Repeat Next-Generation Sequencing Testing on Progression in Men With Metastatic Prostate Cancer Can Identify New Actionable Alterations.

PURPOSE: There are limited data available on the real-world patterns of molecular testing in men with advanced prostate cancer. We thus sought to evaluate next-generation sequencing (NGS) testing in the United States, focused on single versus serial NGS testing, the different disease states of testing (hormone-sensitive v castration-resistant, metastatic vs nonmetastatic), tissue versus plasma circulating tumor DNA (ctDNA) assays, and how often actionable data were found on each NGS test. METHODS: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort clinical-genomic database was used for this retrospective analysis, including 1,597 patients across 15 institutions. Actionable NGS data were defined as including somatic alterations in homologous recombination repair genes, mismatch repair deficiency, microsatellite instability (MSI-high), or a high tumor mutational burden ≥10 mut/MB. RESULTS: Serial NGS testing (two or more NGS tests with specimens collected more than 60 days apart) was performed in 9% (n = 144) of patients with a median of 182 days in between test results. For the second NGS test and beyond, 82.1% (225 of 274) of tests were from ctDNA assays and 76.1% (217 of 285) were collected in the metastatic castration-resistant setting. New actionable data were found on 11.1% (16 of 144) of second NGS tests, with 3.5% (5 of 144) of tests detecting a new BRCA2 alteration or MSI-high. A targeted therapy (poly (ADP-ribose) polymerase inhibitor or immunotherapy) was given after an actionable result on the second NGS test in 31.3% (5 of 16) of patients. CONCLUSION: Repeat somatic NGS testing in men with prostate cancer is infrequently performed in practice and can identify new actionable alterations not present with initial testing, suggesting the utility of repeat molecular profiling with tissue or blood of men with metastatic castration-resistant prostate cancer to guide therapy choices.

Response to bipolar androgen therapy and PD-1 inhibition in a patient with metastatic castration-resistant prostate cancer and a germline CHEK2 mutation.

We present the case of a patient with germline CHEK2-mutated metastatic castration-resistant prostate cancer (mCRPC) who responded to bipolar androgen therapy (BAT) combined with pembrolizumab after progressing through multiple lines of therapy. The patient was diagnosed in his 40s following an elevated screening prostate-specific antigen and biopsy. Over the course of 20 years, he progressed through nearly all standard therapies including androgen deprivation, combined androgen blockade, traditional chemotherapy, targeted therapies and experimental agents. He was ultimately treated with BAT, whereby the patient's cycle was between low (castrate) and high (supraphysiological) testosterone levels. This counterintuitive approach resulted in a marked response to BAT plus pembrolizumab consolidation lasting 13 months. His underlying germline mutation in CHEK2, an important mediator of DNA repair, may have sensitised the cancer cells to the DNA damage caused by BAT. Single case report outcomes should not be used as evidence of efficacy for treatment regimes. Our case supports further investigation into BAT plus immunotherapy for patients with DNA repair-deficient mCRPC.

Foreign accent syndrome as a heralding manifestation of transformation to small cell neuroendocrine prostate cancer.

A man in his 50s with metastatic hormone-sensitive prostate cancer, receiving androgen deprivation therapy and abiraterone acetate/prednisone, presented with an uncontrollable 'Irish brogue' accent despite no Irish background, consistent with foreign accent syndrome (FAS). He had no neurological examination abnormalities, psychiatric history or MRI of the brain abnormalities at symptom onset. Imaging revealed progression of his prostate cancer, despite undetectable prostate-specific antigen levels. Biopsy confirmed transformation to small cell neuroendocrine prostate cancer (NEPC). Despite chemotherapy, his NEPC progressed resulting in multifocal brain metastases and a likely paraneoplastic ascending paralysis leading to his death. We report FAS as the presenting manifestation of transformation to small cell NEPC, a previously undescribed phenomenon. His presentation was most consistent with an underlying paraneoplastic neurological disorder (PND), despite a negative serum paraneoplastic panel. This report enhances the minimal existing literature on FAS and PNDs associated with transformed NEPC.

Remission of progressive metastatic castration-resistant prostate cancer during abiraterone therapy following unilateral adrenalectomy for a functioning adrenal adenoma.

