Publications by authors named "Gillian Vandekerkhove"

17 Publications

  • Page 1 of 1

Development of secondary urothelial carcinoma following complete response to immune checkpoint inhibitors.

Urol Case Rep 2021 Nov 25;39:101762. Epub 2021 Jun 25.

Department of Medical Oncology, BC Cancer - Vancouver, Vancouver, Canada.

The management of metastatic urothelial cancer is rapidly evolving since immune checkpoint inhibitors were introduced. We present the case of a patient with metastatic upper tract urothelial cancer who had a complete response to durvalumab and tremelimumab. This patient then developed multiple non-invasive papillary bladder tumours. Next-generation sequencing revealed that the tumours shared ancestry with the upper tract cancer, although there were key differences, most notably the presence of a missense mutation in the upper tract disease that was absent in the bladder tumours. This illustrates an important practice point in the management of exceptional responders to checkpoint inhibitors.
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http://dx.doi.org/10.1016/j.eucr.2021.101762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254020PMC
November 2021

Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition.

Clin Cancer Res 2021 Aug 3;27(16):4610-4623. Epub 2021 Jun 3.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.

Purpose: Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance.

Experimental Design: We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA).

Results: Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the gene, with an average 50% increase in copy number, changes in mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements.

Conclusions: Our data show that the dominant genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1625DOI Listing
August 2021

Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer.

Nat Commun 2021 01 8;12(1):184. Epub 2021 Jan 8.

Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.

Molecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.
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http://dx.doi.org/10.1038/s41467-020-20493-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794518PMC
January 2021

, , and Defects Differentially Shape Prostate Tumor Driver Genomics and Clinical Aggression.

Clin Cancer Res 2021 Mar 7;27(6):1650-1662. Epub 2021 Jan 7.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: DNA damage repair (DDR) defects are common across cancer types and can indicate therapeutic vulnerability. Optimal exploitation of DDR defects in prostate cancer requires new diagnostic strategies and a better understanding of associated clinical genomic features.

Experimental Design: We performed targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer. Depth-based copy-number calls and heterozygous SNP imbalance were leveraged to expose DDR-mutant allelic configuration and categorize mechanisms of biallelic loss. We used split-read structural variation analysis to characterize tumor suppressor rearrangements. Patient-matched archival primary tissue was analyzed identically.

Results: , and were the most frequently disrupted DDR genes in circulating tumor DNA (ctDNA), collectively mutated in 15% of evaluable cases. Biallelic gene disruption via second somatic alteration or mutant allele-specific imbalance was identified in 79% of patients. A further 2% exhibited homozygous deletions. Tumor suppressors , and were controlled via disruptive chromosomal rearrangements in defective samples, but via oncogene amplification in context of defects. mutations were rare in cases with defects. DDR mutations were re-detected across 94% of serial ctDNA samples and in all available archival primary tissues, indicating they arose prior to metastatic progression. Loss of and , but not , was associated with poor clinical outcomes.

Conclusions: , and defects are each linked to distinct prostate cancer driver genomics and aggression. The consistency of DDR status in longitudinal samples and resolution of allelic status underscores the potential for ctDNA as a diagnostic tool.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3708DOI Listing
March 2021

Activating AKT1 and PIK3CA Mutations in Metastatic Castration-Resistant Prostate Cancer.

Eur Urol 2020 12 22;78(6):834-844. Epub 2020 May 22.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Background: Activating mutations in AKT1 and PIK3CA are undercharacterised in metastatic castration-resistant prostate cancer (mCRPC), but are linked to activation of phosphatidylinositol 3-kinase (PI3K) signalling and sensitivity to pathway inhibitors in other cancers.

Objective: To determine the prevalence, genomic context, and clinical associations of AKT1/PIK3CA activating mutations in mCRPC.

Design, Setting, And Participants: We analysed targeted cell-free DNA (cfDNA) sequencing data from 599 metastatic prostate cancer patients with circulating tumour DNA (ctDNA) content above 2%.

Outcome Measurements And Statistical Analysis: In patients with AKT1/PIK3CA mutations, cfDNA was subjected to PTEN intron sequencing and matched diagnostic tumour tissue was analysed when possible.

