Utilizing digital pathology to quantify stromal caveolin-1 expression in malignant and benign ovarian tumors: Associations with clinicopathological parameters and clinical outcomes

Loss of stromal caveolin-1 (Cav-1) is a biomarker of a cancer-associated fibroblast (CAF) phenotype and is related to progression, metastasis, and poor outcomes in several cancers. The objective of this study was to evaluate the clinical significance of Cav-1 expression in invasive epithelial ovarian cancer (OvCa). Epithelial and stromal Cav-1 expression were quantified in serous OvCa and benign ovarian tissue in two, independent cohorts–one quantified expression using immunohistochemistry (IHC) and the other using multiplex immunofluorescence (IF) with digital image analysis designed to target CAF-specific expression. Cav-1 expression was significantly downregulated in OvCa stroma compared to non-neoplastic stroma using both the IHC (p = 0.002) and IF (p = 1.8x10-13) assays. OvCa stroma showed Cav-1 downregulation compared to tumor epithelium with IHC (p = 1.2x10-24). Conversely, Cav-1 expression was higher in OvCa stroma compared to tumor epithelium with IF (p = 0.002). There was moderate correlation between IHC and IF methods for stromal Cav-1 expression (r2 = 0.69, p = 0.006) whereas there was no correlation for epithelial expression (r2 = 0.006, p = 0.98). Irrespective of the staining assay, neither response to therapy or overall survival correlated with the expression level of Cav-1 in the stroma or tumor epithelium. Our findings demonstrate a loss of stromal Cav-1 expression in ovarian serous carcinomas. Studies are needed to replicate these findings and explore therapeutic implications, particularly for immunotherapy response.

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Utilizing Digital Pathology to Quantify Stromal Caveolin-1 Expression in Malignant and Benign Ovarian Tumors: Associations with Clinicopathological Parameters and Clinical Outcomes

10.1101/2021.08.18.456818 ◽

2021 ◽

Author(s):

Daryoush Saeed-Vafa ◽

Douglas C. Marchion ◽

Susan M McCarthy ◽

Ardeshir Hakam ◽

Alexis Lopez ◽

...

Keyword(s):

Ovarian Tissue ◽

Digital Pathology ◽

Response To Therapy ◽

Clinicopathological Parameters ◽

Specific Expression ◽

Therapeutic Implications ◽

Caveolin 1 ◽

Poor Outcomes ◽

Benign Ovarian Tumors ◽

Invasive Epithelial Ovarian Cancer

AbstractLoss of stromal caveolin-1 (Cav-1) is a biomarker of a cancer-associated fibroblast (CAF) phenotype and is related to progression, metastasis, and poor outcomes in several cancers. The objective of this study was to evaluate the clinical significance of Cav-1 expression in invasive epithelial ovarian cancer (OvCa). Epithelial and stromal Cav-1 expression were quantified in serous OvCa and benign ovarian tissue in two, independent cohorts – one quantified expression using immunohistochemistry (IHC) and the other using multiplex immunofluorescence (IF) with digital image analysis designed to target CAF-specific expression. Cav-1 expression was significantly downregulated in OvCa stroma compared to non-neoplastic stroma using both the IHC (p=0.002) and IF (p=1.8×10-13) assays. OvCa stroma showed Cav-1 downregulation compared to tumor epithelium with IHC (p=1.2×10-24). Conversely, Cav-1 expression was higher in OvCa stroma compared to tumor epithelium with IF (p=0.002). There was moderate correlation between IHC and IF methods for stromal Cav-1 expression (r2= 0.69, p=0.006) whereas there was no correlation for epithelial expression (r2=0.006, p=0.98). Irrespective of the staining assay, neither response to therapy or overall survival correlated with the expression level of Cav-1 in the stroma or tumor epithelium. Our findings demonstrate a loss of stromal Cav-1 expression in ovarian serous carcinomas. Studies are needed to replicate these findings and explore therapeutic implications, particularly for immunotherapy response.

