Background: ErbB2-targeting agents have dramatically changed the therapeutic landscape of ErbB2+ advanced breast cancer (ABC). However, their optimal sequence of administration deserves further investigation.
Methods: The biology of ErbB2 was investigated through sequential treatments in vitro, in ErbB2+ breast cancer cell lines resistant to trastuzumab, pertuzumab, and their combination. We analyzed data from 555 ErbB2+ ABC patients treated with trastuzumab emtansine (T-DM1) and explored the efficacy of T-DM1 in the 371 patients who received it in second-line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.
Results: We show here lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Reduced T-DM1 efficacy is associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. Membrane-HER2 downregulation was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients.
Among 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p=0.0006 and 0.03 for OS and PFS2, respectively).
Conclusions: Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 to cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.