Genomic Analysis of Three Metastatic Prostate Cancer Patients with Exceptional Responses to Carboplatin Indicating Different Types of DNA Repair Deficiency

Platinum-based regimens have not been proved to increase survival from advanced prostate cancer (PCa). Incontrovertible evidence that a proportion of prostate cancers have homologous recombination DNA (HRD) repair defects, and that such genomic aberrations are synthetically lethal with both poly(ADP)-ribose polymerase inhibition and platinum, has increased interest in the utilisation of these drugs against a subset of these diseases. Here in we report three patients with advanced castration-resistant PCa with HRD defects having exceptional responses to carboplatin.     

Clinical Features and Therapeutic Outcomes in Men with Advanced Prostate Cancer and DNA Mismatch Repair Gene Mutations

Mismatch repair (MMR) gene mutations are rare in prostate cancer, and their histological and clinical characteristics are largely unknown. We conducted a retrospective study to explore disease characteristics and treatment outcomes of men with metastatic prostate cancer harboring germline and/or somatic MMR mutations detected using clinical-grade genomic assays. Thirteen patients with a deleterious MMR gene mutation were identified. Median age was 64 yr, 75% had grade group 5 (Gleason sum 9 or 10), 23% had intraductal histology, 46% had metastatic disease at initial diagnosis, and 31% had visceral metastases. Most patients (46%) had MSH6 mutations, 73% demonstrated microsatellite instability, and median tumor mutational load was 18/Mb (range, 3–165 mutations/Mb). Surprisingly, responses to standard hormonal therapies were very durable (median progression-free survival [PFS] of 67 mo to initial androgen deprivation and median PFS of 26 mo to abiraterone/enzalutamide). Two of four men receiving PD-1 inhibitors achieved a ≥50% prostate-specific antigen response at 12 wk, with a median PFS duration in these four men of 9 mo. Despite aggressive clinical and pathological features, patients with MMR-mutated advanced prostate cancer appear to have particular sensitivity to hormonal therapies, as well as anecdotal responses to PD-1 inhibitors. Certain histological features (grade group 5, intraductal carcinoma) should prompt evaluation for MMR deficiency. These data are only hypothesis generating.

Emergence of BRCA Reversion Mutations in Patients with Metastatic Castration-resistant Prostate Cancer After Treatment with Rucaparib

BackgroundPoly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC). BRCA reversion mutations are a known mechanism of acquired resistance to PARP inhibitors in multiple cancer types, although their impact and prevalence in mCRPC remain unknown.ObjectiveTo examine the prevalence of BRCA reversion mutations in the plasma of patients with BRCA+ mCRPC after progression on rucaparib.Design, setting, and participantsMen with BRCA+ mCRPC enrolled in Trial of Rucaparib in Prostate Indications 2 (TRITON2) were treated with rucaparib after progressing on one to two lines of androgen receptor–directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected at the end of treatment after confirmed progression before May 5, 2020, was queried for BRCA reversion mutations using next-generation sequencing (NGS).Outcome measurements and statistical analysisThe association of clinical efficacy and postprogression genomics was measured in 100 patients with BRCA+ mCRPC treated with rucaparib.Results and limitationsNo baseline BRCA reversion mutations were observed in 100 BRCA+ patients. NGS identified somatic BRCA reversion mutations in 39% (39/100) of patients after progression. Reversion rates were similar for BRCA2 and BRCA1, irrespective of germline or somatic status, but higher in samples with a high tumor DNA fraction. Most patients with reversions (74%, 29/39) had two or more reversion mutations occurring subclonally at lower allele frequencies than the original BRCA mutations. The incidence of BRCA reversion mutations increased with the duration of rucaparib treatment. The frequency of reversion mutations was higher in patients with an objective (58%) or a prostate-specific antigen (69%) response compared with those without either (39% and 29%, respectively).ConclusionsThese findings suggest that BRCA reversion mutations are a significant mechanism of acquired resistance to rucaparib in patients with BRCA+ mCRPC, with evidence of subclonal convergence promoting systemic resistance.Patient summaryMen with BRCA mutated metastatic castration-resistant prostate cancer enrolled in TRITON2 were treated with rucaparib after progressing on one to two lines of androgen receptor–directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected after radiographic or prostate-specific antigen progression before May 5, 2020, was analyzed by next-generation sequencing and queried for BRCA reversion mutations.     

