Genomic landscape of metastatic hormone sensitive prostate cancer (mHSPC) vs. metastatic castration-refractory prostate cancer (mCRPC) by circulating tumor DNA (ctDNA).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5043-5043
Author(s):  
Andrew W Hahn ◽  
Edwin Lin ◽  
John Esther ◽  
Neysi Anderson ◽  
Nityam Rathi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Machine Learning ◽  
Drug Targets ◽  
Circulating Tumor Dna ◽  
Erk Pathway ◽  
Genomic Landscape ◽  
Significant Difference ◽  
Chi Squared ◽  
Clinical Annotation ◽  
Hormone Sensitive

5043 Background: mCRPC carries a poor prognosis, and targeted therapies have had minimal success in mCRPC. Novel genomic targets could improve drug development. To date, large ctDNA studies in metastatic prostate cancer have been descriptive with limited or no clinical annotation. Herein, we hypothesize that profiles of genomic alterations (GAs) in ctDNA not only differ significantly between, but can also be used to predict mCRPC vs. mHSPC. These findings could help identify new drug targets for mCRPC treatment. Methods: Men with mHSPC or mCRPC who underwent NGS of ctDNA using G360 (Guardant Health Inc.) at the Huntsman Cancer Institute were included. Men were classified as mCRPC or mHSPC (patients with current or no prior ADT). G360 detects somatic mutations in selected exons of 73 genes, amplifications in 18 genes, and selected fusions in 6 genes. Two-sided students t-test was used to compare the %cfDNA and total GAs. The Chi squared test was used to compare the frequency of each GA. Machine learning (ML) algorithms were trained on GAs and benchmarked by cross-validated performance. GAs contributing to mCRPC vs. mHSPC classification were measured by ML feature importance (e.g. odds ratios, regression coefficients). Results: Of the 259 men included, 119 men had mHSPC and 140 had mCRPC. Men with mCRPC had more GAs (4.5 vs. 1.86, p<0.0001) and higher %cfDNA (9.56% vs. 5.02%, p=0.02). In mHSPC, there was no significant difference in the number of GAs or %cfDNA between men on ADT and those who hadn’t yet started ADT. ML algorithms used GAs to predict mCRPC with 78.1% sensitivity, 64.0% specificity, 76.7% PPV, 65.1% NPV, and 70.3% overall accuracy. mCRPC was enriched with GAs in AR, ARID1A, BRAF, BRCA2, CCNE1, CTNNB1, EGFR, FGFR1, KIT, MET, MYC, PDGFRB, PIK3CA, and TP53. Of note, many of these genes are involved in MAP/ERK signaling. Conclusions: Men with mCRPC have more GAs, higher %cfDNA, and enrichment of GAs in the MAP/ERK pathway compared to men with mHSPC. The distinct GAs seen in mCRPC represent novel therapeutic targets, especially in the MAP/ERK pathway. We also show that machine learning can differentiate mHSPC and mCRPC based on GAs detected in ctDNA.

scholarly journals Impact of pretreatment anemia on upfront abiraterone acetate therapy for metastatic hormone-sensitive prostate cancer: a multicenter retrospective study

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Teppei Okamoto ◽  
Daisuke Noro ◽  
Shingo Hatakeyama ◽  
Shintaro Narita ◽  
Koji Mitsuzuka ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prognostic Factor ◽  
Abiraterone Acetate ◽  
Tumor Burden ◽  
Hazard Ratio ◽  
Historical Cohort ◽  
High Tumor Burden ◽  
Significant Difference ◽  
Hormone Sensitive ◽  
The Impact

