Clinical outcome comparison of Grade Group 1 and Grade Group 2 prostate cancer with and without cribriform architecture at the time of radical prostatectomy

Aims: Invasive cribriform and intraductal carcinoma are associated with aggressive disease in Grade Group 2 (GG2) prostate cancer patients. However, the characteristics and clinical outcome of patients with GG2 prostate cancer without cribriform architecture (GG2−) as compared with those with Grade Group 1 (GG1) prostate cancer are unknown. The aim of this study was to investigate the clinical and pathological characteristics of GG1 and GG2− prostate cancer in radical prostatectomy specimens. Methods and results: We reviewed 835 radical prostatectomy specimens for Grade Group, pT stage, surgical margin status, and the presence of cribriform architecture. Biochemical recurrence-free survival and metastasis were used as clinical outcomes. GG1 prostate cancer was seen in 207 patients, and GG2 prostate cancer was seen in 420 patients, of whom 228 (54%) showed cribriform architecture (GG2+) and 192 (46%) did not. GG2− patients had higher prostate-specific antigen levels (9.4 ng/ml versus 7.0 ng/ml; P < 0.001), more often had extraprostatic extension (36% versus 11%; P < 0.001) and had more positive surgical margins (27% versus 17%; P = 0.01) than GG1 patients. GG2− patients ha

Mismatch repair and treatment resistance in ovarian cancer

BACKGROUND: The treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR) inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy. METHODS: We determined, microsatellite instability (MSI) as a marker for MMR inactivation (analysis of BAT25 and BAT26), MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA) and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR) in 75 ovarian carcinomas and eight ovarian cancer cell lines RESULTS: MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation), SKOV3 (no MLH1 mRNA expression) and 2774 (no altered expression of MMR genes). Overall, there was no association between cisplatin response and MMR status in these eight cell lines. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response). The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation. CONCLUSION: No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation

Concordance of cribriform architecture in matched prostate cancer biopsy and radical prostatectomy specimens

Aims: Invasive cribriform and/or intraductal carcinoma have been identified as independent adverse parameters for prostate cancer outcome. Little is known on biopsy undersampling of cribriform architecture. Our aim was to determine the extent of cribriform architecture undersampling and to find predictive factors for identifying false cribriform-negative cases. Methods and results: We reviewed 186 matched prostate biopsies and radical prostatectomy specimens. Of 97 biopsy grade group 2 (Gleason score 3 + 4 = 7) patients, 22 (23%) had true cribriform-negative (TN), 39 (40%) false-negative (FN) and 36 (37%) true-positive (TP) biopsies. Patients with FN biopsies had higher, although not statistically significant (P = 0.06), median PSA levels than patients with TP biopsies (12 versus 8 ng/ml). A PI-RADS 5 lesion was present in nine of 16 (54%) FN and three of 11 (27%) TN biopsies (P = 0.05). Positive biopsy rate (P = 0.47), percentage Gleason pattern 4 (P = 0.55) and glomeruloid architecture (P = 1.0) were not different. Logistic regression identified PSA as an independent pr

Intraoperative assessment and reporting of radical prostatectomy specimens to guide nerve-sparing surgery in prostate cancer patients (NeuroSAFE)

AIMS: Radical prostatectomy for prostate cancer is frequently complicated by urinary incontinence and erectile dysfunction. Nerve-sparing surgery reduces the risk of post-operative complications and can be optimized using intraoperative frozen sections of the adjacent neurovascular structure (NeuroSAFE). The aim of t

TP53 Mutations in Serum Circulating Cell-Free Tumor DNA As Longitudinal Biomarker for High-Grade Serous Ovarian Cancer

The aim of this study was to determine an optimal workflow to detect TP53 mutations in baseline and longitudinal serum cell free DNA (cfDNA) from high-grade serous ovarian carcinomas (HGSOC) patients and to define whether TP53 mutations are suitable as biomarker for disease. TP53 was investigated in tissue and archived serum from 20 HGSOC patients by a next-generation sequencing (NGS) workflow alone or combined with digital PCR (dPCR). AmpliSeq™-focused NGS panels and customized dPCR assays were used for tissue DNA and longitudinal cfDNAs, and Oncomine NGS panel with molecular barcoding was used for baseline cfDNAs. TP53 missense mutations were observed in 17 tissue specimens and in baseline cfDNA for 4/8 patients by AmpliSeq, 6/9 patients by Oncomine, and 4/6 patients by dPCR. Mutations in cfDNA were detected in 4/6 patients with residual disease and 3/4 patients with disease progression within six months, compared to 5/11 patients with no residual disease and 6/13 patients with progression after six months. Finally, mutations were detected at progression in 5/6 patients, but not during chemotherapy. NGS with molecular barcoding and dPCR were most optimal workflows to detect TP53 mutations in baseline and longitudinal serum cfDNA, respectively. TP53 mutations were undetectable in cfDNA during treatment but re-appeared at disease progression, illustrating its promise as a biomarker for disease monitoring

Prostate Cancer Patients Under Active Surveillance with a Suspicious Magnetic Resonance Imaging Finding Are at Increased Risk of Needing Treatment: Results of the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) Consortium.