Results And Limitations: Of the patients, 6.0% (36/599) harboured somatic clonal activating mutation(s) in AKT1 or PIK3CA. Mutant allele-specific imbalance was common. Clonal mutations in mCRPC ctDNA were typically detected in pretreatment primary tissue and were consistent across serial ctDNA collections. AKT1/PIK3CA-mutant mCRPC had fewer androgen receptor (AR) gene copies than AKT1/PIK3CA wild-type mCRPC (median 4.7 vs 10.3, p =  0.003). AKT1 mutations were mutually exclusive with PTEN alterations. Patients with and without AKT1/PIK3CA mutations showed similar clinical outcomes with standard of care treatments. A heavily pretreated mCRPC patient with an AKT1 mutation experienced a 50% decline in prostate-specific antigen with Akt inhibitor (ipatasertib) monotherapy. Ipatasertib also had a marked antitumour effect in a patient-derived xenograft harbouring an AKT1 mutation. Limitations include the inability to assess AKT1/PIK3CA correlatives in ctDNA-negative patients.

Conclusions: AKT1/PIK3CA activating mutations are relatively common and delineate a distinct mCRPC molecular subtype with low-level AR copy gain. Clonal prevalence and evidence of mutant allele selection propose PI3K pathway dependency in selected patients. The use of cfDNA screening enables prospective clinical trials to test PI3K pathway inhibitors in this population.

Patient Summary: Of advanced prostate cancer cases, 6% have activating mutations in the genes AKT1 or PIK3CA. These mutations can be identified using a blood test and may help select patients suitable for clinical trials of phosphatidylinositol 3-kinase inhibitors.
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http://dx.doi.org/10.1016/j.eururo.2020.04.058DOI Listing
December 2020

Concurrent germline and somatic pathogenic BAP1 variants in a patient with metastatic bladder cancer.

NPJ Genom Med 2020 23;5:12. Epub 2020 Mar 23.

1Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC Canada.

Germline pathogenic variants in the BRCA1-associated protein-1 () gene cause the BAP1 tumor predisposition syndrome (TPDS). BAP1 TPDS is associated with an increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma, and several other cancer subtypes. Here, we report a germline nonsense variant (c.850G>T, p.Glu284Ter) in a patient with bladder cancer and a strong family history of malignancy. Concurrently, we identified a somatic frameshift variant, and as expected, immunostaining validated the loss of BAP1 protein in patient-derived tumor specimens. Together, these data provide strong evidence of pathogenicity in this case. With the addition of bladder cancer to the tumor types reported with germline mutations, our understanding of the BAP1 TPDS continues to evolve, and may affect future screening and surveillance guidelines.
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http://dx.doi.org/10.1038/s41525-020-0121-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089973PMC
March 2020

Identification of Hypermutation and Defective Mismatch Repair in ctDNA from Metastatic Prostate Cancer.

Clin Cancer Res 2020 03 19;26(5):1114-1125. Epub 2019 Nov 19.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.

Purpose: DNA mismatch repair defects (MMRd) and tumor hypermutation are rare and under-characterized in metastatic prostate cancer (mPC). Furthermore, because hypermutated MMRd prostate cancers can respond to immune checkpoint inhibitors, there is an urgent need for practical detection tools.

Experimental Design: We analyzed plasma cell-free DNA-targeted sequencing data from 433 patients with mPC with circulating tumor DNA (ctDNA) purity ≥2%. Samples with somatic hypermutation were subjected to 185 × whole-exome sequencing and capture of mismatch repair gene introns. Archival tissue was analyzed with targeted sequencing and IHC.

Results: Sixteen patients (3.7%) had somatic hypermutation with MMRd etiology, evidenced by deleterious alterations in , or , microsatellite instability, and characteristic trinucleotide signatures. ctDNA was concordant with mismatch repair protein IHC and DNA sequencing of tumor tissue. Tumor suppressors such as , and were inactivated by mutation rather than copy-number loss. Hotspot mutations in oncogenes such as , and were common, and the androgen receptor ()-ligand binding domain was mutated in 9 of 16 patients. We observed high intrapatient clonal diversity, evidenced by subclonal driver mutations and shifts in mutation allele frequency over time. Patients with hypermutation and MMRd etiology in ctDNA had a poor response to AR inhibition and inferior survival compared with a control cohort.

