Limited data from small retrospective analyses investigating the role of second- line trastuzumab-based treatment suggests a benefitial effect in terms of time to progression for the management of progressive disease following first-line trastuzumab use in patients with Her-2/neu positive disease. However, evidence from recent meta-analyses have shown an increased risk for central nervous system involvement with prolonged trastuzumab use, which has been linked to inability of trastuzumab to penetrate the blood-brain barrier, leading to inadequate control of intracranial micrometastases. Nevertheless, studies that have evaluated the outcome of patients with brain metastases have shown that re-introduction of trastuzumab-based regimens appears to provide prolonged post-progression survival following total cranial irradiation. Available data from these retrospective studies and early interim results from randomized trials justify continuation of trastuzumab beyond failure after first-line treatment with this agent. Novel molecular agents such as lapatinib, pertuzumab or everolimus, in combination with different cytotoxic agents or trastuzumab are being investigated for multiple lines of treatment in this context. Final results from prospective randomized trials are awaited to elucidate optimal therapeutic options in patients who have progressed following trastuzumab-based regimens.

Keywords: metastatic Her-2/neu positive breast cancer, trastuzumab, second-line treatment and beyond, brain metastasis