KDM5D predicts response to docetaxel chemotherapy in metastatic castration resistant prostate cancer patients

BackgroundThe administration of docetaxel chemotherapy is one therapeutic option to delay disease progression and increase overall survival in metastatic castration resistant prostate cancer (mCRPC). However, about 15% of patients are primary resistant to chemotherapy and hence would benefit from an alternative mCRPC treatment. Despite intensive research, there are no robust clinical validated biomarkers to predict mCRPC therapy response. Thus, the aim of the study was to determine KDM5D expression in archival radical prostatectomy specimens of patients medicated with docetaxel at time of mCRPC development in order to correlate KMD5D expression with treatment response.MethodsWe used in situ hybridization (ISH) (RNA scope 2.5 HD) to determine KDM5D expression in tissue samples of 28 prostate cancer patients. KDM5D status was correlated to chemotherapy response (PSA and radiographic response).ResultsData revealed that KDM5D is significantly overexpressed in tumor cells (P<0.0001) but also in benign cells (P<0.02) of those patients who responded to chemotherapy compared to non-responders.ConclusionsTo summarize, KDM5D is a promising novel biomarker predicting response to docetaxel chemotherapy already at the time of localized disease and thus potentially avoiding metastatic biopsies in the mCRPC stage of disease.     

Ki-67, topoisomerase IIα and miR-221 have a limited prostate cancer risk stratification ability on a medium-term follow-up: results of a high-risk radical prostatectomy cohort

BackgroundCurrently, no biomarkers are able to differentiate lethal from relatively indolent prostate cancer (PCa) within high-risk diseases. Nonetheless, several molecules are under investigation. Amongst them, topoisomerase-II-alpha (TOPIIA), Ki67 and miR-221 showed promising results. Our aim was to investigate their prognostic role in the context of biochemical recurrence (BCR), clinical recurrence (CR) and PCa-related death (PcD).MethodsWe included 64 consecutive cM0 high-risk PCa [prostate specific antigen (PSA) >20 ng/mL or Gleason Score (GS) >7 or cT >2] undergoing radical prostatectomy (RP). Changes in miR-221 expression and alternative splicing were determined using microarrays. Immunohistochemical determination of Ki67 and TOPIIa were performed using monoclonal antibody MIB-1 and 3F6 respectively. Cox proportional-hazards regression models were used to predict BCR and CR as multivariate analysis. BCR and CR were defined as three consecutive rises in PSA and PSA >0.2 ng/mL and histologically-proven local recurrence or imaging positive for distant metastasis respectively.ResultsWe included 64 men. Mean pre-operative PSA was 26.53 (range, 1.3–135); all GSs were ≥7 and pT was ≥ T3 in 78.13%. Positive margins and lymph-nodes were present in 42.19% and 32.81% respectively. At a mean follow-up of 5.7 years (range, 1.8–12.5), 42.18% experienced BCR (n=27), 29.68% CR (n=19) and 7.81% PcD (n=5). On univariate analysis positive nodes (<0.01), seminal vesicle invasion (0.02) and miR-221 downregulation (P=0.03), but not Ki67 and TOPIIA (both P>0.5) were associated with BCR whereas only PSA (P<0.01), seminal vesicle invasion (P<0.01) and positive nodes (both P<0.01) were linked to CR. No parameters predicted PcD (all P>0.05) or BCR and CR on multivariate analysis (all P>0.05 - miR-221 HR 0.776; 95% CI: 0.503–1.196 for BCR and HR 0.673; 95% CI: 0.412–1.099 for CR). Limitation of the study include its small sample size and limited follow-up.ConclusionsTOPIIA, Ki-67 and miR-221 may not predict BCR, CR or PcD in high-risk PCa patients who underwent RP at a medium-term follow-up. Longer follow-up and larger cohorts are needed to confirm our findings.     

ALP bouncing and LDH normalization in bone metastatic castration-resistant prostate cancer patients under therapy with Enzalutamide: an exploratory analysis

