Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation.

Background and Objective: Prostate cancer (PCa) is a leading cause of cancer mortality in men, with neuroendocrine prostate cancer (NEPC) representing a particularly resistant subtype. The role of transcription factors (TFs) in the progression from prostatic adenocarcinoma (PRAD) to NEPC is poorly understood. This study aims to identify and analyze lineage-specific TF profiles in PRAD and NEPC and illustrate their dynamic shifts during NE transdifferentiation. Methods: A novel algorithmic approach was developed to evaluate the weighted expression of TFs within patient samples, enabling a nuanced understanding of TF landscapes in PCa progression and TF dynamic shifts during NE transdifferentiation. Results: unveiled TF profiles for PRAD and NEPC, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs. Enrichment analysis across multiple clinical cohorts confirmed the lineage specificity and clinical relevance of these lineage-TFs signatures. Functional analysis revealed that lineage-TFs are implicated in pathways critical to cell development, differentiation, and lineage determination. Novel lineage-TF candidates were identified, offering potential targets for therapeutic intervention. Furthermore, our longitudinal study on NE transdifferentiation highlighted dynamic TF expression shifts and delineated a three-phase hypothesis for the process comprised of de-differentiation, dormancy, and re-differentiation. and proposing novel insights into the mechanisms of PCa progression. Conclusion: The lineage-specific TF profiles in PRAD and NEPC reveal a dynamic shift in the TF landscape during PCa progression, highlighting three distinct phases of NE transdifferentiation.

The survival benefit of metastasectomy for metastatic non-clear cell renal cell carcinoma: a retrospective cohort study.

PURPOSE: The aim of this study was to explore the benefit the metastasectomy for patients with metastatic non-clear cell carcinoma (non-ccRCC). METHODS: This study enrolled 120 patients with confirmed metastatic non-ccRCC from the RCC database of our center from 2008 to 2021. Patients without metastasectomy were grouped as radical nephrectomy without metastasectomy patients. The clinical outcomes included overall survival (OS) and progression-free survival (PFS). Cox regression and Kaplan-Meier analyses were used to assess potential factors that predict clinical benefits from metastasectomy. RESULTS: A total of 100 patients received radical nephrectomy alone, while the remaining 20 patients underwent both radical nephrectomy and metastasectomy. There was no significant difference in age between the two groups. Out of 100 patients who underwent radical nephrectomy, 60 were male, and out of 20 patients who had both radical nephrectomy and metastasectomy, 12 were male. Patients who underwent systemic therapy plus radical nephrectomy and metastasectomy had significantly better PFS (27.1 vs. 14.0, p = 0.032) and OS (67.3 vs. 24.0, p = 0.043) than those who underwent systemic therapy plus radical nephrectomy alone. Furthermore, for patients without liver metastasis (n = 54), systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.028) and OS (p = 0.043). Similarly, for patients with metachronous metastasis, systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.043) and OS (p = 0.032). None of the patients experienced serious perioperative complications (Clavien-Dindo Classification ≥ III grade). CONCLUSION: Metastasectomy in patients with metastatic non-ccRCC may provide clinical benefits in terms of improved PFS and OS, especially in patients without liver metastasis and those with metachronous metastasis.

Prognostic significance of circulating tumor DNA in urothelial carcinoma: a systematic review and meta-analysis.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a non-invasive technique that provides valuable insights into molecular profiles and tumor disease management. This study aimed to evaluate the prognostic significance of circulating tumor DNA (ctDNA) in urothelial carcinoma (UC) through a systematic review and meta-analysis. METHODS: A comprehensive search was conducted in MEDLINE, EMBASE, and the Cochrane Library from the inception to December 2023. Studies investigating the prognostic value of ctDNA in UC were included. Hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS) were extracted. Overall meta-analysis and subgroup exploration stratified by metastatic status, ctDNA sampling time, treatment type, and detection method was performed using the R software (version 4.2.2). RESULTS: A total of sixteen studies with 1725 patients were included. Fourteen studies assessed the association between baseline ctDNA status and patient outcomes. Patients with elevated ctDNA levels exhibited significantly worse DFS (HR=6.26; 95% CI, 3.71-10.58, P<0.001) and OS (HR=4.23; 95% CI, 2.72-6.57, P<0.001) regardless of metastatic status, ctDNA sampling time, treatment type and detection methods. Six studies evaluated the prognostic value of ctDNA dynamics in UC. Patients who showed a decrease or clearance in ctDNA levels during treatment or observation demonstrated more favorable DFS (HR=0.26, 95% CI, 0.17-0.41, P<0.001) and OS (HR=0.21, 95% CI, 0.11-0.38, P<0.001) compared to those who did not. The association remained consistent across the subgroup analysis based on metastatic status and detection methods. In the immune checkpoint inhibitor-treated setting, both lower baseline ctDNA level and ctDNA decrease during the treatment were significantly associated with more favorable oncologic outcomes. Furthermore, specific gene mutations such as FGFR3 identified in ctDNA also demonstrated predictive value in UC patients. CONCLUSION: This meta-analysis demonstrates a strong association of ctDNA status and its dynamic change with survival outcomes in UC, suggesting substantial clinical utility of ctDNA testing in prognosis prediction and decision making in this setting.

