Abstract A24: Identifying the genomic and clinical features of AKT1/PIK3CA mutant metastatic prostate cancer using circulating tumor DNA
Authors: Herberts Cameron M. , Murtha Andrew J. , Fu Simon , Wang Gang , Schönlau Elena , Gleave Anna , Yip Steven , Angeles Arkhjamil , Hotte Sebastien , Alshangiti Abdulraheem , Tran Ben , North Scott , Taavitsainen Sinja , Beja Kevin , Vandekerkhove Gillian , Ritch Elie , Saad Fred , Iqbal Nayyer , Gleave Martin E. , Annala Matti , Chi Kim N. , Wyatt Alexander W. 
Published: June 2020

Background: Hotspot activating mutations in AKT1 and PIK3CA represent a rare but potentially unique subset of metastatic prostate cancers (mPCa). The accompanying genomic and clinical features of these patients are currently unknown. Preclinical evidence suggests that unconstrained PI3K signaling via PTEN loss may render androgen receptor (AR)-targeted therapy less effective. Given the availability of agents that target nodes within the PI3K pathway, elucidating the genomic properties of AKT1/PIK3CA mutant patients and their response to AR-targeted therapy will be critical for therapeutic selection.

Methods: We performed deep targeted sequencing on 1,381 cell-free DNA samples from 608 patients with mPCa. Analysis was restricted to patients with hotspot AKT1 or PI3KCA mutations of presumed clonal origin, requiring a variant allele frequency &gt;25% of a sample’s ctDNA fraction. Activating AKT1 and PIK3CA mutations were defined as recurrent hotspot mutations with a cBioPortal annotation, as well as functionally equivalent variants within 5bp of these canonical hotspot positions. Patient records were reviewed for baseline clinical characteristics, as well as time from androgen deprivation therapy (ADT) initiation to castration resistance and overall survival (OS).

Results: 5.9% (36/608) of patients harbored at least 1 clonal hotspot mutation in either AKT1 or PIK3CA, of which p.E17K and p.E545K/Q/A were most common. This population had a significantly higher ctDNA fraction compared to a control cohort of AKT1/PIK3CA wild-type mPCa patients (Mann-Whitney U test, 0.48 vs. 0.21, p &lt; 0.001). There were no differences in PTEN copy number or mutation frequency compared to the control cohort. Although AR mutations and copy number amplifications were observed at similar frequencies, patients harboring AKT1 or PI3KCA mutations had fewer additional copies of AR (median 4.71 vs. 10.33, p=0.011, Mann-Whitney U Test). 30 patients with activating AKT1/PIK3CA mutations had clinical outcomes available. Interestingly, there were no significant differences in time to castration resistance or OS compared to ctDNA-positive patients without activating PI3K defects.

Conclusions: AKT1/PIK3CA mutant mPCa is defined by a genomic landscape featuring high ctDNA-fraction and lower levels of AR amplification. Response to standard-of-care treatment among these patients is typical for ctDNA-positive mPCa. These findings may nominate patients who may benefit from PI3K-targeted therapeutics following resistance on AR-targeted therapy.

Citation Format: Cameron M. Herberts, Andrew J. Murtha, Simon Fu, Gang Wang, Elena Schönlau, Anna Gleave, Steven Yip, Arkhjamil Angeles, Sebastien Hotte, Abdulraheem Alshangiti, Ben Tran, Scott North, Sinja Taavitsainen, Kevin Beja, Gillian Vandekerkhove1, Elie Ritch, Fred Saad, Nayyer Iqbal, Martin E. Gleave, Matti Annala, Kim N. Chi, Alexander W. Wyatt. Identifying the genomic and clinical features of AKT1/PIK3CA mutant metastatic prostate cancer using circulating tumor DNA [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A24.