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Precision Medicine in Focus: Optimizing Biomarker-Driven Treatment Strategies in HR+/HER2– P13KCA-mutant Metastatic Breast Cancer - Episode 4

Beyond PIK3CA Status: A Case-Based Approach to Multifactor Inavolisib Selection

Panelists discuss how to identify ideal candidates for triplet therapy using a case example, emphasizing the importance of endocrine resistance, disease burden, performance status, and careful management of hyperglycemia risk through baseline hemoglobin A1C (HbA1C) assessment and proactive glucose monitoring strategies.

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    Julia Foldi, MD, PhD, presented a representative case of a postmenopausal woman with recurrent hormone receptor–positive, HER2-negative breast cancer featuring liver and bone metastases, primary endocrine resistance, PIK3CA mutation on liquid biopsy, normal baseline HbA1C, and excellent performance status. The patient’s characteristics made her an ideal candidate for triplet therapy based on INAVO120 criteria, leading to excellent response with only brief treatment interruption for manageable grade 2 hyperglycemia controlled with metformin. This case exemplifies how early biomarker identification enables optimal precision medicine implementation.

    The ideal patient for triplet therapy requires endocrine resistance as defined by progression on or within 2 years of endocrine therapy completion, with disease burden and pace of progression serving as additional selection criteria. Timothy J. Pluard, MD, emphasized the importance of tolerability assessment, particularly regarding hyperglycemia risk, noting that patients at higher risk require more aggressive management rather than treatment exclusion. The INAVO120 trial used stringent HbA1C cutoffs of 6% compared with 7% for capivasertib and 6.5% for alpelisib, reflecting the class effect of hyperglycemia with PIK3CA inhibitors.

    Management of diabetes risk requires individualized approaches considering baseline HbA1C, current antidiabetic medications, and optimization potential. Rather than using absolute HbA1C thresholds, clinicians should optimize glycemic control with agents like metformin and SGLT2 inhibitors before treatment initiation. The goal is enabling appropriate patients to receive effective therapy through proactive management rather than exclusion based on comorbidities. This approach requires oncologists to develop pseudoendocrinology expertise given limited endocrinology support availability, emphasizing the importance of comprehensive pretreatment optimization and monitoring strategies.

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