Genomic and Evolutionary Characterization of Concurrent Intraductal Carcinoma and Adenocarcinoma of the Prostate.

Intraductal carcinoma of the prostate (IDC-P) is a lethal prostate cancer subtype that generally coexists with invasive high-grade prostate acinar adenocarcinoma (PAC) but exhibits distinct biological features compared with concomitant adenocarcinoma. In this study, we performed whole-exome, RNA, and DNA-methylation sequencing of IDC-P, concurrent invasive high-grade PAC lesions, and adjacent normal prostate tissues isolated from 22 radical prostatectomy specimens. Three evolutionary patterns of concurrent IDC-P and PAC were identified: early divergent, late divergent, and clonally distant. In contrast to those with a late divergent evolutionary pattern, tumors with clonally distant and early divergent evolutionary patterns showed higher genomic, epigenomic, transcriptional, and pathologic heterogeneity between IDC-P and PAC. Compared with coexisting PAC, IDC-P displayed increased expression of adverse prognosis-associated genes. Survival analysis based on an independent cohort of 505 patients with metastatic prostate cancer revealed that IDC-P carriers with lower risk International Society of Urological Pathology (ISUP) grade 1-4 adenocarcinoma displayed a castration-resistant free survival as poor as those with the highest risk ISUP grade 5 tumors that lacked concurrent IDC-P. Furthermore, IDC-P exhibited robust cell-cycle progression and androgen receptor activities, characterized by an enrichment of cellular proliferation-associated master regulators and genes involved in intratumoral androgen biosynthesis. Overall, this study provides a molecular groundwork for the aggressive behavior of IDC-P and could help identify potential strategies to improve treatment of IDC-P. SIGNIFICANCE: The genomic, transcriptomic, and epigenomic characterization of concurrent intraductal carcinoma and adenocarcinoma of the prostate deepens the biological understanding of this lethal disease and provides a genetic basis for developing targeted therapies.

Retraction to the prognostic value of the pretreatment lung immune prognostic index in patients with metastatic hormone-sensitive and castration-resistant prostate cancer.

[This retracts the article DOI: 10.21037/atm-22-4318.].

Mutations in epigenetic regulator KMT2C detected by liquid biopsy are associated with worse survival in prostate cancer patients.

Background: KMT2 (lysine methyltransferase) family enzymes are epigenetic regulators that activate gene transcription. KMT2C is mainly involved in enhancer-associated H3K4me1, and is also one of the top mutated genes in cancer (6.6% in pan-cancer). Currently, the clinical significance of KMT2C mutations in prostate cancer is understudied. Methods: We included 221 prostate cancer patients diagnosed between 2014 and 2021 in West China Hospital of Sichuan University with cell-free DNA-based liquid biopsy test results in this study. We investigated the association between KMT2C mutations, other mutations, and pathways. Furthermore, we evaluated the prognostic value of KMT2C mutations, measured by overall survival (OS) and castration resistance-free survival (CRFS). Also, we explored the prognostic value of KMT2C mutations in different patient subgroups. Lastly, we investigated the predictive value of KMT2C mutations in individuals receiving conventional combined anti-androgen blockade (CAB) and abiraterone (ABI) as measured by PSA progression-free survival (PSA-PFS). Results: The KMT2C mutation rate in this cohort is 7.24% (16/221). KMT2C-mutated patients showed worse survival than KMT2C-wild type (WT) patients regarding both CRFS and OS (CRFS: mutated: 9.9 vs. WT: 22.0 months, p = 0.015; OS: mutated: 71.9 vs. WT 137.4 months, p = 0.012). KMT2C mutations were also an independent risk factor in OS [hazard ratio: 3.815 (1.461, 9.96), p = 0.006] in multivariate analyses. Additionally, we explored the association of KMT2C mutations with other genes. This showed that KMT2C mutations were associated with Serine/Threonine-Protein Kinase 11 (STK11, p = 0.004) and Catenin Beta 1 (CTNNB1, p = 0.008) mutations. In the CAB treatment, KMT2C-mutated patients had a significantly shorter PSA-PFS compared to KMT2C-WT patients. (PSA-PFS: mutated: 9.9 vs. WT: 17.6 months, p = 0.014). Moreover, KMT2C mutations could effectively predict shorter PSA-PFS in 10 out of 23 subgroups and exhibited a strong trend in the remaining subgroups. Conclusions: KMT2C-mutated patients showed worse survival compared to KMT2C-WT patients in terms of both CRFS and OS, and KMT2C mutations were associated with STK11 and CTNNB1 mutations. Furthermore, KMT2C mutations indicated rapid progression during CAB therapy and could serve as a potential biomarker to predict therapeutic response in prostate cancer.

