Race-related Differences in Sipuleucel-T Response Among Men with Metastatic Castrate-Resistant Prostate Cancer.

PURPOSE: Sipuleucel-T is an autologous cellular immunotherapy that targets prostatic acid phosphatase (PAP) and is available for treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). In this single-arm, two-cohort, multicenter clinical study, potential racial differences in immune responses to sipuleucel-T in men with mCRPC were explored. PATIENTS AND METHODS: Patients' blood samples were obtained to assess serum cytokines, humoral responses, and cellular immunity markers pre- and post-treatment. Baseline cumulative product parameters (total nucleated and CD54+ cell counts, and CD54 upregulation) were evaluated. IgM titers against the immunogen PA2024, the target antigen PAP, prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) were quantified by ELISA. Cytotoxic T lymphocyte activity was determined by ELISpots, and cytokine and chemokine concentrations by Luminex. RESULTS: Twenty-nine African Americans (AA) and 28 non-African Americans (non-AA) with mCRPC received sipuleucel-T. Baseline total nucleated cell count, CD54+ cell count, CD54 expression, and cumulative product parameters were higher in non-AA. Although PSA baseline levels were higher in AA, there were no racial differences in IgM antibody and IFN- ELISpots responses against PA2024, PAP, PSA and PSMA pre- and post-treatment. Expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells, and the levels of Th1 cytokine granulocyte-macrophage colony-stimulating factor and chemokines CCL4 and CCL5, were significantly higher in AA pre- and/or post-treatment. Despite no difference in the overall survival, PSA changes from baseline were significantly different between the two races. CONCLUSIONS: The data suggest that immune correlates in blood differ in AA and non-AA with mCRPC pre- and post-sipuleucel-T.

Phase II Trial of Concurrent Nivolumab and Radiation Therapy for Muscle-Invasive Bladder Cancer of Older or Chemotherapy-Ineligible Patients.

PURPOSE: Bladder cancer is predominantly a disease of older individuals. Concurrent chemotherapy and radiation is a bladder-sparing strategy for management of muscle-invasive bladder cancer; however, many patients are not candidates for chemotherapy due to comorbidities or impaired performance status. We conducted a study in a chemotherapy-ineligible patient population with the objectives of evaluating the safety, efficacy, and quality-of-life effect of the combination of nivolumab and radiation therapy in patients with localized/locally advanced urothelial cancer. METHODS AND MATERIALS: Eligible patients had muscle-invasive bladder cancer and were not candidates for standard chemoradiation strategy due to at least one of the following: performance status of 2, creatinine clearance ≤60 mL/min, cardiac disease, neuropathy, and intolerance to previous treatment. Creatinine clearance ≥40 mL/min, normal marrow, and liver function were required. The primary endpoint was progression-free survival at 12 months. Nivolumab was started within 3 days of radiation therapy and administered at a dose of 240 mg intravenously every 2 weeks for a maximum of 6 months. Radiation therapy was per standard of care for bladder cancer. Imaging and cystoscopy and biopsy evaluation were required at months 3, 6, and 12 and then annually until progression. RESULTS: Twenty patients were enrolled, with a median age of 78.5 years (range, 58-95 years); 80% of patients were >70 years of age, and 8 (40%) were >80 years of age. Median creatinine clearance was 52 mL/min. Nine patients (48%) were progression free at 12 months. Median progression-free survival was 11.4 months (90% CI, 7.5-23.7 months), and median overall survival was 15.6 months (90% CI, 9.1-26.1 months). CONCLUSIONS: Concurrent nivolumab and radiation therapy is tolerable but demonstrated limited efficacy in an older population with multiple comorbidities. Immune correlates demonstrated that patients with baseline programmed cell death ligand 1 combined prognostic score ≥5% had numerically longer progression-free survival.

MRI- and PET-Based Assessment of Radiological and Clinical Factors Associated With Cervical Cancer Response to External Beam Radiation Therapy.

