Current First-Line Landscape and Unmet Needs in HER2-Positive Metastatic Breast Cancer

Segment 1 establishes the current treatment landscape for HER2-positive metastatic breast cancer (mBC) and highlights key unmet clinical needs. Drs. O’Shaughnessy and Rao begin by reaffirming the CLEOPATRA regimen (taxane chemotherapy plus trastuzumab and pertuzumab) as the long-standing first-line standard of care, noting its durable overall survival benefit despite a median progression-free survival (PFS) of approximately 18 months. They emphasize that although many patients derive long-term benefit, most ultimately experience disease progression, underscoring the need for improved strategies.

The discussion highlights several unmet needs, including the lack of evidence-based guidance for treatment sequencing beyond second line, management of patients previously exposed to HER2-directed therapies in the curative setting, and uncertainty around de-escalation or discontinuation of long-term maintenance therapy in patients with prolonged disease control. Central nervous system metastases are identified as a major ongoing challenge due to the high propensity for brain involvement in HER2-positive disease.

Hormone receptor (HR) status is discussed as an important modifier of disease biology, with ER-positive/HER2-positive tumors demonstrating adaptive resistance through estrogen receptor signaling despite HER2 blockade. The panel also reviews the impact of PIK3CA mutations, noting that although patients benefit from CLEOPATRA, outcomes are generally inferior compared with wild-type tumors. Novel frontline regimens, improved CNS-active therapies, and more personalized sequencing approaches are urgently needed as the therapeutic armamentarium rapidly expands.