BackgroundIn bone metastatic castration-resistant prostate cancer (bmCRPC) treated with Enzalutamide commonly used prostate-specific antigen (PSA) can be misleading since initial PSA-flares may occur. In other therapies, bouncing of alkaline phosphatase (ALP-bouncing) was shown to be a promising surrogate for survival outcome. Low lactate dehydrogenase (LDH) is usually associated with better outcome. We evaluated the prognostic ability of ALP-bouncing, LDH, PSA, and the combination of these markers after initiation of Enzalutamide.MethodsEighty-nine patients with bmCRPC and dynamic changes of PSA, LDH and ALP were analyzed. ALP-bouncing, an increase after therapy start followed by a decline below baseline during the first 8 weeks, LDH-normalization and PSA-decline were analyzed regarding their association with survival using Kaplan-Meier analyses and uni- and multivariate (UV and MV) Cox-regression models.ResultsIn Kaplan-Meier analysis a PSA-decline >50%, LDH-normalization and ALP-bouncing were associated with longer median progression-free survival (PFS) with 7 [95% confidence interval (CI): 4.2–9.8] vs. 3 (2.3–3.7) months for PSA-decline (log-rank P<0.01), 6 (4.1–8) vs. 2 (1.2–2.8) for LDH-normalization (P<0.01) and 8 (0–16.3) vs. 3 (1.9–4.1) for ALP-bouncing (P=0.01). Analysis of overall survival (OS) showed similar, not for all parameters significant, results with 17 (11.7–22.3) vs. 12 (7.0–17.1) months for PSA (P=0.35), 17 (13.2–20.8) vs. 7 (5.8–8.2) for LDH-normalization (P<0.01) and 19 (7.9–30.1) vs. 12 (7.7–16.3) for ALP-bouncing (P=0.32). In UV analysis, ALP-bouncing [hazard ratio (HR): 0.5 (0.3–1.0); P=0.02], PSA-decline >50% [HR: 0.5 (0.3–0.7); P<0.01] and LDH-normalization [HR: 0.4 (0.2–0.6); P<0.01] were significantly associated with longer PFS. For OS, LDH-normalization significantly prognosticated longer survival [HR: 0.4 (0.2–0.6); P<0.01]. In MV analysis, LDH-normalization was associated with a trend towards better OS [HR: 0.5 (0.2–1.1); P=0.09]. Comparing ALP-bouncing, LDH-normalization and PSA-decline with a PSA-decline alone, Kaplan-Meier analysis showed significantly longer PFS [11 (0.2–21.8) vs. 4 (0–8.6); P=0.01] and OS [20 (17.7–22.3) vs. 8 (0.3–15.7); P=0.02] in favor of the group presenting with the beneficial dynamics of all three markers. In UV analysis, the presence of favorable changes in the three markers was significantly associated with longer PFS [HR: 0.2 (0.1–0.7); P<0.01] and OS [HR: 0.3 (0.1–0.8); P=0.02].ConclusionsALP-bouncing and LDH-normalization may add to identification of bmCRPC-patients with favorable prognosis under Enzalutamide.     

A Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE): A Comparison of Post-abiraterone Versus Post-enzalutamide Cohorts

BackgroundCyclic high-dose testosterone injections, also known as bipolar androgen therapy (BAT), is a novel treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). BAT has shown clinical activity in prior studies enrolling men with mCRPC and may potentially restore sensitivity to prior androgen receptor (AR)-targeted agents.ObjectiveTo evaluate the clinical activity of BAT in patients progressing on AR-targeted therapy as well as responses to abiraterone or enzalutamide upon rechallenge after BAT.Design, setting, and participantsRESTORE is a multicohort phase II study enrolling asymptomatic mCRPC patients after abiraterone or enzalutamide at Johns Hopkins Hospital (NCT02090114). Participants (29 after abiraterone and 30 after enzalutamide) received 400 mg testosterone cypionate intramuscularly every 28 days, with ongoing luteinizing hormone-releasing hormone agonist/antagonist treatment (ie, BAT). Following progression on BAT, patients were rechallenged with their most recent AR-targeted therapy.Outcome measurements and statistical analysisCoprimary endpoints were >50% decline in PSA from baseline (PSA₅₀) responses to BAT and following AR-targeted therapy rechallenge. Outcomes in the post-abiraterone cohort are presented, as well as updated results from the post-enzalutamide cohort and an exploratory AR-V7 analysis.Results and limitationsNo statistically significant difference in PSA₅₀ response rates to BAT was observed (30% [post-enzalutamide cohort] vs 17% [post-abiraterone cohort], p = 0.4). However, PSA₅₀ responses to AR-targeted therapy rechallenge were higher in the post-enzalutamide cohort (68% vs 16%, p = 0.001). The median time from enrollment to progression following rechallenge with AR-targeted therapy (ie, progression-free survival 2; PFS2) was longer in the post-enzalutamide versus post-abiraterone patients (12.8 vs 8.1 mo, p = 0.04). Outcomes were worse in patients with detectable AR-V7 in circulating tumor cells (median PFS2: 10.3 vs 7.1 mo, p = 0.005).ConclusionsBAT shows clinical activity in mCRPC patients and may be more effective at resensitizing to enzalutamide versus abiraterone.Patient summaryBAT is well tolerated in metastatic castration-resistant prostate cancer patients. The type of prior AR-targeted therapy might affect response to BAT as well as AR-therapy rechallenge. BAT followed by AR-targeted therapy rechallenge did not improve outcomes in AR-V7–positive patients.     

