Newly developed preclinical models reveal broad-spectrum CDK inhibitors as potent drugs for CRPC exhibiting primary resistance to enzalutamide.

Androgen-deprivation therapy is a standard treatment for advanced prostate cancer. However, most patients eventually acquire resistance and progress to castration-resistant prostate cancer (CRPC). In this study, we established new CRPC cell lines, AILNCaP14 and AILNCaP15, from LNCaP cells under androgen-deprived conditions. Unlike most pre-existing CRPC cell lines, both cell lines expressed higher levels of androgen receptor (AR) and prostate-specific antigen (PSA) than parental LNCaP cells. Moreover, these cells exhibited primary resistance to enzalutamide. Since AR signaling plays a significant role in the development of CRPC, PSA promoter sequences fused with GFP were introduced into AILNCaP14 cells to conduct GFP fluorescence-based chemical screening. We identified flavopiridol, a broad-spectrum CDK inhibitor, as a candidate drug that could repress AR transactivation of CRPC cells, presumably through the inhibition of phosphorylation of AR on the serine 81 residue (pARSer81 ). Importantly, this broad-spectrum CDK inhibitor inhibited the proliferation of AILNCaP14 cells both in vitro and in vivo. Moreover, a newly developed liver metastatic model using AILNCaP15 cells revealed that the compound attenuated tumor growth of CRPC harboring highly metastatic properties. Finally, we developed a patient-derived xenograft (PDX) model of CRPC and DCaP CR from a patient presenting therapeutic resistance to enzalutamide, abiraterone, and docetaxel. Flavopiridol successfully suppressed the tumor growth of CRPC in this PDX model. Since ARSer81 was found to be phosphorylated in clinical CRPC samples, our data suggested that broad-spectrum CDK inhibitors might be a potent candidate drug for the treatment of CRPC, including those exhibiting primary resistance to enzalutamide.

Phase 1b study of enzalutamide plus CC-115, a dual mTORC1/2 and DNA-PK inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC).

BACKGROUND: CC-115, a dual mTORC1/2 and DNA-PK inhibitor, has promising antitumour activity when combined with androgen receptor (AR) inhibition in pre-clinical models. METHODS: Phase 1b multicentre trial evaluating enzalutamide with escalating doses of CC-115 in AR inhibitor-naive mCRPC patients (n = 41). Primary endpoints were safety and RP2D. Secondary endpoints included PSA response, time-to-PSA progression, and radiographic progression. RESULTS: Common adverse effects included rash (31.7% Grades 1-2 (Gr); 31.7% Gr 3), pruritis (43.9% Gr 1-2), diarrhoea (37% Gr 1-2), and hypertension (17% Gr 1-2; 9.8% Gr 3). CC-115 RP2D was 5 mg twice a day. In 40 evaluable patients, 80% achieved ≥50% reduction in PSA (PSA50), and 58% achieved ≥90% reduction in PSA (PSA90) by 12 weeks. Median time-to-PSA progression was 14.7 months and median rPFS was 22.1 months. Stratification by PI3K alterations demonstrated a non-statistically significant trend towards improved PSA50 response (PSA50 of 94% vs. 67%, p = 0.08). Exploratory pre-clinical analysis suggested CC-115 inhibited mTOR pathway strongly, but may be insufficient to inhibit DNA-PK at RP2D. CONCLUSIONS: The combination of enzalutamide and CC-115 was well tolerated. A non-statistically significant trend towards improved PSA response was observed in patients harbouring PI3K pathway alterations, suggesting potential predictive biomarkers of response to a PI3K/AKT/mTOR pathway inhibitor. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02833883.

Impact of prostate position-based image-guidance in intensity-modulated radiation therapy for localized prostate cancer.