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LINC-25. BRAF ABERRATIONS IN PEDIATRIC PILOCYTIC ASTROCYTOMAS (PCAs): PREVALENCE AND IMPACT ON CLINICAL OUTCOME

Neuro-Oncology ◽

10.1093/neuonc/noaa222.459 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii383-iii383

Author(s):

Subramaniam Ramanathan ◽

Maya Prasad ◽

Tushar Vora ◽

Mamta Gurav ◽

Ayushi Sahay ◽

...

Keyword(s):

Clinical Outcome ◽

Statistical Significance ◽

Tumor Resection ◽

Brafv600e Mutation ◽

Therapeutic Implications ◽

Pilocytic Astrocytomas ◽

Ffpe Tissues ◽

Braf Fusion ◽

Poor Outcomes ◽

The Impact

Abstract BACKGROUND Increasing knowledge on pilocytic astrocytoma (PCA) biology now points towards an aberration in BRAF/MAPK/ERK pathway which has both diagnostic and therapeutic implications. This study was done to note the impact of BRAF aberrations on clinical outcome in childhood PCA. METHODS FFPE tissues of all childhood PCA diagnosed during 2011–2017 were evaluated for BRAFV600E mutation by Sanger sequencing and KIAA1549 fusion transcripts (16–9;15–9;16-11) by reverse transcriptase polymerase chain reaction. Children undergoing gross tumor resection received no adjuvant treatment. Unresectable tumors (only biopsy) and NF-1 associated PCAs, were treated if clinically indicated. Only patients with documented therapy details/followup were included for analysis. STUDY RESULTS Ninety-eight patients (median age-7.7yrs; boy:girl ratio-1.4) were included. Major sites were: Cerebellum-37(38%), 3rd Ventricle-26(27%), Cerebrum-15(15%). While BRAFV600E mutation was noted in 7/89(8%) specimens, BRAF-fusions were found in 34/85(40%). Following surgery/biopsy, 23(24%) and 21(22%) received adjuvant chemotherapy and radiotherapy respectively. The 1-year/3-year/5-year-EFS of the overall cohort was 90.7%/81.3%/67.4% respectively. Cerebellar tumors did better vis-à-vis other sites(5yr-EFS:74.3% v/s 66.4%;p=0.403). The 5yr-EFS of BRAF-fusion positive tumors (34), tumors without any BRAF aberration (40) and BRAFV600E mutant tumors (7) was 84.8%/ 69.6%/ 42.9% (p=0.215). CONCLUSIONS BRAF-fusion and BRAFV600E mutation were associated with good and poor outcomes respectively. Lack of statistical significance could be attributed to use of radiation as planned therapy in patients from earlier years. Data on BRAF aberrations in PCAs aids decision making regarding adjuvant therapy and choosing appropriate salvage-therapy especially in relapsed/refractory PCAs.

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FRI0224 IDENTIFICATION OF RISK AND PROGNOSTIC FACTORS FOR POLYARTERITIS NODOSA PATIENTS WITH DIGITAL GANGRENE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.817 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 695.2-695

Author(s):