Abstract Background Anemia has been a known prognostic factor in metastatic hormone-sensitive prostate cancer (mHSPC). We therefore examined the effect of anemia on the efficacy of upfront abiraterone acetate (ABI) in patients with mHSPC. Methods We retrospectively evaluated 66 mHSPC patients with high tumor burden who received upfront ABI between 2018 and 2020 (upfront ABI group). We divided these patients into two groups: the anemia-ABI group (hemoglobin < 13.0 g/dL, n = 20) and the non-anemia-ABI group (n = 46). The primary objective was to examine the impact of anemia on the progression-free survival (PFS; clinical progression or PC death before development of castration resistant PC) of patients in the upfront ABI group. Secondary objectives included an evaluation of the prognostic significance of upfront ABI and a comparison with a historical cohort (131 mHSPC patients with high tumor burden who received androgen deprivation therapy (ADT/complete androgen blockade [CAB] group) between 2014 and 2019). Results We found that the anemia-ABI group had a significantly shorter PFS than the non-anemia-ABI group. A multivariate Cox regression analysis showed that anemia was an independent prognostic factor of PFS in the upfront ABI group (hazard ratio, 4.66; P = 0.014). Patients in the non-anemia-ABI group were determined to have a significantly longer PFS than those in the non-anemia-ADT/CAB group (n = 68) (P < 0.001). However, no significant difference was observed in the PFS between patients in the anemia-ABI and the anemia-ADT/CAB groups (n = 63). Multivariate analyses showed that upfront ABI could significantly prolong the PFS of patients without anemia (hazard ratio, 0.17; P < 0.001), whereas ABI did not prolong the PFS of patients with anemia. Conclusion Pretreatment anemia was a prognostic factor among mHSPC patients who received upfront ABI. Although the upfront ABI significantly improved the PFS of mHSPC patients without anemia, its efficacy in patients with anemia might be limited.

scholarly journals MRI-directed biopsy for primary detection of prostate cancer in a population of 223 men: MRI In-Bore vs MRI-transrectal ultrasound fusion-targeted techniques

2021 ◽  
Author(s):  
Maurizio Del Monte ◽  
Stefano Cipollari ◽  
Francesco Del Giudice ◽  
Martina Pecoraro ◽  
Marco Bicchetti ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Detection Rate ◽  
Transrectal Ultrasound ◽  
Focal Therapy ◽  
Malignant Cells ◽  
Median Percentage ◽  
Detection Rates ◽  
Biopsy Core ◽  
Significant Difference ◽  
Chi Squared

Objectives: To compare the detection rates of overall prostate cancer (PCa) and clinically significant PCa (csPCa) and the median percentage of cancer per biopsy core between MRI-guided In-bore and MRI-TRUS fusion-targeted biopsy (TBx). Methods: In this retrospective study, 223 patients who underwent prostate multiparametric MRI (mpMRI) and subsequent MR-directed biopsy were included. For PCa and csPCa detection rate (DR), contingency tables were tested via the Pearson’s chi-squared to explore the variance of the outcome distribution. The percentage of cancer per biopsy core was tested with a two-tailed Mann-Withney test. Results: One hundred and seventeen and 106 patients underwent MRI-TRUS fusion or MRI In-bore TBx, respectively. 402 MRI biopsy targets were identified, of which 206 (51.2%) were biopsied with the MRI-TRUS TBx and 196 (48.8%) with the MRI In-bore TBx technique. Per-patient PCa and csPCa detection rates were 140/223 (62.8%) and 97/223 (43.5%), respectively. PCa-DR was 73/117 (62.4%) and 67/106 (63.2%) for MRI-TRUS and MRI In-Bore TBx (p = 0.9), while csPCa detection rate reached 50/117 (42.7%) and 47/106 (44.3%), respectively (p = 0.81). The median per-patient percentage of malignant tissue within biopsy cores was 50% (IQR: 27–65%) for PCa and 60% (IQR: 35–68%) for csPCa, with a statistically significant difference between the techniques. Conclusion No statistically significant difference in the detection rate of MRI In-bore and MRI-TRUS fusion TBx was found. MRI In-bore TBx showed higher per-core percentage of malignant cells. Advances in knowledge MRI In-bore biopsy might impact risk stratification and patient management considering the higher per-core percentage of malignant cells, especially for patients eligible for active surveillance or focal therapy.