UnCHAARTED territory: The role of docetaxel rechallenge following chemohormonal therapy for metastatic castration-sensitive prostate cancer

ObjectiveTo assess the effectiveness of docetaxel rechallenge (DR) for metastatic castration-resistant prostate cancer (mCRPC) following chemohormonal therapy for metastatic castrate-sensitive prostate cancer (mCSPC). Additionally, we sought to define clinical factors predicting treatment response.Patients and MethodsRetrospective analysis of men treated with docetaxel for mCSPC and then rechallenged in the mCRPC setting from four cancer centers in Ontario, Canada. Prostate specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) following DR were evaluated.ResultsFifty five patients were identified between 2015 and 2020. Prior to DR, 94.5% of patients received androgen-receptor axis targeted therapy, 20% received radium-223, and 1.8% received cabazitaxel. Among 54 evaluable patients, 27.8% had a PSA decline ≥50%. Median PFS was 4.1 months (95% CI, 2.1?4.8) and median OS from androgen deprivation therapy initiation was 38.3 months (95% CI, 32.9?41.0). A Gleason Score of ≥8 was an independent predictor of prolonged PFS (HR 0.32, 95% CI, 0.12?0.81; P=0.02).ConclusionsDR following chemohormonal therapy for mCSPC produced a meaningful PSA response in approximately one-quarter of patients, with relatively short PFS. The impact of Gleason Score on docetaxel response warrants further investigation.     

El índice nutricional pronóstico como factor pronóstico independiente para la respuesta al tratamiento,la supervivencia y la elección del fármaco en el cáncer de próstata metastásico resistente a la castración tratado con acetato de abiraterona o enzalutamida

PurposeWe designed this study to identify the prognostic value of baseline prognostic nutritional index (PNI) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate or enzalutamide.MethodsOne hundred one mCRPC patients were included. PNI was calculated using formula 10 × serum albumin value (g/dl) + .005 × total lymphocyte count (per mm³). ROC analysis was used for determining prognostic PNI value.ResultsThe statistically significant cut-off value for PNI was 46.62. Initial PSA response and PSA kinetics (early PSA response and 30-50%-90% PSA response at any time) were much better in PNI>46.62 group than the PNI ≤46.62 group (P<.01). In multivariate analysis, baseline PNI level >46.62 was an independent predictor of PSA-PFS (HR: .42; P<.01), radiologic PFS (HR: .53; P<.01), and OS (HR: .42; P<.01). In the PNI≤46.62 group, median OS was 7.4 months (95% CI: 4.1-10.7) for the abiraterone acetate subgroup vs. 17.6 months (95% CI: 10.1-25.1) for enzalutamide subgroups (P<.01).ConclusionPNI is a useful, independent prognostic marker for mCRPC patients treated with either abiraterone acetate or enzalutamide. Using pre-treatment PNI may help clinicians in the prediction of survival and decision making based on abiraterone acetate or enzalutamide.     

PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: Multicenter validation in patients from the Chinese Prostate Cancer Consortium

ObjectiveDocetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) in China. We have previously shown that time to nadir (TTN) of prostate-specific antigen (PSA) is an important prognostic factor in patients from a single center in Northwestern China. In this study, we performed a multicenter validation of the prognostic role of TTN in additional Chinese patients with mCRPC receiving docetaxel treatment.Materials and methodsThe data were gathered from 170 eligible Chinese patients who received docetaxel chemotherapy from January 2007 to October 2018 in 11 Chinese Prostate Cancer Consortium member hospitals in China. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS) and progression-free survival (PFS).ResultsPatients with a TTN ≥ 15 weeks had a longer OS and PFS compared to those with a TTN < 15 weeks (43 vs. 15 months, P < 0.001; 24 vs. 6 months, P < 0.001, respectively). In addition, Patients with a TTN ≥ 15 weeks and PSA nadir <4.55ng/ml were associated with longer OS than others (HR 0.093, 95% CI 0.044-0.188, P < 0.001; HR 4.002, 95% CI 1.890–8.856, P = 0.001, respectively) and TTN, PSA nadir, PSA baseline (optimal threshold 56.07 ng/ml), and PSA reduction (optimal threshold 50%) were associated with PFS (HR 0.238, 95% CI 0.149–0.382, P < 0.001; HR 1.676, 95% CI 1.033–2.722, P = 0.037; HR 1.770, 95% CI 1.134–2.763, P = 0.012; HR 0.573, 95% CI 0.428–0.756, P < 0.001; respectively). Furthermore, patients with a PSA nadir <4.55 ng/ml had longer OS and PFS compared to other patients when TTN was ≥15 weeks.ConclusionIn this multicenter validation study, TTN and PSA nadir remain important prognostic markers in predicting therapeutic outcomes in Chinese men who receive chemotherapy for mCRPC.     

