Cancer, 2021
Authors
Daniel H Kwon, Jonathan Chou, Steven M Yip, Melissa A Reimers, Li Zhang, Francis Wright, Mallika S Dhawan, Hala T Borno, Arpita Desai, Rahul R Aggarwal, Alexander W Wyatt, Eric J Small, Ajjai S Alva, Kim N Chi, Felix Y Feng, Vadim S Koshkin
Publication Abstract

Background: DNA damage repair mutations (DDRm) are common in patients with metastatic castration-resistant prostate cancer (mCRPC). The optimal standard therapy for this population is not well described.

Methods: A multi-institutional, retrospective study of patients with mCRPC and DDRm was conducted. Patient data, including systemic therapies and responses, were collected. The decline in prostate-specific antigen ≥ 50% from baseline (PSA50) and overall survival (OS) from the treatment start were compared by mutation and treatment type. A multivariable Cox proportional hazards model for OS was created that controlled for DDRm, first-line treatment received for mCRPC, and clinical factors.

Results: The most common DDRm observed among 149 men with mCRPC were BRCA1/2 (44%), CDK12 (32%), and ATM (15%). The majority received first-line abiraterone (40%) or enzalutamide (30%). The PSA50 rate with first-line abiraterone was lower for CDK12 (52%) than BRCA1/2 (89%; P = .02). After first-line abiraterone or enzalutamide, the median OS was longest with second-line carboplatin-chemotherapy (38 months) in comparison with abiraterone or enzalutamide (33 months), docetaxel (17 months), or cabazitaxel (11 months; P = .02). PSA50 responses to carboplatin-based chemotherapy were higher for BRCA1/2 (79%) than ATM (14%; P = .02) or CDK12 (38%; P = .08). In a multivariable analysis, neither the specific DDRm type nor the first-line treatment was associated with improved OS.

Conclusions: Responses to standard therapies were generally superior in patients with BRCA1/2 mutations and inferior in patients with ATM or CDK12 mutations. The DDRm type did not independently predict OS. After progression on first-line abiraterone or enzalutamide, carboplatin-based chemotherapy was associated with the longest OS. These findings may inform treatment discussions and clinical trial design and require prospective validation.

Lung Cancer, 2021
Authors
Selina K Wong, Deepu Alex, Ian Bosdet, Curtis Hughesman, Aly Karsan, Stephen Yip, Cheryl Ho
Publication Abstract

Objectives: MET exon 14 skipping is a potentially targetable molecular alteration. The goals of this study were to identify patients treated in British Columbia with MET exon 14 skipping to understand prevalence, biology and response to treatment, and to identify molecular signatures that may predict for response or resistance to targeted MET therapy in the setting of advanced disease.

Materials and methods: A retrospective review was completed of patients found to have MET exon 14 skipping alterations between January 2016-September 2019. Information was collected on baseline characteristics, response to systemic treatments, and outcomes.

Results: Out of 1934 advanced, non-squamous and never-smoking squamous NSCLC patients tested, 41 patients were found to have MET exon 14 skipping (2.1 %). MET alteration types: 2% CBL binding-domain mutations, 34 % poly-pyrimidine tract deletions, 63 % splice donor mutations or deletions. The most common co-mutation was TP53 (22 %). Thirty-three patients received systemic therapy. Physician-assessed disease control was 68 % among 19 evaluable patients treated with crizotinib, 80 % among 10 evaluable patients treated with platinum-based chemotherapy, and 70 % among 10 evaluable patients treated with immunotherapy. Median time to treatment discontinuation was 3.0, 2.8, and 2.4 months, respectively. Median overall survival for metastatic patients treated with any systemic therapy was 15.4 months. In this small cohort, there were no clear correlations between molecular aberrations and response, time to treatment discontinuation, or survival for crizotinib, chemotherapy, and immunotherapy.

Conclusion: The prevalence of MET exon 14 skipping in a North American population was 2.1 %. Unlike other targetable mutations, patients were older and more commonly current or former smokers. Patients with MET exon 14 skipping alteration demonstrate disease control with crizotinib, platinum-based chemotherapy and immunotherapy. Co-mutations with TP53 were commonly noted, but correlation between co-mutations and efficacy of therapy were not identified in this cohort.