BACKGROUND/PURPOSE: The long-term clinical impact of prostate position-based image-guided radiotherapy (IGRT) for localized prostate cancer remains unclear. MATERIALS AND METHODS: We retrospectively compared clinical outcomes following intensity-modulated radiation therapy (IMRT) with cone-beam computed tomography-based prostate position-based IGRT (P-IGRT) or without P-IGRT (non-P-IGRT). From June 2011, we applied P-IGRT in IMRT for intermediate-risk (IR) prostate cancer (PCa) (D'Amico risk classification) (76 Gy in 38 fractions, with smaller margins). Clinical outcomes of patients who received P-IGRT between June 2011 and June 2019 were retrospectively compared with those of patients with IR PCa who received IMRT without P-IGRT between October 2002 and May 2011 in our institution (74 Gy in 37 fractions). RESULTS: A total of 222 consecutive patients were analyzed: 114 in the P-IGRT cohort and 108 in the non-P-IGRT cohort. The median follow-up period after IMRT was 7.1 years for the P-IGRT cohort and 10.8 years for the non-P-IGRT cohort. The biochemical failure-free rate was significantly better in the P-IGRT cohort (94.9% for the P-IGRT cohort vs 82.7% for the non-P-IGRT cohort at 10 years, p = 0.041). The rate of rectal bleeding which needs intervention including the use of suppositories was significantly lower in the P-IGRT cohort (p < 0.001). CONCLUSIONS: The use of P-IGRT with higher doses and smaller margins was correlated with significantly better biochemical control, and a lower incidence of rectal bleeding in IMRT for intermediate-risk prostate cancer. The enhanced accuracy using P-IGRT has the potential to independently improve disease control and reduce late rectal bleeding.

Clinical factors predicting the outcome of salvage radiotherapy for patients with biochemical recurrence after radical prostatectomy.

BACKGROUND: It remains unclear which patients with biochemical recurrence after prostatectomy are most suitable for salvage radiotherapy. We evaluated the parameters related to outcomes. METHODS: We retrospectively evaluated patients who underwent salvage therapy for biochemical recurrence after prostatectomy between 2005 and 2019. This study aimed to evaluate biochemical recurrence-free survival (bRFS) after salvage radiotherapy and elucidate the parameters associated with bRFS. The bRFS rate was calculated using the Kaplan-Meier method, and the parameters associated with bRFS were evaluated using Cox regression analysis. RESULTS: This study included 67 patients treated with salvage radiotherapy with a median age of 67 years at salvage radiotherapy. The median follow-up period after salvage radiotherapy was 7.3 years. The 5-year bRFS rate following salvage radiotherapy was 47.1%. Univariate analysis showed that PSA doubling time < 6 months, positive surgical margin, and pathological Gleason score ≥ 8 were significantly associated with shorter bRFS (p < 0.001, p = 0.036, p = 0.047, respectively). Multivariable analysis showed that a PSA doubling time < 6 months and positive surgical margins were significantly associated with shorter bRFS (p = 0.001 and p = 0.018, respectively). No serious adverse events were observed. CONCLUSIONS: In our hospital, approximately half of the patients are under long-term control with salvage radiotherapy. A PSA doubling time of < 6 months and positive surgical margins were suggested to be associated with poor outcomes of salvage radiotherapy.

Prostate cancer and liquid biopsies: Clinical applications and challenges.

Liquid biopsy has emerged as a valuable and minimally invasive tool for real-time detection of clinically actionable abnormalities across various cancer types. Its applicability is particularly compelling in the realm of prostate cancer, where novel therapeutic agents, including those targeting DNA repair systems, are under development. Despite these advancements, challenges persist in effectively screening for prostate cancer, enhancing risk stratification, and determining optimal approaches for treating advanced disease. Consequently, there is a pressing need for improved biomarkers to aid clinicians in decision-making within these contexts. Cell-free DNA and extracellular vesicle analysis have demonstrated promise in diagnosis, prognostication, assessment of treatment responses, and identification of emerging mechanisms of resistance. Nevertheless, obstacles must be addressed before liquid biopsies can be integrated into routine clinical practice. These challenges encompass preanalytical considerations such as sample collection and storage, methods of extracellular vesicle isolation and enrichment, and the need for enhanced interpretation of generated sequencing data. This review provides a comprehensive overview of current clinical opportunities in managing prostate cancer through blood-based liquid biopsy, highlighting the progress made, and acknowledging the challenges that remain. Additionally, we discuss the next steps required for the effective implementation of liquid biopsies in guiding personalized treatment strategies for prostate cancer.

Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer.