Conclusions: Hypermutated MMRd mPC is associated with oncogene activation and subclonal diversity, which may contribute to a clinically aggressive disposition in selected patients. In patients with detectable ctDNA, cell-free DNA sequencing is a practical tool to prioritize this subtype for immunotherapy..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1623DOI Listing
March 2020

Morphologic and genomic characterization of urothelial to sarcomatoid transition in muscle-invasive bladder cancer.

Urol Oncol 2019 11 1;37(11):826-836. Epub 2019 Oct 1.

Department of Urology, Inselspital, Bern University Hospital, University of Bern, Switzerland. Electronic address:

Introduction: The sarcomatoid morphology of muscle-invasive bladder cancer (MIBC) is associated with unfavorable prognosis. However, the genomic, transcriptomic, and proteomic relationship between conventional urothelial and synchronous sarcomatoid morphology is poorly defined.

Methods: We compiled a cohort of 21 MIBC patients with components of conventional urothelial and adjacent sarcomatoid morphology within the same tumor focus. We performed comprehensive pathologic and immunohistochemical characterization and in 4 selected cases, subjected both morphologic components to targeted DNA sequencing and whole transcriptome analysis.

Results: Synchronous sarcomatoid and urothelial morphology from the same MIBC foci shared truncal somatic mutations, indicating a common ancestral clone. However, additional mutations or copy number alterations restricted to the either component suggested divergent evolution at the genomic level. This was confirmed at the transcriptome level since while the urothelial component exhibited a basal-like subtype (TCGA2014: cluster III, LundTax: basal/squamous-like), the sarcomatoid morphology was predominantly cluster IV (claudin-low). Protein expression was consistent with a basal-like phenotype in both morphologies in 18/21 of cases. However, most cases had evidence of active epithelial-to-mesenchymal transition (E-Cad ↓ and Zeb1 or TWIST1 ↑) from urothelial toward the sarcomatoid morphology. Drug response signatures nominated different targets for each morphology and proposed agents under clinical investigation in liposarcoma or other sarcoma. PD-L1 expression was higher in the sarcomatoid than the urothelial component.

Conclusions: Conventional urothelial and adjacent sarcomatoid morphologies of MIBC arise from the same common ancestor and share a basal-like phenotype. However, divergence between the morphologies at the genome, transcriptome, and proteome level suggests differential sensitivity to therapy.
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http://dx.doi.org/10.1016/j.urolonc.2019.09.025DOI Listing
November 2019

Morphologic and genomic characterization of urothelial to sarcomatoid transition in muscle-invasive bladder cancer.

Urol Oncol 2019 09 26;37(9):573.e19-573.e29. Epub 2019 Jul 26.

Department of Urology, Inselspital, Bern University Hospital, University of Bern, Switzerland. Electronic address:

Introduction: The sarcomatoid morphology of muscle-invasive bladder cancer (MIBC) is associated with unfavorable prognosis. However, the genomic, transcriptomic, and proteomic relationship between conventional urothelial and synchronous sarcomatoid morphology is poorly defined.

Methods: We compiled a cohort of 21 MIBC patients with components of conventional urothelial and adjacent sarcomatoid morphology within the same tumor focus. We performed comprehensive pathologic and immunohistochemical characterization and in 4 selected cases, subjected both morphologic components to targeted DNA sequencing and whole transcriptome analysis.

Results: Synchronous sarcomatoid and urothelial morphology from the same MIBC foci shared truncal somatic mutations, indicating a common ancestral clone. However, additional mutations or copy number alterations restricted to the either component suggested divergent evolution at the genomic level. This was confirmed at the transcriptome level since while the urothelial component exhibited a basal-like subtype (TCGA2014: cluster III, LundTax: basal/squamous-like), the sarcomatoid morphology was predominantly cluster IV (claudin-low). Protein expression was consistent with a basal-like phenotype in both morphologies in 18/21 of cases. However, most cases had evidence of active epithelial-to-mesenchymal transition (E-Cad ↓ and Zeb1 or TWIST1 ↑) from urothelial toward the sarcomatoid morphology. Drug response signatures nominated different targets for each morphology and proposed agents under clinical investigation in liposarcoma or other sarcoma. PD-L1 expression was higher in the sarcomatoid than the urothelial component.

