 9.4 years. In the adjuvant setting, the EFS rate was approximately 88%, Vahdat notes.

These results suggest a significant role of copper in the progression of metastases in patients with TNBC, prompting further exploration into the use of copper depletion as a therapeutic approach.

Vahdat explains that the study also incorporated extensive scientific analysis, which revealed that copper depletion with tetrathiomolybdate effectively reduced levels of bone marrow–derived progenitor cells, which have been linked to relapse in patients with TNBC. Additionally, lower levels of lysyl oxidase 2 were observed in patients who remained with NED, indicating a potential biomarker for stable disease.

Additionally, the study found that copper depletion normalized the collagen microenvironment, which may hinder tumor cell dissemination, Vahdat explains.

Preclinical findings supported this phenomenon, showing that although copper depletion does not impact primary tumor size, it significantly reduced metastasis risk by decreasing the number of disseminated tumor cells and preventing their subsequent detachment and invasion, she continues.

Copper depletion with tetrathiomolybdate is a promising strategy to mitigate metastasis risk in TNBC, Vahdat concludes, noting that further research is needed to fully understand the mechanisms of copper depletion and optimize its clinical application in this high-risk patient population.

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Linda Vahdat, MD, MBA, discusses the role of copper depletion in reducing the risk of metastatic disease development in triple-negative breast cancer.

Dr Vahdat on Recent Data on ADCs in Metastatic TNBC

Linda Vahdat, MD, MBA, professor of medicine, Geisel School of Medicine at Dartmouth, section chief, Medical Oncology, interim section chief, Hematology, Dartmouth Cancer Center, discusses recent clinical trial data for antibody-drug conjugates (ADCs) being evaluated in patients with metastatic triple-negative breast cancer (TNBC), highlighting sacituzumab tirumotecan (SKB264/MK-2870) and enfortumab vedotin-ejfv (Padcev).

Sacituzumab tirumotecan, an ADC targeting TROP-2, has a belotecan payload, which is a novel topoisomerase I inhibitor. The agent was evaluated vs physician’s choice of chemotherapy in the phase 3 OptiTROP-Breast01 study (NCT05347134) in patients with locally recurrent or metastatic TNBC that was relapsed/refractory to at least 2 chemotherapy regimens for unresectable, locally advanced, or metastatic disease.

Findings from the trial’s interim analysis presented at the 

 showed that at a median follow-up of 5.1 months, patients treated with sacituzumab tirumotecan (n = 130) achieved a median progression-free survival (PFS) of 5.7 months (95% CI, 4.3-7.2) compared with 2.3 months (95% CI, 1.6-2.7) for those in the chemotherapy group (n = 133) per blinded independent central review assessment (HR, 0.31; 95% CI, 0.22-0.45; 

 < .00001). In the final PFS analysis at the median follow-up of 10.4 months, the median PFS was 6.7 months (95% CI, 5.5-8.0) for the sacituzumab tirumotecan arm vs 2.5 months (95% CI, 1.7-2.7) for the chemotherapy arm (HR, 0.32; 95% CI, 0.22-0.44; 

Additionally, an interim analysis for overall survival (OS) at a median follow-up of 10.4 months showed that the median OS was not reached (95% CI, 11.2–not evaluable [NE]) in the sacituzumab tirumotecan arm vs 9.4 months (95% CI, 8.5-11.7) in the chemotherapy arm (HR, 0.53; 95% CI, 0.36-0.78; 

The phase 2 EV-202 study (NCT04225117) investigated enfortumab vedotin in patients with advanced solid tumors, including hormone receptor–positive, HER2-negative breast cancer and TNBC.

Findings from the TNBC cohort presented at the 2024 ASCO Annual Meeting showed that evaluable patients (n = 42) experienced an overall response rate of 19.0%; however, Vahdat acknowledges that the disease control rate (DCR) was 57.1%. At a median follow-up of 11.76 months, the median OS was 12.91 months (95% CI, 10.28-NE]. Vahdat emphasizes the need for further research on enfortumab vedotin, given its potential benefit in this challenging treatment landscape.

Linda Vahdat, MD, discusses recent antibody-drug conjugate data in metastatic triple-negative breast cancer.

Linda Vahdat, MD, MBA

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Dr Vahdat on the Role of Copper Depletion in Reducing Metastatic Disease Risk in TNBC

Dr Vahdat on Recent Data on ADCs in Metastatic TNBC