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Activating AKT1 and PIK3CA Mutations in Metastatic Castration-Resistant Prostate Cancer

Cameron Herberts¹, Andrew J Murtha¹, Simon Fu²

¹Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.

European Urology

|May 27, 2020

Abstract

Background:

Activating mutations in AKT1 and PIK3CA are undercharacterised in metastatic castration-resistant prostate cancer (mCRPC), but are linked to activation of phosphatidylinositol 3-kinase (PI3K) signalling and sensitivity to pathway inhibitors in other cancers.

Objective:

To determine the prevalence, genomic context, and clinical associations of AKT1/PIK3CA activating mutations in mCRPC.

Design, Setting, And Participants:

We analysed targeted cell-free DNA (cfDNA) sequencing data from 599 metastatic prostate cancer patients with circulating tumour DNA (ctDNA) content above 2%.

Outcome Measurements And Statistical Analysis:

In patients with AKT1/PIK3CA mutations, cfDNA was subjected to PTEN intron sequencing and matched diagnostic tumour tissue was analysed when possible.

Results And Limitations:

Of the patients, 6.0% (36/599) harboured somatic clonal activating mutation(s) in AKT1 or PIK3CA. Mutant allele-specific imbalance was common. Clonal mutations in mCRPC ctDNA were typically detected in pretreatment primary tissue and were consistent across serial ctDNA collections. AKT1/PIK3CA-mutant mCRPC had fewer androgen receptor (AR) gene copies than AKT1/PIK3CA wild-type mCRPC (median 4.7 vs 10.3, p = 0.003). AKT1 mutations were mutually exclusive with PTEN alterations. Patients with and without AKT1/PIK3CA mutations showed similar clinical outcomes with standard of care treatments. A heavily pretreated mCRPC patient with an AKT1 mutation experienced a 50% decline in prostate-specific antigen with Akt inhibitor (ipatasertib) monotherapy. Ipatasertib also had a marked antitumour effect in a patient-derived xenograft harbouring an AKT1 mutation. Limitations include the inability to assess AKT1/PIK3CA correlatives in ctDNA-negative patients.

Conclusions:

AKT1/PIK3CA activating mutations are relatively common and delineate a distinct mCRPC molecular subtype with low-level AR copy gain. Clonal prevalence and evidence of mutant allele selection propose PI3K pathway dependency in selected patients. The use of cfDNA screening enables prospective clinical trials to test PI3K pathway inhibitors in this population.

Patient Summary:

Of advanced prostate cancer cases, 6% have activating mutations in the genes AKT1 or PIK3CA. These mutations can be identified using a blood test and may help select patients suitable for clinical trials of phosphatidylinositol 3-kinase inhibitors.

Insights

Activating mutations in AKT1 or PIK3CA genes occur in 6% of advanced prostate cancer cases. Blood tests can identify these mutations, helping select patients for phosphatidylinositol 3-kinase inhibitor clinical trials.

Area of Science:

Oncology
Genetics
Molecular Biology

Background:

Activating mutations in AKT1 and PIK3CA are understudied in metastatic castration-resistant prostate cancer (mCRPC).
These mutations are associated with phosphatidylinositol 3-kinase (PI3K) pathway activation and drug sensitivity in other cancers.

Purpose of the Study:

To determine the prevalence, genomic context, and clinical associations of AKT1/PIK3CA activating mutations in mCRPC.
To identify a distinct molecular subtype of mCRPC based on these mutations.

Main Methods:

Targeted cell-free DNA (cfDNA) sequencing was performed on 599 mCRPC patients with detectable circulating tumor DNA (ctDNA).
PTEN intron sequencing and tumor tissue analysis were conducted for patients with AKT1/PIK3CA mutations.
Statistical analyses were used to compare AR gene copy numbers and clinical outcomes.

Main Results:

Somatic activating mutations in AKT1 or PIK3CA were found in 6.0% (36/599) of mCRPC patients.
AKT1/PIK3CA-mutant mCRPC exhibited fewer androgen receptor (AR) gene copies compared to wild-type (median 4.7 vs 10.3, p=0.003).
One heavily pretreated patient with an AKT1 mutation showed a significant PSA decline with ipatasertib (Akt inhibitor) monotherapy.

Conclusions:

Activating AKT1/PIK3CA mutations are relatively common in mCRPC, defining a molecular subtype with low AR copy gain.
The findings suggest PI3K pathway dependency in a subset of mCRPC patients.
cfDNA screening facilitates the identification of patients for PI3K inhibitor clinical trials.

Read full analysis

Keywords:

Castration-resistant prostate cancer Cell-free DNA Circulating tumour DNA Genomic sequencing Hotspot mutation Liquid biopsy Phosphatidylinositol 3-kinase Precision oncology

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