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There are two primary types of drugs that target human epidermal growth factor receptor 2 (HER2). One is an antibody-based drug against the HER2 protein and the other is a small molecule compound that inhibits phosphorylation of the HER2 intracellular domain. For many years, antibody-based therapies have been central to the treatment of HER2-positive breast cancer. It is well known that trastuzumab has dramatically changed the treatment for HER2-positive breast cancer and its prognosis (1). Lapatinib, which became available after trastuzumab, also inhibited HER1 phosphorylation and was initially expected to be effective even against HER2negative disease. Therefore, a study including HER2negative advanced recurrent breast cancer was conducted, but the results demonstrated effectiveness only for HER2positive breast cancer (2). The MA.31 trial comparing trastuzumab or lapatinib with taxanes as first-line treatment for HER2-positive advanced recurrence found that lapatinib was inferior to trastuzumab (3). Lapatinib never replaced trastuzumab for first-line treatment. Lapatinib in combination with trastuzumab improved progression free survival (PFS) compared to lapatinib alone, but the improvement was modest so it was positioned as a palliative treatment with few side effects (4). In the NeoALTTO trial using paclitaxel plus either lapatinib or trastuzumab or both for patients with HER2-positive preoperative breast cancer, the pCR (pathological complete response) rate was significantly increased in patients receiving combined trastuzumab and lapatinib (5). However, the parallel ALTTO study did not show a significant improvement in DFS (disease free survival) in postoperative cases and was not used for perioperative treatment (6). The next agent used in combination therapy with trastuzumab was not a small molecule compound, but pertuzumab, which is a similar anti-HER2 antibody that emerged after lapatinib and took its place. The CLEOPATRA study used the combination as a firstline treatment for advanced recurrence of HER2-positive breast cancer and both PFS and overall survival were significantly prolonged (7). Trastuzumab, pertuzumab and taxane combination therapy is the standard regimen for first-line HER2-positive breast cancer. In addition, in the APHINITY study, pertuzumab added to trastuzumab plus a taxane showed improvement compared with conventional trastuzumab and taxane combinations, especially in nodepositive cases (8). This combination is used in perioperative treatment of breast cancer with high HER2-positive recurrence risk. T-DM1, a trastuzumab-based antibody-drug conjugate that was developed around the same time as pertuzumab, showed significantly better PFS and OS than lapatinib plus capecitabine in the EMILIA study (9). This study positioned the small molecule compound lapatinib in a later therapeutic line. In the MARIANNE study, which is a firstline treatment for advanced and recurrent disease, T-DM1 had similar results to trastuzumab plus docetaxel (10). Editorial

The counterattack of anti-HER2 small molecule compounds has started