Overall Survival and Treatment Patterns in Metastatic Castration-Resistant Prostate Cancer Patients Based on PTEN Status

Academic Background

Prostate cancer is one of the most common malignant tumors among men worldwide and a leading cause of cancer-related deaths. Approximately 10%-20% of prostate cancer patients will develop castration-resistant prostate cancer (CRPC), with most CRPC patients further progressing to metastatic castration-resistant prostate cancer (mCRPC), which is usually fatal. Although current treatments can improve survival, the outcomes among mCRPC patients vary significantly due to differences in disease biology and burden. Research has shown that whole-exome sequencing (WES) can provide a clearer understanding of mCRPC, including detecting androgen receptor mutations, gene fusions, and PTEN gene loss.

PTEN is a lipid phosphatase that controls processes like cell survival, proliferation, and metabolism by regulating the PI3K/AKT/mTOR signaling pathway. PTEN loss can lead to abnormal activation of the PI3K pathway, triggering various cancers, including prostate cancer. Early loss of PTEN function is associated with poor prognosis. Immunohistochemical (IHC) evaluations show that 40%-50% of mCRPC patients exhibit PTEN loss of function (LOF). Previous studies have indicated that PTEN LOF detected by IHC is associated with a 56%-73% increased risk of death.

However, comprehensive genomic profiling (CGP) detects biomarkers at the nucleotide level and may be more reliable than IHC. Currently, data on the prognostic/predictive significance of PTEN LOF detected by CGP in mCRPC patients are limited. This study aims to evaluate the prognostic and predictive effects of PTEN LOF detected by CGP in the real-world clinical setting of U.S. cancer clinics.

Source of the Paper

The paper was written by Shilpa Gupta, MD, Tumy To, PhD, MPH, Ryon Graf, PhD, Edward E. Kadel III, BS, Norelle Reilly, MD, and Husam Albarmawi, PhD, from Cleveland Clinic Foundation, Genentech, Inc., and Foundation Medicine, Inc., respectively. The paper was published on March 28, 2024, in JCO Precision Oncology, DOI: https://doi.org/10.1200/po.23.00562.

Research Methods

This study is a retrospective real-world cohort analysis of male patients diagnosed with mCRPC between January 1, 2018, and June 30, 2021. The database used for the study is the de-identified Flatiron Health-Foundation Medicine (FH-FMI) cancer clinical genomic database, which includes electronic health records and genomic data of patients. PTEN status was analyzed using comprehensive genomic profiling on tumor samples via NGS, and the overall survival of patients with different PTEN statuses treated with different modalities was compared using Kaplan-Meier methods and multivariable Cox models.

Research Workflow

a) Research Workflow: 1. Data Collection: Electronic health records and genomic data were collected from 280 cancer clinics across the U.S. and de-identified for analysis. 2. Tumor Sample Analysis: Tumor samples were screened for over 300 cancer-related genes, including PTEN, using Foundation Medicine’s FoundationOne CDx and FoundationOne Solid Tumor Test via NGS. 3. Data Analysis: Kaplan-Meier methods and multivariable Cox models were applied to analyze the relationship between PTEN status and overall survival of patients, and to associate this with first-line and second-line treatment types.

A total of 524 patients were studied, comprising 291 with normal PTEN and 233 with PTEN LOF. High-throughput genomic sequencing technology was used to ensure the accuracy and comprehensiveness of the detection results.

b) Main Research Results: 1. Overall Survival: PTEN LOF was significantly associated with reduced overall survival (hazard ratio 1.61, 95% CI 1.07-2.42, p=0.024). Among patients treated with novel hormone therapy (NHT), median survival for the PTEN LOF group and PTEN normal group were 18.2 months and 24.3 months, respectively. Among those treated with taxane therapy, median survival for the PTEN LOF group and PTEN normal group were 9.4 months and 11.8 months, respectively. 2. Treatment Patterns: First-line treatment patterns for PTEN LOF and PTEN normal groups were similar, mainly consisting of abiraterone and enzalutamide. However, fewer patients in the PTEN LOF group received second-line treatment. There was no evidence that first-line treatment type (NHT or taxane) affected the relationship between PTEN LOF and survival.

c) Conclusion: This study demonstrates that PTEN LOF detected by CGP is associated with significantly reduced survival in mCRPC patients. PTEN LOF patients have poorer prognoses and a lack of targeted treatments for this genetic mutation, indicating an unmet medical need in this patient group.

d) Research Highlights: 1. Novelty: Combining large-scale clinical genomic data and real-world clinical data revealed the prognostic significance of PTEN LOF via more reliable NGS technology. 2. Clinical Significance: Provides valuable information for treatment decision-making for mCRPC patients, emphasizing the need for targeted treatment strategies for PTEN LOF. 3. Large Data Volume, High Reliability: The use of extensive real-world clinical and genomic data enhances the reliability and generalizability of the study results.

Through this research, scientists have gained a deeper understanding of the role of PTEN LOF in prostate cancer and provided directions for the development of new treatments in the future.