| Literature DB >> 32864625 |
Pedram Razavi1,2,3, Maura N Dickler4,5, Payal D Shah6, Weiyi Toy7, David N Brown8, Helen H Won9, Bob T Li4, Ronglai Shen10, Neil Vasan4,11, Shanu Modi4,11, Komal Jhaveri4,11, Betty Ann Caravella11,12, Sujata Patil11,10, Pier Selenica8, Stephen Zamora4, Aimee M Cowan4, Elizabeth Comen4,11, Andy Singh13, Anne Covey12, Michael F Berger7,11,8,9, Clifford A Hudis4,11,14, Larry Norton4,11, Rebecca J Nagy13, Justin I Odegaard13, Richard B Lanman13, David B Solit4,7,11,9, Mark E Robson4,11, Mario E Lacouture4,11, Edi Brogi11,8, Jorge S Reis-Filho7,8, Mary Ellen Moynahan4,11, Maurizio Scaltriti7,11,8, Sarat Chandarlapaty15,16,17.
Abstract
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.Entities:
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Year: 2020 PMID： 32864625 PMCID： PMC7450824 DOI： 10.1038/s43018-020-0047-1
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347