Blood 2021
Authors
Gerben Duns, Elena Viganò, Daisuke Ennishi, Clementine Sarkozy, Stacy S Hung, Elizabeth A Chavez, Katsuyoshi Takata, Christopher Rushton, Aixiang Jiang, Susana Ben-Neriah, Bruce Woolcock, Graham W Slack, Eric D Hsi, Jeffrey W Craig, Laura K Hilton, Sohrab Shah, Pedro Farinha, Anja Mottok, Randy D Gascoyne, Ryan D Morin, Kerry J Savage, David W Scott, Christian Steidl
Publication Abstract

Primary mediastinal large B-cell lymphoma (PMBL) is a type of aggressive B-cell lymphoma that typically affects young adults, characterized by presence of a bulky anterior mediastinal mass. Lymphomas with gene expression features of PMBL have been described in non-mediastinal sites, raising questions about how these tumors should be classified. Here, we investigated whether these "non-mediastinal PMBLs" are indeed PMBLs or instead represent a distinct group within DLBCL. From a cohort of 325 de novo DLBCL cases, we identified tumors from patients without evidence of anterior mediastinal involvement that expressed a PMBL expression signature (nm-PMBLsig-pos, n=16, 5%). The majority of these tumors expressed MAL and CD23 - proteins typically observed in bona fide PMBL (bf-PMBL). Evaluation of clinical features of nm-PMBLsig-pos cases revealed close associations with DLBCL, and the majority displayed a germinal center B-cell-like cell-of-origin (GCB). In contrast to bf-PMBL, nm-PMBLsig-pos patients presented at an older age, did not show pleural disease, and bone/bone marrow involvement was observed in three cases. However, while clinically distinct from bf-PMBL, nm-PMBL-sig-pos tumors resembled bf-PMBL at the molecular level with upregulation of immune response, JAK-STAT, and NF-kB signatures. Mutational analysis revealed frequent somatic gene mutations in SOCS1, IL4R, ITPKB and STAT6, as well as CD83 and BIRC3, with the latter genes being significantly more frequently affected than in GCB-DLBCL and bf-PMBL. Our data establish nm-PMBLsig-pos lymphomas as a group of DLBCL with distinct phenotypic and genetic features, and potential implications for gene expression- and mutation-based subtyping of aggressive B-cell lymphoma and related targeted therapies.

The Journal Of Pathology Clinical Research 2021
Authors
David Gonzalez, Joaquin Mateo, Albrecht Stenzinger, Federico Rojo, Michelle Shiller, Alexander W Wyatt, Frédérique Penault-Llorca, Leonard G Gomella, Ros Eeles, Anders Bjartell
Publication Abstract

Analysis of the genomic landscape of prostate cancer has identified different molecular subgroups with relevance for novel or existing targeted therapies. The recent approvals of the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib in the metastatic castration-resistant prostate cancer (mCRPC) setting signal the need to embed molecular diagnostics in the clinical pathway of patients with mCRPC to identify those who can benefit from targeted therapies. Best practice guidelines in overall biospecimen collection and processing for molecular analysis are widely available for several tumour types. However, there is no standard protocol for molecular diagnostic testing in prostate cancer. Here, we provide a series of recommendations on specimen handling, sample pre-analytics, laboratory workflow, and testing pathways to maximise the success rates for clinical genomic analysis in prostate cancer. Early involvement of a multidisciplinary team of pathologists, urologists, oncologists, radiologists, nurses, molecular scientists, and laboratory staff is key to enable optimal workflow for specimen selection and preservation at the time of diagnosis so that samples are available for molecular analysis when required. Given the improved outcome of patients with mCRPC and homologous recombination repair gene alterations who have been treated with PARP inhibitors, there is an urgent need to incorporate high-quality genomic testing in the routine clinical pathway of these patients.