BACKGROUND: The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial. METHODS: Germline DNA from 549 Japanese men with metastatic and/or castration-resistant PCa was sequenced for 27 cancer-predisposing genes. The associations between pathogenic variants and clinical outcomes were examined. Further, for comparison, DNA from prostate biopsy tissue samples from 80 independent patients with metastatic PCa were analysed. RESULTS: Forty-four (8%) patients carried germline pathogenic variants in one of the analysed genes. BRCA2 was most frequently altered (n = 19), followed by HOXB13 (n = 9), PALB2 (n = 5) and ATM (n = 5). Further, the BRCA1, BRCA2, PALB2 and ATM variants showed significant association with a short time to castration resistance and overall survival (hazard ratio = 1.99 and 2.36; 95% CI, 1.15-3.44 and 1.23-4.51, respectively), independent of other clinical variables. Based on log-rank tests, the time to castration resistance was also significantly short in patients with BRCA1, BRCA2, PALB2 or ATM somatic mutations and TP53 mutations. CONCLUSIONS: Germline variants in BRCA1, BRCA2, PALB2 or ATM are independent prognostic factors of the short duration of response to hormonal therapy in advanced PCa.

Detection of von Hippel-Lindau gene mutation in circulating cell-free DNA for clear cell renal cell carcinoma.

The therapeutic landscape of metastatic clear cell renal cell carcinoma (ccRCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy or evaluate the response in real time. To evaluate the clinical utility of circulating tumor DNA (ctDNA) analysis in ccRCC, we established a highly sensitive assay to detect mutations in von Hippel-Lindau gene (VHL) using a combination of digital PCR and multiplex PCR-based targeted sequencing. The unique assay could detect VHL mutations with a variant allele frequency (VAF) <1.0%. Further, we profiled the mutation status of VHL in 76 cell-free DNA (cfDNA) and 50 tumor tissues from 56 patients with ccRCC using the assay. Thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%-4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%-2.88%). In serial ctDNA analysis from one patient, we confirmed that the VAF of VHL mutation changed consistent with tumor size by radiographic imaging during systemic treatment. In conclusion, VHL mutation in cfDNA was detected only in a small number of patients even using the highly sensitive assay; nevertheless, we showed the potential of ctDNA analysis as a novel biomarker in ccRCC.

Establishment and characterization of a novel treatment-related neuroendocrine prostate cancer cell line KUCaP13.

The prevalence of neuroendocrine prostate cancer (NEPC) arising from adenocarcinoma (AC) upon potent androgen receptor (AR) pathway inhibition is increasing. Deeper understanding of NEPC biology and development of novel therapeutic agents are needed. However, research is hindered by the paucity of research models, especially cell lines developed from NEPC patients. We established a novel NEPC cell line, KUCaP13, from tissue of a patient initially diagnosed with AC which later recurred as NEPC. The cell line has been maintained permanently in vitro under regular cell culture conditions and is amenable to gene engineering with lentivirus. KUCaP13 cells lack the expression of AR and overexpress NEPC-associated genes, including SOX2, EZH2, AURKA, PEG10, POU3F2, ENO2, and FOXA2. Importantly, the cell line maintains the homozygous deletion of CHD1, which was confirmed in the primary AC of the index patient. Loss of heterozygosity of TP53 and PTEN, and an allelic loss of RB1 with a transcriptomic signature compatible with Rb pathway aberration were revealed. Knockdown of PEG10 using shRNA significantly suppressed growth in vivo. Introduction of luciferase allowed serial monitoring of cells implanted orthotopically or in the renal subcapsule. Although H3K27me was reduced by EZH2 inhibition, reversion to AC was not observed. KUCaP13 is the first patient-derived, treatment-related NEPC cell line with triple loss of tumor suppressors critical for NEPC development through lineage plasticity. It could be valuable in research to deepen the understanding of NEPC.

The association between missense polymorphisms in SRD5A2 and HSD3B1 and treatment failure with abiraterone for castration-resistant prostate cancer.

