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|Ref Type||Journal Article|
|Authors||Razavi P, Dickler MN, Shah PD, Toy W, Brown DN, Won HH, Li BT, Shen R, Vasan N, Modi S, Jhaveri K, Caravella BA, Patil S, Selenica P, Zamora S, Cowan AM, Comen E, Singh A, Covey A, Berger MF, Hudis CA, Norton L, Nagy RJ, Odegaard JI, Lanman RB, Solit DB, Robson ME, Lacouture ME, Brogi E, Reis-Filho JS, Moynahan ME, Scaltriti M, Chandarlapaty S|
|Title||Alterations in PTEN and ESR1 promote clinical resistance to alpelisib plus aromatase inhibitors.|
|Abstract Text||Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for PIK3CA mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PTEN R130*||Her2-receptor negative breast cancer||predicted - resistant||Alpelisib + Letrozole||Case Reports/Case Series||Actionable||In a Phase I/II trial, combination of Piqray (Alpelisib) and Femara (letrozole) resulted in no clinical benefit in a patient with hormone receptor positive, ERBB2 (HER2)-negative breast cancer harboring PTEN R130* (PMID: 32864625; NCT01870505).||32864625|