Tumor cytoreduction results in better response to androgen ablation—a preliminary report of palliative transurethral resection of the prostate in metastatic hormone sensitive prostate cancer

ObjectivesTo investigate the oncologic influence of transurethral resection of the prostate (TURP) as a cytoreductive surgery in metastatic hormone sensitive prostate cancer (mHSPC), in the setting of continuous complete androgen blockade (CAB).Materials and methodsMedical histories of 146 consecutive Chinese males with newly diagnosed mHSPC, registered in our institution in 2006 and 2007, were reviewed. All of these patients received CAB as initial systematic therapy. Demographics and cancer control outcomes from 39 mHSPC patients who underwent TURP for a relief of bladder outlet obstruction were compared with those of the other 107 who received CAB only when they were still hormone-sensitive. Median follow-up was 15 months (3 to 27 months).ResultsAge at diagnosis, baseline PSA, and biopsy Gleason score were comparable between the 2 groups. Patients who underwent a TURP had lower PSA nadir (median 0.15 ng/ml vs. 0.82 ng/ml, P = 0.015) and longer time to PSA nadir (11.2 months vs. 6.4 months, P < 0.001). More patients in the non-TURP group developed hormone refractory prostate cancer (P = 0.007). The TURP group had a tendency towards longer disease-specific survival and overall survival (24.4 months vs. 24.1 months and 24.4 months vs. 22.9 months, respectively), though this did not reach statistical significance.ConclusionsTURP resulted in a better and more prolonged response to hormone therapy in mHSPC, with a trend towards positive influence in disease specific survival and overall survival. To date, our preliminary report is the first study regarding long-term survival of cytoreductive surgery in mHSPC, and further investigations are warranted.     

The prognostic factors of effective ketoconazole treatment for metastatic castration-resistant prostate cancer: who can benefit from ketoconazole therapy?

We investigated the prognostic value of some variables of effective ketoconazole treatment for metastatic castration-resistant prostate cancer (mCRPC). In total, 163 patients with mCRPC were eligible, receiving ketoconazole 200–400 mg three times daily with replacement doses of prednisone. Progression-free survival (PFS) was calculated from the beginning of the ketoconazole therapy to the onset of disease progression. The prognostic value of different variables for PFS was assessed by Cox regression analysis. The median PFS was 2.6 months (0.5–8.6 months) for these patients. The serum testosterone level changed during therapy, which decreased when the prostate-specific antigen (PSA) declined; the serum testosterone level increased as the levels of PSA relapsed. The median PFS values for patients associated with different factors were the following: 1.4 and 3.5 months for a nadir PSA of ≥0.2 and <0.2 ng ml⁻¹, respectively (hazard rate (HR)=4.767, P<0.001); 3.1 and 1.6 months for a baseline testosterone of ≥0.1 and <0.1 ng ml⁻¹, respectively (HR=2.865, P=0.012); 2.8 and 1.9 months for a baseline haemoglobin of ≥120 and <120 g l⁻¹, respectively (HR=1.605, P<0.001); and 3.0 and 1.9 months for a PSA doubling time (PSADT) of ≥2.0 and <2.0 months, respectively (HR=1.454, P=0.017). A risk model was constructed according to the four factors that divided patients into three subgroups of low risk (0–1 factors), moderate risk (2 factors) and high risk (3–4 factors) with PFS values of 3.6, 3.0 and 1.4 months, respectively (HR=1.619, P<0.001). A nadir PSA of ≥0.2 ng ml⁻¹, a baseline testosterone of <0.1 ng ml⁻¹, a baseline haemoglobin of <120 g l⁻¹ and a PSADT of <2 months were associated with a poor PFS. This risk model could provide evidence to predict the survival benefit of ketoconazole therapy.     

The efficacy of abiraterone acetate in treating Taiwanese chemo-refractory metastatic castration-resistant prostate cancer patients

ObjectiveTo evaluate the efficacy of abiraterone acetate in combination with prednisolone in Taiwanese men with metastatic castrate-resistant prostate cancer (mCRPC) who failed docetaxel-based chemotherapy.Materials and methodsIn this single-arm, open label study, 30 mCRPC patients with prostate specific antigen (PSA) progression after docetaxel chemotherapy were enrolled. All patients were treated with abiraterone acetate 1000 mg once daily and prednisolone 5 mg twice daily. The primary end-point was PSA response rate (defined as proportion of patients achieving a PSA decline of ≥50%). Secondary end-points were overall survival and time-to-PSA progression.ResultsAmong 28 patients who received one or more cycles of treatment, 15 (53.6%) men achieved PSA response [95% confidence interval (CI) 33.9–72.5]. The median time-to-PSA progression was 5.5 months (95% CI 3.1–7.9). The median interval from stopping abiraterone to death was 3.4 months (95% CI 0.1–21.0), and the median overall survival was 19.2 months (95% CI 13.0–25.4). The PSA responders had better overall survival compared with PSA nonresponders, in both univariate (log rank test, p = 0.007) and multivariate (Cox regression, p = 0.001; relative risk: 0.31; 95% CI: 0.12–0.76) analysis. Both a high Gleason score (≥8) and viscera involvement did not have an unfavorable response to abiraterone treatment.ConclusionA combination of abiraterone acetate and prednisolone can improve the overall survival in Taiwanese mCRPC patients who fail prior docetaxel chemotherapy.     