Introduction In the era of MRI-guided external beam radiation therapy (EBRT), complete radiological response (CR) is often seen in cervical cancer (CC) with 4-6 weeks of chemotherapy and EBRT. The clinical and radiological factors associated with this observation were investigated in this study. Materials and methods One hundred and twenty-four CC patients treated with concurrent chemotherapy, EBRT, and brachytherapy (BT) from January 2008 to July 2015 were retrospectively screened. Initial primary gross tumor volume (GTVINITIAL) was estimated after contouring on a planning CT scan registered with pre-EBRT PET and MRI. The maximum standardized uptake value (SUV) of GTVINITIAL from each PET scan report was collected. Spearman's rank correlation coefficient (rho) values were calculated to assess the relationships among age, tumor size, and SUV. Tumor radiological response during EBRT prior to BT was calculated by contouring the final primary gross tumor volume (GTVFINAL) using MRI obtained prior to BT. CR rates during EBRT were estimated from GTVINITIAL and GTVFINAL and compared by the level of various factors using Fisher's exact test (two-sided).  Results Forty-eight patients met the inclusion criteria of the study with a median age of 50 years. The median GTVINITIAL was 82 cc. The median SUV was 14.9. A significant correlation was seen between SUV and GTVINITIAL with a larger tumor size associated with a higher SUV. CR rates were numerically higher for patients who were aged <50 years, or with >37.5 Gy radiation dose at or before the second MRI, or with GTVINITIAL <100 cc, or with no nodes involved or with stages IB or IIA. Conclusions Our study identified higher CC primary tumor CR rates during EBRT in younger patients (<50) with smaller tumors (100 cc) without nodal involvements as well as a positive correlation between PET FDG (18F-fluorodeoxyglucose)-SUV and CC primary tumor size.

A Phase 1 study Combining Pexidartinib, Radiation Therapy, and Androgen Deprivation Therapy in Men With Intermediate- and High-Risk Prostate Cancer.

PURPOSE: This study aimed to evaluate a combination of radiation therapy (RT), androgen deprivation therapy (ADT), and pexidartinib (colony-stimulating factor 1 receptor [CSF1R]) inhibitor in men with intermediate- and high-risk prostate cancer. CSF1R signaling promotes tumor infiltration and survival of tumor-associated macrophages, which in turn promote progression and resistance. Counteracting protumorigenic actions of tumor-associated macrophages via CSF1R inhibition may enhance therapeutic efficacy of RT and ADT for prostate cancer. METHODS AND MATERIALS: In this phase 1 study, the treatment regimen consisted of pexidartinib (800 mg, administered as a split-dose twice daily) and ADT (both for a total of 6 months), and RT that was initiated at the start of month 3. RT volumes included the prostate and proximal seminal vesicles. The delivered dose was 7920 cGy (180 cGy per fraction) using intensity modulated RT with daily image guidance for prostate localization. The primary objective was to identify the maximum tolerated dose based on dose-limiting toxicities. RESULTS: All 4 enrolled patients who were eligible to receive RT had T1 stage prostate cancer, 2 were intermediate risk, and 2 were high risk. The median age was 62.5 years, and the prostate-specific antigen levels were in the range 6.4 to 10.7 ng/mL. The patients' individual Gleason scores were 3 + 3, 4 + 3, 4 + 4, and 4 + 5. All 4 patients reported ≥1 adverse events before RT. Grade 1 hypopigmentation was observed in 1 patient, and grade 3 pulmonary embolus in another. One patient experienced fatigue and joint pain, and another elevated amylase and pruritus (all grade 3 toxicities). Five of the 6 adverse events noted in 3 patients were all grade 3 toxicities attributable to pexidartinib, qualifying as dose-limiting toxicities and ultimately resulting in the study closure. CONCLUSIONS: The combination was not well tolerated and does not warrant further investigation in men with intermediate- and high-risk prostate cancer.

Clinical Efficacy of Enzalutamide vs Bicalutamide Combined With Androgen Deprivation Therapy in Men With Metastatic Hormone-Sensitive Prostate Cancer: A Randomized Clinical Trial.

