De-escalation of neoadjuvant therapy for HER2-positive early breast cancer: an overview

About 15–20% of invasive breast cancer (BC) patients have overexpression of human epidermal growth factor receptor 2 (HER2) (1). Recently the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) issued a guideline to improve the diagnostic approach to more rigorous interpretation criteria for in situ hybridization (ISH) (2). In practice the new guideline resulted in a slight decrease in HER2 positive (HER2) rate (3). Continuous refinement of HER2 testing is critical for example to identify tumors that display heterogeneity of HER2 expression and which represents a distinct subset of HER2 BC associated with resistance to anti-HER2 therapies (4). In the last two decades anti-HER2 targeted agents were developed improving patients’ outcomes (5). Adjuvant therapy with trastuzumab (H) significantly improved disease-free and overall survival in earlystage HER BC and subsequently the additional antiHER2 blockade with pertuzumab (P) or sequencing treatment with neratinib showed additional reduction in the recurrence risk. More recently, adjuvant trastuzumab emtansine (TDM1) benefit patients at high risk of recurrence after neoadjuvant therapy that did not achieve pathological complete response (pCR) (6). Anti-HER2 therapies have significantly improved patients’ outcomes, nonetheless these advances are associated with increase toxicity, greater costs and clearly an over-treatment for a substantial number of patients. Adjuvant trials have tried to better tailor therapy in HER2 BC with less chemotherapy exposure (APT Trial) or “chemo” free regimen (ATEMPT). The APT trial included patients with <3 cm tumors and node negative HER2 BC to receive reduced chemotherapy regimen and standard H duration in patients demonstrated striking results with a 7-year DFS of 93% and OS of 95% (7). Recently, data presented from ATEMPT trial in the same population now treated with 1-year TDM1 monotherapy showed excellent outcomes with 3-year DFS of 97.7% and similar toxicity compared to APT regimen (8). Several trials evaluated a short duration of adjuvant H, 9 weeks or 6 months vs. 12 months with conflicting results nevertheless identifying a sub-group of patients, e.g., T1, N0, estrogen receptor (ER) positive which may benefit of this strategy (9). These studies highlight the need to an individualized approach for HER2 treatment and the potential to deescalate standard therapy. Here we review the data on neoadjuvant trials in HER2 BC which used a de-escalation design and describe the results and predictive biomarkers to better select patients for these regimens.