T-DM1 in Advanced Breast Cancer: What Can Be Learned From HER2 Positivity?

By: Justine Landin, PhD
Posted: Friday, September 13, 2024

HER2 positivity (or gain) was surprisingly observed in soluble blood proteins during disease progression with targeted treatment of advanced HER2-positive breast cancer, according to Patrizio Giacomini, MD, of the National Cancer Institute Regina Elena, Rome, and colleagues. Although HER2 expression in tumor tissue was suppressed by the antibody drug-conjugate ado-trastuzumab emtansine (T-DM1), there was a corresponding gain of HER2 in the blood of most patients (81%). This HER2 gain was associated with better survival compared with HER2 loss. The findings of this single-arm, minimally interventional cohort study were published in the Journal of Experimental & Clinical Cancer Research.

“HER2 gain is adaptively selected in tumor tissues and recapitulated in blood by HER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies but favorable to the host during treatment with a strongly cytotoxic antibody-drug conjugate such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2,” proposed the study investigators.

Samples from prospectively enrolled patients from the studies LiqBreasTrack (n = 20) and LiqERBcept (n = 17) were included in analyses. Blood samples and archival primary and metastatic breast cancer tissue were obtained at baseline and at disease progression during treatment with T-DM1 (3.6 mg/kg every 21 days). HER2 DNA copy numbers and soluble blood proteins were tested in parallel using digital polymerase chain reaction and enzyme-linked immunosorbent assay and associated with survival.

HER2 DNA copy numbers were suppressed by T-DM1, but HER2 gain was observed within soluble blood proteins in the majority of patients (30 of 37). Additionally, HER2 in soluble blood proteins was preferentially released by dying breast cancer cell lines treated with T-DM1. This HER2 gain was also found to be associated with a longer progression-free survival than HER2 loss within blood proteins (282 vs 133 days, P = .047), particularly when developing HER2-bypass alterations during T-DM1 treatment were excluded (n = 11, 349 vs 139 days, P = .009).

Disclosure: The study authors reported no conflicts of interest.

Journal of Experimental & Clinical Cancer Research

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