Molecular Testing in Prostate Cancer

2014 ◽  
pp. 277-300
Author(s):  
Manal Y. Gabril ◽  
George M. Yousef
Keyword(s):  
Prostate Cancer ◽  
Molecular Testing

scholarly journals Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5830
Author(s):  
T. Hedley Carr ◽  
Carrie Adelman ◽  
Alan Barnicle ◽  
Iwanka Kozarewa ◽  
Sally Luke ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Phase Ii ◽  
Phase Iii ◽  
Response To Treatment ◽  
Homologous Recombination Repair ◽  
Molecular Testing ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Recombination Repair

Background: Phase III randomized trial data have confirmed the activity for olaparib in homologous recombination repair (HRR) mutated metastatic castration-resistant prostate cancer (mCRPC) post next-generation hormonal agent (NHA) progression. Preclinical data have suggested the potential for a combined effect between olaparib and NHAs irrespective of whether an HRR gene alteration was present. NCT01972217 was a randomised double-blind Phase II study which evaluated olaparib and abiraterone versus placebo and abiraterone in mCRPC patients who had received prior chemotherapy containing docetaxel. The study showed that radiologic progression was significantly delayed by the combination of olaparib and abiraterone regardless of homologous recombination repair mutation (HRRm) status. The study utilized tumour, blood (germline), and circulating tumour DNA (ctDNA) analysis to profile patient HRRm status, but tumour tissue provision was not mandated, leading to relatively low tissue acquisition and DNA sequencing success rates not representative of real-world testing. Patients and methods: Further analysis of germline and ctDNA samples has been performed for the trial to characterize HRRm status more fully and robustly analyse patient response to treatment. Results: Germline and plasma testing increased the HRRm characterized population from 27% to 68% of 142 randomized patients. Tumour-derived variants were detectable with high confidence in 78% of patients with a baseline plasma sample (71% of randomized patients). There was high concordance across methodologies (plasma vs. tumour; plasma vs. germline). The HR for the exploratory analysis of radiographic progression-free survival was 0.54 (95% CI: 0.32–0.93) in favour of olaparib and abiraterone in the updated HRR wild type (HRRwt) group (n = 73) and 0.62 (95% CI: 0.23–1.65) in the HRRm group (n = 23). Conclusion: Our results confirm the value of plasma testing for HRRm status when there is insufficient high-quality tissue for multi-gene molecular testing. We show that patients with mCRPC benefit from the combination of olaparib and abiraterone treatment regardless of HRRm status. The combination is currently being further investigated in the Phase III PROpel trial.

Genomic/genetic testing patterns for patients with metastatic castrate-resistant prostate cancer: Results from a real-world study in the United States.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 49-49
Author(s):  
Andrea Leith ◽  
Amanda Ribbands ◽  
Matthew Last ◽  
Alicia Gayle ◽  
Sarah Payne ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
United States ◽  
Genetic Testing ◽  
Real World ◽  
Patient Characteristics ◽  
The United States ◽  
Molecular Testing ◽  
Cancer Disease ◽  
The Us ◽  
Castrate Resistant

