Current Primary Systemic Therapy and Future Perspectives in patients with HER2-positive Breast Cancer

Abstract

HER2‐positive breast cancer outcomes continue to improve due to mainly anti‐HER2 therapy with cytotoxic chemotherapy. As anti‐HER2 targeting therapies, trastuzumab, lapatinib, trastuzumab emtansine, and pertuzumab are standard treatments. In primary systemic therapy trastuzumab is the only anti‐HER2 agent to result in a survival benefit. The administration of other HER2‐directed agents remains clinical investigation. Pathological complete response (pCR) in neoadjuvant setting likely predicts clinical benefit in patients with HER2‐positive early breast cancer. Then, pCR has been a potential surrogate marker for survival, although the magnitude has varied according to intrinsic subtypes. NeoALTTO trial showed a significant increase in pCR with neoadjuvant lapatinib plus trastuzumab versus trastuzumab alone, but survival did not differ between treatment groups. ALTTO trial also did not confirm the survival benefit with the same treatment regimen. In NeoSphere trial patients given neoadjuvant pertuzumab, trastuzumab, and docetaxel had a significantly improved pCR rate compared with those given trastuzumab and docetaxel, although there was no impact on survival. The role of pertuzumab is being evaluated in the randomized phase III study. In addition to escalation attempts of anti‐HER2 targeting therapy, de‐escalation trials are also on goings. In patients with small tumors the study of adjuvant paclitaxel and trastuzumab showed excellent outcome. As for identification of predictive markers, it is indicated that tumor infiltrating lymphocytes could be predictor sensitivity to combination chemotherapy with trastuzumab. Some biologic features are implicated in response heterogeneity to HER2 targeting, including hormone receptor status, alterations in signaling pathways and host factors such as antitumor immune response. We now need to identify patients with resistance to conventional anti‐HER2 therapy and patients who don't need more intensive regimens.