Abstract P1-01-19: Predicting response to capivasertib in AKT1 mutant advanced breast cancer

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Abstract Introduction: Activation of the PI3K-AKT and mTOR pathways is a major feature of the biology of breast cancer (BC), with these pathways altered or dysregulated in most BC. Oncogenic mutations in AKT1, most frequently E17K, are found in ∼5% of advanced BC and are targetable by the approved AKT inhibitor capivasertib. We conducted genomic and transcriptomic analysis of a cohort of AKT1 mutant metastatic BCs with the aim to identify determinants of response to capivasertib. Methods: We identified 39 AKT1 mutant BC from the plasmaMATCH clinical trial (18/39; NCT03182634), the FAKTION clinical trial (7/39 NCT01992952), and the ABC-BIO tissue collection study (14/39; CCR3991). FFPE extracted DNA was subject to whole exome sequencing (WES), and RNA to Truseq RNA sequencing. Clonal dominance was assessed in circulating tumour DNA (ctDNA) using Guardant360. Allelic imbalance at the AKT1 locus and clonal dominance of the AKT1 mutation were associated with progression free survival (PFS) in plasmaMATCH Cohorts C (capivasertib plus fulvestrant) and D (capivasertib alone) combined. Results:WES at median coverage 93x (range 55-169x) reconfirmed AKT1 mutations in 33/39 (85%) samples: 25/33 (76%) E17K; 3/33 (12%) L52R; 1/33 (3%) E49K; 1/33 (3%) L52R+C77F; 1/33 (3%) L52R+E375K; 1/33 (3%) S129L; 1/33 (3%) Q79K. 6/39 discordant samples principally reflected AKT1 mutations identified in ctDNA analysis which were not present in the single site tissue biopsy. Most common pathogenic alterations found in the AKT1 mutated cohort were TP53 9/33 (27%), CDH1 5/33 (15%), GATA3 3/33 (9%) and MAP3K1 2/33 (6%). Rates of mutations in PIK3CA (2/33; 6%) and ESR1 (2/33; 6%) were reduced compared to those expected in ER+HER- metastatic BC sets. Analysis of the AKT1 locus revealed amplification of AKT1 gene in 14/33 (42%) and loss of heterozygosity (LOH) of the wild type allele in 10/33 (30%). Overall LOH and/or amplification (allelic imbalance) was observed in 18/33 (55%) of AKT1 mutant tumours. 15/33 (46%) of the patients with confirmed AKT1 mutations had received treatment with capivasertib in PlasmaMATCH. Median PFS in patients was 13.08 months (10/15 patients) with allelic imbalance and 3.19 months without allelic imbalance (5/15 patients; HR 8.798, 95% CI1.58-49.00, P=0.004, log rank test). RNA sequencing data was obtained for 36/39 samples with median 13M reads (range 11-49M) including 31/33 of the confirmed mutant samples in WES. PAM50 subtypes for the cohort were LumA (12/31), LumB (7/31), HER2Enriched (7/31), Basal (1/31) and normal-like (2/31). RNAseq showed increased (0.87 log fold change, P=0.035) expression of AKT1 in tumours with allelic imbalance compared to those without, and high expression levels of mutant transcript. Finally, in plasmaMATCH, clonality of the AKT1 mutation was assessed in ctDNA, with 16/24 (67%) patients having clonally dominant AKT1 mutations. Median PFS in patients with clonally dominant mutations was 10.2 months and subclonal mutations 3.2 months (HR 3.1, 95% CI0.9-10.5, P=0.014, log rank test). Conclusions: Breast cancers with mutations in AKT1 frequently have allelic imbalance favouring the mutation, resulting in increased expression of mutant transcript. Allelic imbalance of AKT1, and/or clonally dominant AKT1 mutations, were prognostic for significantly greater PFS of patients treated with capivasertib. Citation Format: Sarah Mearns, Alex Pearson, Ros Cutts, Heena Shah, Li-Xuan Sim, Belinda Kingston, Kathryn Dunne, Marta Lubowiecki, Andriani Hadjiconstanti, Hannah Johnson, Lucy Kilburn, Laura Moretti, Andrew M. Wardley, Iain R. Macpherson, Richard D. Baird, Rebecca Roylance, Angela Casbard, Margherita Carucci, Sacha J Howell, Robert H Jones, Judith Bliss, Alistair Ring, Alistair Ring. Predicting response to capivasertib in AKT1 mutant advanced breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-01-19.

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