When to Introduce ADCs in HR+/HER2– mBC

Treatment Sequencing in Dual Mutation Scenarios

Treatment sequencing becomes complex when patients develop dual mutations, particularly the combination of PIK3CA and ESR1 mutations following progression on the inavolisib regimen. Clinical decision-making depends heavily on the duration of benefit from the initial PI3K inhibitor therapy, disease characteristics, and patient performance status. Prolonged benefit from inavolisib therapy supports continued endocrine sensitivity and consideration of oral selective estrogen receptor degrader therapy, whereas rapid progression suggests aggressive disease requiring chemotherapy evaluation.

Patient selection for the inavolisib regimen requires careful consideration of the aggressive disease biology typical of patients who experience relapse within 12 months of adjuvant therapy. These patients often present with more challenging clinical scenarios and require tolerance for multiple simultaneous toxicities, including stomatitis, fatigue, diarrhea, and potential hyperglycemia. The combination therapy demands “cancer Olympian” candidates with excellent performance status and adequate hemoglobin A1C levels.

Disease burden and distribution significantly influence treatment decisions in dual-mutation scenarios. Bone-only disease may support continued endocrine-based approaches, whereas visceral disease with high burden or symptomatic presentation might necessitate transition to chemotherapy. The integration of biomarker data with clinical factors creates individualized treatment algorithms that optimize both efficacy and quality-of-life considerations.