Importance: Black patients have been underrepresented in prospective clinical trials of advanced prostate cancer. This study evaluated the efficacy of enzalutamide compared with bicalutamide, with planned subset analysis of Black patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is a disease state responsive to androgen deprivation therapy (ADT). Objective: To compare the efficacy of enzalutamide vs bicalutamide in combination with ADT in men with mHSPC, with a subset analysis of Black patients. Design, Setting, and Participants: In this randomized clinical trial, a phase 2 screening design enabled a nondefinitive comparison of the primary outcome by treatment. Patients were stratified by race (Black or other) and bone pain (present or absent). Accrual of at least 30% Black patients was required. This multicenter trial was conducted at 4 centers in the US. Men with mHSPC with no history of seizures and adequate marrow, renal, and liver function were eligible. Data analysis was performed from February 2019 to March 2020. Interventions: Participants were randomized 1:1 to receive oral enzalutamide (160 mg daily) or bicalutamide (50 mg daily) in addition to ADT. Main Outcomes and Measures: The primary end point was the 7-month prostate-specific antigen (PSA) response (SMPR) rate, a previously accepted surrogate for overall survival (OS) outcome. Secondary end points included adverse reactions, time to PSA progression, and OS. Results: A total of 71 men (median [range] age, 65 [51-86] years) were enrolled; 29 (41%) were Black, 41 (58%) were White, and 1 (1%) was Asian. Thirty-six patients were randomized to receive enzalutamide, and 35 were randomized to receive bicalutamide. Twenty-six patients (37%) had bone pain and 37 patients (52%) had extensive disease. SMPR was achieved in 30 of 32 patients (94%; 95% CI, 80%-98%) taking enzalutamide and 17 of 26 patients (65%; 95% CI, 46%-81%) taking bicalutamide (P = .008) (difference, 29%; 95% CI, 5%-50%). Among Black patients, the SMPR was 93% (95% CI, 69%-99%) among those taking enzalutamide and 42% (95% CI, 19%-68%) among those taking bicalutamide (P = .009); among non-Black patients, the SMPR was 94% (95% CI, 74%-99%) among those taking enzalutamide and 86% (95% CI, 60%-96%) among those taking bicalutamide. The 12-month PSA response rates were 84% with enzalutamide and 34% with bicalutamide. Conclusions and Relevance: The findings of this randomized clinical trial comparing enzalutamide with bicalutamide suggest that enzalutamide is associated with improved outcomes compared with bicalutamide, in terms of the rate and duration of PSA response, in Black patients with mHSPC. Trial Registration: ClinicalTrials.gov Identifier: NCT02058706.

Should all prostate needle biopsy Gleason score 4 + 4 = 8 prostate cancers be high risk? Implications for shared decision-making and patient counselling.

OBJECTIVES: To estimate the probability of downgrading to Gleason score ≤7 at radical prostatectomy for men with a prostate needle biopsy demonstrating Gleason score 8 (4 + 4). METHODS: This is a retrospective review of men with Gleason score 8 (4 + 4) prostate cancer on needle biopsy who then underwent a radical prostatectomy at the Karmanos Cancer Institute or the University of Michigan. Men with any pattern 5 on the diagnostic biopsy were excluded. The objective was to estimate the proportion of patients whose tumors were downgraded to Gleason score ≤7 at radical prostatectomy and to identify clinical and biopsy parameters associated with downgrading. RESULTS: Median age of our cohort was 63 years (IQR: 59, 67.5) and median follow-up was 15 months (IQR: 7, 37). Of the 105 men that met inclusion criteria, 59% (62/105) were downgraded to Gleason score ≤7 at radical prostatectomy. Having ≤2 cores demonstrating Gleason score 8, ≤50% maximal tumor involvement of any individual core positive for Gleason score 8, or the presence of Gleason pattern 3 (such as 3 + 4, 4 + 3, or 3 + 3) in other biopsy cores were all independently associated with downgrading in our multivariable model. Depending on the absence, presence, or combination of these 3 factors, patients had an estimated 6% to 82% probability of having their tumor downgraded at radical prostatectomy. CONCLUSIONS: Men with low volume Gleason 8 (4 + 4) and/or the presence Gleason pattern 3 on prostate needle biopsy often have their tumors downgraded at radical prostatectomy. The presence of these preoperative biopsy parameters could affect pretreatment counseling and impact patient management.

Phase II, Multicenter, Randomized Trial of Docetaxel plus Prednisone with or Without Cediranib in Men with Chemotherapy-Naive Metastatic Castrate-Resistant Prostate Cancer.

LESSONS LEARNED: The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC).The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. BACKGROUND: Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). METHODS: This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. RESULTS: The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). CONCLUSION: Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

The use of 3'-deoxy-3'-18F-fluorothymidine (FLT) PET in the assessment of long-term survival in breast cancer patients treated with neoadjuvant chemotherapy.