A single-center,multidisciplinary experience with radium-223 dichloride in men with metastatic castrate-resistant prostate cancer

IntroductionWe aimed to investigate several clinical and biochemical parameters, including palliative external beam radiation therapy (EBRT) to predict survival in patients with metastatic castrate-resistant prostate cancer (mCRPC) treated with radium-223 (²²³Ra).MethodsWe tested known and possible prognostic parameters, including palliative EBRT, both prior and concurrent to ²²³Ra. Logrank test (Kaplan-Meier method) and Cox regression analysis were used to predict overall survival (OS).ResultsA total of 133 patients were treated with ²²³Ra; median age was 72 years. Median OS was 9.0 (95% confidence interval [CI] 7.4–10.6) months. By univariate analysis (log-rank test), baseline Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 (p=0.001), ≥5 cycles of ²²³Ra (p<0.001), baseline hemoglobin (Hb) ≥120 g/L (p <0.001), baseline total alkaline phosphatase (tALP) <110 U/L (p=0.001), and any prostate-specific antigen (PSA) decline at week 12 (p=0.013) were associated with increased OS. EBRT prior and/or concurrent to ²²³Ra showed a trend (p=0.051) towards inferior OS by univariate analysis only. By multivariate analysis, significant factors were PS 0–1 (hazard ratio [HR] 1.94, 95% CI 1.3–2.9, p=0.001), Hb ≥120 g/L (HR 0.5, 95% CI 0.3–0.9, p=0.011), and absence of docetaxel use prior to ²²³Ra (HR 1.86, 95% CI 1.08–3.22, p=0.026). With baseline Hb, tALP, and ECOG PS, we were able to divide patients into three groups with different median OS (months): 23.0 (95% CI 12.8–33.2), 8.0 (95% CI 6.7–9.3), and 5.0 (95% CI 3.1–6.9) for low-, intermediate-, and high-risk, respectively (p<0.001).ConclusionsWe found that ²²³Ra therapy can result in an OS of close to two years in carefully selected patients. Earlier administration of ²²³Ra therapy to fitter patients with mCRPC should be tested.     

Urinary exosome-based androgen receptor-variant 7 detection in metastatic castration-resistant prostate cancer patients

BackgroundAndrogen receptor variant 7 (AR-V7) detection provides important information for the clinical management of abiraterone in metastatic castration-resistant prostate cancer (mCRPC). We performed a non-invasive urine-derived exosomal AR-V7 analysis of mCRPC patients.MethodsA total of 34 mCRPC patients were recruited including 16 patients treated with abiraterone (ABI) with stable prostate-specific antigen (PSA)/radiograph response (the ABI-Sta group) and 18 were resistant to abiraterone (the ABI-Res group). Urine was collected from patients and healthy control patients for the analysis. Exosomal ribonucleic acid was isolated from urine. Urinary exosome-based androgen receptor-variant 7 was detected by quantitative real-time polymerase chain reaction assay. Characteristics of patients and survival data were collected. The correlation between AR-V7 expression and the therapeutic effect/survival outcomes of abiraterone was analyzed.ResultsUrine is the ideal biological sample for exosome separation and AR full-length analysis. Positive urine-derived exosomal AR-V7 was detected in 32.4% (11 of 34) of the mCRPC patients’ urine samples. Positive AR-V7 was more common in the ABI-Res patients than the ABI-Sta patients (50.0% vs. 12.5%, respectively; P=0.009), and was associated with a higher PSA progression rate and poorer overall survival (OS) (P=0.0031, and P=0.0012, respectively).ConclusionsThe present study showed that the detection of urine-derived exosomal AR-V7 provides a sensitive and feasible clinical workflow. The predicting role of urine-derived exosomal AR-V7 in mCRPC patients should be further verified using studies with greater sample sizes.     

Prognostic effect of preoperative serum albumin to globulin ratio in patients treated with cytoreductive nephrectomy for metastatic renal cell carcinoma

BackgroundAccurate identification of ideal candidates for cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) is an unmet need. We tested the association between preoperative value of systemic albumin to globulin ratio (AGR) and overall survival (OS) as well as cancer-specific survival (CSS) in mRCC patients treated with CN.MethodsmRCC patients treated with CN were included. The overall population was therefore divided into two AGR groups using cut-off of 1.43 (low, <1.43 vs. high, ≥1.43). Univariable and multivariable Cox regression analyses tested the association between AGR and OS as well as CSS. The discrimination of the model was evaluated with the Harrel’s concordance index (C-index). The clinical value of the AGR was evaluated with decision curve analysis (DCA).ResultsAmong 613 mRCC patients, 159 (26%) patients had an AGR <1.43. Median follow-up was 31 (IQR: 16–58) months. On univariable analysis, low preoperative serum AGR was significantly associated with both OS (HR: 1.55, 95% CI: 1.26–1.89, P<0.001) and CSS (HR: 1.55, 95% CI: 1.27–1.90, P<0.001). On multivariable analysis, AGR <1.43 was associated with worse OS (HR: 1.51, 95% CI: 1.23–1.85, P<0.001) and CSS (HR: 1.52, 95% CI: 1.24–1.86, P<0.001). The addition of AGR only minimally improved the discrimination of a base model that included established clinicopathologic features (C-index=0.640 vs. C-index=0.629). On DCA, the inclusion of AGR marginally improved the net benefit of the prognostic model. Low AGR remained independently associated with OS and CSS in the IMDC intermediate risk group (HR: 1.52, 95% CI: 1.16–1.99, P=0.002).ConclusionsIn our study, low AGR before CN was associated with worse OS and CSS, particularly in intermediate risk patients.     