Treatments for metastatic hormone-sensitive prostate cancer: A systematic review.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 346-346
Author(s):  
Belal Firwana ◽  
Mohamad Bassam Sonbol ◽  
Fade A. Mahmoud ◽  
Konstantinos Arnaoutakis
Keyword(s):  
Prostate Cancer ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
P Value ◽  
Free Survival ◽  
Appropriate Treatment ◽  
Individual Trial ◽  
Efficacy Outcome ◽  
Significant Difference ◽  
Hormone Sensitive

346 Background: Over the past few years, the treatment of metastatic hormone sensitive prostate cancer (mHSPC) was revolutionized with the addition of docetaxel (DOC) or abiraterone (ABI) to the previous standard of care androgen deprivation treatment (ADT). Here, we sought to compare the effectiveness of docetaxel and abiraterone directly against ADT and indirectly to each other. Methods: We included randomized controlled trials (RCT) evaluating the efficacy of treatments in adults with newly diagnosed mHSPC. First-line treatments with DOC and ABI were considered. Efficacy outcome measures are overall survival (OS) and failure-free survival as (FFS) as defined by individual trial. If FFS was not reported, biochemical progression-free survival was considered FFS due to its specificity. The overall effect was pooled using the DerSimonian random effects model. Testing for subgroup difference was conducted using meta-regression method. Results: A total of five RCTs were included; three RCTs compared DOC+ADT versus ADT involving 2,992 participants, and two RCT compared ABI+ADT versus ADT involving 2,201 participants. The addition of DOC to ADT showed a significant improvement in OS compared to ADT monotherapy (HR 0.77, 95% CI 0.66 to 0.89) as well did the addition of ABI to ADT (HR 0.62, 95% CI 0.53 to 0.71). p-value for subgroup interaction was <0.05, suggesting a significant difference between pooled DOC and ABI effects, favoring the addition of ABI vs. DOC to ADT. Similar effects were found in significantly improving FFS when adding DOC (HR 0.64, 95% CI 0.58 to 0.70) or ABI (HR 0.30, 95% CI 0.27 to 0.34) to ADT compared to ADT monotherapy. p-value for interaction subgroup interaction was again significant <0.05 favoring the addition of ABI vs. DOC to ADT. Conclusions: The addition of either DOC or ABI to ADT showed significant improvement in OS and FFS when compared to ADT monotherapy in patients with mHSPC. Test for interaction suggests better outcome of ABI in comparison against DOC. Discussion with patients is encouraged to choose the appropriate treatment considering the adverse event profile for each. Further head-to-head comparison is needed to determine the effect.

scholarly journals Docetaxel vs. Novel Hormonal Agent for Upfront Management of De Novo Metastatic Hormone-Sensitive Prostate Cancer: A Comprehensive Report of a Single-Center Experience

2021 ◽  
Author(s):  
Sunny Guin ◽  
Bobby K. Liaw ◽  
Tomi Jun ◽  
Kristin Ayers ◽  
Bonny Patel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prognostic Value ◽  
Proportional Hazards ◽  
De Novo ◽  
Standard Of Care ◽  
Cox Proportional Hazards ◽  
Post Treatment ◽  
Real World Data ◽  
Significant Difference ◽  
Hormone Sensitive