中晚期前列腺癌临床治疗分析

目的 :探讨放疗、内分泌治疗和联合治疗对前列腺癌的临床疗效及PSA的临床诊断价值。　方法 :回顾总结 1986～ 1997年 5 0例C期以上前列腺癌临床治疗资料 ,比较不同治疗方法的客观生存率及PSA在治疗前后的变化。　结果 :治疗前 93 .7%病人PSA >4μg/L ,内分泌治疗后PSA水平下降 80 %～ 86 % ;80 %肿瘤发展病人PSA升高 1倍以上。手术去势组C期病人 2年和 5年生存率为 10 0 %和 6 6 % ;D期为 82 %和 36 %。放疗组C、D期 2年和 5年生存率分别为 10 0 %、5 0 %和 5 0 %、0。放疗联合去势术治疗C期病人 2年和 5年生存率为 10 0 %和 77%。药物治疗组 2年生存率为 90 %。　结论 :PSA是诊断前列腺癌及评价治疗预后的敏感指标。放疗联合内分泌治疗是C期前列腺癌的有效治疗方法 ,内分泌治疗D期前列腺癌优于放疗     

血清PSA、FPSAR与前列腺癌病理分级、临床分期的相关性研究

目的 :探讨前列腺癌病人血清前列腺特异抗原 (PSA)、血清游离前列腺特异抗原百分率 (FPSAR)与前列腺癌病理分级、临床分期的相关性。　方法 :分别检测经病理检查确诊为前列腺癌的 4 2例病人血清PSA、FPSAR ,并根据标本苏木精 伊红染色切片中肿瘤的组织学形态及临床资料对病人分别进行病理分级、临床分期。采用Spearman等级相关分析 ,分析PSA、FPSAR与前列腺癌病理分级、临床分期的关系。 　结果 :前列腺癌病人PSA值越高 ,癌症恶性程度越高 ,PSA值与前列腺癌病理改变呈明显正相关性 (P <0 .0 5 ) ,而与前列腺癌的临床分期无相关性 (P >0 0 5 ) ;前列腺癌病人FPSAR值与前列腺癌病理改变呈正相关 ,与病人临床分期呈负相关 (P <0 .0 5 )。结论 :与PSA值相比 ,FPSAR值预测前列腺癌的病理分级、临床分期和预后可能更为准确     

Outcome Following Active Surveillance of Men with Screen-detected Prostate Cancer. Results from the Göteborg Randomised Population-based Prostate Cancer Screening Trial

Background

Active surveillance (AS) has emerged as a treatment strategy for reducing overtreatment of screen-detected, low-risk prostate cancer (PCa).

Objective

To assess outcomes following AS of men with screen-detected PCa.

Design, setting, and participants

Of the 968 men who were diagnosed with screen-detected PCa between 1995 and 2010 in the Göteborg randomised, population-based PCa screening trial, 439 were managed with AS and were included in this study. Median age at diagnosis was 65.4 yr of age, and median follow-up was 6.0 yr from diagnosis.

Intervention

The study participants were followed at intervals of 3–12 mo and were recommended to switch to deferred active treatment in case of a progression in prostate-specific antigen, grade, or stage.

Outcome measurements and statistical analysis

The end points—overall survival (OS), treatment-free survival, failure-free (no relapse after radical treatment) survival, and cancer-specific survival—were calculated for various risk groups (very low, low, intermediate, and high) with Kaplan-Meier estimates. A Cox proportional hazards model as well as a competing risk analysis were used to assess whether risk group or age at diagnosis was associated with failure after AS.

Results and limitations

Forty-five per cent of all screen-detected PCa were managed with AS, and very low-risk and low-risk PCa constituted 60% of all screen-detected PCa. Thirty-seven per cent (162 of 439) switched from surveillance to deferred active treatment, and 39 men failed AS. The 10-yr OS, treatment-free survival, and failure-free survival were 81.1%, 45.4%, and 86.4%, respectively (Kaplan-Meier estimates). Men with low-, intermediate-, and high-risk tumours had a hazard ratio for failure of 2.1 (p = 0.09), 3.6 (p = 0.002), and 4.6 (p = 0.15), respectively, compared to very low-risk tumours (Cox regression). Only one PCa death occurred, and one patient developed metastasis (both in the intermediate-risk group). The main limitation of this study is the relatively short follow-up.