OBJECTIVE: To assess the role of serial FLT-PET scans during early neoadjuvant treatment as a prognostic marker of response to treatment and survival. METHODS: This study is a prospective cohort study which draws from a larger original study which examined the utility of FLT-PET imaging across multiple cancers. Our cohort consisted of patients who had biopsy-confirmed breast cancer amenable to surgical resection. These patients underwent serial FLT-PET scans: the first scan prior to starting neoadjuvant chemotherapy (NAC), and a second scan shortly after starting NAC. SUVmean was derived using an isocontour ROI drawn approximately half way between the SUVmax and background on three planes for each scan. The change in mean standardized uptake value (SUVmean) for the primary tumor between these two scans was then calculated, and patients were stratified into "responder" and "non-responder" groups based on a cut-off of 20% arithmetic decrease in SUVmean between the two scans. The rates of pathologic complete response (pCR) on subsequent surgical excision, overall survival (OS), and progression-free survival (PFS) were then compared between the two groups to assess for significant difference between responders and non-responders. RESULTS: 16 patients (n = 16) met criteria for inclusion and successfully underwent FLT-PET scans in the prescribed sequence of events. Seven of these patients had a decrease of 20% or larger between the two serial PET scans, making them "responders". The remaining nine patients were "non-responders" to NAC based on PET imaging. Between responders and non-responders, there was no significant difference in median PFS (7.9 years versus 3.7 years; p = 0.425) and median OS (7.5 years versus 5.0 years; p = 0.944). In the 14 patients who underwent surgical resection (n = 14), there was no significant difference in the rate of achieving pCR (33% vs. 14%; p = 0.5846) between responders and non-responders. CONCLUSION: Further study of a larger sample size is needed to examine the potential role for FLT-PET in predicting response to neoadjuvant treatment, particularly in correlating with long-term overall and progression-free survival. Our study is limited by small sample size, but does suggest that FLT-PET has a role in the long-term prognosis of breast cancer treated with NAC and surgical resection which is worthy of further study.

Biomarkers and Bone Imaging Dynamics Associated with Clinical Outcomes of Oral Cabozantinib Therapy in Metastatic Castrate-Resistant Prostate Cancer.

PURPOSE: Cabozantinib is a multitargeted tyrosine kinase inhibitor that demonstrated remarkable responses on bone scan in metastatic prostate cancer. Randomized trials failed to demonstrate statistically significant overall survival (OS). We studied the dynamics of biomarker changes with imaging and biopsies pretherapy and posttherapy to explore factors that are likely to be predictive of efficacy with cabozantinib.Experimental Design: Eligibility included patients with metastatic castrate-resistant prostate cancer with normal organ function and performance status 0-2. Cabozantinib 60 mg orally was administered daily. Pretherapy and 2 weeks post, 99mTc-labeled bone scans, positron emission tomography with 18F-sodium fluoride (NaF-PET) and 18F-(1-(2'-deoxy-2'-fluoro-ß-D-arabinofuranosyl) thymine (FMAU PET) scans were conducted. Pretherapy and posttherapy tumor biopsies were conducted, and serum and urine bone markers were measured. RESULTS: Twenty evaluable patients were treated. Eight patients had a PSA decline, of which 2 had a decline of ≥50%. Median progression-free survival (PFS) and OS were 4.1 and 11.2 months, respectively, and 3 patients were on therapy for 8, 10, and 13 months. The NaF-PET demonstrated a median decline in SUVmax of -56% (range, -85 to -5%, n = 11) and -41% (range, -60 to -25%, n = 9) for patients who were clinically stable and remained on therapy for ≥4 or <4 cycles, respectively. The FMAU PET demonstrated a median decline in SUVmax of -44% (-60 to -14%) and -42% (-63% to -23%) for these groups. The changes in bone markers and mesenchymal epithelial transition/MET testing did not correlate with clinical benefit. CONCLUSIONS: Early changes in imaging and tissue or serum/urine biomarkers did not demonstrate utility in predicting clinical benefit with cabozantinib therapy.

Overexpression of the Pluripotent Stem Cell Marker Podocalyxin in Prostate Cancer.

BACKGROUND/AIM: Podocalyxin, a member of the CD34 family of cell surface sialomucins, is overexpressed in human embryonal carcinoma cell lines, as well as in several cancer types, and is associated with poor prognosis. Podocalyxin variants are associated with an increased risk and aggressiveness of prostate cancer. Herein podocalyxin protein expression in prostate cancer was characterized. MATERIALS AND METHODS: Expression of podocalyxin as well as of TRA-1-60 and TRA-1-81 antigens was assessed immunohistochemically in 84 radical prostatectomy specimens and in adjacent normal tissues. RESULTS: Podocalyxin expression and H-scores were considerably higher in prostate tumors compared to normal tissues. High TRA-1-60 and TRA-1-81 staining was detected, however, in a much smaller percentage of prostate tumors, while their expression and H-scores were low in normal tissues. Similar trends for all three proteins were observed in prostatic intraepithelial neoplasia. CONCLUSION: Overexpression of podocalyxin in prostate cancer renders the protein a putative immunohistochemical marker of prostate cancer that may contribute to stratification of patients for optimal treatment.