Abstract Background: Upfront docetaxel or novel hormonal agents (NHA) such as abiraterone and enzalutamide have become the standard of care for metastatic hormone sensitive prostate cancer (mHSPC). However, data comparing the efficacy of docetaxel and NHAs in this setting are limited.Patients and Methods: This was a retrospective cohort study of patients with de novo mHSPC treated with upfront docetaxel or an NHA between January 1, 2014 and April 30, 2019 within the Mount Sinai Health System. Clinical data were extracted from the medical record. The primary outcome was failure-free survival (FFS), defined as the time to next treatment. The primary predictor was treatment with docetaxel or NHA. FFS was compared between the two groups using the Kaplan Meier method and multivariable Cox proportional hazards models. We additionally assessed the prognostic value of post-treatment PSA.Results: We identified 94 de novo mHSPC patients; 52 and 42 treated with upfront docetaxel and NHAs, respectively. NHAs were associated with significantly longer FFS compared to docetaxel (20.7 vs. 10.1 months, p=0.023). In a multivariable model adjusting for demographics and clinical factors, docetaxel was independently associated with worse FFS compared to NHAs (HR 1.96, 95% CI 1.12−3.45, p=0.019). High metastasis burden patients had a significantly longer FFS with NHAs than docetaxel (25.12 vs. 9.63 months, p=0.014), while there was no significant difference in FFS among low metastasis burden patients (NHA 20.71 vs. Docetaxel 26.5 months, p=0.9). Regardless of treatment, lower post-treatment PSA levels were associated with improved FFS (58.95 vs. 11.57 vs. 9.4 months for PSA ≤0.2, 0.2-0.4, >0.4ng/ml, respectively; p<0.001) Conclusion: Comparative analysis of real-world data demonstrated longer FFS in de novo mHSPC treated with NHA compared to docetaxel. In addition, the depth of PSA response following combination treatment may hold prognostic value for mHSPC outcomes.

Circulating tumor DNA-targeted sequencing to reveal germline and somatic alterations that can guide decision-making in metastatic castration-resistant prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17556-e17556
Author(s):  
Baijun Dong ◽  
Liancheng Fan ◽  
Bin Yang ◽  
Wei Chen ◽  
Yonghong Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Circulating Tumor Dna ◽  
Targeted Sequencing ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Genomic Landscape ◽  
Platinum Based Chemotherapy ◽  
Somatic Alterations ◽  
Multiple Treatments ◽  
Tumor Dna

e17556 Background: The genomic landscape of metastatic castration-resistant prostate cancer (mCRPC) is dynamic with the application of multiple treatments. The circulating tumor DNA (ctDNA), which reveals germline and somatic alterations, provides a mini-invasive tool for monitoring tumor evolution. Methods: We performed an exploratory analysis of 299 ctDNA samples from 8 centers through application of multiple-gene deep targeted sequencing. Results: The most common recurrent genomic alterations were in AR(34.7%), TP53(18.9%), CDK12(15.4%), BRCA2(13.3%), and the majority of these clinically actionable gene alterations were identified in somatic level (CDK12 100% in somatic). The results showed the frequency of AR amplification and TP53 defect significantly increased in post-second and later line treatment group compared with treatment-naive group. AR amplification and TP53 or RB1 defect were associated with resistance to abiraterone or docetaxel. CDK12 was more frequently altered in our cohort than those in previous reports which mainly focused on Caucasian population. The patients with CDK12 defect showed rapid resistance to abiraterone and limited efficacy of Poly (ADP-ribose) polymerase inhibitors (PARPi). However, these patients seemed to benefit from chemotherapy, especially platinum-based chemotherapy. Conclusions: This multi-institutional real-world study explored the genomic landscape and captured the significant diversity of mCRPC at different treatment stages by liquid biopsy. These findings established genomic drivers associated with resistance to multiple treatments (including PARPi and platinum-based chemotherapy) in mCRPC. Hence, ctDNA targeted sequencing can help guide clinical decision making in mCRPC throughout the whole treatment process. CDK12 might be able to be a novel predictive biomarker to guide treatment selection in mCRPC.