Missense polymorphism in HSD3B1, encoding 3ß-hydroxysteroid dehydrogenase-1, was associated with outcome after abiraterone treatment. Other androgen-metabolizing enzymes may be involved in therapeutic effect in abiraterone. In this study, we investigated the significance of polymorphisms in genes involved in androgen and abiraterone metabolisms in prostate cancer patients treated with abiraterone. A total of 99 Japanese male castration-resistant prostate cancer patients treated with abiraterone between 2014 and 2018 were included. Genomic DNA was obtained from whole blood samples, and genotyping on SRD5A2 (rs523349), CYP17A1 (rs743572), CYP17A1 (rs2486758), and AKR1C3 (rs12529) was performed by PCR-based technique. Among the 99 patients, 32 (32.3%), 49 (49.5%), and 18 patients (18.2%) carried GG, GC, and CC alleles in SRD5A2, respectively. CC allele was associated with lower risk of treatment failure (hazard ratio, 0.43; 95% confidence interval, 0.20-0.87; P = 0.017) on multivariate analyses, compared with GG/GC alleles. In the combination model using HSD3B1 and SRD5A2 polymorphisms, compared with the combination of AA in HSD3B1 and GG/GC in SRD5A2, other combinations were associated with lower risk of treatment failure (hazard ratio, 0.34; 95% confidence interval, 0.17-0.62; P = 0.0003) on multivariate analyses. This study showed that SRD5A2 genetic variation was associated with the risk of treatment failure in abiraterone. Combinational use of genetic variation in HSD3B1 with SRD5A2 genetic variation augmented the ability of prognostic stratification.

[The Clinical Utility of Liquid Biopsies as Biomarkers in Metastatic Prostate Cancer].

With increasing treatment options for metastatic prostate cancer(mPC), there is a growing attention to circulating tumor cells(CTC)and circulating tumor DNA(ctDNA)as minimally invasive biomarkers to facilitate precision medicine. CTC count and ctDNA abundance have been reported to be prognostic factors. In addition, on-treatment changes in these values might also be associated with the treatment response. Androgen receptor gene alterations, including ligand-binding domain mutations, copy number amplification, or structural rearrangements, are identified in most metastatic castration-resistant prostate cancer(mCRPC)and associated with treatment response to androgen receptor pathway inhibitors. Alterations in different DNA damage repair genes, including BRCA2, ATM, CDK12, or mismatch repair genes, are linked to favorable response to targeted therapies such as poly(adenosine diphosphate-ribose)polymerase(PARP)inhibitors or immune checkpoint inhibitors. Overactivation of the PI3K signaling pathway is mainly caused by PTEN loss, and several clinical trials are underway to assess the treatment effect of the targeted therapies such as Akt inhibitors. To disseminate treatment strategies using CTC and ctDNA in clinical practice, we will require prospective biomarker-driven clinical trials, development of novel targeted therapies, and exploration of other molecular characteristics such as epigenome.

[Clinical Outcomes of Anteroposterior Dissection Holmium Laser Enucleation of the Prostate for Benign Prostatic Hyperplasia].

Holmium laser enucleation of the prostate (HoLEP) is a standard surgical procedure for treatment of benign prostatic hyperplasia (BPH). A low incidence of postoperative urinary incontinence in association with anteroposterior dissection HoLEP was recently reported. We evaluated 66 patients with BPH who underwent anteroposterior dissection HoLEP from March 2013 to November 2014. The International Prostate Symptom Score (IPSS), quality of life (QOL) index, maximum flow rate (Qmax), and post-void residual urine volume (PVR) were assessed preoperatively and at 1 and 3 months after treatment. The incidence of postoperative urinary incontinence, which was defined as the requirement of more than one pad per day, was compared between the first and second half of the patient population. Postoperative urination parameters (IPSS, QOL index, Qmax, and PVR) were significantly improved. The incidence of urinary incontinence at 3 months was significantly lower in the second half (4%) than first half (28%) of the patient population (p＝0.020). In conclusion, anteroposterior dissection HoLEP is an effective procedure for the treatment of BPH and can reduce the rate of postoperative urinary incontinence, even in low-volume institutes.

CLINICAL OUTCOMES OF EXTERNAL-BEAM RADIOTHERAPY COMBINED WITH NEOADJUVANT ANDROGEN DEPRIVATION THERAPY FOR HIGH-RISK PROSTATE CANCER.