The prognostic value of the pretreatment lung immune prognostic index in patients with metastatic hormone-sensitive and castration-resistant prostate cancer.

Background: The lung immune prognostic index (LIPI) was first reported to predict the effectiveness of immune checkpoint inhibitors in patients with metastatic non-small cell lung cancer and there are no studies investigating the predictive value of LIPI for patients with PCa. This study explores the prognostic value of the LIPI in patients with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). Methods: Data from 502 patients with mHSPC primarily treated with maximal androgen blockade (MAB; 89% of patients received MAB) and 158 patients with mCRPC who received abiraterone were retrospectively analyzed. All cases were classified into LIPI-good, LIPI-intermediate, and LIPI-poor groups based on their LIPI score as calculated with the derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase level. The potential for LIPI to be used in predicting mCRPC-free survival (CFS), prostate-specific antigen (PSA) response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) was analyzed. A propensity score matching (PSM) methodology was performed to balance the baseline factors of the different groups. Results: In the mHSPC cohort, patients of the LIPI-good (mCFS: 25.7 months; mOS: 93.3 months), LIPI-intermediate (mCFS: 14.8 months; mOS: 51.9 months), and LIPI-poor group (mCFS: 6.8 months; mOS: 18.5 months) had sequentially worse clinical outcomes (P<0.001 for all pairwise comparisons). The results remained consistent after PSM. Multivariate Cox regression further confirmed that LIPI was an independent predictor of survival outcomes. Subgroup analysis verified that LIPI was associated with an unfavorable prognosis in all subgroups except for cases with visceral metastases or those receiving abiraterone or docetaxel. As for patients with mCRPC receiving abiraterone, LIPI was also an indicator of poor prognosis. Specifically, cases in the LIPI-good, LIPI-intermediate, and LIPI-poor groups had a ladder-shaped worse PSA response [71.4% (50/70) vs. 56.5% (39/69) vs. 36.8% (7/19); P=0.015], PSA-PFS (14.9 vs. 9.3 vs. 3.1 months; P<0.001), and OS (14.6 vs. 32.3 vs. 53.4 months; P<0.001). The results were robust even after PSM. Multivariate Cox regression confirmed that LIPI was an independent prognosticator of PSA-PFS and OS in patients with mCRPC treated with abiraterone. Conclusions: This study demonstrated that the baseline LIPI was a significant prognostic biomarker for patients with both mHSPC and mCRPC and could potentially facilitate risk classification and clinical decision-making.

Multidisciplinary Team (MDT) Discussion Improves Overall Survival Outcomes for Metastatic Renal Cell Carcinoma Patients.