Conclusions

A large proportion of men with screen-detected PCa can be managed with AS. AS appears safe for men with low-risk PCa.     

Eleven-Year Outcome of Patients with Prostate Cancers Diagnosed During Screening After Initial Negative Sextant Biopsies

Background

The appropriate way of biopsying a prostate remains controversial. Is sextant biopsy still adequate with repeat screening?

Objective

Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), lateralized sextant biopsies were applied. In this analysis we use distant end points to study the fate of prostate cancers (PCa) potentially missed by initial biopsies.

Design, setting, and participants

This retrospective study included 19 970 men ages 55–74 identified from the Rotterdam population registry and screened repeatedly for PCa between 1993 and 2005. PCa detected later in men with initially negative biopsies were considered as missed. Rescreening every 4 yr and a complete follow-up of 11 yr allowed an inventory of progressive and deadly disease in these men.

Intervention

Sextant biopsies initially, later lateralized, in screen-positive men.

Measurements

The fate of PCa potentially missed by initial sextant biopsies in terms of progression-free and PCa-specific survival were the main outcome measures. Kaplan-Meier analysis was used to evaluate differences between subgroups.

Results and limitations

In 3056 men with negative biopsies at the first screen, 287 PCa were subsequently detected. Of these 287 cases, 26 developed progressive disease and 7 died of PCa. Poor outcomes were encountered mainly in 20 interval cases. The seven PCa deaths in men with initially negative biopsies amounted to only 0.03% compared to the 0.35% PCa death rate in the whole population of 19 970 men. Limitations include the retrospective character of this analysis.

Conclusions

The number of potentially missed cancers with a poor outcome in terms of progression-free survival and deaths from PCa is very low. Despite some limitations, our data show that lateralized sextant biopsy is not obsolete if repeated screening is applied.     

Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019

BackgroundInnovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.ObjectiveTo present the results from the APCCC 2019.Design, setting, and participantsSimilar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.Outcome measurements and statistical analysisThe panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.Results and limitationsPanellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.ConclusionsThese voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.Patient summaryThe Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.     

Adjuvant High-Dose Intensity-Modulated Radiotherapy after Radical Prostatectomy for Prostate Cancer: Clinical Results in 104 Patients

Background

Approximately 25% of patients treated with adjuvant radiotherapy (RT) will develop a biochemical failure within 5 yr after RT when doses of 60–64 Gray (Gy) are used.

Objective

To report on the safety and biochemical outcome of adjuvant intensity-modulated RT (IMRT) with doses >70 Gy.

Design, setting, and participants

Between 1999 and 2008, 104 patients underwent radical prostatectomy (RP) followed by adjuvant IMRT with or without androgen deprivation (AD) with a median follow-up of 36 mo. Indications for adjuvant IMRT were capsule perforation, seminal vesicle invasion (SVI) and/or positive surgical margins at prostatectomy specimen. All patients were irradiated at a single tertiary academic centre. AD was initiated on the basis of SVI, a preprostatectomy prostate-specific antigen level >20 ng/ml, Gleason score ≥4 + 3 (n = 36), or personal preference of the referring urologist (n = 32).

Intervention

A median dose of 74 Gy was prescribed to the planning target volume using IMRT in all patients. AD consisted out of a luteinising hormone-releasing hormone analogue for 6 mo.

Measurements

We report on acute and late toxicity, biochemical relapse–free survival (bRFS), and clinical progression. The Kaplan-Meier method was used to estimate bRFS. Univariate analysis was used to examine the influence of patient- and treatment-related factors on bRFS.

Results and limitations

With respect to acute toxicity, no patients developed grade 3 gastrointestinal (GI) toxicity, and eight patients developed grade 3 genitourinary (GU) toxicity (8%). With respect to late toxicity, no patients developed grade 3 GI toxicity, and four patients (4%) developed grade 3 GU toxicity. A urethral stricture was observed in six patients (6%). The 3- and 5-yr actuarial bRFS was 93%. On univariate analysis, bRFS rates were worse when SVI (p < 0.02), Gleason score ≥4 + 3 (p < 0.02), or negative surgical margins (p < 0.02) were present. AD did not influence bRFS. Six patients had a clinical relapse.