(Purpose) We investigated the outcome of external-beam radiotherapy (EBRT) with neoadjuvant androgen deprivation therapy (NeoADT) for high-risk prostate cancer defined by National Comprehensive Cancer Network (NCCN) guideline. (Patients and method) From 2002 to 2013, 70 patients with high-risk prostate cancer (PSA ≥20 ng/ml or clinical T stage ≥T3a, Gleason score ≥8) were treated with NeoADT and EBRT. EBRT consisted of three-dimensional conformal or intensity modulated radiotherapy with or without whole-pelvic radiation. Biochemical failure was defined according to the Phoenix definition. Biochemical progression-free survival (bPFS) and overall survival (OS) were calculated by Kaplan-Meier method, and prognostic factors for bPFS were analyzed by using the Cox proportional hazard model. (Result) The median age and initial prostate-specific antigen (PSA) level were 72 years old and 25.2 ng/ml, respectively. 43 patients had PSA level ≥20 ng/ml, 51 patients had clinical stage ≥T3a, 27 patients had Gleason score ≥8. The number of risk factors patients possessed was 1 (RiskN-1) in 31 patients, 2 (RiskN-2) in 27 patients and 3 (RiskN-3) in 12 patients. Median EBRT dose and duration of Neo ADT were 74 Gy and13.0 months, respectively. Whole-pelvic radiation was administered in 7 patients. After median follow-up of 4.8 years, biochemical and clinical failure occurred in 23 and 2 patients, respectively. No patients died of cancer. Five-year/8-year bPFS and OS were 63%/54% and 100%/91%, respectively. In multivariate analysis, three high-risk factor of NCCN guideline (PSA, clinical stage, Gleason score) did not predict outcome after EBRT independently, but RiskN (-1 vs -2, 3, HR 35.35, 95%CI 2.51-498.05, p<0.01) and pre-EBRT PSA (continuous, hazard ratio 1.31, 95%CI 1.01-1.71, p<0.05) were the significant predictors of bPFS. Five-year/8-year bPFS in RiskN-1 group and RiskN-2 or -3 group were 89%/79% and 47%/39%, respectively. Grade 3/4 adverse events (CTCAE ver4.0-JCOG) occurred in 2 patients. (Conclusion) Median dose of 74 Gy EBRT with intermediate-term NeoADT was safe and beneficial for high-risk prostate cancer. The number of risk factors and pre-EBRT PSA level were the independent prognostic factors for biochemical progression-free survival.

[Scrotal desmoid tumor in a patient with familial adenomatous polyposis].

A 46-year-old man presented to our hospital for further examination following a positive fecal occult blood test. He also had a painless, palpable scrotal mass that had been present for several years, but he had not previously sought treatment. Colonoscopy demonstrated multiple adenomatous polyps and colon cancer ; when taken together with his family history, these findings led to the diagnosis of familial adenomatous polyposis. A computed tomography scan revealed a right intrascrotal tumor, and the patient was referred to our department. Together with digestive surgeons, we carried out scrotal mass resection and colectomy under general anesthesia. On scrotal exploration, a large, solid mass was identified ; it was separate from the testis and epididymis. Although the mass was adhered to the surface of the corpus cavernosum penis, we were able to completely resect the mass along with part of the corpus cavernosum penis. The tumor was composed of abundant collagen fibers and mature fibroblasts. Histopathology revealed the right scrotal mass to be a desmoid tumor. The patient is alive with no evidence of disease 24 months after surgery.

[THE IMPACT OF LOWER URINARY TRACT SYMPTOMS ON GENERIC HEALTH-RELATED QUALITY OF LIFE IN MALE PATIENTS WITHOUT CO-MORBIDITY].

PURPOSE: We investigated the impact of lower urinary tract symptoms (LUTS) on generic health-related quality of life (HRQOL) in male patients without co-morbidity. PATIENTS AND METHOD: From 2003 to 2011, a total 567 men who presented out urological department completed the questionnaires including International Prostate Symptom Score (IPSS), incontinence-frequency score (IFS) from the UCLA prostate cancer index, MOS 36-Item Short-Form Health Survey (SF-36). Among 230 patients with no coexisting morbidity, the relations between each LUTS score of IPSS indices and IFS and 8 domain scores of SF-36 were analyzed by Pearson's product-moment correlation and stepwise multiple regression analysis. RESULT: Univariate analysis showed that the IFS had a significant correlation with all of 8 domain scores of SF-36, and also the IPSS item scores of urgency, nocturia and straining correlated significantly with multiple domain scores of SF-36. In multiple regression analysis, the proportionate contributions of LUTS to each SF-36 domain scores were low (R2 was 10% or less). Incontinence was considered as the most influential factor that had a negative impact on HRQOL in 7 SF-36 domains of physical functioning, role-physical, bodily pain, general health perception, vitality, social functioning and mental health. Additionally, nocturia, straining and urgency were significantly associated with deficit of HRQOL in 4 SF-36 domains (role-physical, general health perception, role-emotional, mental health), 2 domains (bodily pain, social functioning) and 1 domain (role-emotional) of SF-36, respectively. CONCLUSION; Among LUTS, incontinence, nocturia and straining were the most important symptoms in association with the negative impact on generic HRQOL measured by SF-36.

