Inhibition of PIM kinase in tumor associated macrophages suppresses inflammasome activation and sensitizes prostate cancer to immunotherapy.

Immunotherapy has changed the treatment paradigm for many types of cancer, but immune checkpoint inhibitors (ICIs) have not shown benefit in prostate cancer (PCa). Chronic inflammation contributes to the immunosuppressive prostate tumor microenvironment (TME) and is associated with poor response to ICIs. The primary source of inflammatory cytokine production is the inflammasome. Here, we identify PIM kinases as important regulators of inflammasome activation in tumor associated macrophages (TAMs). Analysis of clinical data from a cohort of treatment naïve, hormone responsive PCa patients revealed that tumors from patients with high PIM1/2/3 display an immunosuppressive TME characterized by high inflammation (IL-1ß and TNFα) and a high density of repressive immune cells, most notably TAMs. Strikingly, macrophage-specific knockout of PIM reduced tumor growth in syngeneic models of prostate cancer. Transcriptional analyses indicate that eliminating PIM from macrophages enhanced the adaptive immune response and increased cytotoxic immune cells. Combined treatment with PIM inhibitors and ICIs synergistically reduced tumor growth. Immune profiling revealed that PIM inhibitors sensitized PCa tumors to ICIs by increasing tumor suppressive TAMs and increasing the activation of cytotoxic T cells. Collectively, our data implicate macrophage PIM as a driver of inflammation that limits the potency of ICIs and provides preclinical evidence that PIM inhibitors are an effective strategy to improve the efficacy of immunotherapy in prostate cancer.

Driver mutations associated with signatures of platinum sensitivity in germ cell tumors.

We sought to evaluate the genomic and transcriptomic landscapes in primary and metastatic germ cell tumors (GCTs; N = 138) to uncover factors that drive cisplatin resistance. Prevalence was calculated for platinum-resistant alterations (PRAs; KRAS, TP53, and KIT mutations, and MDM2 amplification) and high copy number amplifications (CNA ≥ 6 copies). Tumors were designated as chemo-naïve (PreC, N = 66) or post-chemotherapy (PostC, N = 17). A transcriptomic signature associated with platinum sensitivity (PSS, high suggests increased sensitivity) was applied. KIT mutations were observed in 14.5% of primary versus 1.8% of met and 0% of lymph. TP53 mutations were identified in 10% of primary GCTs versus 17% of met and 16.7% of lymph. MDM2 CNAs were similar between sites. PRA-positive PreC GCTs had significantly lower average PSS scores compared to PRA-negative tumors. Lower PSS scores in chemo-naïve tumors were associated with PRAs, suggesting a potential mechanism for platinum resistance.

Perioperative Use of ctDNA to Guide Treatment for Urothelial Carcinoma: The Future is Now.

 Muscle-invasive bladder cancer represents a potentially curable disease, yet often disease recurs and is ultimately fatal. Outcomes for patients with localized urothelial carcinoma are heterogeneous with some patients cured with surgery alone, deriving no benefit from perioperative systemic therapy, while others are left with residual disease and may benefit from additional therapy. Neoadjuvant chemotherapy increases cure rates but comes with significant toxicity. Recently, adjuvant nivolumab has demonstrated significant improvement in disease free survival (DFS), and overall survival analysis is pending. With more therapies approved for urothelial cancer within the last 5 years than ever before, there is incredible potential to improve clinical outcomes and potentially cure more patients with integrated multimodal therapy. Biomarkers are needed to dichotomize those most likely to benefit from perioperative systemic therapy for residual disease, and de-escalate therapy for those likely to be cured with surgery alone. Ultrasensitive assays for circulating tumor DNA (ctDNA) have emerged as a method to identify patients at high risk of recurrence after definitive therapy and may benefit from escalated therapy, while also identifying those least likely to benefit from systemic therapy. Studies have demonstrated that the presence of ctDNA after surgery is prognostic of disease recurrence across multiple cancer types, including bladder cancer, but questions remain as to the utility of these tests, and whether they can be predictive of benefit of adjuvant therapy. Although these liquid biopsies hold significant promise to transform perioperative treatment, prospective studies are needed to validate their utility as prognostic and predictive biomarkers. To bridge this knowledge gap, contemporary clinical trials are incorporating ctDNA as an integral biomarker to guide therapy for MIBC.