49 Background: In May 2020, Olaparib was approved for HRRm mCRPC post progression on abiraterone and enzalutamide, and rucaparib was approved for BRCAm mCPRC following progression on androgen receptor targeted inhibitors and prior taxane therapy for mCRPC. HRRm are associated with approximately 25% of mCRPC and may be derived from germline or somatic origin. Somatic and germline alterations can be detected by tumour testing, but to differentiate between these, independent germline testing is needed. This study examined real-world genomic/genetic testing (GT) patterns in patients (pts) diagnosed with mCRPC in the United States (US). Methods: Data were drawn from the Adelphi Prostate Cancer Disease Specific Programme; a point-in-time survey administered to oncologists (onc), urologists (uro) and surgeons (sur) between January and August 2020 in the US. Physicians (phys) completed an attitudinal survey and a patient record form for the next four to nine mCRPC pts seen. Study variables included patient demographics, clinical factors and GT patterns. HRRm testers were defined as phys who tested for HRRm. Pts were identified as positive, negative or unknown depending on the outcome of the HRRm test. Results: A total of 72 phys (69% onc/ 29% uro/ 1% sur; 40% academic vs. 60% community) reported on 346 mCRPC pts. 41% of phys were based in the Northeast, 24% Midwest, 23% South and 13% in the West region of the US. 65 phys (90%) reported having access to overall GT; of these 5% identified as having access to germline tests only, while 94% were able to test for germline and somatic mutations. Challenges to conducting GT overall were ‘cost per test’ (50%), ‘having to send out for the tests (within country)’ (25%), ‘inadequate sample available’ (25%) and ‘patient refusal’ (25%). GT was typically conducted at identification of castrate-resistance (52%), metastases (51%) and at initial diagnosis (49%). 72% of total phys were HRRm testers; for these, patient characteristics primarily driving HRRm testing included Ashkenazi Jewish heritage (63%) and ECOG of 2-4 (58%). Other common drivers were family history, young diagnosis age and hormone therapy failure (all 46%). 132 (38% of 326) mCRPC pts were tested for HRRm; 39% of tested pts were identified with a HRRm. Most common HRRm tested were BRCA1 (90%), BRCA2 (89%) and ATM (55%). Conclusions: In this study majority of US phys had access to GT, but testing was only performed in 38% of pts with mCRPC. The higher than expected % of pts identified with an HRRm suggest that molecular testing was prioritised in high risk populations, as identified by the phys. With the recent approval of olaparib and rucaparib, GT may become more routine in clinical practice to identify eligible pts. Broader testing may also depend on addressing other barriers to testing including cost and testing logistics/practicalities.

scholarly journals Biomarker, Molecular, and Technologic Advances in Urologic Pathology, Oncology, and Imaging

2017 ◽  
Vol 141 (4) ◽  
pp. 499-516
Author(s):  
Carla L. Ellis ◽  
Lara R. Harik ◽  
Cynthia Cohen ◽  
Adeboye O. Osunkoya
Keyword(s):  
Prostate Cancer ◽  
Chromosomal Translocation ◽  
Robotic Prostatectomy ◽  
Nerve Sparing ◽  
Molecular Testing ◽  
Inguinal Lymphadenectomy ◽  
Emerging Trends ◽  
Technical Advances ◽  
Targeted Gene Expression ◽  
Light Fluorescence

Urologic pathology is evolving rapidly. Emerging trends include the expanded diagnostic utility of biomarkers and molecular testing, as well as adapting to the plethora of technical advances occurring in genitourinary oncology, surgical practice, and imaging. We illustrate those trends by highlighting our approach to the diagnostic workup of a few selected disease entities that pathologists may encounter, including newly recognized subtypes of renal cell carcinoma, pheochromocytoma, and prostate cancer, some of which harbor a distinctive chromosomal translocation, gene loss, or mutation. We illustrate applications of immunohistochemistry for differential diagnosis of needle core renal biopsies, intraductal carcinoma of the prostate, and amyloidosis and cite encouraging results from early studies using targeted gene expression panels to predict recurrence after prostate cancer surgery. At our institution, pathologists are working closely with urologic surgeons and interventional radiologists to explore the use of intraoperative frozen sections for margins and nerve sparing during robotic prostatectomy, to pioneer minimally invasive videoscopic inguinal lymphadenectomy, and to refine image-guided needle core biopsies and cryotherapy of prostate cancer as well as blue-light/fluorescence cystoscopy. This collaborative, multidisciplinary approach enhances clinical management and research, and optimizes the care of patients with urologic disorders.