[Risk factors for recurrence in pT3aN0M0 renal cell carcinoma according to 2009 TNM classification].

The TNM classification of renal cell carcinoma was updated in 2009. In this new classification system, T3a consists of tumors with renal vein involvement and tumors with fat invasion. To assess risk factors for recurrence, we retrospectively reviewed 89 patients with pT3aN0M0 renal cell carcinoma who underwent radical or partial nephrectomy between 1992 and 2011. Analyzed risk factors for recurrence were age, gender, tumor size, grade, v factor, infiltrative growth (INF), adjuvant interferon, surgical technic (radical or partial), clinical T classification, renal vein thrombus, and pathological fat invasion. The median follow-up was 52.2 months. Five-year recurrence-free survival rate was 69.0%. Within the pT3a subcategory, the five-year recurrence-free survival was 76.7% in patients with fat invasion only, 42.9% in patients with renal vein thrombus only, and 28.6% in patients with the two concomitant features. On univariate analysis, tumor size, grade, INF, clinical T classification, and renal vein thrombus were significantly associated with recurrence. On multivariate analysis, INF (p = 0.023, HR 3.927) was an independent risk factor for recurrence. In pT3aN0M0 renal cell carcinoma, INF significantly affects recurrence, and patients with both fat invasion and renal vein thrombus have worst prognosis.

[Clinical outcomes after non-ischemic partial nephrectomy for clinical T1 renal tumors using soft coagulation versus microwave tissue coagulation].

PURPOSE: We have performed non-ischemic partial nephrectomy for clinical T1 renal tumors using microwave tissue coagulation (MTC group) or soft coagulation (soft coagulation group). The clinical outcomes were retrospectively compared between the two groups. MATERIALS AND METHODS: A total of 36 patients were analyzed in this study (22 in the MTC group and 14 in the soft coagulation group). The anatomical characteristics of the renal tumors were assessed using the R.E.N.A.L Nephrometry Score. Renal function was assessed by the estimated glomerular filtration rate. RESULTS: The preoperative estimated glomerular filtration rate was 72.1 ml/min in the MTC group and 65.6 ml/min in the soft coagulation group (p = 0.05). The R.E.N.A.L Nephrometry Score was not significantly different between the two groups. Clavian grade > or = 2 postoperative complications occurred in one patient (4.5%) in the MTC group and one patient (7.1%) in the soft coagulation group. Postoperative local recurrence and distant metastasis occurred in one patient (8.3%) in the soft coagulation group and no patients in the MTC group, which was not a significant difference between the two groups. The median postoperative decrease in estimated glomerular filtration rate was 11.5% in the MTC group and 3.6% in the soft coagulation group. Postoperative renal preservation tended to be better in the soft coagulation group than in the MTC group, but this difference was not significant. CONCLUSION: The use of soft coagulation in non-ischemic partial nephrectomy for the treatment of clinical T1 renal tumors is as effective as that of MTC.

Spatial Pattern of Intraprostatic Recurrence after Definitive External-Beam Radiation Therapy for Prostate Cancer: Implications for Focal Boost to Intraprostatic Dominant Lesion.

Purpose: We retrospectively investigated spatial pattern associations between primary and recurrent tumor sites after definitive external-beam radiation therapy (EBRT) for prostate cancer, using positron emission tomography/computed tomography (PET/CT) with a prostate-specific membrane antigen (PSMA)-targeted probe, 18F-FSU-880. Methods and Materials: We used data from our prior phase 2 trial involving patients who received PET/CT with 18F-FSU-880, which was designed to evaluate the tumor detection efficacy of PSMA-PET/CT for recurrent prostate cancer. Data from patients with local intraprostatic recurrence detected by PSMA-PET/CT after definitive EBRT were retrospectively analyzed. The prostate and seminal vesicles were divided into 14 sections. Two diagnostic radiologists separately re-evaluated the intraprostatic location of the primary tumor on magnetic-resonance imaging and that of the recurrent tumor on PSMA-PET/CT, respectively, and the rate of overlap between primary and recurrent tumors was calculated. The overlap rate was defined as "the number of sections that overlapped between the primary tumor and recurrent tumor" divided by "the total number of sections of recurrent tumor". A recurrent tumor was considered to be at the same location as the primary tumor when the overlap rate was equal to or greater than 75%, and a partial overlap was defined as an overlap rate between 25 and 74%. Results: Twelve patients had local recurrence detected by PSMA-PET/CT. The median time to diagnosis of local recurrence was 9.1 (range, 2.2-12.3) years after definitive EBRT. The recurrent tumor was detected at the same location in 25.0%, and a partial overlap was noted in 41.7%. Conclusions: Local intraprostatic recurrence after definitive EBRT often occurs at the same site or at a partially overlapping site adjacent to the primary intraprostatic dominant lesion. Our results support the merit of focal dose-escalation for intraprostatic dominant lesions in definitive EBRT.

