Comparison of circulating tumor DNA between African American and Caucasian patients with metastatic castrate-resistant prostate cancer post-abiraterone and/or enzalutamide.

BACKGROUND: African American men are much more likely than Caucasian men to be diagnosed with and to die of prostate cancer. Genetic differences likely play a role. The cBioPortal database reveals that African American men with prostate cancer have higher rates of CDK12 somatic mutations compared to Caucasian men. However, this does not account for prior prostate cancer treatments, which are particularly important in the castrate-resistant setting. We aimed to compare somatic mutations based on circulating tumor DNA (ctDNA) in metastatic castration-resistant prostate cancer (mCRPC) between African American and Caucasian men after exposure to abiraterone and/or enzalutamide. METHODS: This single-institution retrospective study characterizes the somatic mutations detected on ctDNA for African American and Caucasian men with mCRPC who had progressed after abiraterone and/or enzalutamide from 2015 through 2022. We evaluated the gene mutations and types of mutations in this mCRPC cohort. RESULTS: There were 50 African American and 200 Caucasian men with CRPC with available ctDNA data. African American men were younger at the time of diagnosis (p = 0.008) and development of castration resistance (p = 0.006). African American men were more likely than Caucasian men to have pathogenic/likely pathogenic (P/LP) mutations in CDK12 (12% vs. 1.5%; p = 0.003) and copy number amplifications and P/LP mutations in KIT (8.0% vs. 1.5%; p = 0.031). African American men were also significantly more likely to have frameshift mutations (28% vs. 14%; p = 0.035). CONCLUSIONS: Compared to Caucasian men, African American men with mCRPC after exposure to abiraterone and/or enzalutamide had a higher incidence of somatic CDK12 P/LP mutations and KIT amplifications and P/LP mutations based on ctDNA. African American men also had more frameshift mutations. We hypothesize that these findings have potential implications for tumor immunogenicity.

Clinical and Genetic Analysis of Metastatic Prostate Cancer to the Central Nervous System: A Single-Institution Retrospective Experience.

BACKGROUND: Prostate cancer (PC) rarely metastasizes to the central nervous system (CNS). In this retrospective single-institution study at a tertiary cancer center, we aimed to evaluate the clinical and genetic characteristics of advanced PC patients with CNS metastases. PATIENTS AND METHODS: Between January 2010 and March 2020, 12 out of 579 patients with extracranial metastatic PC were identified to have CNS metastases based on imaging, including six patients with brain metastases (BMs), five patients with dural metastases, and one unknown. These patients were followed up through March 2022. Clinical data were compared to the overall cohort of patients evaluated at our cancer center during that decade. Genetics information was also analyzed for the patients with available data via cell-free DNA (cfDNA) blood samples. RESULTS: Median time from development of extracranial metastatic disease to development of CNS metastases was 5.5 years (95% CI, 1.8-7.0). Median overall survival (mOS) from diagnosis of CNS metastases was 6.1 months (95% CI, 5.8-8.2). Notably, there was no significant difference in mOS after development of extracranial metastases in patients with CNS metastases (6.4 years; 95% CI, 4.6-7.9) compared to the patients without known CNS metastases (5.2 years; 95% CI, 4.6-5.7) (P = .91). For the cohort with CNS metastases, nine patients had germline testing and seven patients had somatic testing via cfDNA. CONCLUSION: PC patients with CNS metastases did not often die from a neurological cause. With advancing therapies, the overall prognosis of metastatic PC continues to improve, and CNS metastases will become more common.

Family history and pathogenic/likely pathogenic germline variants in prostate cancer patients.