Conclusions

Adjuvant high-dose IMRT after prostatectomy is safe and bRFS is excellent.     

Role of Surveillance Biopsy with No Cancer as a Prognostic Marker for Reclassification: Results from the Canary Prostate Active Surveillance Study

Background

Many patients who are on active surveillance (AS) for prostate cancer will have surveillance prostate needle biopsies (PNBs) without any cancer evident.

Long-term Distress After Radical Prostatectomy Versus Watchful Waiting in Prostate Cancer: A Longitudinal Study from the Scandinavian Prostate Cancer Group-4 Randomized Clinical Trial

Background

Studies enumerating the dynamics of physical and emotional symptoms following prostate cancer (PCa) treatment are needed to guide therapeutic strategy. Yet, overcoming patient selection forces is a formidable challenge for observational studies comparing treatment groups.

Objective

To compare patterns of symptom burden and distress in men with localized PCa randomized to radical prostatectomy (RP) or watchful waiting (WW) and followed up longitudinally.

Design, setting, and participants

The three largest, Swedish, randomization centers for the Scandinavian Prostate Cancer Group-4 trial conducted a longitudinal study to assess symptoms and distress from several psychological and physical domains by mailed questionnaire every 6 mo for 2 yr and then yearly through 8 yr of follow-up.

Intervention

RP compared with WW.

Outcome measurements and statistical analysis

A questionnaire was mailed at baseline and then repeatedly during follow-up with questions concerning physical and mental symptoms. Each analysis of quality of life was based on a dichotomization of the outcome (yes vs no) studied in a binomial response, generalized linear mixed model.

Results and limitations

Of 347 randomized men, 272 completed at least five questionnaires during an 8-yr follow-up period. Almost all men reported that PCa negatively influenced daily activities and relationships. Health-related distress, worry, feeling low, and insomnia were consistently reported by approximately 30–40% in both groups. Men in the RP group consistently reported more leakage, impaired erection and libido, and fewer obstructive voiding symptoms. For men in the WW group, distress related to erectile symptoms increased gradually over time. Symptom burden and distress at baseline was predictive of long-term outlook.

Conclusions

Cancer negatively influenced daily activities among almost all men in both treatment groups; health-related distress was common. Trade-offs exist between physiologic symptoms, highlighting the importance of tailored treatment decision-making. Men who are likely to experience profound long-term distress can be identified early in disease management.     

Prostate Cancer Prevention Trial and European Randomized Study of Screening for Prostate Cancer Risk Calculators: A Performance Comparison in a Contemporary Screened Cohort

Background

Several models can predict the risk of prostate cancer (PCa) on biopsy.

Objective

To evaluate the performance of the Prostate Cancer Prevention Trial (PCPT) and European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculators in detecting PCa in a contemporary screened cohort.

Design, setting, and participants

We analyzed prebiopsy characteristics of 525 consecutive screened patients submitted to biopsy, as required by the risk calculators, in one European center between 2006 and 2007.

Measurements

Comparisons were done using tests of accuracy (area under the receiver operating characteristic curve [AUC-ROC]), calibration plots, and decision curve analysis. Biopsy predictors were identified by univariate and multivariate logistic regression.

Results and limitations

PCa was detected in 35.2% of the subjects. Among predictors included in the calculators, the logarithmic transformations of prostate volume and prostate-specific antigen (PSA), digital rectal examination, previous biopsy status, and age were significantly associated with PCa; transrectal ultrasound abnormalities and family history were not. AUC-ROC for the ERSPC calculator was significantly higher than the PCPT calculator and PSA alone (80.1%, 74.4%, and 64.3%, respectively). Calibration plots showed better performance for the ERSPC calculator; nevertheless, ERSPC may underestimate risk, while PCPT tends to overestimate predictions. Decision curve analysis displayed higher net benefit for the ERSPC calculator; 9% and 23% unnecessary biopsies can be avoided if a threshold probability of 20% and 30%, respectively, is adopted. In contrast, the PCPT model displayed very limited benefit. Our findings apply to a screened European cohort submitted to extended biopsy schemes; consequently, caution should be exerted when considering different populations.

Conclusions

The ERSPC risk calculator, by incorporating several risks factors, can aid in the estimation of individual PCa risk and in the decision to perform biopsy. The ERSPC calculator outperformed the PCPT model, which is of very limited value, in a contemporary cohort of screened patients.