Phase I Trial of the Combination of Docetaxel, Prednisone, and Pasireotide in Metastatic Castrate-Resistant Prostate Cancer.

BACKGROUND: Pasireotide (SOM230; Novartis Inc, Basel, Switzerland) is a multitargeted somatostatin receptor analogue likely to treat the neuroendocrine, and docetaxel resistant components within metastatic castrate-resistant prostate cancer (mCRPC). This phase I trial tested the combination of pasireotide, docetaxel, and prednisone in pretreated mCRPC. PATIENTS AND METHODS: Chemotherapy naive mCRPC patients received docetaxel 75 mg/m2 intravenously every 21 days and pasireotide intramuscularly every 28 days at escalating dose levels of 40, 60, and 80 mg. Maximum tolerated dose and recommended phase II dose (RP2D) were assessed. RESULTS: Eighteen patients were enrolled with a median age of 65 (range, 49-75) years, and pretherapy prostate-specific antigen of 259.9 ng/mL. The dose-limiting toxicities were Grade 4 hyperglycemia unresponsive to therapy and Grade 4 neutropenia lasting for > 7 days in 1 patient each occurring at the 80-mg dose level of pasireotide. The RP2D was determined at 60 mg every 28 days. Four patients at the 60 mg dose had Grade 3 or 4 hyperglycemia, which responded adequately to therapy. Median time to progression and survival were 7.2 and 18.3 months, respectively. Three of 6 patients with circulating tumor cells ≥5 converted to circulating tumor cells < 5 post therapy. The insulin like growth factor-1 levels revealed a median 51% decrease after therapy. The neuron-specific enolase and chromogranin did not show any marked change. CONCLUSION: The addition of pasireotide to docetaxel and prednisone is clinically feasible at a dose level of 60 mg every 28 days. The combination showed potential for clinical efficacy but needs to be compared with the standard docetaxel and prednisone regimen.

A phase 2 study of vorinostat in locally advanced, recurrent, or metastatic adenoid cystic carcinoma.

PURPOSE: Vorinostat is a histone deacetylase inhibitor (HDACi). Based on a confirmed partial response (PR) in an adenoid cystic carcinoma (ACC) patient treated with vorinostat in a prior phase 1 trial, we initiated this phase 2 trial. METHODS: Vorinostat was administered orally 400 mg daily, 28 day cycles. The primary objective was to evaluate response rate (RR). Exploratory studies included whole exome sequencing (WES) of selected patients. RESULTS: Thirty patients were enrolled. Median age of patients was 53 years (range 21-73). Median number of cycles was 5 (range 1-66). Lymphopenia (n = 5), hypertension (n = 3), oral pain (n = 2), thromboembolic events (n = 2) and fatigue (n = 2) were the only grade 3 adverse events (AEs) that occurred in more than 1 patient. Eleven patients were dose reduced secondary to drug-related AEs. Two patients had a partial response (PR), with response durations of 53 and 7.2 months. One patient had a minor response with a decrease in ascites (for 19 cycles). Stable disease was the best response in 27 patients. Targeted and WES of 8 patients in this trial identified mutations in chromatin remodeling genes highlighting the role of the epigenome in ACC. CONCLUSION: Vorinostat demonstrated efficacy in patients with ACC supporting the inclusion of HDACi in future studies to treat ACC.

A Pilot Trial Evaluating Zoledronic Acid Induced Changes in [18F]FMAU-Positron Emission Tomography Imaging of Bone Metastases in Prostate Cancer.