BACKGROUND: Recent literature highlights the importance of germline genetic testing in prostate cancer (PCa) patients. Surprisingly, a literature review indicates that family history (FH) records are incomplete in the major published studies from prostate cancer patients. METHODS: Prospective family history data were gathered from 496 men in a single institution with a personal history of PCa who underwent germline genetic testing using a panel of at least 79 genes. Comprehensive first degree FH were obtained in all PCa of patients and analysis of prevalent FH was assessed at the time of sample collection. RESULTS: Pathogenic/likely pathogenic variants (PV/LPVs) were not associated with age at diagnosis, race, or presence of metastasis. One or more first degree relatives (FDR) with any cancer was not predictive for germline PV/LPVs for men with PCa (p = .96). Separate analysis of patients with one or more FDR with breast, prostate, ovarian, or pancreatic cancer revealed that only FDR with breast or ovarian cancer was predictive for PV/LPVs (p = .028, p = .015 respectively). Patients with a FDR with breast cancer had 1.8 increased risk of PV/LPVs, and patients with a FDR with ovarian cancer had 2.9 increased risk of PV/LPV. CONCLUSION: In men with a personal history of PCa, germline PV/LPVs were associated with a FDR with breast or ovarian cancer. Notably having FDRs with PCa does not predict for PV/LPVs. These data emphasize the contribution of FH in a data set with complete ascertainment of FH.

TP53 Gain-of-Function Mutations in Circulating Tumor DNA in Men With Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Circulating tumor DNA (ctDNA), which can be assessed by liquid biopsy, can provide valuable genomic information that may affect treatment response in prostate cancer. The aim of this study was to characterize TP53 mutations and treatment history in prostate cancer. PATIENTS AND METHODS: This study included 143 patients with metastatic castration-resistant prostate cancer who had undergone ctDNA sequencing via Guardant360 testing. The presence or absence of TP53 mutations was analyzed along with treatment history for this group. TP53 mutations were further classified as gain of function (GOF) or not GOF, and analyzed with prior therapies. RESULTS: Chi-square analysis was performed for treatment history and TP53 status (further specified as all TP53 mutations or only TP53 GOF mutations). There were no associations between prior receipt of abiraterone/enzalutamide therapy and all TP53 mutations, or between docetaxel therapy and all TP53 mutations. However, TP53 GOF mutations had a positive association with prior abiraterone/enzalutamide therapy (P = .047). There was no association of TP53 GOF mutations with prior docetaxel therapy. The most frequent alterations co-occurring with all TP53 mutations were in AR, BRAF, EGFR, MYC, and PIK3CA. Common coalterations with TP53 GOF mutations included AR, BRAF, EGFR, RB1, NF1, and PIK3CA. There was an association of RB1 mutations with TP53 GOF mutations, versus RB1 mutations and no TP53 GOF mutations (P = .0036). CONCLUSION: TP53 GOF mutations may provide a valuable pathway to delineate metastatic castration-resistant prostate cancer TP53 mutations into therapeutic categories. Association with disease progression while receiving abiraterone/enzalutamide therapy was apparent in this study; however, further studies are needed to elaborate the therapeutic and prognostic implications.

Recycling Discarded Drugs: Improving Access to Oral Antineoplastic Drugs.

It is common for patients to have limited access to oral antineoplastics or to discontinue treatment because of cost. Such oral treatments are also discontinued because of toxicity, disease progression, or death, resulting in unused portions of these medications. Policies for the subsequent use or destruction of unused drugs exist, but none completely address the need for methods of recycling back to the patients in need. This article addresses this wastefulness and ways to minimize it so that more patients benefit.

Advanced blood management strategies for elective joint arthroplasty.

There is a high prevalence of anemia detected in the preoperative work-up of elective surgical patients preparing for total joint replacement. The impact of anemia in this population has significant implications due to elevations in postoperative morbidity and mortality. By using current clinical guidelines and medical evidence, clinicians can improve outcomes for these patients by employing a three-phase approach, focused on preoperative assessment, intraoperative hemostasis, and postoperative blood product management. Strategies to optimize preoperative hemoglobin levels, reduce intraoperative blood losses, and decrease postoperative transfusion rates can independently and collectively improve overall patient care and surgical outcomes following lower extremity total joint arthroplasty.