Data from key clinical trials are shaping treatment strategies for early-stage HER2-positive breast cancer, with a focus on optimizing HER2-targeted therapies in both neoadjuvant and adjuvant settings. These findings, highlighted at an OncLive State of the Science Summit™ (SOSS) on breast cancer, emphasize the importance of personalized treatment approaches based on individual patient and disease characteristics.
Neoadjuvant Therapy and Pathologic Complete Response
For patients with stage II/III HER2-positive breast cancer, neoadjuvant HER2-targeted therapy is now a standard of care. Pivotal studies, such as the NeoSphere (NCT00545688) and TRYPHAENA (NCT00976989) trials, have evaluated the combination of trastuzumab and pertuzumab with taxanes, with or without carboplatin. The NeoSphere trial was particularly significant as it led to the FDA approval of pertuzumab in the neoadjuvant setting based on pCR as the primary endpoint. In the NeoSphere trial, patients were randomized to receive docetaxel and trastuzumab, docetaxel, trastuzumab, and pertuzumab, trastuzumab and pertuzumab without chemotherapy, or docetaxel and pertuzumab. The pCR rate was highest in the docetaxel, trastuzumab, and pertuzumab arm.
Tailoring Chemotherapy and Antibody Delivery
While docetaxel has been commonly used in clinical trials, weekly paclitaxel can also be used with similar results. The method of delivering anti-HER2 antibodies, whether intravenously (IV) or subcutaneously, does not significantly impact efficacy. The FeDeriCa trial compared IV trastuzumab and pertuzumab to a subcutaneous formulation (Phesgo) and found similar pharmacokinetics and pCR rates. The PHranceSCa trial (NCT03674112) further demonstrated that most patients preferred the subcutaneous formulation after experiencing both options.
Adjuvant Therapy and the Role of T-DM1
For patients with residual disease after neoadjuvant therapy, the KATHERINE trial (NCT01772472) established ado-trastuzumab emtansine (T-DM1; Kadcyla) as the standard of care. Patients in the trial were randomized to T-DM1 or trastuzumab, and those receiving T-DM1 had significantly improved disease-free survival (DFS) and overall survival (OS). An update presented at the 2023 San Antonio Breast Cancer Symposium showed a continued improvement in 7-year invasive DFS and OS with T-DM1 compared to trastuzumab in the adjuvant setting.
De-escalation and Escalation Strategies
Ongoing clinical trials are exploring strategies to de-escalate therapy for patients at lower risk of recurrence, such as administering anti-HER2 antibodies without chemotherapy or in combination with hormone therapy for ER-positive tumors. Conversely, trials are also investigating the escalation of therapy for patients with residual disease, including the addition of new drugs like tucatinib and fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd).
Impact on Clinical Practice
The evolving landscape of HER2-positive breast cancer treatment is marked by personalized approaches that consider disease stage, patient risk factors, and response to neoadjuvant therapy. The integration of HER2-targeted therapies, along with strategic de-escalation or escalation based on individual patient profiles, is driving improvements in outcomes for this patient population.