Application of metastatic biopsy based on “When,Who, Why,Where, How (4W1H)” principle in diagnosis and treatment of metastatic castration-resistance prostate cancer

BackgroundTo determine the feasibility of secondary biopsy of metastatic castration-resistance prostate cancer based on the “4W1H—When, Who, Why, Where, How” principle and analyze the factors that affect tumor detection. Its application will further direct the patients for individualized precision therapy.MethodsA total of 55 patients were collected for secondary biopsy (27 prostate biopsies and 55 metastases biopsies). The parameters of biopsy location, computed tomography attenuation coefficient, lesion size, core number, laboratory tests, and the use of bone protection were evaluated. Histopathological data and the pathogenesis and etiology classification were used to guide precision treatment.ResultsFifteen/27 patients had a positive prostate biopsy, and 47/55 had positive metastasis biopsy. Bone metastasis biopsy was positive in 21/29 of cases. Also, parenchymal organs and lymph node biopsies were positive. In the prostate rebiopsy, significant differences were observed between total prostate volume (P=0.028), prostate-specific antigen (PSA) density (P=0.047), PSA velocity (P=0.036), and positive biopsy results. In the bone metastasis biopsy, we divided the patients into biopsy-positive and -negative groups. The computed tomography attenuation coefficient, PSA, alkaline phosphatase, and hemoglobin were related to tumor positive detection. However, the lesion size, core number, bone-sparing agents and previous treatments did not affect tumor detection.ConclusionsIn metastatic castration-resistant prostate cancer (mCRPC) patients, the “4W1H” principle was applied in the second biopsy. The biopsy site, image, and laboratory variables affected the positive of tumor tissue. Further pathological analysis of tumor tissue is essential to guide the precision medicine of mCRPC etiological classification.     

Prediction for survival following docetaxel-based chemotherapy in Taiwanese men with castration-resistant metastatic prostate cancer

IntroductionDocetaxel-based chemotherapy has been demonstrated to improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of this study is to analyze the possible prognostic factors associated with survival and to attract physicians' attention to high-risk patients.Material and methodsThirty-nine consecutive patients with mCRPC who received docetaxel-based chemotherapy between July 2007 and November 2013 were enrolled in this study. The Kaplan–Meier curve was used to assess the association between prostate-specific antigen (PSA) response (defined as PSA level decreases ≥ 50%), and overall survival and cancer-specific survival. Cox regression analysis was performed to identify the independent significant predictors of overall survival and cancer-specific survival.ResultsTwenty-one of the 39 patients (54%) experienced PSA response and the median overall survival was 13.51 months (range, 3–43 months). Patients with PSA response had longer time to PSA nadir level compared with patients without PSA response (p = 0.010). PSA response was an independent factor of overall survival and cancer-specific survival from Cox regression analysis (p = 0.014 and p = 0.05, respectively). In both univariate and multivariate analysis, cycles of chemotherapy, time to PSA nadir, and time to PSA progression were significant predictors for overall survival.ConclusionThe present study showed that PSA response demonstrated significance as a predictor for clinical outcome. However, Charlson comorbidity index (CCI) is not related to survival. A further prospective analysis is warranted.     

Wnt-pathway Activating Mutations Are Associated with Resistance to First-line Abiraterone and Enzalutamide in Castration-resistant Prostate Cancer