Association of basophil to lymphocyte ratio (BLR) with clinical outcomes in metastatic hormone sensitive prostate cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17049-e17049
Author(s):  
Katherine Emilie Rhoades Smith ◽  
Limeng Wan ◽  
Yuan Liu ◽  
Jacqueline T Brown ◽  
Greta Russler ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Outcomes ◽  
Laboratory Data ◽  
Progression Free Survival ◽  
Continuous Variable ◽  
Cancer Center ◽  
Lymphocyte Ratio ◽  
Potential Biomarker ◽  
Significant Difference ◽  
Hormone Sensitive

e17049 Background: There is limited biomarker data available for metastatic hormone sensitive prostate cancer (mHSPC). Inflammatory markers found on routine clinical lab data, including leukocyte to lymphocyte ratios calculated from complete blood counts (CBC), is associated with clinical outcomes (CO) in different malignancies. We investigated the association between basophil-to-lymphocyte ratio (BLR) and CO in a racially diverse patient population with mHSPC. Methods: We performed a retrospective multicenter review from Winship Cancer Institute at Emory University and Georgia Cancer Center for Excellence at Grady Memorial Hospital (2014 – 2020). Demographics, disease characteristics, and laboratory data were collected at the start of upfront therapy with either docetaxel (DOC) or abiraterone (ABI). Overall survival (OS) and progression-free survival (PFS) were used to measure CO. Results: Included were 165 patients with mHSPC with a median follow-up time of 22.6 months. 89 (53.9%) were Black and 76 (46.1%) were Non-Black (White, Asian, or Hispanic). 106 (63%) had Gleason scores of 8-10 and 105 (63.6%) were classified as high-volume disease (per CHAARTED trial criteria). 92 (55.8%) received DOC and 73 (44.2%) received ABI. Worse CO were associated with high BLR at an optimal cut of 0.0265 (range 0 – 0.81 , mean of 0.03, standard deviation 0.09). Elevated BLR is associated with decreased OS (HR 3.51, 1.79 – 6.91, p <0.001) and PFS (HR 1.85, 1.14 – 3.00, p 0.013) in multivariable analyses (MVA). High BLR and low BLR groups were similar except for age as a continuous variable, which was associated with high BLR. Otherwise, there were no significant difference for all reported clinical characteristics, including drug (DOC vs ABI), race (Black vs Non-Black), Gleason, disease volume (per CHARRTED criteria), ECOG, or BMI. Conclusions: In mHSPC, high baseline BLR is associated with worse OS and PFS. Our results are the first to identify that BLR is associated with CO in mHSPC. Further study is needed to validate BLR as a potential biomarker.[Table: see text]

The prognostic significance of homologous recombination repair pathway alterations in metastatic hormone-sensitive prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 150-150
Author(s):  
Justin Shaya ◽  
Aaron Lee ◽  
Angelo Cabal ◽  
Justine Panian ◽  
James Michael Randall ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Cox Regression ◽  
De Novo ◽  
Prognostic Significance ◽  
Parp Inhibitors ◽  
Homologous Recombination Repair ◽  
Significant Difference ◽  
Recombination Repair ◽  
Hormone Sensitive