Conclusions: Conventional urothelial and adjacent sarcomatoid morphologies of MIBC arise from the same common ancestor and share a basal-like phenotype. However, divergence between the morphologies at the genome, transcriptome, and proteome level suggests differential sensitivity to therapy.
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http://dx.doi.org/10.1016/j.urolonc.2019.06.021DOI Listing
September 2019

Randomized Phase 1 Trial of Pembrolizumab with Sequential Versus Concomitant Stereotactic Body Radiotherapy in Metastatic Urothelial Carcinoma.

Eur Urol 2019 05 19;75(5):707-711. Epub 2019 Jan 19.

Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.

Preclinical data indicate that radiotherapy works synergistically with pembrolizumab, but the effect and toxicity of this combination may depend on radiotherapy timing. We conducted a randomized phase 1 trial combining pembrolizumab with either sequential (A) or concomitant (B) stereotactic body radiotherapy (SBRT) in metastatic urothelial carcinoma (mUC). No dose-limiting toxicity occurred. Treatment-related adverse events (trAEs; Common Terminology Criteria for Adverse Events v4.0) of grade 1-2 occurred in six of nine and all nine patients in arms A and B, respectively. One grade 3 trAE occurred in arm B. No grade 4-5 trAEs occurred. Overall response rates of 0% and 44.4% were noted in arms A and B, respectively, as per Response Evaluation Criteria in Solid Tumors v1.1. The trial was not powered to compare efficacy between arms. Targeted sequencing of tissue DNA and circulating tumor DNA (ctDNA) revealed high genomic concordance. Treatment response was associated with ctDNA fraction decline. We conclude that sequential and concomitant SBRT can be safely combined with pembrolizumab in mUC and that the effect of SBRT timing on efficacy is worth exploring further. PATIENT SUMMARY: This study assessed the safety of pembrolizumab combined with radiotherapy at two different time points in metastatic bladder cancer. We conclude that the combination treatment was well tolerated.
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http://dx.doi.org/10.1016/j.eururo.2019.01.009DOI Listing
May 2019

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer.

Eur Urol 2019 04 10;75(4):667-675. Epub 2019 Jan 10.

Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada. Electronic address:

Background: Several systemic therapeutic options exist for metastatic castrate-sensitive prostate cancer (mCSPC). Circulating tumor DNA (ctDNA) can molecularly profile metastatic castration-resistant prostate cancer and can influence decision-making, but remains untested in mCSPC.

Objective: To determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically relevant information to a prostate biopsy.

Design, Setting, And Participants: We collected plasma cell-free DNA (cfDNA) from 53 patients newly diagnosed with mCSPC and, where possible, during treatment. Targeted sequencing was performed on cfDNA and DNA from diagnostic prostate tissue.

Results And Limitations: The median ctDNA fraction was 11% (range 0-84%) among untreated patients but was lower (1.0%, range 0-51%) among patients after short-term (median 22d) androgen deprivation therapy (ADT). TP53 mutations and DNA repair defects were identified in 47% and 21% of the cohort, respectively. The concordance for mutation detection in matched samples was 80%. Combined ctDNA and tissue analysis identified potential driver alterations in 94% of patients, whereas ctDNA or prostate biopsy alone was insufficient in 19 cases (36%). Limitations include the use of a narrow gene panel and undersampling of primary disease by prostate biopsy.

Conclusions: ctDNA provides additional information to a prostate biopsy in men with de novo mCSPC, but ADT rapidly reduces ctDNA availability. Primary tissue and ctDNA share relevant somatic alterations, suggesting that either is suitable for molecular subtyping in de novo mCSPC. The optimal approach for biomarker development should utilize both a tissue and liquid biopsy at diagnosis, as neither captures clinically relevant somatic alterations in all patients.