PURPOSE: We conducted a pilot trial utilizing [18F]FMAU [1-(2'-deoxy-2'-[18F]fluoro-ß-D-arabinofuranosyl thymine] as a tumor tracer in positron emission tomography (PET) and evaluated its reproducibility, and changes in maximum and peak standardized uptake value (SUVmax and SUVpeak) with zoledronic acid treatment in castrate resistant prostate cancer (CRPC) patients with bone metastases (BM). PROCEDURES: Eligible patients had CRPC with radiographic evidence of BM and creatinine clearance >30 ml/min. Two baseline [18F]FMAU-PET scans (about 1 week apart, range 2-12 days) were obtained for testing reproducibility. Zoledronic acid 4 mg was infused over 15 min within 1 week after second scan and a third PET scan was obtained 7 days later. The bony lesion with the highest uptake on the first scan was compared with later scans. Bone turnover markers and prostate-specific antigen (PSA) were obtained pre- and post-therapy. PET response was defined as decline in SUVmean of ≥15 % after zoledronic acid. RESULTS: Eleven patients were evaluated, median age was 65 years, five were African-American and six were Caucasian, and median PSA level was 36.3 ng/ml (range 1.0-1209.3). Notably, the range of absolute percent SUVmax changes varied between 0.77 and 54.7, and only nine measurements were greater than one (1.09-2.19). Zoledronic acid did not appreciably change FMAU uptake. No clinical response was noted. Urine N-telopeptide (NTx) was markedly decreased in all patients after zoledronic acid and serum bone-specific alkaline phosphatase (BSAP) registered a modest change. Urine NTx correlated more closely with SUV max than serum BSAP. CONCLUSIONS: FMAU tracer was able to detect bone metastases in CRPC patients but uptake was highly variable in bony lesions. Zoledronic acid did not produce an appreciable change in scans. Future investigations of FMAU tracer as a marker of early response in CRPC is recommended.

The influence of PSA autoantibodies in prostate cancer patients: a prospective clinical study-II.

The U.S. Preventive Services Task Force (USPSTF) has recommended against PSA-based screening for prostate cancer due to potential possibilities of false-results. Since no alternative test is available to replace it, we have initiated a trial with the purpose of establishing whether Galectin-3 (Gal-3) serum level and/or the patients' immune response to PSA and Gal-3 antigens could complement the PSA test as diagnostic tools for prostate cancer patients. A blind, prospective, single institution, pilot study was conducted. A total of 95 men were recruited and classified into 5 different groups: healthy controls (Group1), newly diagnosed patients (Group2), no recurrence after local therapy (Group3), rising PSA after local therapy (Group4), and metastatic patients (Group5). The primary endpoints were the levels of serum PSA, PSA autoantibodies (AAPSA), Gal-3, and Gal-3 autoantibodies (AAGal-3). Data were analyzed by Spearman's rank correlation (rho) and least squares linear regression modeling. The expression levels of PSA, AAPSA, Gal-3, and AAGal-3 were determined in both healthy controls and prostate cancer patients. Negative correlations were observed between PSA and AAPSA levels among all 95 men combined (rho = -0.321, P = 0.0021; fitted slope -0.288, P = 0.0048), and in metastatic patients (rho = -0.472, P = 0.0413; fitted slope -1.145, P = 0.0061). We suggest an association between PSA and AAPSA, whereby the AAPSA may alter PSA levels. It provides a novel outlook for prostate cancer diagnosis, and should serve as a basis for an all-inclusive diagnostic trial centering on patients with metastasis.

Outcomes of nonsurgical management of locally advanced carcinomas of the sinonasal cavity.

OBJECTIVE: To determine the outcome of definitive concurrent chemoradiation with platinum for locally advanced sinonasal carcinomas. STUDY DESIGN: Retrospective cohort. METHODS: Twenty-three nonsurgically and definitively treated patients diagnosed between July 1998 and February 2009 were analyzed. Patients with adenoid cystic carcinoma or adenocarcinoma were treated with photons and neutrons; the other histologies received photons alone. The vast majority received chemotherapy. Descriptive statistics were utilized, and Kaplan-Meier estimates were computed. RESULTS: Female (57%) and Caucasian (74%) preponderance were observed. Eighty-seven percent were unresectable; the maxillary and nasoethmoid sites were equally prevalent. Intensity-modulated radiation therapy (IMRT) and photons alone were utilized in 74% and 70%, respectively. Platinum agents were given in 95% of chemotherapy patients. Complete response was observed in 64% of patients. Median progression-free survival (PFS) and overall survival (OS) were 28.8 and 65.3 months, respectively. Three-year PFS and OS rates were 44% and 72%, respectively; 5-year PFS and OS rates were 30% and 60%, respectively. Intensity-modulated radiation therapy and a maxillary site of origin showed a trend toward superior PFS; higher-dose regimens were associated with somewhat shorter PFS. Relapse was observed in 59% of patients, predominantly local. There were few unanticipated adverse effects, and no grade IV/V events were reported. CONCLUSION: Advanced sinonasal carcinomas are chemoradiosensitive tumors, albeit with a high propensity for local relapse. There is a definite indication for IMRT and a potential curative role of platinum-based chemoradiation regimens. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:855-861, 2017.

