Bevacizumab confers additional advantage to the combination of trastuzumab plus pertuzumab in trastuzumab‑refractory breast cancer model.

We investigated antitumor activity of trastuzumab (T)/T-DM1 + pertuzumab (P) + bevacizumab (B) in T-sensitive (BT474) and T-resistant (BT474HerR) BC models in order to test whether or not the addition of an anti-angiogenic drug can provide a supplementary advantage to the antitumor activity of double HER2–mAB combination.,In addition to the antitumor activity (xenograft model), we tested antiproliferative effect, and HER2-mediated signals of different antibodies (T or P or T-DM1) in HER2-amplified T-sensitive, T-resistant and HER2-amplified/PIK3CA mutated (HCC1954) BT cell lines by 3D ON-TOP clonogenic growth assay and Western blots.,Data show (1) T, T-DM1 or P blocked p-AKT (>60 %), p-ERK (>50 %) following heregulin in only T-sensitive cells, (2) T/T-DM1 + P, T/T-DM1 + B, and P + B reduced tumor growth as compared to any single-agent treatment, (3) T + P + B achieved almost complete regression of tumor growth, decreased cell proliferation, and inhibited tumor-induced angiogenesis, in both models, (4) antitumor activity of T + P + B was associated with the pharmacodynamic knockdown of p-AKT, and (5) T-DM1 + P caused complete regression of tumor volume in both models.,Our data demonstrate that B imparts a significant advantage when combined with T + P in the resistant model, in contrast to T-DM1 + P, as the triple combination of T-DM1 + P + B and the double combination of T-DM1 + P showed a comparable antitumor activity. Our study reveals the preclinical evidence in favor of the inclusion of B when combined with T + P in T-resistant BC patients.