BACKGROUND: The inclusion criterion for active surveillance (AS) is low- or intermediate-risk prostate cancer. The predictive value of the presence of a suspicious lesion at magnetic resonance imaging (MRI) at the time of inclusion is insufficiently known. OBJECTIVE: To evaluate the percentage of patients needing active treatment stratified by the presence or absence of a suspicious lesion at baseline MRI. DESIGN SETTING AND PARTICIPANTS: A retrospective analysis of the data from the multicentric AS GAP3 Consortium database was conducted. The inclusion criteria were men with grade group (GG) 1 or GG 2 prostate cancer combined with prostate-specific antigen <20 ng/ml. We selected a subgroup of patients who had MRI at baseline and for whom MRI results and targeted biopsies were used for AS eligibility. Suspicious MRI was defined as an MRI lesion with Prostate Imaging Reporting and Data System (PI-RADS)/Likert ≥3 and for which targeted biopsies did not exclude the patient for AS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was treatment free survival (FS). The secondary outcomes were histological GG progression FS and continuation of AS (discontinuation FS). RESULTS AND LIMITATIONS: The study cohort included 2119 patients (1035 men with nonsuspicious MRI and 1084 with suspicious MRI) with a median follow-up of 23 (12-43) mo. For the whole cohort, 3-yr treatment FS was 71% (95% confidence interval [CI]: 69-74). For nonsuspicious MRI and suspicious MRI groups, 3-yr treatment FS rates were, respectively, 80% (95% CI: 77-83) and 63% (95% CI: 59-66). Active treatment (hazard ratio [HR] = 2.0, p < 0.001), grade progression (HR = 1.9, p < 0.001), and discontinuation of AS (HR = 1.7, p < 0.001) were significantly higher in the suspicious MRI group than in the nonsuspicious MRI group. CONCLUSIONS: The risks of switching to treatment, histological progression, and AS discontinuation are higher in cases of suspicious MRI at inclusion. PATIENT SUMMARY: Among men with low- or intermediate-risk prostate cancer who choose active surveillance, those with suspicious magnetic resonance imaging (MRI) at the time of inclusion in active surveillance are more likely to show switch to treatment than men with nonsuspicious MRI

Cribriform architecture in radical prostatectomies predicts oncological outcome in Gleason score 8 prostate cancer patients

The Gleason score is an important parameter for clinical outcome in prostate cancer patients. Gleason score 8 is a heterogeneous disease including Gleason score 3 + 5, 4 + 4, and 5 + 3 tumors, and encompasses a broad range of tumor growth patterns. Our objective was to characterize individual growth patterns and identify prognostic parameters in Gleason score 8 prostate cancer patients. We reviewed 1064 radical prostatectomy specimens, recorded individual Gleason 4 and 5 growth patterns as well as presence of intraductal carcinoma, and evaluated biochemical recurrence- and metastasis-free survival. Gleason score 8 disease was identified in 140 (13%) patients, of whom 76 (54%) had Gleason score 3 + 5, 46 (33%) 4 + 4, and 18 (13%) 5 + 3 disease. Invasive cribriform and/or intraductal carcinoma (n = 87, 62%) was observed more frequently in Gleason score 4 + 4 (93%) than 3 + 5 (47%; P < 0.001) and 5 + 3 (44%; P < 0.001) patients. Gleason pattern 5 was present in 110 (79%) men: as single cells and/or cords in 99 (90%) and solid fields in 32 (29%) cases. Solid field pattern 5 coexisted with cribriform architecture (23/32, 72%) more frequently than nonsolid pattern 5 cases (36/78, 46%, P = 0.02). In multivariable analysis including age, prostate-specific antigen, pT-stage, surgical margin status, and lymph node metastases, presence of cribriform architecture was an independent parameter for biochemical recurrence-free (hazard ratio (HR) 2.0, 95% confidence interval (CI) 1.0–3.7; P = 0.04) and metastasis-free (HR 3.5, 95% CI 1.0–12.3; P = 0.05) survival. In conclusion, invasive cribriform and/or intraductal carcinoma occurs more frequently in Gleason score 4 + 4 prostate cancer patients than in Gleason score 3 + 5 and 5 + 3, and is an independent parameter for biochemical recurrence and metastasis. Therefore, cribriform architecture has added value in risk stratification of Gleason score 8 prostate cancer patients

Reasons for Discontinuing Active Surveillance : Assessment of 21 Centres in 12 Countries in the Movember GAP3 Consortium

Background: Careful assessment of the reasons for discontinuation of active surveillance (AS) is required for men with prostate cancer (PCa). Objective: Using Movember's Global Action Plan Prostate Cancer Active Surveillance initiative (GAP3) database, we report on reasons for AS discontinuation. Design, setting, and participants: We compared data from 10 296 men on AS from 21 centres across 12 countries. Outcome measurements and statistical analysis: Cumulative incidence methods were used to estimate the cumulative incidence rates of AS discontinuation. Results and limitations: During 5-yr follow-up, 27.5% (95% confidence interval [CI]: 26.4-28.6%) men showed signs of disease progression, 12.8% (95% CI: 12.0-13.6%) converted to active treatment without evidence of progression, 1.7% (95% CI: 1.5-2.0%) continued to watchful waiting, and 1.7% (95% CI: 1.4-2.1%) died from other causes. Of the 7049 men who remained on AS, 2339 had follow-up for >5 yr, 4561 had follow-up for Conclusions: Our descriptive analyses of current AS practices worldwide showed that 43.6% of men drop out of AS during 5-yr follow-up, mainly due to signs of disease progression. Improvements in selection tools for AS are thus needed to correctly allocate men with PCa to AS, which will also reduce discontinuation due to conversion to active treatment without evidence of disease progression. Patient summary: Our assessment of a worldwide database of men with prostate cancer (PCa) on active surveillance (AS) shows that 43.6% drop out of AS within 5 yr, mainly due to signs of disease progression. Better tools are needed to select and monitor men with PCa as part of AS. (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.Peer reviewe