150 Background: Little is known about the clinical course of patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) who harbor alterations in the homologous recombination repair (HRR) pathway. Here, we examine the outcomes of men with mHSPC with HRR alterations. Methods: Single center, retrospective analysis of men with mHSPC who underwent next generation sequencing from 2015-2020. The primary endpoint was to assess the time from diagnosis of mHSPC to onset of castrate resistance (mCRPC), as defined by PCWG3 criteria, in pts with HRR alterations vs wild type (WT). Both somatic and germline HRR alterations were permitted. Univariate and multivariate Cox regression were used to assess the effect of HRR alterations on time to mCRPC. Secondary endpoints included time to mCRPC stratified by HRR gene and time to treatment failure (TTF) in HRR altered vs WT pts, stratified by therapy. Results: We identified 151 men with mHSPC for the study. Median age was 66 years and 62% (n = 93) had de novo metastatic disease. 25% (n = 37) had HRR alterations detected and the most common alterations were in BRCA2 (n = 15), ATM (n = 10), CDK12 (n = 7). 78.4% (n = 29) of alterations were somatic and 13.5% (n = 5) of pts had co-alterations in 2 HRR genes. Time to mCRPC was significantly decreased in pts with HRR alterations vs WT (12.7 vs 16.1 mos, HR- 1.95, p- 0.02). In multivariate analysis, the effect of HRR alterations on time to mCRPC remained statistically significant when adjusting for age, mHSPC therapy, presence of visceral metastases, and PSA (adjusted HR- 1.69, p-0.02). Stratified by individual HRR gene, pts with BRCA2, CDK12, or co-occurring alterations had significantly decreased time to mCRPC compared to other HRR alterations (Table). In terms of mHSPC therapy, 45.7% were treated with ADT alone, 27.8% with an androgen receptor signaling inhibitor (ARSI), and 26.5% with docetaxel. TTF was inferior in HRR altered vs WT pts (10.8 vs 13.8 mos, p-0.004, HR- 1.84). Stratified by therapy, TTF was inferior in HRR altered vs WT pts treated with ADT alone (8.9 vs 13.3 mos, p- 0.019, HR-1.94) and there was no significant difference in TTF in HRR altered vs WT pts treated with either the addition of an ARSI or docetaxel. Conclusions: HRR alterations are associated with worsened outcomes in mHSPC patients. Given the established role of PARP inhibitors in mCRPC, these data highlight an opportunity to explore the use of PARP inhibitors in mHSPC to potentially improve outcomes. [Table: see text]

scholarly journals Prediction of Pathological Upgrading at Radical Prostatectomy in Prostate Cancer Eligible for Active Surveillance: A Texture Features and Machine Learning-Based Analysis of Apparent Diffusion Coefficient Maps

2021 ◽  
Vol 10 ◽  
Author(s):  
Jinke Xie ◽  
Basen Li ◽  
Xiangde Min ◽  
Peipei Zhang ◽  
Chanyuan Fan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Machine Learning ◽  
Diffusion Coefficient ◽  
Radical Prostatectomy ◽  
Apparent Diffusion Coefficient ◽  
Texture Features ◽  
Training Cohort ◽  
Machine Learning Methods ◽  
Significant Difference ◽  
Apparent Diffusion

ObjectiveTo evaluate a combination of texture features and machine learning-based analysis of apparent diffusion coefficient (ADC) maps for the prediction of Grade Group (GG) upgrading in Gleason score (GS) ≤6 prostate cancer (PCa) (GG1) and GS 3 + 4 PCa (GG2).Materials and methodsFifty-nine patients who were biopsy-proven to have GG1 or GG2 and underwent MRI examination with the same MRI scanner prior to transrectal ultrasound (TRUS)-guided systemic biopsy were included. All these patients received radical prostatectomy to confirm the final GG. Patients were divided into training cohort and test cohort. 94 texture features were extracted from ADC maps for each patient. The independent sample t-test or Mann−Whitney U test was used to identify the texture features with statistically significant differences between GG upgrading group and GG non-upgrading group. Texture features of GG1 and GG2 were compared based on the final pathology of radical prostatectomy. We used the least absolute shrinkage and selection operator (LASSO) algorithm to filter features. Four supervised machine learning methods were employed. The prediction performance of each model was evaluated by area under the receiver operating characteristic curve (AUC). The statistical comparison between AUCs was performed.ResultsSix texture features were selected for the machine learning models building. These texture features were significantly different between GG upgrading group and GG non-upgrading group (P &lt; 0.05). The six features had no significant difference between GG1 and GG2 based on the final pathology of radical prostatectomy. All machine learning methods had satisfactory predictive efficacy. The diagnostic performance of nearest neighbor algorithm (NNA) and support vector machine (SVM) was better than random forests (RF) in the training cohort. The AUC, sensitivity, and specificity of NNA were 0.872 (95% CI: 0.750−0.994), 0.967, and 0.778, respectively. The AUC, sensitivity, and specificity of SVM were 0.861 (95%CI: 0.732−0.991), 1.000, and 0.722, respectively. There had no significant difference between AUCs in the test cohort.ConclusionA combination of texture features and machine learning-based analysis of ADC maps could predict PCa GG upgrading from biopsy to radical prostatectomy non-invasively with satisfactory predictive efficacy.

