Trastuzumab is a humanized mAb directed against the extracellular domain of the tyrosine kinase receptor HER2. Trastuzumab has shown clinical activity in HER2-overexpressing breast cancers and, at present, is currently approved for patients whose tumours have this abnormality, in both the metastatic and the adjuvant setting. Several issues about its optimal use, however, are still unresolved. One of the reasons for these uncertainties lies in the absence of conclusive data about its mechanism of action and possible primary or acquired resistance mechanisms. Therefore, clinical questions such as how to optimize patient selection, how to prevent resistance to trastuzumab, or what is the optimal management of those patients whose tumours progress during treatment still await convincing answers. This review summarises the current knowledge on the preclinical and clinical evidence about the mechanism of action of trastuzumab and on the mechanisms underlying the development of resistance and also briefly discusses their possible clinical implications.

Patients with brain metastases (BM) from human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent a difficult-to-treat population. Trastuzumab emtansine (T-DM1) has shown potential activity in this subset of patients in small clinical series. KAMILLA is an ongoing, phase IIIb study of T-DM1 in patients with HER2-positive locally advanced/metastatic breast cancer (MBC) with prior HER2-targeted therapy and chemotherapy. Patients received T-DM1 3.6 mg/kg every 3 weeks (intravenously) until unacceptable toxicity, withdrawal of consent, or disease progression. Tumor response and clinical outcomes in patients with baseline BM were evaluated in this post-hoc, exploratory analysis. The main outcome measures were best overall response rate (BOR; complete response + partial response) and clinical benefit rate (CBR; complete response + partial response + stable disease lasting ≥6 months) by RECIST v1.1 criteria, progression-free survival (PFS), overall survival (OS), and safety. Of 2002 treated patients, 398 had baseline BM. In 126 patients with measurable BM, the BOR and CBR were 21.4% (95% CI 14.6-29.6) and 42.9% (95% CI 34.1-52.0), respectively. A reduction in the sum of the major diameters of BM ≥30% occurred in 42.9% (95% CI 34.1-52.0), including 49.3% (95% CI 36.9-61.8) of 67 patients without prior radiotherapy to BM. In the 398 patients with baseline BM, median PFS and OS were 5.5 (95% CI 5.3-5.6) months and 18.9 (95% CI 17.1-21.3) months, respectively. Adverse event (AE) profile was broadly similar in patients with and without baseline BM, although nervous system AEs were more common in patients with (208 [52.3%]) versus without (701 [43.7%]) baseline BM. This exploratory analysis of patients with HER2-positive MBC and BM enrolled in a prospective clinical trial shows that T-DM1 is active and well-tolerated in this population. T-DM1 should be explored further in this setting.