Chemokine signaling and MAPK/ERK pathway for advanced prostate cancer treatment response.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS275-TPS275
Author(s):  
Yazan Numan ◽  
Jonathan Zhao ◽  
Song Tang ◽  
Youbin Zhang ◽  
Qiang Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Targeted Therapy ◽  
Treatment Response ◽  
Specific Antigen ◽  
Treatment Resistance ◽  
Predictive Biomarker ◽  
High Response Rate ◽  
Erk Signaling ◽  
Molecular Testing ◽  
Castration Resistant Prostate Cancer

TPS275 Background: Androgen deprivation therapy (ADT) is the backbone of therapy for metastatic hormone sensitive prostate cancer (mHSPC). Despite a high response rate, the majority of patients progress to metastatic castration-resistant prostate cancer (mCRPC). Both disease settings are heterogeneous with variable responses to treatment. While prostate specific antigen is an important biomarker for prognosis and disease monitoring, it has limitations. Biomarkers predictive of disease response and progression are critically needed. Circulating tumor cells (CTCs) are shed from tumors and are found in blood during advanced stages of disease. Serial characterization of CTCs serves as a real-time ‘liquid biopsy’ for molecular profiling of PC. Recent reports suggest that phenotypic & genomic heterogeneity in CTCs and cell-free DNA (cfDNA) is associated with response to AR-targeted therapy highlighting the importance of CTC as a predictive biomarker. In addition, there is a high concordance between mutations in CTCs’ DNA and CRPC tissue through whole cell exome sequencing. We showed that atypical chemokine receptor CXCR7 is up-regulated following AR-targeted therapies, activating MAPK/ERK signaling and resulting in treatment resistance (Li et al., Cancer Res. 2019). To examine the potential of CXCR7/MAPK/ERK signaling in predicting treatment response, we propose to evaluate MAPK/ERK gene signature, pERK and AR level in CRPC or mHSPC patients receiving systemic therapy. Methods: Men with new CRPC or mHSPC are eligible prior to initiating new therapy for the respective disease setting of ADT + AR targeted therapy or chemotherapy. For CRPC arm, we will collect samples at baseline, 3, 6 months & at time of progression. For mHSPC arm, samples are collected at baseline, after 7 months & at progression. We will enroll 120 patients. Collected samples are subjected to identification, isolation, and enumeration of CTCs. Our primary molecular testing will include AR and pERK staining. CfDNA exome and methylome analysis will be performed to evaluate genomic heterogeneity and epigenomic alterations. We will explore pairwise association among biomarkers of interest, stratified by subgroups, using measures of association.

scholarly journals Molecular Testing in Patients With Castration-Resistant Prostate Cancer and Its Impact on Clinical Decision Making

2017 ◽  
pp. 1-11 ◽  
Author(s):  
Derrick L. Tao ◽  
Shawna Bailey ◽  
Tomasz M. Beer ◽  
Erik Foss ◽  
Brooke Beckett ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Decision Making ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Pten Expression ◽  
Molecular Testing ◽  
Castration Resistant Prostate Cancer ◽  
Molecular Abnormalities ◽  
Castration Resistant ◽  
Guided Therapy

Purpose Metastatic castration-resistant prostate cancer (CRPC) is the lethal form of the disease. Many groups have performed mutational or immunohistochemistry (IHC) testing in metastatic CRPC to identify treatment targets. However, the frequency with which mutational or IHC data have an impact on clinical decision making and the outcomes of molecularly guided therapy in CRPC are largely unknown. We report our institution’s experience with mutational and IHC testing in patients with metastatic CRPC and its impact on clinical decision making and patient outcomes. Methods Between 2012 and 2015, 59 patients with CRPC underwent metastatic tissue biopsies and were genotyped with a 37–cancer gene panel in a Clinical Laboratory Improvement Amendments–certified laboratory. PTEN expression by IHC testing was also measured in 35 of these samples. A retrospective chart review was performed to determine whether the genomic information was acted upon and the outcome of patients whose treatment was guided by molecular testing. Results Forty-six of 59 patients with CRPC (78.0%) had biopsies with adequate tumor for mutational testing. Thirty-one of 46 subjects (67.4%) had mutations identified by sequencing. Of the 35 patients with CRPC whose biopsies were evaluated for PTEN expression by IHC testing, 13 had PTEN loss. Two patients had treatment on the basis of molecular testing, and one of these subjects had greater tumor control with molecularly guided therapy than his immediate prior therapy. Conclusion Targeted sequencing and IHC can identify clinically informative molecular abnormalities in CRPC. Despite this, a small minority of patients in our series underwent therapies guided by mutational or IHC testing. Actionability of abnormalities identified in metastatic CRPC may be improved with access to clinical trials, insurance approval for unapproved uses of existing anticancer drugs, and larger gene sequencing panels that include more frequently mutated genes.