Emerging innovative treatment strategies for advanced clear cell renal cell carcinoma.

Dramatic advances in biological discoveries, since the 1990s, have continued to reshape the treatment paradigm of metastatic renal cell carcinoma (RCC). Von Hippel Lindau (VHL) gene alterations are associated with pro-angiogenic activity and are central to the pathogenesis of clear cell RCC (ccRCC), the most predominant histologic subtype of RCC. Antiangiogenic strategies revolving around this VHL/HIF/VEGF axis have been shown to improve survival in metastatic ccRCC. The discovery of immune checkpoints and agents that target their inhibition introduced a new treatment paradigm for patients with RCC. While initially approved as monotherapy, studies investigating immune checkpoint inhibitor combinations have led to their approval as the new standard of care, providing durable responses and unprecedented improvements in clinical outcome. Despite these advances, the projected 14 390 deaths in 2024 from RCC underscore the need to continue efforts in expanding and optimizing treatment options for patients with metastatic RCC. This article reviews key findings that have transformed the way we understand and treat metastatic RCC, in addition to highlighting novel treatment strategies that are currently under development.

Germline genetic testing for prostate cancer: Ordering trends in the era of expanded hereditary cancer screening recommendations.

PURPOSE: The availability of targeted therapies for advanced prostate cancer led to the expansion of national guidelines recommending germline genetic testing. The aim of this study was to describe recent trends in germline test ordering patterns for patients with prostate cancer. MATERIALS AND METHODS: A retrospective cohort analysis of patients with prostate cancer who underwent germline testing through a single commercial laboratory (Invitae Corporation) between 2015-2020 was performed. Ordering trends between provider medical specialties were compared. Our primary hypothesis was that the proportion of tests ordered by urologists would increase over time. RESULTS: In total, 17,256 prostate cancer patients underwent germline genetic testing; 14,400 patients had an ordering provider with an associated medical specialty and were included in the final comparison cohort. Total prostate cancer patients undergoing germline testing increased quarterly from 21 in Q2 of 2015 to 1,509 in Q3 of 2020. The proportion of tests ordered by urologists increased from 0% in Q2 2015 to 8.3% in Q3 2020 (P < 0.001). Compared to medical genetics, medical oncology, and other specialties, urology ordered more tests for patients under 70 years old (66% vs 51%-55%, P <0.004) and for patients who reported negative family history (25% vs 12%-20%, P = 0.012). CONCLUSIONS: As awareness and indications for germline testing continue to expand, aggregate ordering volume is increasing, and urologists are becoming more involved in facilitating testing. This highlights the continued importance of educating urologists on the indications for and implications of germline genetic testing, as well as providing tools to support implementation.

Association of Tumor Mutational Burden and Microsatellite Instability With Response and Outcomes in Patients With Urothelial Carcinoma Treated With Immune Checkpoint Inhibitor.

BACKGROUND: Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI. METHODS: Patients from 15 institutions were treated with ICI monotherapy. Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (≥10 vs. <10 mut/Mb) and continuous variable. RESULTS: We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2 + L. For the 1L/upfront: median [m] OS was numerically longer in patients with TMB ≥10 versus TMB <10: mOS 35 versus 26 months (HR = 0.6) and with MSI-H and MSI-S (mOS NR vs. 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR = 0.96, P = .01). For 2 + L: mOS was numerically longer in patients with TMB ≥10 versus TMB <10: (20 vs. 12 months; HR = 0.9); mOS was 12 and 17 months for patients with MSI-H and MSI-S, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB ≥10 versus TMB <10: 61 versus 17 months; (HR = 0.2, P = .02) and with MSI-H and MSI-S (NR vs. 24 months). CONCLUSIONS: Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Further validation is needed.

Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 Study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors are cornerstones of first-line treatment for advanced renal cell carcinoma; however, optimal treatment sequencing after progression is unknown. This study aimed to assess clinical outcomes of tivozanib-nivolumab versus tivozanib monotherapy in patients with metastatic renal cell carcinoma who have progressed following one or two lines of therapy in the post-ICI setting. METHODS: TiNivo-2 is a multicentre, randomised, open-label, phase 3 trial at 190 sites across 16 countries, in Australia, Europe, North America, and South America. Patients with advanced renal cell carcinoma and progression during or after one to two previous lines of therapy (including one ICI) were randomised 1:1 to tivozanib (0·89 mg per day, orally) plus nivolumab (480 mg every 4 weeks, intravenously) or tivozanib (1·34 mg per day, orally). Randomisation was stratified by immediate previous therapy (ICI or non-ICI) and International Metastatic Renal Cell Carcinoma Database Consortium risk category. The primary endpoint was progression-free survival (PFS), defined as the time from randomisation to first documentation of objective progressive disease according to RECIST 1·1 or death from any cause, whichever came first, by independent radiology review. Efficacy was evaluated in the intention-to-treat population, and safety was assessed in patients who received one or more doses of the study drug. This trial was registered on ClinicalTrials.gov (NCT04987203) and is active and not recruiting. FINDINGS: From Nov 4, 2021, to June 16, 2023, 343 patients were randomly assigned to tivozanib-nivolumab (n=171) or tivozanib monotherapy (n=172). Median follow-up was 12·0 months. Median PFS was 5·7 months (95% CI 4·0-7·4) with tivozanib-nivolumab and 7·4 months (5·6-9·2) with tivozanib monotherapy (hazard ratio 1·10, 95% CI 0·84-1·43; p=0·49). Among those with an ICI as their immediate previous therapy (n=244), median PFS was 7·4 months (95% CI 5·6-9·6) with tivozanib-nivolumab and 9·2 months (7·4-10·0) with tivozanib monotherapy. With non-ICIs as the most recent therapy, lower median PFS was observed, with no difference between groups (tivozanib-nivolumab 3·7 months [95% CI 2·7-5·4] and with tivozanib monotherapy 3·7 months [1·9-7·2]). Serious adverse events occurred in 54 (32%) of 168 patients receiving tivozanib-nivolumab and 64 (37%) of 171 patients receiving tivozanib monotherapy. One (<1%) treatment-related death occurred (tivozanib group). INTERPRETATION: These data further support that ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma. Furthermore, these data suggest that tivozanib monotherapy has efficacy in the post-ICI setting. FUNDING: Aveo Pharmaceuticals.

Comparison of outcomes of radical and partial nephrectomy for sarcomatoid renal cell carcinoma: analysis of the national cancer database.

PURPOSE: To compare outcomes of radical (RN) and partial nephrectomy (PN) in Sarcomatoid Renal Cell Carcinoma (sRCC) utilizing a large national cohort. As RN is the reference standard for localized RCC with clinically aggressive features, PN in sRCC has been seldom studied. METHODS: We performed a retrospective cohort analysis of the National Cancer Database from 2004 to 2019 for patients who underwent PN and RN for sRCC (T1-T3N0-N1M0). We performed multivariable analyses (MVA) to determine factors associated with PN and all-cause mortality (ACM), and Kaplan-Meier Analysis (KMA) for overall survival (OS) in Charlson 0 patients who underwent PN vs. RN according to clinical stage. RESULTS: The cohort consisted of 5,265 patients [RN 4,582 (87.0%)/PN 683 (13.0%)]. Increased odds of receiving PN was associated with papillary RCC (OR = 1.69, p = 0.015); inversely with increasing age (OR = 0.99, p = 0.004), cT2-cT3 (OR = 0.23, p < 0.001), and cN1 (OR = 0.2, p < 0.001). Worsened ACM was associated with positive margins (HR = 1.59, p < 0.001), male (HR = 1.1, p = 0.044), Charlson [Formula: see text]2 (HR = 1.47, p < 0.001), cT2-cT3 (HR 1.17-1.39, p < 0.001-0.035), and cN1 (HR = 1.59, p < 0.001). Improved ACM was noted with PN (HR = 0.64, p < 0.001), increasing household income (HR = 0.77-0.79, p < 0.001), and private insurance (HR = 0.80, p = 0.018). KMA showed PN had improved 5-year OS compared to RN in cT1 (86.5% vs. 63.2%, p < 0.001), and cT3 (61.0% vs. 44.0% p < 0.001), but not cT2 (p = 0.67). CONCLUSION: In select patients, PN with negative margins may not compromise outcomes and may provide benefit when indicated. Patients with private insurance and highest income experienced improved survival suggesting disparity in care.