Despite advances and introduction of new therapies in the last decade, metastatic castration-resistant prostate cancer (mCRPC) has a poor prognosis. The development of androgen axis-targeted therapies such as abiraterone acetate, enzalutamide and darolutamide can prolong survival in mCPRC; however, resistance remains a barrier to prolonged response, necessitating exploration into resistance mechanisms and locoregional therapies. Here, we describe a patient with mCRPC that was progressing on abiraterone acetate. He was also found to have primary hyperaldosteronism from a functional adrenal adenoma, and thus he had a partial adrenalectomy to remove this tumour. Pathology confirmed an aldosterone-producing adrenal adenoma. After his adrenalectomy, he had a sharp decline in both his PSA (prostate specific antigen) and testosterone levels, and he enjoyed a year-long period of remission after his adrenalectomy. We propose several explanations for his response, the most likely being that his adenoma was producing both aldosterone and androgens. This is a unique case of mCRPC responding to partial adrenalectomy from a functional adrenal adenoma, and it raises insights that warrant further investigation into underlying mechanisms of resistance to androgen-targeted therapies.

Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor response in metastatic renal cell carcinoma.

BACKGROUND: Immunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers of response are lacking to predict patients who will have a favorable or unfavorable response to immunotherapy. This study aimed to use the OmniSeq transcriptome-based platform to develop biomarkers of response to immunotherapy. METHODS: Two cohorts of patients were retrospectively collected. These included an investigational cohort of patients with mRCC treated with immune checkpoint inhibitor therapy from five institutions, and a subsequent validation cohort of patients with mRCC treated with combination ipilimumab and nivolumab from two institutions (Duke Cancer Institute and Cleveland Clinic Taussig Cancer Center). Tissue-based RNA sequencing was performed using the OmniSeq Immune Report Card on banked specimens to identify gene signatures and immune checkpoints associated with differential clinical outcomes. A 5-gene expression panel was developed based on the investigational cohort and was subsequently evaluated in the validation cohort. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were extracted by retrospective chart review. Objective response rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1. RESULTS: The initial investigation cohort identified 86 patients with mRCC who received nivolumab (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), or pembrolizumab (6%, 5/86). A gene expression score was created using the top five genes found in responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). The ORR in patients with high gene expression (GEhigh) on the 5-gene panel was 29% (14/48), compared with low gene expression (GElow) 3% (1/38, χ2 p=0.001). The validation cohort was comprised of 62 patients who received ipilimumab/nivolumab. There was no difference between GEhigh and GElow in terms of ORR (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 to 3.89), or OS (HR 0.96, 95% CI 0.51 to 1.83). Similarly, no differences in ORR, PFS or OS were observed when patients were stratified by tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) expression by immunohistochemistry or RNA expression, or CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) RNA expression. The International Metastatic RCC Database Consortium (IMDC) risk score was prognostic for OS but not PFS. CONCLUSION: A 5-gene panel that was associated with improved ORR in a predominantly nivolumab monotherapy population of patients with mRCC was not predictive for radiographic response, PFS, or OS among patients with mRCC treated with ipilimumab and nivolumab.

Making National Cancer Institute-Designated Comprehensive Cancer Center Knowledge Accessible to Community Oncologists via an Online Tumor Board: Longitudinal Observational Study.

BACKGROUND: Expert knowledge is often shared among multidisciplinary academic teams at tumor boards (TBs) across the country, but these conversations exist in silos and do not reach the wider oncology community. OBJECTIVE: Using an oncologist-only question and answer (Q&A) website, we sought to document expert insights from TBs at National Cancer Institute-designated Comprehensive Cancer Centers (NCI-CCCs) to provide educational benefits to the oncology community. METHODS: We designed a process with the NCI-CCCs to document and share discussions from the TBs focused on areas of practice variation on theMednet, an interactive Q&A website of over 13,000 US oncologists. The faculty translated the TB discussions into concise, non-case-based Q&As on theMednet. Answers were peer reviewed and disseminated in email newsletters to registered oncologists. Reach and engagement were measured. Following each Q&A, a survey question asked how the TB Q&As impacted the readers' practice. RESULTS: A total of 23 breast, thoracic, gastrointestinal, and genitourinary programs from 16 NCI-CCC sites participated. Between December 2016 and July 2021, the faculty highlighted 368 questions from their TBs. Q&As were viewed 147,661 times by 7381 oncologists at 3515 institutions from all 50 states. A total of 277 (75%) Q&As were viewed every month. Of the 1063 responses to a survey question on how the Q&A affected clinicians' practices, 646 (61%) reported that it confirmed their current practice, 163 (20%) indicated that a Q&A would change their future practice, and 214 (15%) reported learning something new. CONCLUSIONS: Through an online Q&A platform, academics at the NCI-CCCs share knowledge outside the walls of academia with oncologists across the United States. Access to up-to-date expert knowledge can reassure clinicians' practices, significantly impact patient care in community practices, and be a source of new knowledge and education.