scholarly journals A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 116-116
Author(s):  
Phuoc T. Tran ◽  
Ryan Phillips ◽  
William Shi ◽  
Su Jin Lim ◽  
Emmanuel S. Antonarakis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Randomized Trial ◽  
Phase Ii ◽  
Cell Receptor ◽  
Circulating Tumor Dna ◽  
Oncologic Outcomes ◽  
Radiation Fields ◽  
Oligometastatic Prostate Cancer ◽  
Hormone Sensitive ◽  
Grade 3

116 Background: Mounting evidence supports metastatic ablation for oligometastatic prostate cancer (OMPC). Importantly, biomarkers to determine patients who benefit most from complete ablation are unknown. We hypothesize that stereotactic ablative radiation (SABR) will improve oncologic outcomes in men with OMPC. Methods: In this phase II randomized trial, men with recurrent hormone-sensitive OMPC (1-3 radiation fields) were stratified by primary management (radiotherapy vs surgery), PSA doubling time, and prior androgen deprivation therapy and randomized 2:1 to SABR or observation (OBS). The primary endpoint was progression at 6 months by PSA (≥ 25% increase and ≥ nadir + 2 ng/mL), conventional imaging (RECIST 1.1 criteria or new lesion on bone scan), or symptomatic decline. Tissue, liquid and imaging correlatives were analyzed as biomarkers. Results: From 5/2016-3/2018, 54 patients were randomized. Progression at six months occurred in 19% of SABR patients and 61% of observation patients [p=0.005]. SABR improved median PFS (not reached vs 5.8 months, HR 0.30, p = 0.0023). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at six months (16% vs 63%, p = 0.006). No toxicity ≥ grade 3 was observed. T-cell receptor sequencing identified increased clonotypic expansion (p = 0.03) following SABR and correlation between baseline clonality and progression with SABR only. Analysis of circulating tumor DNA (ctDNA) and germline mutations identified a mutation profile that was associated with benefit from SABR. Conclusions: SABR for OMPC improves outcomes and is enhanced by total consolidation of disease identified by PSMA-targeted PET. SABR induces a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit from SABR. These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates. Clinical trial information: NCT02680587.

Genomic Landscape of Prostate Cancer and Opportunities for Precision Oncology

2018 ◽  
Author(s):  
Sheng-Yu Ku ◽  
Panagiotis J Vlachostergios ◽  
Himisha Beltran
Keyword(s):  
Prostate Cancer ◽  
Treatment Resistance ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Optimal Timing ◽  
Driver Gene ◽  
Precision Oncology ◽  
Castration Resistant Prostate Cancer ◽  
Molecular Features ◽  
Genomic Landscape

Recent metastatic biopsy programs combined with advances in sequencing technologies have provided new insights into the genomic landscape of castration-resistant prostate cancer (CRPC), identifying actionable targets and diverse resistance mechanisms. Here, we describe the molecular features of CRPC and how these findings are being translated into the clinic. Current challenges include tumor heterogeneity, the timing and potential cooperation of multiple driver gene aberrations, and the optimal timing and use of molecular profiling in the clinic including both tissue-based and liquid biopsy biomarkers (ie, circulating tumor cells and circulating tumor DNA). We summarize potential therapeutic strategies and ongoing molecularly-driven clinical trials. This review contains 5 figures, 2 tables and 57 references Key Words: androgen receptor, biomarkers, castrate-resistant prostate cancer, DNA repair, genomics, heterogeneity, precision oncology, targeted therapy, treatment resistance

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