Bipolar androgen therapy for treatment of metastatic castration-resistant prostate cancer: A case series.

INTRODUCTION: Advanced prostate cancer treatment has improved with androgen receptor signaling inhibitors (ARPI), yet many patients develop metastatic castration-resistant prostate cancer (mCRPC), characterized by sustained androgen receptor (AR) signaling. Bipolar androgen therapy (BAT) introduces supraphysiologic testosterone levels to inhibit tumor growth, offering novel treatment for mCRPC by exploiting AR-dependent mechanisms. CASE PRESENTATIONS: Case 1: A 53-year-old man with mCRPC, post multiple systemic therapies, initiated BAT and pembrolizumab, achieving PSA reduction and improved quality of life before progression. The patient exhibited AR amplification, which may have contributed to favorable response to BAT. Case 2: A 73-year-old man with recurrent prostate cancer, stable on ADT and abiraterone, experienced PSA decline with BAT to an undetectable level, maintaining stability post-therapy discontinuation. Case 3: A 73-year-old man with metastatic prostate cancer, initially resistant to enzalutamide, achieved clinical benefit and disease control with BAT, although he did not meet PSA response criteria, patient had remarkable response upon enzalutamide rechallenge. Case 4: A 90-year-old man with localized prostate cancer, refractory to multiple treatments, experienced symptom relief and PSA reduction with BAT before progression. CONCLUSION: BAT represents a promising treatment strategy for mCRPC. This case series underscores BAT's potential to induce significant clinical and biochemical responses, resensitize tumors to ARPIs, and improve patients' quality of life. Despite eventual progression in some cases, BAT offers a period of disease control. Further research is needed to optimize patient selection and understand the molecular determinants of BAT responsiveness.

Dissecting the Significance of Acid Phosphatase 1 Gene Alterations in Prostate Cancer.

PURPOSE: The acid phosphatase 1 (ACP1) gene encodes low-molecular-weight protein tyrosine phosphatase, which is overexpressed in prostate cancer (PC) and a potential therapeutic target. We analyzed ACP1 expression in primary/metastatic PC and its association with molecular profiles and clinical outcomes. METHODS: NextGen sequencing of DNA (592-gene/whole-exome sequencing)/RNA(whole-transcriptome sequencing) was performed for 5,028 specimens. ACP1-High/ACP1-Low expression was defined as quartile (Q4/1) of RNA transcripts per million (TPM). DNA mutational profiles were analyzed for ACP1-quartile-stratified samples. Gene set enrichment analysis was used for Hallmark collection of pathways. PD-L1+(≥2+, ≥5%; SP142) was tested by immunohistochemistry. Tumor microenvironment's (TME) immune cell fractions were estimated by RNA deconvolution/quanTIseq. Overall survival (OS) was assessed from initial diagnosis/treatment initiation to death/last follow-up. RESULTS: We included 3,058 (60.8%) samples from the prostate, 634 (12.6%) from lymph node metastases (LNMs), and 1,307 (26.0%) from distant metastases (DMs). ACP1 expression was higher in LNM/DM than prostate (49.8/47.9 v 44.1 TPM; P < .0001). TP53 mutations were enriched in ACP1-Q4 (37.9%[Q4] v 27.0%[Q1]; P < .001) among prostate samples. Pathways associated with cell cycle regulation and oxidative phosphorylation were enriched in ACP1-Q4, whereas epithelial-mesenchymal transition and tumor necrosis factor-alpha signaling via nuclear factor kappa-light-chain-enhancer of activated B-cell pathways were enriched in ACP1-Q1. Neuroendocrine and androgen receptor signaling was increased in ACP1-Q4. M2 macrophages and natural killer cell fractions were increased, whereas T cells and M1 macrophages were decreased in ACP1-Q4. While OS differences between ACP1-Q1/Q4 were not statistically significant, there was a trend for worse OS among ACP1-Q4 prostate samples (Q4 v Q1: hazard ratio [HR], 1.19 [95% CI, 0.99 to 1.42]; P = .06) and DM (HR, 1.12 [95% CI, 0.93 to 1.36]; P = .22) but not LNM (HR, 0.98 [95% CI, 0.74 to 1.29]; P = .87). CONCLUSION: ACP1-High tumors exhibit a distinct molecular profile and cold TME, highlighting ACP1's potential role in PC pathogenesis and novel therapeutic targeting.