BackgroundWnt signaling is a cellular pathway involved in embryogenesis, development, and neoplasia. Wnt-pathway activation may accelerate prostate cancer androgen-independent growth and mediate antiandrogen resistance. Since 10–20% of advanced prostate cancers harbor Wnt-activating mutations, we aimed to characterize the clinical features and response to novel antiandrogens in such patients.ObjectiveTo determine whether men with metastatic castration-resistant prostate cancer (mCRPC) who harbor Wnt-pathway mutations have poorer responses to first-line novel hormonal therapies: abiraterone/enzalutamide.Design, setting, and participantsPatients with mCRPC who received first-line abiraterone or enzalutamide were retrospectively evaluated. Using tumor DNA analyses, we queried for activating mutations in CTNNB1 or inactivating mutations in APC or RNF43, all of which are predicted to stimulate Wnt signaling. Presence or absence of at least one Wnt-activating alteration was correlated with clinical-pathologic characteristics and treatment outcomes.Outcome measurements and statistical analysisTime to prostate-specific antigen (PSA) progression, overall survival (OS), and PSA response were measured. Cox regression models were used to test associations between Wnt status and clinical-pathologic outcomes; Kaplan-Meier and log-rank analyses were used to compare time-to-event endpoints.Results and limitationsOf 137 patients evaluated, 11% (n = 15) had tumor DNA analysis showing at least one Wnt-stimulating alteration. Patients with Wnt-activating mutations had numerically fewer T3/T4 tumors than Wnt wild-type patients (31% vs 51%), but were otherwise generally balanced. Median time to PSA progression on first-line abiraterone/enzalutamide was shorter in Wnt-activated patients (6.5 vs 9.6 mo, hazard ratio [HR] 2.34, p = 0.003), as was OS (23.6 vs 27.7 mo, HR 2.28, p = 0.01). PSA responses were numerically worse in Wnt-activated patients (53% vs 75%, p = 0.12). Presence of Wnt-activating alterations (adjusted HR [aHR] 2.33, p = 0.007) and use of previous chemotherapy (aHR 1.83, p = 0.004) were both independently associated with increased hazard of progression.ConclusionsPatients with somatic Wnt-pathway activating mutations have worse outcomes to first-line abiraterone/enzalutamide than Wnt wild-type patients. Our data suggest that additional genomically informed therapies are needed for this relevant subset of mCRPC patients.Patient summaryIn this report, we retrospectively examined outcomes of metastatic prostate cancer patients with or without Wnt-pathway mutations who received abiraterone or enzalutamide for the first time, in order to examine whether these mutations affect the prognosis. Our study suggested that patients who have Wnt-pathway activating mutations derived less benefit from abiraterone and enzalutamide when compared to patients without these mutations. We conclude that Wnt-pathway mutations might decrease the effectiveness of abiraterone and enzalutamide, and we propose that the Wnt pathway might be a good therapeutic target for these patients, in order to potentially reverse or prolong resistance to abiraterone and enzalutamide in men with Wnt mutations.     

Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA

BackgroundBeta-emitting Lu-177-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new option for metastatic castration-resistant prostate cancer (mCRPC), but its antitumor effect can decrease over time.ObjectiveTo report the safety and activity of alpha-emitting Ac-225-PSMA-617 RLT in mCRPC that has progressed after Lu-177-PSMA.Design, setting, and participantsTwenty-six patients were treated under a compassionate use protocol. The eligibility criteria included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy, progression after Lu-177-PSMA, and positive PSMA-ligand uptake. The median number of previous mCRPC regimens was 6. Ac-225-PSMA-617 was given every 8 wk until progression/intolerable side effects.Outcome measurements and statistical analysisProstate-specific antigen (PSA) decline, PSA progression-free survival (PSA-PFS), clinical progression-free survival (cPFS), overall survival (OS), and toxicity were measured.Results and limitationsSixty-one cycles of Ac-225-PSMA-617 (median number of cycles 2; median activity 9 MBq) were administered. A PSA decline of ≥50% was achieved in 17/26 patients. The median PSA-PFS, cPFS, and OS periods were 3.5 (95% confidence interval [CI] 1.8–11.2), 4.1 (95% CI 3–14.8), and 7.7 (95% CI 4.5–12.1) mo, respectively. Liver metastases were associated with shorter PSA-PFS (median 1.9 vs 4.0 mo; p = 0.02), cPFS (median 1.8 vs 5.2 mo; p = 0.001), and OS (median 4.3 vs 10.4 mo; p = 0.01). Hematological grade 3/4 toxicities were anemia (35%), leucopenia (27%), and thrombocytopenia (19%). All patients experienced grade 1/2 xerostomia. Two and six patients stopped due to hematological toxicity and xerostomia, respectively. A limitation is the retrospective design.ConclusionsAc-225-PSMA-617 showed measurable antitumor effect after Lu-177-PSMA failure in late-stage mCRPC. Grade 3/4 hematological side effects were observed in up to one-third of patients, and xerostomia led to treatment halt in a relevant number of patients.Patient summaryAc-225-labeled prostate-specific membrane antigen (PSMA)-617 therapy showed substantial antitumor effect in late metastatic castration-resistant prostate cancer after Lu-177-PSMA failure. However, dry mouth is a common side effect that caused about a quarter of patients to stop therapy.     

The influence of 18F-fluorodeoxyglucose positron emission tomography/computed tomography on the N- and M-staging and subsequent clinical management of intrahepatic cholangiocarcinoma