Purpose: Multidisciplinary team (MDT) discussion is a widely used model to manage patients diagnosed with cancer. However, there has been no direct evidence to prove its effect on the prognosis of metastatic renal cell carcinoma (mRCC) patients, so this study explored the impact of MDT discussion on mRCC patient survival. Methods: The clinical data of 269 mRCC patients were retrospectively collected from 2012 to 2021. The cases were grouped into the MDT and non-MDT groups, then subgroup analysis was performed according to different histology types, as well as exploring the role of MDT in patients who have undergone multiple-line therapy. Overall survival (OS) and progression free survival (PFS) were set as the study endpoint. Results: Approximately half (48.0%, 129/269) of the patients were in the MDT group, with univariable survival analyses showing these patients had remarkably longer median OS (MDT group: 73.7 months; non-MDT group: 33.2 months, hazard ratio (HR): 0.423 (0.288, 0.622), p<0.001) and longer median PFS (MDT group: 16.9 months, non-MDT group: 12.7 months, HR: 0.722 (0.542, 0.962), p=0.026). Furthermore, MDT management resulted in longer survival for both ccRCC and non-ccRCC subgroups. Patients in the MDT group were more likely to receive multi-line therapy (MDT group: 79/129, 61.2% vs non-MDT group: 56/140, 40.0%, p<0.001), and within this patient group, MDT management still resulted in longer OS (MDT group: 94.0 months; non-MDT group: 43.5 months, p=0.009). Conclusion: MDT is associated with prolonged overall survival in mRCC independent of histology, ensuring that patients receive better management and precise treatment.

Neuroendocrine differentiation predicts the therapeutic efficacy of abiraterone and docetaxel as first-line therapy in metastatic castration-resistant prostate cancer.

PURPOSE: We aim to explore the predictive value of neuroendocrine differentiation (NED) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone or docetaxel as first-line therapy. METHODS: We retrospectively analyzed data of 262 mCRPC patients receiving abiraterone or docetaxel as first-line mCRPC treatment. NED was evaluated using prostate biopsy samples at the time of mCRPC by immunohistochemical staining. Kaplan-Meier curves and Cox regression were used to assess the association between NED and treatment outcomes including PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS). RESULTS: NED was confirmed in 100/262 (38.2%) mCRPC patients, with 76/100 (76.0%) and 24/100 (24.0%) men harboring NED < 10% and NED ≥ 10%, respectively. 203/262 (77.5%) and 59/262 (22.5%) patients received abiraterone and docetaxel, respectively. In abiraterone treatment, NED was associated with a significantly shorter median PSA-PFS (mPSA-PFS, 7.5 vs. 10.3-Mo, P < 0.001), median rPFS (mrPFS, 15.9 vs. 19.5-Mo, P = 0.010), and median OS (mOS, 23.2 vs. 34.3-Mo, P = 0.014)). Likewise, for mCRPC patients receiving docetaxel, the positive detection of NED also predicted shorter mPSA-PFS (3.8 vs. 5.9-Mo, P = 0.052), mrPFS (8.4 vs. 20.4-Mo, P = 0.016) and mOS (13.6 vs. 29.0-Mo, P = 0.033). The adverse prognostic trait of NED is consistent in most subgroups. Additionally, patients' survival outcomes deteriorated as the NED proportion grew in both therapies. After propensity score matching, NED-positive patients showed comparable prognosis in abiraterone and docetaxel therapy. CONCLUSION: For mCRPC patients receiving abiraterone or docetaxel, NED and its proportion were critical predictive factors. NED detection at mCRPC might aid in predicting patients' outcomes and optimizing treatment decisions.

Regional location of lymph node metastases predicts survival in patients with de novo metastatic prostate cancer.

To report the regional locations of metastases and to estimate the prognostic value of the pattern of regional metastases in men with metastatic hormone-sensitive prostate cancer (mHSPC), we retrospectively analyzed 870 mHSPC patients between November 28, 2009, and February 4, 2021, from West China Hospital in Chengdu, China. The patients were initially classified into 5 subgroups according to metastatic patterns as follows: simple bone metastases (G1), concomitant bone and regional lymph node (LN) metastases (G2), concomitant bone and nonregional LN (NRLN) metastases (G3), lung metastases (G4), and liver metastases (G5). In addition, patients in the G3 group were subclassified as G3a and G3b based on the LN metastatic plane (below or above the diaphragm, respectively). The associations of different metastatic patterns with castration-resistant prostate cancer-free survival (CFS) and overall survival (OS) were analyzed by univariate and multivariate analyses. The results showed that patients in G1 and G2 had relatively favorable clinical outcomes, patients in G3a and G4 had intermediate prognoses, and patients in G3b and G5 had the worst survival outcomes. We observed that patients in G3b had outcomes comparable to those in G5 but had a significantly worse prognosis than patients in G3a (median CFS: 8.2 months vs 14.3 months, P = 0.015; median OS: 38.1 months vs 45.8 months, P = 0.038). In conclusion, metastatic site can predict the prognosis of patients with mHSPC, and the presence of concomitant bone and NRLN metastases is a valuable prognostic factor. Furthermore, our findings indicate that the farther the NRLNs are located, the more aggressive the disease is.