Incidence of Erectile Dysfunction and Testosterone Deficiency in Testicular Cancer Survivors.

PURPOSE: The aim of this project was to characterize the incidence of men's health disorders, specifically focusing on the incidence of erectile dysfunction (ED) and testosterone deficiency (TD) in a large, nationwide study of testicular cancer (TC) survivors treated in a centralized health care system. PATIENTS AND METHODS: We conducted a retrospective cohort study of US veterans diagnosed with TC from 1990 to 2021. These veterans were compared with an age-matched and race-matched control group of US veterans without a diagnosis of TC. ED and TD were defined by the presence of diagnosis codes or at least a 6-month prescription for medications treating these conditions or both. Time was measured from the date of TC diagnosis (for patients with TC and matched TC patient date for the corresponding noncancer controls). Impact of chemotherapy among TC survivors on ED and TD was evaluated using multivariable Cox regression models. RESULTS: The cohort included 1754 patients with TC compared with 7117 noncancer controls, with a mean age at diagnosis of 42 years. Patients with TC were significantly more likely than controls to experience ED (HR, 2.97; 95% CI, 2.68-3.28; P < .001) and TD (HR, 6.71; 95% CI, 5.78-7.81; P < .001). However, within the TC group, there was no significant difference in the incidence of ED and TD when stratified by receipt of chemotherapy (P = .9 and P = .066, respectively). CONCLUSIONS: Men's health disorders arise commonly in the lives of TC survivors. It is important for treating physicians to identify these and conduct sexual health assessments as part of survivorship care.

First-line Systemic Therapy Following Adjuvant Immunotherapy in Renal Cell Carcinoma: An International Multicenter Study.

BACKGROUND AND OBJECTIVE: Adjuvant pembrolizumab significantly improved overall survival (OS) in renal cell carcinoma (RCC), but real-world data on sequential treatment are scarce. We sought to evaluate the clinical outcomes of first-line (1L) systemic therapy following adjuvant immune oncology (IO)-based regimens. METHODS: A retrospective study including patients with recurrent RCC following adjuvant IO across 29 international institutions was conducted. The primary endpoint was progression-free survival (PFS) on 1L systemic therapy estimated using the Kaplan-Meier method. Preplanned subanalyses of clinical outcomes by type of 1L systemic therapy, recurrence timing, and International Metastatic RCC Database Consortium (IMDC) risk groups were performed. Treatment-related adverse events leading to treatment discontinuation, dose reduction, or corticosteroid use were assessed. KEY FINDINGS AND LIMITATIONS: A total of 94 patients were included. Most received adjuvant pembrolizumab (n = 37, 39%), atezolizumab (n = 28, 30%), or nivolumab + ipilimumab (n = 15, 16%). The cohort included 49 (52%) patients who had recurrence within 3 mo of the last adjuvant IO dose, whereas 45 (48%) recurred beyond 3 mo. Bone metastases were significantly higher in tumors recurring at <3 mo (10/49, 20%) than those recurring at >3 mo (1/45, 2.2%; p = 0.008). Most patients received 1L vascular endothelial growth factor-targeted therapy (VEGF-TT; n = 37, 39%), IO + VEGF-TT (n = 26, 28%), or IO + IO (n = 12, 13%). The remaining underwent local therapy. The median follow-up for the 1L systemic therapy cohort was 15 mo. The 18-mo PFS and OS rates were 45% (95% confidence interval [CI]: 34-60) and 85% (95% CI: 75-95), respectively. Treatment-related adverse events occurred in 32 (42%) patients and included skin toxicity (n = 7, 9.2%), fatigue (n = 6, 7.9%), and diarrhea/colitis (n = 4, 5.3%). Limitations included selecting patients from large academic centers and the short follow-up period. CONCLUSIONS AND CLINICAL IMPLICATIONS: A subset of patients with recurrent RCC following adjuvant IO respond to systemic therapies, including VEGF-TT and IO-based regimens. Notably, patients with favorable-risk disease may derive more benefit from VEGF-TT than from IO therapies in this setting. Future approaches utilizing radiographic tools and biomarker-based liquid biopsies are warranted to detect occult metastatic disease and identify candidate patients for adjuvant IO therapy. PATIENT SUMMARY: Adjuvant pembrolizumab significantly improved overall survival in renal cell carcinoma (RCC). There are limited data on clinical outcomes after the recurrence of RCC tumors following adjuvant immunotherapy. In this study, we find that patients respond to subsequent systemic therapies across different treatment options.