Molecular features of prostate cancer after neoadjuvant therapy in the phase 3 CALGB 90203 trial.

BACKGROUND: The phase 3 CALGB 90203 (Alliance) trial evaluated neoadjuvant chemohormonal therapy for high-risk localized prostate cancer before radical prostatectomy. We dissected the molecular features of post-treated tumors with long-term clinical outcomes to explore mechanisms of response and resistance to chemohormonal therapy. METHODS: We evaluated 471 radical prostatectomy tumors, including 294 samples from 166 patients treated with 6 cycles of docetaxel plus androgen deprivation therapy before radical prostatectomy and 177 samples from 97 patients in the control arm (radical prostatectomy alone). Targeted DNA sequencing and RNA expression of tumor foci and adjacent noncancer regions were analyzed in conjunction with pathologic changes and clinical outcomes. RESULTS: Tumor fraction estimated from DNA sequencing was significantly lower in post-treated tumor tissues after chemohormonal therapy compared with controls. Higher tumor fraction after chemohormonal therapy was associated with aggressive pathologic features and poor outcomes, including prostate-specific antigen-progression-free survival. SPOP alterations were infrequently detected after chemohormonal therapy, while TP53 alterations were enriched and associated with shorter overall survival. Residual tumor fraction after chemohormonal therapy was linked to higher expression of androgen receptor-regulated genes, cell cycle genes, and neuroendocrine genes, suggesting persistent populations of active prostate cancer cells. Supervised clustering of post-treated high-tumor-fraction tissues identified a group of patients with elevated cell cycle-related gene expression and poor clinical outcomes. CONCLUSIONS: Distinct recurrent prostate cancer genomic and transcriptomic features are observed after exposure to docetaxel and androgen deprivation therapy. Tumor fraction assessed by DNA sequencing quantifies pathologic response and could be a useful trial endpoint or prognostic biomarker. TP53 alterations and high cell cycle transcriptomic activity are linked to aggressive residual disease, despite potent chemohormonal therapy.

Effects of thienopyridine class antiplatelets on bleeding outcomes following robot-assisted radical prostatectomy.

This study aimed to assess the effects of thienopyridine-class antiplatelet agents (including ticlopidine, clopidogrel, and prasugrel) on bleeding complications in patients who underwent robot-assisted radical prostatectomy. This cohort study used a database for robot-assisted radical prostatectomy at 23 tertiary centers nationwide between 2011 and 2022. Patients who received thienopyridines (thienopyridine group) were compared with those who received aspirin monotherapy (aspirin group). The primary outcome was the incidence of bleeding complications. High-grade complications were defined as Clavien-Dindo grade III or higher. The risks of these outcomes were evaluated using inverse probability of treatment weighted regression models. The study results demonstrated that thienopyridine therapy was associated with a higher risk of overall bleeding complications (OR: 3.62, 95%CI 1.54-8.49). The increased risks of the thienopyridine group were detected for low-grade bleeding complications (OR: 3.20, 95%CI 1.23-8.30) but not for high-grade bleeding complications (OR: 5.23, 95%CI 0.78-34.9). The increased risk of bleeding complications was not observed when thienopyridine was discontinued (OR: 2.52, 95%CI 0.83-7.70); however, it became apparent when it was continued perioperatively (OR: 4.35, 95%CI 1.14-16.61). In conclusion, thienopyridine increased the incidence of bleeding complications, particularly low-grade bleeding complications, following robot-assisted radical prostatectomy. These bleeding effects emerged when thienopyridine was continued perioperatively.