Positive associations between galectin-3 and PSA levels in prostate cancer patients: a prospective clinical study-I.

Galectin-3 (Gal-3), an oncogenic pro-inflammatory protein, has been suggested as a possible complementary diagnostic candidate to prostate specific antigen (PSA) blood test for prostate cancer patients. The presence of the proteins in the circulation (biomarkers) may elicit an intrinsic humoral immune reaction by generating autoantibodies, which consequently could alter the detection levels. Here, we report the associations of the two prostate cancer biomarkers, Gal-3 and PSA in patients at different clinical states of prostate cancer while taking into account the autoantibody levels. A blind, prospective, single institution, pilot study was conducted. A total of 95 men were classified into 5 groups: healthy controls (Group1), newly diagnosed patients (Group2), no recurrence after local therapy (Group3), rising PSA after local therapy (Group4), and metastatic patients (Group5). Gal-3 and PSA level were divided by their respective autoantibodies, which yielded relative PSA and relative Gal-3 levels. After the adjustments, Spearman's rank correlations and linear regression modeling revealed the positive associations between relative Gal-3 and relative PSA levels among all 95 men combined (rho = 0.446, P < 0.0001; fitted slope 0.448, P < 0.0001), in Group2 (rho = 0.616, P = 0.0050; fitted slope 0.438, P =0.0011), and Group3 (rho = 0.484, P = 0.0360; fitted slope 0.470, P = 0.0187). The data show positive associations of relative Gal-3 and relative PSA levels in prostate cancer patients, notably at early clinical time course. Allowing for the influence of autoantibodies, Gal-3 level might be considered as a potential biomarker since it is positively associated with PSA level.

Anti-androgenic activity of absorption-enhanced 3, 3'-diindolylmethane in prostatectomy patients.

Consumption of cruciferous vegetables is associated with a decreased risk of developing prostate cancer. Antineoplastic effects of cruciferous vegetables are attributable to bioactive indoles, most prominently, 3, 3'-diindolylmethane (DIM). In addition to effects on proliferation and apoptosis, DIM acts as an antiandrogen in prostate cancer cell lines. This study characterized the effects of prostatic DIM on the androgen receptor (AR) in patients with prostate cancer. Men with localized prostate cancer were treated with a specially formulated DIM capsule designed for enhanced bioavailability (BR-DIM) at a dose of 225 mg orally twice daily for a minimum of 14 days. DIM levels and AR activity were assessed at the time of prostatectomy. Out of 28 evaluable patients, 26 (93%) had detectable prostatic DIM levels, with a mean concentration of 14.2 ng/gm. The mean DIM plasma level on BR-DIM therapy was 9.0 ng/mL; levels were undetectable at baseline and in follow-up samples. AR localization in the prostate was assessed with immunohistochemistry. After BR-DIM therapy, 96% of patients exhibited exclusion of the AR from the cell nucleus. In contrast, in prostate biopsy samples obtained prior to BR-DIM therapy, no patient exhibited AR nuclear exclusion. Declines in PSA were observed in a majority of patients (71%). Compliance was excellent and toxicity was minimal. In summary, BR-DIM treatment resulted in reliable prostatic DIM levels and anti-androgenic biologic effects at well tolerated doses. These results support further investigation of BR-DIM as a chemopreventive and therapeutic agent in prostate cancer.

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888) in Combination with Irinotecan in Patients with Advanced Solid Tumors.

PURPOSE: PARP is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitor-mediated DNA damage. This phase I study determined the MTD, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib, an orally bioavailable PARP1/2 inhibitor, in combination with irinotecan. EXPERIMENTAL DESIGN: Patients with advanced solid tumors were treated with 100 mg/m(2) irinotecan on days 1 and 8 of a 21-day cycle. Twice-daily oral dosing of veliparib (10-50 mg) occurred on days 3 to 14 (cycle 1) and days -1 to 14 (subsequent cycles) followed by a 6-day rest. PK studies were conducted with both agents alone and in combination. Paired tumor biopsies were obtained after irinotecan alone and veliparib/irinotecan to evaluate PARP1/2 inhibition and explore DNA damage signals (nuclear γ-H2AX and pNBS1). RESULTS: Thirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m(2) irinotecan (days 1 and 8) combined with veliparib 40 mg twice daily (days -1-14) on a 21-day cycle. Of 31 response-evaluable patients, there were six (19%) partial responses. Veliparib exhibited linear PK, and there were no apparent PK interactions between veliparib and irinotecan. At all dose levels, veliparib reduced tumor poly(ADP-ribose) (PAR) content in the presence of irinotecan. Several samples showed increases in γ-H2AX and pNBS1 after veliparib/irinotecan compared with irinotecan alone. CONCLUSIONS: Veliparib can be safely combined with irinotecan at doses that inhibit PARP catalytic activity. Preliminary antitumor activity justifies further evaluation of the combination. Clin Cancer Res; 22(13); 3227-37. ©2016 AACR.