The therapeutic efficacy of radical prostatectomy and external beam radiation therapy in patients with different pathological patterns of prostate cancer.

BACKGROUND: We aim to investigate the prognostic value of different pathological patterns of non-adenocarcinoma prostate cancers (PCa) in radical prostatectomy (RP) and external beam radiation therapy (EBRT). METHODS: Data of 470,258 localized PCa patients between 2004 and 2016 were collected from the Surveillance, Epidemiology, and End Results database. Propensity score matching was performed to balance the baseline characteristics of patients in different groups. Kaplan-Meier curves and Cox regression were used for survival analysis. Overall survival (OS) and cancer-specific survival (CSS) were set as endpoints. RESULTS: Totally, 1044 patients with non-adenocarcinoma patterns of PCa were included. Patients with small cell neuroendocrine carcinoma (SCNC) and neuroendocrine differentiation (NED) harbored the worst prognosis in both RP and EBRT among all pathological groups. RP exhibited superior effects to EBRT for this group of cases. Ductal carcinoma (DA) was also related to poorer survival outcomes versus PAC in both local therapies. Yet, for men with DA, both RP and EBRT still improved patients' prognosis against no local therapy (NLT), with RP being the superior modality. Cases harboring mucinous adenocarcinoma (MA) and signet ring cell carcinoma (SRCC) shared comparable clinical outcomes to men with PAC. However, for cases with MA, neither RP nor EBRT was related to better survival outcomes against NLT, while for patients with SRCC, both RP and EBRT prolonged patients' survival with similar effects. CONCLUSIONS: Our study provided a comprehensive view of the treatment effect of RP and EBRT in non-adenocarcinoma PCa patients. These findings could facilitate clinicians in making therapeutic decision-making for non-adenocarcinoma patients.

Chronological Liquid Biopsy Reveals the Impact of Platinum-Based Chemotherapy on a Prostate Cancer Patient's CDK12 Mutation: A Case Report.

CDK12 (Cyclin-Dependent Kinase 12)-mutated prostate cancer patients often respond badly to current therapies. Immunotherapy and platinum-based chemotherapy are recommended based on the molecular features of CDK12-mutated tumors, but the reported patient outcomes are still unsatisfying. Here we report a prostate cancer patient with CDK12 somatic mutation who received multiple therapy options, including platinum-based chemotherapy and immunotherapy. His sequential circulating tumor DNA (ctDNA) -based liquid biopsy tests showed that his original CDK12 mutation fell undetectable twice. This phenomenon was observed only when he was responding well to platinum-based chemotherapy. His responses to immunotherapy were not satisfying. This case indicates that platinum-based chemotherapy can be a good option for treating patients with CDK12 mutation. More importantly, dynamic ctDNA-based liquid biopsies to monitor patients' CDK12 mutation status are critical in evaluating patients' response and tolerance during platinum-based chemotherapy, therefore may lead to a better overall prognosis. In conclusion, CDK12-mutated prostate cancer patients are likely to benefit from platinum-based chemotherapy, especially with the help of dynamic ctDNA-based liquid biopsies to monitor their CDK12 mutation status.

Plasma Exosomal AKR1C3 mRNA Expression Is a Predictive and Prognostic Biomarker in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Aldo-keto reductase family 1 member C3 (AKR1C3) is important in prostate cancer progression, being a potential biomarker in metastatic castration-resistant prostate cancer (mCRPC). Previous explorations of AKR1C3 are mainly based on tissue samples. This study investigates using plasma-based liquid biopsy to validate the prognostic and predictive value of AKR1C3 in patients with mCRPC . MATERIALS AND METHODS: We prospectively recruited 62 patients with mCRPC. All patients received repeated prostate biopsies at the time of mCRPC diagnosis, and immunohistochemistry (IHC) staining was used to detect protein expression of AKR1C3 in the tissues. We took their blood simultaneously and performed digital droplet polymerase chain reaction (ddPCR) to measure expression levels of AKR1C3 in the exosomes. The detected plasma and tissue AKR1C3 expression levels were analyzed for patients' overall survival (OS) and progression-free survival under first-line abiraterone use (ABI-PFS). RESULTS: All other baseline characteristics were balanced between the 2 groups. 15/62 (24.2%) and 25/62 (40.3%) patients showed AKR1C3-EXO positive (≥20 copies/20 µL) and AKR1C3-IHC positive, respectively. Positive AKR1C3-EXO expression was associated with decreased patients' survival [ABI-PFS: 3.9 vs 10.1 months, P < .001; OS: 16.2 vs 32.5 months, P < .001]. AKR1C3-IHC positivity was also correlated with ABI-PFS and OS (P = .010, P = .016). In patients with worse baseline blood tests (including higher alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) level and lower hemoglobin (HB) level), and lower ISUP/WHO group (<4), their OS was significantly worse when showing AKR1C3-EXO positive. CONCLUSION: AKR1C3-EXO is associated with patient prognosis regarding OS and ABI-PFS and can be used as a biomarker in mCRPC.

