Alpelisib is a selective inhibitor of phosphoinositide 3-kinase (PI3K)α, shown to improve outcomes for PIK3CA-mutant, hormone receptor–positive metastatic breast cancers when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA (ctDNA) among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (NCT01870505). The trial’s primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function PTEN mutations in 25% of patients with resistance. ESR1 activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight PTEN loss as a recurrent mechanism of resistance to PI3Kα inhibition.

Alpelisib 是磷酸肌醇 3 激酶 (PI3K)α 的选择性抑制剂，与抗雌激素治疗联合使用可改善PIK3CA突变、激素受体阳性转移性乳腺癌的预后。为了揭示耐药机制，我们对 alpelisib 与芳香酶抑制剂联合使用的 I/II 期试验 (NCT01870505) 中的此类患者的肿瘤和血浆循环肿瘤 DNA (ctDNA) 进行了详细的纵向分析。该试验的主要目标是确定斑丘疹作为最常见的 3 级不良事件 (33%) 的安全性。在 44 名可评估患者中，观察到的临床获益率为 52%。将基因改变与结果联系起来，我们在 25% 的耐药患者中发现了功能丧失的PTEN突变。在治疗期间， ESR1激活突变的数量和等位基因比例也有所增加，并且与耐药性相关。这些数据表明，介导对 alpelisib 或抗雌激素耐药的基因组改变可能会促进疾病进展，并强调PTEN丢失是对 PI3Kα 抑制的耐药性的反复机制。