BackgroundIntrahepatic cholangiocarcinoma (ICC) is a highly metastatic cancer. ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) enables sensitive tumor and metastasis detection. Our aim is to evaluate the influence of pre-treatment PET/CT on the N- and M-staging and subsequent clinical management in ICC patients.MethodsBetween August 2010 and August 2018, 660 consecutive ICC patients, without prior anti-tumor treatments nor other malignancies, were enrolled. The diagnostic performance of PET/CT on the N- and M-staging was compared with conventional imaging, and the preoperative staging accuracy and treatment re-allocation by PET/CT were retrospectively calculated. Survival difference was compared between patients receiving PET/CT or not after propensity score matching.ResultsPatients were divided into group A (n=291) and group B (n=369) according to whether PET/CT was performed. Among 291 patients with both PET/CT and conventional imaging for staging in group A, PET/CT showed significantly higher sensitivity (83.0% vs. 70.5%, P=0.001), specificity (88.3% vs. 74.9%, P<0.001) and accuracy (86.3% vs. 73.2%, P<0.001) than conventional imaging in diagnosing regional lymph node metastasis, as well as higher sensitivity (87.8% vs. 67.6%, P<0.001) and accuracy (93.5% vs. 89.3%, P=0.023) in diagnosing distant metastasis. Overall, PET/CT improved the accuracy of preoperative staging from 60.1% to 71.8% (P<0.001), and modified clinical treatment strategy in 5.8% (17/291) of ICC patients, with unique roles in different tumor-node-metastasis (TNM) stages. High tumor-to-non-tumor ratio (TNR) predicted poor overall survival [hazard ratio (HR) = 2.17; 95% confidence interval (CI): 1.49–3.15; P<0.001]. Furthermore, patients performing PET/CT had longer overall survival compared with those without PET/CT (HR =0.74; 95% CI: 0.58–0.93; P=0.011) after propensity score matching.ConclusionsPET/CT was valuable for diagnosing regional lymph node metastasis and distant metastasis in ICC patients, and facilitated accurate tumor staging and optimal treatment allocation.     

Assessment of the bone scan index in a randomized placebo-controlled trial of tasquinimod in men with metastatic castration-resistant prostate cancer (mCRPC)

IntroductionDrug development and clinical decision making for patients with metastatic prostate cancer (PC) have been hindered by a lack of quantitative methods of assessing changes in bony disease burden that are associated with overall survival (OS). Bone scan index (BSI), a quantitative imaging biomarker of bone tumor burden, is prognostic in men with metastatic PC. We evaluated an automated method for BSI calculation for the association between BSI over time with clinical outcomes in a randomized double-blind trial of tasquinimod (TASQ) in men with metastatic castration-resistant PC (mCRPC).MethodsBone scans collected during central review from the TASQ trial were analyzed retrospectively using EXINIbone^BSI, an automated software package for BSI calculation. Associations between BSI and other prognostic biomarkers, progression-free survival, OS, and treatment were evaluated over time.ResultsOf 201 men (57 TASQ and 28 placebo), 85 contributed scans at baseline and week 12 of sufficient quality. Baseline BSI correlated with prostate-specific antigen and alkaline phosphatase levels and was associated with OS in univariate (hazard ratio [HR] = 1.42, P = 0.013) and multivariate (HR = 1.64, P<0.001) analyses. BSI worsening at 12 weeks was prognostic for progression-free survival (HR = 2.14 per BSI doubling, P<0.001) and OS (HR = 1.58, P = 0.033) in multivariate analyses including baseline BSI and TASQ treatment. TASQ delayed BSI progression.ConclusionsBSI and BSI changes over time were independently associated with OS in men with mCRPC. A delay in objective radiographic bone scan progression with TASQ is suggested; prospective evaluation of BSI progression and response criteria in phase 3 trials of men with mCRPC is warranted.     

Baseline basophil and basophil-to-lymphocyte status is associated with clinical outcomes in metastatic hormone sensitive prostate cancer

BackgroundBiomarkers have the potential to provide clinical guidance, but there is limited data for biomarkers in metastatic hormone sensitive prostate cancer (mHSPC).MethodsWe performed a retrospective multicenter review from Winship Cancer Institute at Emory University and Georgia Cancer Center for Excellence at Grady Memorial Hospital (2014–2020) in the United States of America (USA). We collected demographics, disease characteristics, and laboratory data, including complete blood counts (CBC) at the start of upfront therapy. We evaluated overall survival (OS) and progression-free survival (PFS) associated with baseline lab values.Results165 patients were included with a median follow-up time of 33.5 months (mo). 105 (63.6%) had Gleason scores of 8-10 and 108 (65.9%) were classified as high-volume disease. 92 patients received upfront docetaxel (55.8%) and 73 received upfront abiraterone (44.2%). Univariate analyses (UVA) and multivariable analyses (MVA) identified worse clinical outcomes (CO) associated with elevated basophils and basophil-to-lymphocyte ratio (BLR). Based on MVA, elevated basophils (defined as ≥0.1, optimal cut) were associated with a hazard ratio (HR) of 3.51 (95% CI 1.65–7.43, P 0.001) for OS and HR of 1.88 (95% CI 1.05-3.38, P 0.034) for PFS. Our MVA also found that BLR ≥0.0142 was associated with HR 2.11 (95% CI 1.09–4.10, P 0.028) for OS; however, PFS was not statistically significant.ConclusionWe conclude that elevated baseline basophils and BLR are associated with worse clinical outcomes in mHSPC. Although results require further validation, BLR is a potential prognostic biomarker.