DNA-Damaging Therapies in Patients With Prostate Cancer and Pathogenic Alterations in Homologous Recombination Repair Genes.

PURPOSE: Outcomes data for DNA-damaging therapeutics for men with prostate cancer (PC) and non-BRCA1/2 homologous recombination repair (HRR) mutations are limited. We evaluated outcomes by HRR alteration in men with PC treated with poly(ADP-ribose)polymerase inhibitors (PARPi) and/or platinum chemotherapy. METHODS: Retrospective data from the PROMISE consortium were used. Clinical outcomes differences were assessed between patients with BRCA1/2 mutations (cohort A) and those with HRR mutations without direct BRCA complex interaction (cohort B: ATM, CDK12, CHEK1, CHEK2, and FANCL). Outcomes in patients with HRR mutations with direct BRCA complex interaction were also explored (cohort C: RAD51B/C/D, RAD54L2, BARD1, GEN1, PALB2, FANCA, and BRIP1). RESULTS: One hundred and forty-six patients received PARPi (cohort A: 94, cohort B: 45, cohort C: 7) and 104 received platinum chemotherapy (cohort A: 48, cohort B: 44, cohort C: 10). PSA50 response rate to PARPi was higher in cohort A (61%) than cohort B (5%), P < .001. Median clinical/radiographic progression-free survival (crPFS) with PARPi in cohort A was significantly longer than in cohort B: 15.9 versus 8.7 months, P = .005. PSA50 response rate to platinum therapy was higher in cohort A (62%) than in cohort B (32%), P = .024, although crPFS was not significantly different. PSA50 response rate to PARPi and platinum was 40% and 32%, respectively, in cohort C. In multivariable analysis, cohort A had significantly improved overall survival and crPFS compared with cohort B with PARPi but not platinum chemotherapy. CONCLUSION: Patients with BRCA1/2-mutated PC had significantly improved outcomes to PARPi but not platinum chemotherapy compared with those with HRR mutations without direct BRCA complex interaction.

Molecular analysis of primary and metastatic sites in patients with renal cell carcinoma.

BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.

Clinical implications of Wnt pathway genetic alterations in men with advanced prostate cancer.

BACKGROUND: Aberrant Wnt signaling has been implicated in prostate cancer tumorigenesis and metastasis in preclinical models but the impact of genetic alterations in Wnt signaling genes in men with advanced prostate cancer is unknown. METHODS: We utilized the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database for this retrospective analysis. Patients with activating mutations in CTNNB1 or RSPO2 or inactivating mutations in APC, RNF43, or ZNRF3 were defined as Wnt-altered, while those lacking such alterations were defined as Wnt non-altered. We compared patient characteristics and clinical outcomes as well as co-occurring genetic alterations according to Wnt alteration status. RESULTS: Of the 1498 patients included, 193 (12.9%) were Wnt-altered. These men had a statistically significant 2-fold increased prevalence of liver and lung metastases as compared with Wnt non-altered patients at the time of initial diagnosis, (4.66% v 2.15% ; 6.22% v 3.07%), first metastatic disease diagnosis (10.88% v 5.29%; 13.99% v 6.21%), and CRPC development (11.40% v 6.36%; 12.95% v 5.29%). Wnt alterations were associated with more co-occurring alterations in RB1 (10.4% v 6.2%), AR (38.9% vs 25.7%), SPOP (13.5% vs 4.1%), FOXA1 (6.7% vs 2.8%), and PIK3CA (10.9% vs 5.1%). We found no significant differences in overall survival or other clinical outcomes from initial diagnosis, first metastatic disease, diagnosis of CRPC, or with AR inhibition for mCRPC between the Wnt groups. CONCLUSIONS: Wnt-altered patients with prostate cancer have a higher prevalence of visceral metastases and are enriched in RB1, AR, SPOP, FOXA1, and PIK3CA alterations. Despite these associations, Wnt alterations were not associated with worse survival or treatment outcomes in men with advanced prostate cancer.