Patient Summary: In men with advanced prostate cancer, tumor DNA shed into the bloodstream can be measured via a blood test. The information from this test provides complementary information to a prostate needle biopsy and could be used to guide management strategies. Sequencing data were deposited in the European Genome-phenome Archive (EGA) under study identifier EGAS00001003351.
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http://dx.doi.org/10.1016/j.eururo.2018.12.042DOI Listing
April 2019

Frequent mutation of the untranslated region in prostate cancer.

Commun Biol 2018 24;1:122. Epub 2018 Aug 24.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada.

Prostate cancer has a low somatic mutation rate but non-coding regions remain underexplored. We sequenced the untranslated regions (UTRs) of 72 established driver genes in 428 patients with metastatic prostate cancer and identified 3'-UTR mutations in 12% of patients. The mutations were predominantly insertions or deletions, covered the entire UTR without motif enrichment, and were not detected in other cancers. lies in head-on orientation with the androgen-regulated non-coding gene , resulting in strong prostate lineage-specific bidirectional transcription across the 3'-UTR. This suggests transcriptional activity as a cause for the localized hypermutation. The indel-dominant pattern of somatic mutation extends into the coding region, where it is shaped by clonal selection to yield a cluster of non-frameshift indels inside the forkhead domain. Somatic 3'-UTR mutations may prove useful for diagnostic and screening approaches, given their high frequency and lineage specificity.
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http://dx.doi.org/10.1038/s42003-018-0128-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123809PMC
August 2018

Biallelic tumour suppressor loss and DNA repair defects in de novo small-cell prostate carcinoma.

J Pathol 2018 10 28;246(2):244-253. Epub 2018 Aug 28.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.

Small-cell prostate carcinoma (SCPC) is an aggressive malignancy that is managed similarly to small-cell lung cancer. SCPC can evolve from prostate adenocarcinoma in response to androgen deprivation therapy, but, in rare cases, is present at initial cancer diagnosis. The molecular aetiology of de novo SCPC is incompletely understood, owing to the scarcity of tumour tissue and the short life-expectancy of patients. Through a retrospective search of our regional oncology pharmacy database, we identified 18 patients diagnosed with de novo SCPC between 2004 and 2017. Ten patients had pure SCPC pathology, and the remainder had some admixed adenocarcinoma foci, but all were treated with first-line platinum-based chemotherapy. The median overall survival was 28 months. We performed targeted DNA sequencing, whole exome sequencing and mRNA profiling on formalin-fixed paraffin-embedded archival tumour tissue. We observed frequent biallelic deletion and/or mutation of the tumour suppressor genes TP53, RB1, and PTEN, similarly to what was found in treatment-related SCPC. Indeed, at the RNA level, pure de novo SCPC closely resembled treatment-related SCPC. However, five patients had biallelic loss of DNA repair genes, including BRCA1, BRCA2, ATM, and MSH2/6, potentially underlying the high genomic instability of this rare disease variant. Two patients with pure de novo SCPC harboured ETS gene rearrangements involving androgen-driven promoters, consistent with the evolution of de novo SCPC from an androgen-driven ancestor. Overall, our results reveal a highly aggressive molecular landscape that underlies this unusual pathological variant, and suggest opportunities for targeted therapy strategies in a disease with few treatment options. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5137DOI Listing
October 2018

Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer.

Cancer Discov 2018 04 24;8(4):444-457. Epub 2018 Jan 24.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Primary resistance to androgen receptor (AR)-directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in and were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in , previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of amplifications did not outperform standard prognostic biomarkers, gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers. Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0937DOI Listing
April 2018

Clinical utility of emerging liquid biomarkers in advanced prostate cancer.