A phase II trial of ganetespib, a heat shock protein 90 Hsp90) inhibitor, in patients with docetaxel-pretreated metastatic castrate-resistant prostate cancer (CRPC)-a prostate cancer clinical trials consortium (PCCTC) study.

INTRODUCTION: Heat shock protein 90 (Hsp90) has been studied as a therapeutic target in many cancers. In preclinical trials, the Hsp90 ATPase inhibitor ganetespib demonstrated potent inhibition of solid tumor growth, with superior potency than prior Hsp90 inhibitors. Given the promising preclinical outcome and favorable pharmacologic properties of ganetespib, we conducted a phase II trial of single-agent ganetespib in patients with metastatic, castrate-resistant prostate cancer (mCRPC). The primary objective of the study was to determine the 6-month progression-free survival (PFS) rate. METHODS: Patients with mCRPC who had been previously treated with docetaxel were enrolled after meeting eligibility criteria. All patients received ganetespib at 200 mg/m(2) on days 1, 8, and 15 of every 28 days (one cycle). Subjects who tolerated therapy were continued on ganetespib until disease progression. Considering that Hsp90 acetylation may confer insensitivity to Hsp90 inhibitors and maspin inhibits protein deacetylation, maspin-associated molecular markers were evaluated. RESULTS: Eighteen patients were recruited into the trial; most were Caucasian, had performance status 1, had received prior docetaxel, and were heavily pretreated. Of the 17 patients who were treated, none attained 6-month PFS. Only 2 patients achieved PFS > 4 months. The median PFS was 1.9 months. As per the study design, the trial was terminated after the interim analysis. The most frequent types of Grade 3 toxicity were dehydration, diarrhea, and fatigue. Molecular markers provided little additional insight regarding drug activity. CONCLUSIONS: Ganetespib demonstrated minimal clinical activity in men with mCRPC. The true 6-month PFS rate was, at most, 0.20. Possible reasons for this include selection of a heavily pretreated patient population and lack of agent potency in patients with mCRPC.

Phase II Trial of Carboplatin, Everolimus, and Prednisone in Metastatic Castration-resistant Prostate Cancer Pretreated With Docetaxel Chemotherapy: A Prostate Cancer Clinical Trial Consortium Study.

OBJECTIVE: To conduct a phase II trial of the combination of carboplatin, prednisone, and everolimus in metastatic castrate-resistant prostate cancer (mCRPC) as mTOR inhibition can overcome resistance to chemotherapy in prostate cancer. METHODS: Patients with progressive mCRPC pretreated with docetaxel-based regimen were eligible. Performance status of 0-1 and adequate bone marrow, renal, and liver function were required. Primary end point was time to progression. Treatment consisted of carboplatin (starting dose equal to area under the curve (AUC of 5) intravenously every 21 days along with oral everolimus 5 mg once daily and prednisone 5 mg twice daily. RESULTS: Twenty-six patients were enrolled with median age of 69 years with 8 patients of African American origin. Grade 3 or 4 thrombocytopenia or neutropenia in 4 of 6 initial patients required dose adjustment of carboplatin to AUC of 4 for subsequent patients. There were no pharmacokinetic interactions between carboplatin and everolimus. The median time to progression was 2.5 months (90% confidence interval [CI], 1.8-4.3 months), and median overall survival was 12.5 months (90% CI, 7.7-18.7 months). Of 10 patients, 8 that demonstrated positive nuclear phosphorylated AKT (pAKT) staining on immunohistochemistry progressed within 9 weeks, whereas 2 patients with negative staining continued without progression for prolonged durations of 30 and 48 weeks. TSC1 gene mutations did not correlate with clinical outcome. CONCLUSION: The addition of the mTOR inhibitor everolimus to carboplatin demonstrated minimal clinical efficacy in metastatic prostate cancer. pAKT testing warrants further evaluation as a predictive marker of response to everolimus therapy.