Detecting HRD in whole-genome and whole-exome sequenced breast and ovarian cancers.

Breast and ovarian cancers harboring homologous recombination deficiency (HRD) are sensitive to PARP inhibitors and platinum chemotherapy. Conventionally, detecting HRD involves screening for defects in BRCA1, BRCA2, and other relevant genes. Recent analyses have shown that HRD cancers exhibit characteristic mutational patterns due to the activities of HRD-associated mutational signatures. At least three machine learning tools exist for detecting HRD based on mutational patterns. Here, using sequencing data from 1,043 breast and 182 ovarian cancers, we trained Homologous Recombination Proficiency Profiler (HRProfiler), a machine learning method for detecting HRD using six mutational features. HRProfiler's performance is assessed against prior approaches using additional independent datasets of 417 breast and 115 ovarian cancers, including retrospective data from a clinical trial involving patients treated with PARP inhibitors. Our results demonstrate that HRProfiler is the only tool that robustly and consistently predicts clinical response from whole-exome sequenced breast and ovarian cancers.

Emerging Novel Functional Imaging and Immunotherapy in Renal Cell Carcinoma and Current Treatment Sequencing Strategies After Immunotherapy.

The management of renal cell carcinoma (RCC) has advanced significantly in the past two decades. Many promising functional imaging modalities such as radiolabeled tracer targeting carbonic anhydrase IX and prostate-specific membrane antigen are under development to detect primary kidney tumors, stage systemic disease, and assess treatment response in RCC. Immune checkpoint inhibitors targeting PD-1 and cytotoxic T-cell lymphocyte-4 have changed the treatment paradigm in advanced RCC. Trials investigating novel mechanisms such as LAG-3 immune checkpoint inhibition, chimeric antigen receptor T-cell therapies, and T-cell engagers targeting RCC-associated antigens are currently ongoing. With the rapidly changing treatment landscape of RCC, the treatment sequence strategies will continue to evolve. Familiarity with the toxicities associated with the therapeutic agents and how to manage them are essential to achieve optimal patient outcomes. This review summarizes the recent developments of functional imaging and immunotherapy strategies in RCC, and the evidence supports treatment sequencing.

Characterization of Wnt Signaling Pathway Aberrations in Metastatic Prostate Cancer.

Wnt (wingless-type) signaling pathway (WSP) alterations have been identified in patients with prostate cancer and are implicated in disease progression and hormonal resistance. In this study, we utilized a multi-institutional dataset to characterize molecular alterations in the canonical and noncanonical WSPs in prostate cancer. Patients with prostate cancer who underwent tissue-based genomic sequencing were investigated. Tumors with somatic activating mutations in CTNNB1 or RSPO2 or inactivating mutations in either APC or RNF43 were characterized as having aberrant canonical Wnt signaling (WSP-activated). Overall survival analyses were restricted to microsatellite-stable (MSS) tumors lacking RNF43 G659fs* mutations. We also investigated noncanonical WSP by evaluation of ROR1, ROR2, and WNT5 in WSP-activated versus WSP wild-type (WSP-WT) tumors. Of 4,138 prostate cancer samples, 3,684 were MSS. Among MSS tumors, 42.4% were from metastatic sites, of which 19.1% were WSP activated, and 57.6% were from the prostate, of which 10.1% were WSP activated. WSP-activated tumors were more prevalent in metastatic sites than in primary prostate cancer. WSP-activated prostate cancer exhibited more SPOP mutations and higher expression of canonical WSP activators than WSP-WT tumors. ROR1 gene expression was elevated in WSP-activated tumors from both primary and metastatic sites. M2 macrophages predominated the tumor microenvironment in WSP-activated tumors. There was no significant difference in overall survival between patients with WSP-activated and WSP-WT prostate cancer. WSP-activated prostate cancer demonstrated a more immunosuppressed tumor microenvironment and a pronounced upregulation of ROR1 gene expression, underscoring its potential involvement in the crosstalk between canonical and noncanonical WSPs. Implications: Our findings may provide a rationale for developing novel therapeutic strategies targeting Wnt-activated prostate cancer.