Management of men with metastatic castration-resistant prostate cancer following potent androgen receptor inhibition: a review of novel investigational therapies.

BACKGROUND: Androgen-targeted therapy and chemotherapy are currently the mainstay of treatment in metastatic castration resistant prostate cancer (mCRPC). When progression occurs despite these therapeutic strategies, additional FDA-approved treatment options are lacking. However, there is a vast amount of emerging data surrounding novel investigational therapies in this space. METHODS: We reviewed and summarized the body of literature surrounding the current treatment options for mCRPC. Medline and Pubmed as well as abstracts from international congresses were utilized to gather relevant literature surrounding investigational treatment of mCRPC. We highlight the results of recent trials investigating the use of novel strategies to treat mCRPC. RESULTS: Androgen-targeted therapy and chemotherapy will remain foundational in the treatment of mCRPC. However, heavily pretreated patients who have developed resistance may benefit from novel therapeutic strategies. The use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) has now gained FDA approval for patients with homologous recombination repair (HRR) gene mutations. Novel androgen receptor (AR) degraders and the use of radioligand therapy (RLT) with Lu-PSMA-617 (Lu-PSMA) are under investigation. Immune-directed therapies, including programmed death (PD-1) inhibition, bi-specific T-cell engager (BiTE) technology, and chimeric antigen receptor (CAR) T-cell therapy, have shown promise in early phase trials. Further understanding of resistance mechanisms has led to additional therapeutic targets, including targeting the PI3K-Akt-mTOR pathway and enhancer of zester homolog 2 (EZH2). CONCLUSIONS: Based on our review of the literature, exciting new therapeutic strategies exist for the treatment of mCRPC. In particular, PARPi, AR degraders, PSMA-targeted therapies, immune-directed therapies, and agents targeting resistance mechanisms as monotherapy or in combination could improve patient outcomes. Additional data from randomized trials are necessary to understand the efficacy and tolerability of these treatment strategies.

LRP1B mutations are associated with favorable outcomes to immune checkpoint inhibitors across multiple cancer types.

BACKGROUND: Low-density lipoprotein receptor-related protein 1b (encoded by LRP1B) is a putative tumor suppressor, and preliminary evidence suggests LRP1B-mutated cancers may have improved outcomes with immune checkpoint inhibitors (ICI). METHODS: We conducted a multicenter, retrospective pan-cancer analysis of patients with LRP1B alterations treated with ICI at Duke University, Johns Hopkins University (JHU) and University of Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) to ICI and pathogenic or likely pathogenic (P/LP) LRP1B alterations compared with LRP1B variants of unknown significance (VUS). Secondary outcomes were the associations with progression-free survival (PFS) and overall survival (OS) by LRP1B status. RESULTS: We identified 101 patients (44 Duke, 35 JHU, 22 UM) with LRP1B alterations who were treated with ICI. The most common tumor types by alteration (P/LP vs VUS%) were lung (36% vs 49%), prostate (9% vs 7%), sarcoma (5% vs 7%), melanoma (9% vs 0%) and breast cancer (3% vs 7%). The ORR for patients with LRP1B P/LP versus VUS alterations was 54% and 13%, respectively (OR 7.5, 95% CI 2.9 to 22.3, p=0.0009). P/LP LRP1B alterations were associated with longer PFS (HR 0.42, 95% CI 0.26 to 0.68, p=0.0003) and OS (HR 0.62, 95% CI 0.39 to 1.01, p=0.053). These results remained consistent when excluding patients harboring microsatellite instability (MSI) and controlling for tumor mutational burden (TMB). CONCLUSIONS: This multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUS LRP1B alterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted.

PD-L1 Assay Concordance in Metastatic Renal Cell Carcinoma and Metastatic Urothelial Carcinoma.