The tumor-repressing effect of CYP27A1 on renal cell carcinoma by 27-HC arising from cholesterol metabolism.

As a key approach to mediate cholesterol metabolism, the role of the CYP27A1/27-HC axis in renal cell carcinoma (RCC) remains unclear. Analysis of CYP27A1 expression from public databases and metastatic cases in our center suggested that CYP27A1 was obviously downregulated in RCC tissues, and survival analysis further showed its correlation with favorable clinicopathological features and prognosis. In vitro, up and downregulation of CYP27A1 expression in RCC cell lines could definitely illustrate its anticipation involving apoptosis, proliferation, invasion, migration, and clonality. This could be achieved through upregulation of 27-HC concentration, which mediates the activation of signaling pathways of apoptosis and cell cycle arrest. Further, recovery of CYP27A1 expression could definitely inhibit the proliferation of RCC tumors in vivo. This is the first study to explore the role of the CYP27A1/27-HC axis in RCC. Attempts to maintain the normal function of the axis may be a potential strategy in the treatment of RCC, and the predictive value of CYP27A1 detection on the efficacy of targeted therapy in metastatic RCC is also worthy of attention.

Integrated multi-omics analyses reveal that BCAM is associated with epigenetic modification and tumor microenvironment subtypes of clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common and highly heterogeneous subtype of renal cell carcinoma. Dysregulated basal cell adhesion molecule (BCAM) gene is associated with poor prognosis in various cancers. However, the dysregulated functions and related multi-omics features of BCAM in ccRCC stay unclear. RESULTS: BCAM expression was aberrantly downregulated in ccRCC and correlated with adverse pathological parameters and poor prognosis. Low mRNA expression of BCAM was remarkably associated with its CpG methylation levels and BAP1 mutation status. Patients with lower-expressed BCAM concomitant with BAP1 mutation had a worse prognosis. Using RNA-seq data from The cancer genome atlas, we found that compared to the BCAM-high expression subgroup, ccRCC patients in the BCAM-low expression subgroup had significantly higher levels of immune infiltration, higher immune checkpoint expression levels and lower TIDE (tumor immune dysfunction and exclusion) score, indicating potential better response to immunotherapy. Data from the Clinical Proteomic Tumor Analysis Consortium further validated the association between low BCAM expression and CD8 + inflamed phenotype at protein level. Meanwhile, our results suggested that the angiogenesis-related pathways were enriched in the BCAM-high expression subgroup. More importantly, according to the data from the GDSC database, we revealed that the BCAM-high expression subgroup should be more sensitive to anti-angiogenetic therapies, including sorafenib, pazopanib and axitinib. CONCLUSIONS: These results suggest that BCAM could serve as a biomarker distinguishing different tumor microenvironment phenotypes, predicting prognosis and helping therapeutic decision-making for patients with ccRCC.

Homologous recombination deficiency (HRD) score in aggressive prostatic adenocarcinoma with or without intraductal carcinoma of the prostate (IDC-P).

