Prospective-Retrospective Analysis of PTEN Immunohistochemistry Assay for Prediction of Outcomes in Recurrent and Metastatic Prostate Cancer
Abstract
Hormonal therapies are currently used in a number of settings in patients with advanced prostate cancer; however, not all patients benefit equally from these therapies and these drugs are not without burdensome side effects. Thus, a major unmet clinical need is to develop test that help physicians identify which patients with recurrent or metastatic prostate cancer will maximally benefit from hormonal therapies and which patients might be better off with other types of therapy. In the last few years, we have made great strides in determining which genes are commonly abnormal in prostate tumors. Yet despite these advances, few of these genetic alterations have been tested to determine whether they predict for response to hormonal therapies. This is in part because it has been difficult to highly validate tests to detect these genetic alterations in large cohorts of prostate cancer patients. We have developed a robust, highly analytically validated and cost-effective immunohistochemistry (IHC)-based test to detect loss of PTEN, a tumor suppressor gene whose DNA is commonly lost in prostate tumors. PTEN loss, as detected by our test in the primary prostate tumor, is associated with prostate cancer recurrence and death in multiple large cohorts of surgically treated patients. In animal models, PTEN loss is associated with development of castrate-resistant prostate cancer. Now, we propose to test whether PTEN loss in the primary tumor is associated with a decreased response to hormonal therapies in the context of two recent, practice-changing Phase III clinical trials for which we have pre-approval to access specimens. In Aim 1, we will test whether PTEN status modifies overall survival benefit associated with treatment in ECOG 3805 (CHAARTED). This Phase III clinical trial demonstrated a benefit for docetaxel chemotherapy at the time of starting androgen deprivation therapy (ADT) for men with metastatic disease. We will perform our PTEN test on prostate tumors from ~300 patients with available tissue to determine whether patients with PTEN loss may benefit more in terms of survival from the addition of chemotherapy to the ADT regimen compared to those without PTEN loss. In Aim 2, we will test whether PTEN status modifies the survival benefit associated with treatment in RTOG 96-01. This Phase III clinical trial demonstrated a survival benefit for androgen receptor-targeted therapy with bicalutamide at the time of radiation therapy for patients with prostate-specific antigen (PSA) recurrence after radical prostatectomy. We will assess PTEN status in ~550 tumors from this trial to determine whether the relative benefit of adding bicalutamide to radiation therapy is less in patients with PTEN loss compared to those without PTEN loss. The proposed studies will be the first to apply a genetic test to two of the largest contemporary clinical trials in prostate cancer, examining whether PTEN status in the primary tumor predicts for response to hormonal therapies during disease progression. If validated in either trial, this would be sufficient evidence to begin the design of dedicated, prospective clinical trials in which physicians tailor individual patient’s treatment plans based on their PTEN test results. If the test improves patient survival in these studies, it could be immediately and cheaply implemented in any hospital in the country. Ultimately, this could become one of the first genetic tests to help determine which patients with advanced prostate cancer may maximally benefit from hormonal therapies and which patients should receive alternative treatment regimens.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710425
Entities
People
- Tamara L Lotan
Organizations
- Johns Hopkins University
- United States Army