scholarly journals The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer

2020 ◽  
Author(s):  
Jonathan I. Epstein ◽  
Mahul B. Amin ◽  
Samson W. Fine ◽  
Ferran Algaba ◽  
Manju Aron ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Active Surveillance ◽  
Needle Biopsy ◽  
Intraductal Carcinoma ◽  
Secretory Cells ◽  
Molecular Testing ◽  
Lower Grade ◽  
Global Score ◽  
Gleason Pattern ◽  
Grade Groups

Context.— Controversies and uncertainty persist in prostate cancer grading. Objective.— To update grading recommendations. Data Sources.— Critical review of the literature along with pathology and clinician surveys. Conclusions.— Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace “tertiary grade pattern” in radical prostatectomy (RP) with “minor tertiary pattern 5 (TP5),” and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) “atypical intraductal proliferation (AIP)” is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.

scholarly journals Active Surveillance of Prostate Cancer: Use, Outcomes, Imaging, and Diagnostic Tools

2016 ◽  
pp. e235-e245 ◽  
Author(s):  
Jeffrey J. Tosoian ◽  
Stacy Loeb ◽  
Jonathan I. Epstein ◽  
Baris Turkbey ◽  
Peter L. Choyke ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Active Surveillance ◽  
The United States ◽  
Consensus Conference ◽  
Adverse Outcomes ◽  
Low Risk ◽  
Diagnostic Tools ◽  
Molecular Testing ◽  
Increased Risk ◽  
Considerable Morbidity

Active surveillance (AS) has emerged as a standard management option for men with very low-risk and low-risk prostate cancer, and contemporary data indicate that use of AS is increasing in the United States and abroad. In the favorable-risk population, reports from multiple prospective cohorts indicate a less than 1% likelihood of metastatic disease and prostate cancer–specific mortality over intermediate-term follow-up (median 5–6 years). Higher-risk men participating in AS appear to be at increased risk of adverse outcomes, but these populations have not been adequately studied to this point. Although monitoring on AS largely relies on serial prostate biopsy, a procedure associated with considerable morbidity, there is a need for improved diagnostic tools for patient selection and monitoring. Revisions from the 2014 International Society of Urologic Pathology consensus conference have yielded a more intuitive reporting system and detailed reporting of low-intermediate grade tumors, which should facilitate the practice of AS. Meanwhile, emerging modalities such as multiparametric magnetic resonance imaging and tissue-based molecular testing have shown prognostic value in some populations. At this time, however, these instruments have not been sufficiently studied to consider their routine, standardized use in the AS setting. Future studies should seek to identify those platforms most informative in the AS population and propose a strategy by which promising diagnostic tools can be safely and efficiently incorporated into clinical practice.

scholarly journals Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology

2019 ◽  
Vol 17 (5) ◽  
pp. 479-505 ◽  
Author(s):  
James L. Mohler ◽  
Emmanuel S. Antonarakis ◽  
Andrew J. Armstrong ◽  
Anthony V. D’Amico ◽  
Brian J. Davis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Practice ◽  
Genetic Testing ◽  
Risk Stratification ◽  
Hormonal Therapy ◽  
Advanced Disease ◽  
Treatment Options ◽  
Molecular Testing ◽  
Nccn Guidelines ◽  
Localized Disease

The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.

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