BACKGROUND: Intraductal carcinoma of the prostate (IDC-P) is a subtype of prostate cancer featured by poor prognosis. Previous studies suggested IDC-P could have a potentially unstable genome. Homologous recombination deficiency (HRD) score is a result-oriented method to describe the genomic instability status. This study investigates the association of HRD scores with IDC-P and other clinicopathological factors and the prognostic implication of HRD scores in an aggressive prostate cancer cohort. METHODS: This study involved 123 PCa patients, including high-risk localized (M0) and de novo metastatic (M1) diseases. HRD score is calculated based on over 10,000 single-nucleotide polymorphisms distributed across the human genome. We explored the association between HRD scores and clinicopathological characteristics, genomic alterations, and patients' prognoses using rank-sum tests, chi-square tests, Kaplan-Meier curves, and Cox proportional hazards method. RESULTS: The median HRD score of this cohort is 21.0, with 65 (52.8%) patients showing HRD score≥21. Tumors with IDC-P displayed higher HRD scores than adenocarcinoma (P=0.002); other high HRD score-related factors included M1 (P =0.008) and high ISUP grades (4-5) (P=0.001). MYC mutations were associated with high HRD scores (P<0.001) in the total cohort. TP53 mutations (P=0.010) and HRR pathway mutations (P=0.028) corresponded to high HRD scores in IDC-P positive and non-IDC-P patients, respectively, but not vice versa. HRD scores higher than 21 indicated significantly worse survival in the total cohort. CONCLUSIONS: M1, high Gleason score, and IDC-P pathology represent higher HRD scores in PCa. Tumors with IDC-P might have different driven mechanisms for high HRD scores than non-IDC-P. HRD score displayed prognostic value in this aggressive prostate cancer cohort.

Predictors of efficacy of corticosteroid switching from abiraterone plus prednisone to dexamethasone in patients with metastatic castration-resistant prostate cancer.

Corticosteroid switching can reverse abiraterone resistance in some patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we investigated the potential biomarkers for predicting the efficacy of corticosteroid switching during treatment with abiraterone acetate (AA). We retrospectively analyzed 101 mCRPC patients receiving corticosteroid switching from West China Hospital and Sun Yat-Sen University Cancer Center between January 2016 and December 2018. All cases received AA plus prednisone as first-line therapy during mCRPC. Primary end points were biochemical progression-free survival (bPFS) and overall survival (OS). The risk groups were defined based on multivariate analysis. A total of 42 (41.6%) and 25 (24.8%) patients achieved 30% and 50% decline in prostate-specific antigen (PSA), respectively, after corticosteroid switching. The median bPFS and median OS on AA plus dexamethasone were 4.9 (95% confidence interval [CI]: 3.7-6.0) months and 18.8 (95% CI: 16.2-30.2) months, respectively. Aldo-keto reductase family 1 member C3 (AKR1C3) expression (hazard ratio [HR]: 2.15, 95% Cl: 1.22-3.80, P = 0.008) and baseline serum alkaline phosphatase (ALP; HR: 4.95, 95% Cl: 2.40-10.19, P < 0.001) were independent predictors of efficacy before corticosteroid switching in the multivariate analysis of bPFS. Only baseline serum ALP >160 IU l-1 (HR: 3.41, 95% Cl: 1.57-7.38, P = 0.002) together with PSA level at switch ≥50 ng ml-1 (HR: 2.59, 95% Cl: 1.22-5.47, P = 0.013) independently predicted poorer OS. Based on the predictive factors in multivariate analysis, we developed two risk stratification tools to select candidates for corticosteroid switching. Detection of serum ALP level, PSA level, and tissue AKR1C3 expression in mCRPC patients could help make clinical decisions for corticosteroid switching.

Circulating tumour DNA reveals genetic traits of patients with intraductal carcinoma of the prostate.

OBJECTIVES: To investigate the genetic alterations of patients with prostate cancer (PCa) with and without intraductal carcinoma of the prostate (IDC-P). PATIENTS AND METHODS: We performed targeted sequencing of plasma cell-free DNA on 161 patients with prostate adenocarcinoma (PAC) with IDC-P and 84 without IDC-P. Genomic alterations were compared between these two groups. The association between genetic alterations and patients' survival outcomes was also explored. RESULTS: We identified that 29.8% (48/161) and 21.4% (18/84) of patients with and without IDC-P harboured genomic alterations in DNA repair pathways, respectively (P = 0.210). Pathogenic germline DNA repair alterations were frequently detected in IDC-P carriers compared to IDC-P non-carriers (11.8% [19/161] vs 2.4% [two of 84], P = 0.024). Germline BReast CAncer type 2 susceptibility protein (BRCA2) and somatic cyclin-dependent kinase 12 (CDK12) defects were specifically identified in IDC-P carriers relative to PAC (BRCA2: 8.7% [14/161] vs 0% and CDK12: 6.8% [11/161] vs 1.2% [one of 84]). Patients with IDC-P had a distinct androgen receptor (AR) pathway alteration, characterised by an enrichment of nuclear receptor corepressor 2 (NCOR2) mutations compared with patients with pure PAC (21.1% [34/161] vs 6.0% [five of 84], P = 0.004). Increased AR alterations were detected in patients harbouring tumours with an IDC-P proportion of ≥10% vs those with an IDC-P proportion of <10% (6.4% [five of 78] vs 18.1% [15/83], P = 0.045). For IDC-P carriers, tumour protein p53 (TP53) mutation was associated with shorter castration-resistant-free survival (median 10.9 vs 28.9 months, P = 0.026), and BRCA2 alteration was related to rapid prostate-specific antigen progression for those receiving abiraterone treatment (median 9.1 vs 11.9 months, P = 0.036). CONCLUSION: Our findings provide genomic evidence explaining the aggressive phenotype of tumours with IDC-P, highlighting the potential therapeutic strategies for this patient population.