Cancer Genet 2018 12 25;228-229:151-158. Epub 2017 Aug 25.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6. Electronic address:

The therapeutic landscape of advanced prostate cancer (PCa) has rapidly expanded in recent years. Despite significant improvements in patient overall survival, it remains challenging to determine the optimal therapy and sequence of therapies for individual patients. The development of molecular biomarkers will be key for patient stratification, and for monitoring response and resistance to therapy. In this context, minimally-invasive blood-based "liquid" biopsies are attractive as a practical surrogate for solid tumor tissue, providing a window into metastatic disease. Circulating tumor cells and circulating cell-free tumor DNA in particular have demonstrated remarkable potential to inform on PCa patient outcomes through the detection of specific genomic and transcriptomic alterations. This review covers recent advances in the development of clinically-informative liquid biomarkers for advanced PCa.
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http://dx.doi.org/10.1016/j.cancergen.2017.08.003DOI Listing
December 2018

Circulating Tumor DNA Reveals Clinically Actionable Somatic Genome of Metastatic Bladder Cancer.

Clin Cancer Res 2017 Nov 31;23(21):6487-6497. Epub 2017 Jul 31.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.

Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer, but therapy selection will depend on practical tumor molecular stratification. Circulating tumor DNA (ctDNA) is established in several solid malignancies as a minimally invasive tool to profile the tumor genome in real-time, but is critically underexplored in bladder cancer. We applied a combination of whole-exome sequencing and targeted sequencing across 50 bladder cancer driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive bladder cancer, including 37 with metastatic disease. The majority of patients with metastasis, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total cfDNA (median 16.5%, range 3.9%-72.6%). Twelve percent of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic bladder cancer with 95% of patients harboring deleterious alterations to , or , and 70% harboring a mutation or disrupting rearrangement affecting chromatin modifiers such as Targetable alterations in MAPK/ERK or PI3K/AKT/mTOR pathways were robustly detected, including amplification of (20% of patients) and activating hotspot mutations in A (20%), with the latter mutually exclusive to truncating mutations in A novel gene fusion was identified in consecutive samples from one patient. Our study demonstrates that ctDNA provides a practical and cost-effective snapshot of driver gene status in metastatic bladder cancer. The identification of a wide spectrum of clinically informative somatic alterations nominates ctDNA as a tool to dissect disease pathogenesis and guide therapy selection in patients with metastatic bladder cancer. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1140DOI Listing
November 2017

Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer.

Eur Urol 2017 07 1;72(1):34-42. Epub 2017 Mar 1.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada. Electronic address:

Background: Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these mutations associate with differential response to androgen receptor (AR)-directed therapy.

Objective: To determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies and to establish whether biallelic DNA repair gene loss is detectable in matched circulating tumor DNA (ctDNA).

Design, Setting, And Participants: We recruited 319 mCRPC patients and performed targeted germline sequencing of 22 DNA repair genes. In patients with deleterious germline mutations, plasma cell-free DNA was also sequenced.

Outcome Measurements And Statistical Analysis: Prostate-specific antigen response and progression were assessed in relation to initial androgen deprivation therapy (ADT) and subsequent therapy for mCRPC using Kaplan-Meier analysis.

Results And Limitations: Of the 319 patients, 24 (7.5%) had deleterious germline mutations, with BRCA2 (n=16) being the most frequent. Patients (n=22) with mutations in genes linked to homologous recombination were heterogeneous at initial presentation but, after starting ADT, progressed to mCRPC with a median time of 11.8 mo (95% confidence interval [CI] 5.1-18.4). The median time to prostate-specific antigen progression on first-line AR-targeted therapy in the mCRPC setting was 3.3 mo (95% CI 2.7-3.9). Ten out of 11 evaluable patients with germline BRCA2 mutations had somatic deletion of the intact allele in ctDNA. A limitation of this study is absence of a formal control cohort for comparison of clinical outcomes.

Conclusions: Patients with mCRPC who have germline DNA repair defects exhibit attenuated responses to AR-targeted therapy. Biallelic gene loss was robustly detected in ctDNA, suggesting that this patient subset could be prioritized for therapies exploiting defective DNA repair using a liquid biopsy.

Patient Summary: Patients with metastatic prostate cancer and germline DNA repair defects exhibit a poor response to standard hormonal therapies, but may be prioritized for potentially more effective therapies using a blood test.
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http://dx.doi.org/10.1016/j.eururo.2017.02.023DOI Listing
July 2017
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