Scientific Reports, 2021
Authors
Emmalyn Chen, Clinton L Cario, Lancelote Leong, Karen Lopez, César P Márquez, Carissa Chu, Patricia S Li, Erica Oropeza, Imelda Tenggara, Janet Cowan, Jeffry P Simko, June M Chan, Terence Friedlander, Alexander W Wyatt, Rahul Aggarwal, Pamela L Paris, Peter R Carroll, Felix Feng, John S Witte
Publication Abstract

Prostate cancer is the most commonly diagnosed neoplasm in American men. Although existing biomarkers may detect localized prostate cancer, additional strategies are necessary for improving detection and identifying aggressive disease that may require further intervention. One promising, minimally invasive biomarker is cell-free DNA (cfDNA), which consist of short DNA fragments released into circulation by dying or lysed cells that may reflect underlying cancer. Here we investigated whether differences in cfDNA concentration and cfDNA fragment size could improve the sensitivity for detecting more advanced and aggressive prostate cancer. This study included 268 individuals: 34 healthy controls, 112 men with localized prostate cancer who underwent radical prostatectomy (RP), and 122 men with metastatic castration-resistant prostate cancer (mCRPC). Plasma cfDNA concentration and fragment size were quantified with the Qubit 3.0 and the 2100 Bioanalyzer. The potential relationship between cfDNA concentration or fragment size and localized or mCRPC prostate cancer was evaluated with descriptive statistics, logistic regression, and area under the curve analysis with cross-validation. Plasma cfDNA concentrations were elevated in mCRPC patients in comparison to localized disease (OR5ng/mL = 1.34, P = 0.027) or to being a control (OR5ng/mL = 1.69, P = 0.034). Decreased average fragment size was associated with an increased risk of localized disease compared to controls (OR5bp = 0.77, P = 0.0008). This study suggests that while cfDNA concentration can identify mCRPC patients, it is unable to distinguish between healthy individuals and patients with localized prostate cancer. In addition to PSA, average cfDNA fragment size may be an alternative that can differentiate between healthy individuals and those with localized disease, but the low sensitivity and specificity results in an imperfect diagnostic marker. While quantification of cfDNA may provide a quick, cost-effective approach to help guide treatment decisions in advanced disease, its use is limited in the setting of localized prostate cancer.

Clinical Case Reports 2021
Authors
Heidi M Britton, Adrian B Levine, Yaoqing Shen, Karen Mungall, Jonathan Serrano, Matija Snuderl, Erin Pleasance, Steven J M Jones, Janessa Laskin, Marco A Marra, Shahrad R Rassekh, Rebecca Deyell, Stephen Yip, Sylvia Cheng, Chris Dunham
Publication Abstract

This is the first report of a NACC2-NTRK2 fusion in a histological glioblastoma. Oncogenomic analysis revealed this actionable fusion oncogene in a pediatric cerebellar glioblastoma, which would not have been identified through routine diagnostics, demonstrating the value of clinical genome profiling in cancer care.

Communications biology, 2021
Authors
Leung, Jacky K, Imamura, Yusuke, Kato, Minoru, Wang, Jun, Mawji, Nasrin R, Sadar, Marianne D
Publication Abstract
Therapies for lethal castration-resistant prostate cancer (CRPC) are an unmet medical need. One mechanism underlying CRPC and resistance to hormonal therapies is the expression of constitutively active splice variant(s) of androgen receptor (AR-Vs) that lack its C-terminus ligand-binding domain. Transcriptional activities of AR-Vs and full-length AR reside in its N-terminal domain (NTD). Ralaniten is the only drug proven to bind AR NTD, and it showed promise of efficacy in Phase 1 trials. The peptidyl-prolyl isomerase Pin1 is frequently overexpressed in prostate cancer. Here we show that Pin1 interacted with AR NTD. The inhibition of Pin1 expression or its activity selectively reduced the transcriptional activities of full-length AR and AR-V7. Combination of Pin1 inhibitor with ralaniten promoted cell cycle arrest and had improved antitumor activity against CRPC xenografts in vivo compared to individual monotherapies. These findings support the rationale for therapy that combines a Pin1 inhibitor with ralaniten for treating CRPC.