Inherited Mutations in Chinese Men With Prostate Cancer.

BACKGROUND: Although China accounts for 7.8% of worldwide new prostate cancer (PCa) cases and 14.5% of new deaths according to GLOBOCAN 2020, the risk of PCa associated with germline mutations is poorly defined, hampered in part by lack of nationwide evidence. Here, we sequenced 19 PCa predisposition genes in 1,836 Chinese patients with PCa and estimated disease risk associated with inherited mutations. PATIENTS AND METHODS: Patients were recruited from 4 tertiary cancer centers (n=1,160) and a commercial laboratory (n=676). Germline DNA was sequenced using a multigene panel, and pathogenic/likely pathogenic (P/LP) mutation frequencies in patients with PCa were compared with populations from the gnomAD (Genome Aggregation Database) and ChinaMAP (China Metabolic Analytics Project) databases. Clinical characteristics and progression-free survival were assessed by mutation status. RESULTS: Of 1,160 patients from hospitals, 89.7% had Gleason scores ≥8, and 65.6% had metastases. P/LP mutations were identified in 8.49% of Chinese patients with PCa. Association with PCa risk was significant for mutations in ATM (odds ratio [OR], 5.9; 95% CI, 3.1-11.1), BRCA2 (OR, 15.3; 95% CI, 10.0-23.2), MSH2 (OR, 15.8; 95% CI, 4.2-59.6), and PALB2 (OR, 5.9; 95% CI, 2.7-13.2). Compared with those without mutations, patients with mutations in ATM, BRCA2, MSH2, or PALB2 showed a poor outcome with treatment using androgen deprivation therapy and abiraterone (hazard ratio, 2.19 [95% CI, 1.34-3.58] and 2.47 [95% CI, 1.23-4.96], respectively) but similar benefit from docetaxel. CONCLUSIONS: The present multicenter study confirmed that a significant proportion of Chinese patients with PCa had inherited mutations and identified predisposition genes in this underreported ethnicity. These data provide empirical evidence for precision prevention and prognostic estimation in Chinese patients with PCa.

Efficacy and Safety of Individualized Schedule of Sunitinib by Drug Monitoring in Patients with Metastatic Renal Cell Carcinoma.

PURPOSE: To investigate the survival benefit and safety of individualized schedules for sunitinib in patients with metastatic renal cell carcinoma (mRCC) through plasma concentration monitoring. METHODS: A total of 105 patients with mRCC were enrolled. The schedule was adjusted in two ways: therapeutic drug monitoring (TDM) and toxicity-adjusted schedule (TAS). One group of patients were without any schedule adjustment (maintained schedule, MAS). Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were compared. The relationship between AEs and steady-state concentration or consecutive monitoring curves was explored. Further monitoring of individualized schedules was also conducted. RESULTS: Based on the plasma concentration, the schedules of 18 patients were adjusted in the TDM group. The schedules were adjusted in 37 patients due to severe AEs in the TAS group, while 50 patients were without any schedule adjustment. The median PFS and OS were better in the TDM group than the other two groups (p = 0.001 and p = 0.004, respectively). Univariate and multivariate analyses indicated that TDM could decrease the risk of death independently (p = 0.026). Moreover, the incidence of grades 3/4 AEs decreased from 88.9% to 33.3% in the TDM group (p = 0.001). Sunitinib concentration in 150-200ng/mL was regarded as a "transitional zone" due to severe AEs mainly happened when concentration elevated over it. After TDM, further plasma concentration monitoring indicated that individualized schedules enabled sunitinib concentration to fluctuate in a much safer range. CONCLUSION: Treatment-related toxicities could be minimized through plasma concentration monitoring. Patients with adjusted schedules by therapeutic drug monitoring could achieve better survival benefits.