Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer

Treatment of early-stage HER2-positive breast cancer continues to evolve rapidly. Increased utilization of the neoadjuvant approach has been driven by high pathologic complete response (pCR) rates and the results of the KATHERINE trial, which demonstrated substantial benefit with T-DM1 as adjuvant therapy in patients without pCR.

The APHINITY trial, in contrast, explored adjuvant pertuzumab (PTZ) added to standard chemotherapy and trastuzumab with dual anti-HER2 antibodies continued to complete a year of therapy. The preplanned time-driven interim analysis presented now in JCO shows a significant iDFS benefit of 3.2% favoring PTZ at 6 years of follow-up (HR, 0.76; 0.64–0.91). Overall survival was not different: 94.8% versus 93.9% (P = .17). Examining relevant subgroups, the two-thirds of patients in APHINITY who had lymph node–positive disease had an improvement in their iDFS with PTZ of 4.5% at 6 years, whereas the node-negative population did extremely well overall, with an iDFS of 95% whether or not they received PTZ. Contrary to the first report of this study at 4 years of follow-up, now both HR-positive and HR-negative subgroups benefited from PTZ in terms of iDFS (2.5% improvement in HR-negative and 3% in HR-positive patients).

APHINITY provides several important findings and lessons:

1. Early reports of a trial do not always reflect later or final results. The change in benefit from negative to positive in the HR-positive subgroup is supported biologically and clinically by the known later relapse rate in this population.
2. Node-negative HER2-positive patients do very well with standard therapy. This has implications for decision-making in patients with a clinically node-negative HER2-positive tumor when they are being considered for neoadjuvant therapy. In my practice, I have SLNB done preoperatively in this specific circumstance as it will change my approach to the neoadjuvant regimen and chemotherapy intensity.
3. Pertuzumab is generally safe, and cardiac events occurred infrequently in both groups. Importantly, late cardiac events were rare. Diarrhea remains an issue with the addition of PTZ, but it is short-lived and most troublesome during chemotherapy combined with dual anti-HER2 antibodies.
4. De-escalation trial strategies are warranted in lower-risk HER2-positive breast cancer given the excellent outcomes with standard therapy.