BACKGROUND: Immune checkpoint inhibitors are now standard of care for many patients with metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC). Given real-world limitations in programmed death-ligand 1 (PD-L1) testing, concordance studies between PD-L1 assays are needed. We undertook comparisons of Dako 28-8 and Ventana SP142 assays in mRCC and Dako 22C3 and Ventana SP263 assays in mUC. PATIENTS AND METHODS: Thirty-two patients with mRCC and 18 patients with mUC who had received immune checkpoint inhibitor therapy were identified. Formalin-fixed paraffin-embedded tumor samples for patients with mRCC were evaluated with Dako 28-8 and Ventana SP142 PD-L1 immunohistochemistry assays. For patients with mUC, formalin-fixed paraffin-embedded tumor samples were evaluated with Dako 22C3 and Ventana SP263 PD-L1 immunohistochemistry assays. RESULTS: The majority (29/32; 91%) of mRCC cases were concordant between assays. The majority (17/18; 94%) of mUC cases were also concordant between assays. CONCLUSIONS: There was strong concordance between PD-L1 assays chosen for comparison in both mRCC and mUC, with similar performance characteristics. One limitation is the small number of cases in this study; larger comparison studies are needed for this biomarker in mRCC and mUC.

Immunotherapy Is Changing First-Line Treatment of Metastatic Renal-Cell Carcinoma.

The incidence of renal-cell carcinoma has been increasing each year, with nearly one third of new cases diagnosed at advanced or metastatic stage. The advent of targeted therapies for metastatic renal-cell carcinoma (mRCC) has underscored the need to subtype tumors according to tumor-immune expression profiles that may more reliably predict treatment outcomes. Over the past 2 decades, several vascular endothelial growth factor (VEGF) and tyrosine kinase inhibitors have been the mainstay for first- and second-line treatment of mRCC. Very recently, immunotherapy checkpoint inhibitors have significantly changed the treatment landscape for patients with mRCC, particularly for first-line treatment of intermediate to poor risk mRCC patients. Now, combination immunotherapy as well as combinations of immunotherapy with targeted agents can significantly alter disease outcomes. The field of immuno-oncology for mRCC has unveiled a deeper understanding of the immunoreactivity inherent to these tumors, and as a result combination therapy is evolving as a first-line modality. This review provides a timeline of advances and controversies in first-line treatment of mRCC, describes recent advances in understanding the immunoreactivity of these tumors, and addresses the future of combination anti-VEGF and immunotherapeutic platforms.

Consent for organ donation after circulatory death at U.S. transplant centers.

BACKGROUND: Despite calls for a controlled organ donation after circulatory death (cDCD) consent process that is more rigorous, consistent, and transparent, little is known about the cDCD consent processes utilized by U.S. hospitals. The objective of this research was to describe the cDCD consent policies of U.S. transplant hospitals, including consent for antemortem interventions (AMI), in order to inform the development of a more rigorous and sound consent process. METHODS: Cross-sectional study data of cDCD policies of U.S. transplant hospitals were collected between July 2013 and October 2014. Respondents submitted their policies for investigator review and/or completed a 25-item Web-based survey describing their hospital's cDCD and AMI policies. There were 209 U.S. adult transplant hospitals identified through the Organ Procurement and Transplantation Network (OPTN). RESULTS: One hundred responses were received, representing 48% of all 209 U.S. transplant hospitals and 60% of the 168 transplant centers with an identified knowledgeable informant. In 79 policies (79%), organ procurement organization representatives (OPOs) are given sole responsibility for obtaining signed cDCD consent. Thirty-four policies (34%) give OPOs the responsibility for obtaining written AMI consent, 13 policies give it to treating physicians, and 6 policies state that AMI consent must be obtained collaboratively. Treating physicians have no delineated responsibilities in the cDCD and AMI consent process in 70 (70%) and 58 (58%) policies, respectively. We observed wide variability in the acceptability of first-person authorization (FPA) for cDCD and AMI; FPA was rejected as evidence of consent for cDCD and AMI in 7 and 11 policies, respectively. CONCLUSIONS: The cDCD consent policies of U.S. transplant hospitals are highly variable and inconsistent in addressing key aspects of the consent process. The major policy differences observed raise questions about what constitutes a sound and comprehensive cDCD consent policy.