Dr Vahdat on the Potential for Copper Depletion in High-Risk TNBC Management

“Tumor cells don’t come with their own infrastructure when they want to spread. They hijack the infrastructure that is needed for tumors to grow and spread. Copper is important for cells to hijack infrastructure.”

Linda T. Vahdat, MD, MBA, section chief of Medical Oncology and interim section chief of Hematology at Dartmouth Health, as well as a professor of medicine at the Darthmouth College Geisel School of Medicine, discussed the rationale for depleting copper levels in a phase 2 trial (NCT06134375) inpatients with triple-negative breast cancer (TNBC) at high risk of recurrence.

Vahdat argued that although TNBC accounts for only approximately 17% of all breast cancer diagnoses, it is disproportionately aggressive, representing approximately 50% of all metastasis-related deaths. This disparity is particularly evident in patients who complete neoadjuvant therapy but retain significant residual disease, as they face a relapse risk of approximately 60% within 5 years, she noted.

According to Vahdat, the traditional understanding of how cancer spreads must be re-evaluated. She explained that tumor cells do not arrive with their own infrastructure to facilitate spreading; instead, they hijack the existing biological infrastructure required for growth and metastasis. Research has identified copper as an essential trace element that supports these hijacked resistance pathways, influencing cancer cell bioenergetics, the formation of the pre-metastatic niche, and stromal remodeling that promotes immune evasion, Vahdat reported. Consequently, Vahdat emphasized that depleting copper to approximately 30% of normal levels is a strategic choice designed to maintain normal cell function and starve the tumor of the resources necessary to hijack physiological processes.

To supplement this biological theory, Vahdat and colleagues previously completed a pilot phase 2 clinical trial (NCT00195091) involving 75 high-risk patients to test the safety and efficacy of the copper-depletion pill known as tetrathiomolybdate. The results showed that the treatment was effective and well tolerated in high-risk adjuvant patients, as well as those with stage IV TNBC with no evidence of disease. Furthermore, the study confirmed that copper depletion significantly reduced VEGFR2-positive endothelial progenitor cell levels and LOXL-2 levels, normalizing the collagen microenvironment to mirror observations seen in preclinical models.