Cancer Detection & Diagnosis Research-2022-Comprehensive genomic profiling of aggressive hormone sensitive prostate cancer

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Despite a high rate of screening resulting in early identification of most of the 174,650 new cases of prostate cancer in the USA, there are still about 31,620 deaths for metastatic and treatment resistant disease. To enable gene profiling of the samples to identify prognostic and predictive biomarkers we have collected tumor samples from 988 unique patients enrolled on two completed phase 3 trials:  E3805 CHAARTED: ChemoHormonal Therapy versus Androgen Ablation Trial for Extensive Disease in Prostate cancer. Sweeney et al, N Eng J Med 2015, 373(8):737-46.  MRC PR08 STAMPEDE: Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial, James, N. D., et al Lancet 2016, 387(10024):1163-1177. This offers a very unique opportunity to study gene profiles and identify biomarkers associated with a good versus poor response to hormonal therapy for metastatic hormone sensitive prostate cancer (mHSPC). This 5- year R01 application focuses on assessing genomic profiles related to alterations of tumor suppressor genes leading to loss of function of p53, PTEN and RB1. Preclinical and clinical data supports the hypothesis that the presence of mutations in these tumor suppressors genes are associated with a poor response to ADT. The samples from the two trials provide the opportunity for the first time to prospectively assess whether one or more of these mutations can identify patients prior to starting treatment who are destined to have a poor response to ADT. In turn, the presence of one or more of these mutations may identify patients who benefit from adding in docetaxel early. This may allow accurate patient selection and spare patients who did not benefit from early docetaxel the side effects of this chemotherapeutic. We will first perform whole exome sequencing of the tumor and germline DNA and comprehensive RNA profile using the Affymetrix platform from the CHAARTED trial to efficiently and comprehensively interrogate the genome. We will then develop clinicogenomic models to determine whether more accurate prognostication and prediction of benefit from early docetaxel can be achieved with a combination of variables from the exome mutation and/or gene expression profiles (GEP) and/or clinical factors. Having locked down models, we will then attempt to validate the prognostic and predictive models in the STAMPEDE samples. It is also worth highlighting, this broad approach with whole exome sequencing and GEP will also allow us to interrogate and other explore other hypotheses based on emerging preclinical and clinical data such as those pertaining to DNA Damage Repair genes (e.g. BRCA2). This work may also lead to identification of pathways to target to prevent emergence of resistance to ADT and improve the survival of men with mHSPC.