Prostate Cancer and Prostatic Diseases, 2021
Authors
Takayuki Sumiyoshi, Kim N Chi, Alexander W Wyatt
Publication Abstract

There has been a rapid expansion in treatment options for the management of metastatic prostate cancer, but individual patient outcomes can be variable due to inter-patient tumor heterogeneity. Fortunately, the disease can be stratified on the basis of common somatic features, providing potential for the development of clinically useful prognostic and predictive biomarkers. Tissue biopsy programs and studies leveraging circulating tumor DNA (ctDNA) have revealed specific genomic alterations that are associated with aggressive disease biology. In this review, we discuss the potential for genomic subtyping to improve prognostication and to help guide treatment selection. We summarize data on associations between AR pathway alterations and patient response to AR signaling inhibitors and other standards of care. We describe the links between detection of different types of DNA damage repair defects and clinical outcomes with targeted therapies such as poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors or immune checkpoint inhibitors. PI3K signaling pathway inhibitors are also in advanced clinical development and we report upon the potential for these and other novel targeted therapies to have impact in specific molecular subsets of metastatic prostate cancer. Finally, we discuss the growing use of blood-based analytes for prognostic and predictive biomarker development, and summarize ongoing prospective biomarker-driven clinical trials.

Scientific Reports, 2021
Authors
Chandra Lebovitz, Nicole Wretham, Maryam Osooly, Katy Milne, Tia Dash, Shelby Thornton, Basile Tessier-Cloutier, Paalini Sathiyaseelan, Svetlana Bortnik, Nancy Erro Go, Elizabeth Halvorsen, Rachel A Cederberg, Norman Chow, Nancy Dos Santos, Kevin L Bennewith, Brad H Nelson, Marcel B Bally, Wan L Lam, Sharon M Gorski.
Publication Abstract

Pathological links between neurodegenerative disease and cancer are emerging. LRRK2 overactivity contributes to Parkinson's disease, whereas our previous analyses of public cancer patient data revealed that decreased LRRK2 expression is associated with lung adenocarcinoma (LUAD). The clinical and functional relevance of LRRK2 repression in LUAD is unknown. Here, we investigated associations between LRRK2 expression and clinicopathological variables in LUAD patient data and asked whether LRRK2 knockout promotes murine lung tumorigenesis. In patients, reduced LRRK2 was significantly associated with ongoing smoking and worse survival, as well as signatures of less differentiated LUAD, altered surfactant metabolism and immunosuppression. We identified shared transcriptional signals between LRRK2-low LUAD and postnatal alveolarization in mice, suggesting aberrant activation of a developmental program of alveolar growth and differentiation in these tumors. In a carcinogen-induced murine lung cancer model, multiplex IHC confirmed that LRRK2 was expressed in alveolar type II (AT2) cells, a main LUAD cell-of-origin, while its loss perturbed AT2 cell morphology. LRRK2 knockout in this model significantly increased tumor initiation and size, demonstrating that loss of LRRK2, a key Parkinson's gene, promotes lung tumorigenesis.

The Journal of Molecular Diagnostics, 2021
Authors
Elizabeth R Starks, Lucas Swanson, T Roderick Docking, Ian Bosdet, Sarah Munro, Richard A Moore, Aly Karsan
Publication Abstract

Clinical reporting of solid tumor sequencing requires accurate assessment of the accuracy and reproducibility of each assay. Somatic mutation variant allele fractions may be below 10% in many samples due to sample heterogeneity, tumor clonality, and/or sample degradation in fixatives such as formalin. The toolkits available to the clinical sequencing community for correlating assay design parameters with assay sensitivity remain limited, and large-scale empirical assessments are often relied upon due to the lack of clear theoretical grounding. To address this uncertainty, we developed a theoretical model for predicting the expected variant calling sensitivity for a given library complexity and sequencing depth. We found that binomial models were appropriate when assay sensitivity was only limited by library complexity or sequencing depth, but that functional scaling for library complexity was necessary when both library complexity and sequencing depth were co-limiting. We empirically validated this model with sequencing experiments using a series of DNA input amounts and sequencing depths. Based on these findings, we propose a workflow for determining the limiting factors to sensitivity in different assay designs, and present the formulas for these scenarios. The approach described here provides designers of clinical assays with the methods to theoretically predict assay design outcomes a priori, potentially reducing burden in clinical tumor assay design and validation efforts.

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