D. Xu ◽

X. Tian ◽

X. Zeng ◽

F. Zhang ◽

L. Zhao ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Prognostic Factors ◽

Retrospective Study ◽

Polyarteritis Nodosa ◽

Lupus Erythematosus ◽

Disease Duration ◽

Response To Therapy ◽

Smoking History ◽

Systemic Lupus ◽

Poor Outcomes

Background:Polyarteritis nodosa (PAN) is a segmental, necrotizing vascular disease that primarily impacts medium-sized muscle arteries. The estimated annual incidence of PAN is still lacking in China. Digital gangrene is an ischemic manifestation of the limb. However, the causes and the treatment methods vary from case to case, and the outcome is unpredictable. These features emphasize the need to identify measurable variables that accelerate digital gangrene development in PAN patients. However, little effort has been made to identify the clinical and laboratory factors that affect PAN patients with digital gangrene to anticipate their natural history and response to therapy.Objectives:Many patients with polyarteritis nodosa (PAN) complicated with digital gangrene have poor outcomes and related research information is limited. This study was carried out to identify the associated risk and prognostic factors.Methods:We conducted a retrospective study of 148 PAN patients admitted to Peking Union Medical College Hospital (PUMCH) from September 1986 to December 2018. The characteristics, therapeutic regimens, and outcome data for patients with and without gangrene were compared. The Kaplan–Meier method and Cox hazard regression model were used to evaluate the prognostic factors.Results:Forty-seven (31.8%) PAN patients had digital gangrene complications. The average age was 40.4±17.9 years and the average disease duration was 11 (4-27) months. The presence of digital gangrene was correlated with smoking history [odds ratio (OR), 4.27; 95% confidence interval (95% CI), 1.56-11.66] and eosinophil elevation (28.12; 10.30-76.8). Thirty-two (68.1%) gangrene patients received methylprednisolone pulse therapy and all of these patients were treated with cyclophosphamide. Nine patients suffered irreversible organ injury and two died. Disease duration ≥ 24 months and elevated serum C-reactive protein (CRP) were identified as hazardous factors for poor prognosis in patients with gangrene (P=0.003, HR=8.668, 95% CI 2.11, 35.55 andP=0.042, HR=27.062, 95% CI 1.13, 648.57, respectively).Conclusion:Smoking history and eosinophil elevation in PAN patients were more prone to digital gangrene and high serum CRP level predicted poor outcomes. PAN patients with smoking history and elevated eosinophils need to be seriously evaluated by clinicians. Furthermore, the CRP level should be efficiently controlled for good prognosis.References:[1]De Virgilio A, Greco A, Magliulo G, Gallo A, Ruoppolo G, Conte M, et al. Polyarteritis nodosa: A contemporary overview. Autoimmun Rev. 2016;15:564-70.[2]Pagnoux C, Seror R, Henegar C, Mahr A, Cohen P, Le Guern V, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis Rheum. 2010;62:616-26.[3]Xu D, You X, Wang Z, Zeng Q, Xu J, Jiang L, et al. Chinese Systemic Lupus Erythematosus Treatment and Research Group Registry VI: Effect of Cigarette Smoking on the Clinical Phenotype of Chinese Patients with Systemic Lupus Erythematosus. PLoS One. 2015;10:e0134451.Acknowledgments:NoDisclosure of Interests:Dong Xu: None declared, Xinping Tian: None declared, Xiaofeng Zeng Consultant of: MSD Pharmaceuticals, Fengchun Zhang: None declared, Lin Zhao: None declared, Shangzhu Zhang: None declared, Jiaxin Zhou: None declared, Jiu-liang Zhao: None declared, Xiaodan Kong: None declared

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Prediction of short-term antidepressant response using probabilistic graphical models with replication across multiple drugs and treatment settings

Neuropsychopharmacology ◽

10.1038/s41386-020-00943-x ◽

2021 ◽

Author(s):

Arjun P. Athreya ◽

Tanja Brückl ◽

Elisabeth B. Binder ◽

A. John Rush ◽

Joanna Biernacka ◽

...

Keyword(s):

Depressive Symptoms ◽

Graphical Models ◽

Selective Serotonin Reuptake Inhibitors ◽

Probabilistic Graphical Models ◽

Sociodemographic Factors ◽

Response To Therapy ◽

Antidepressant Response ◽

Symptom Profiles ◽

Poor Outcomes ◽

Multiple Drugs

AbstractHeterogeneity in the clinical presentation of major depressive disorder and response to antidepressants limits clinicians’ ability to accurately predict a specific patient’s eventual response to therapy. Validated depressive symptom profiles may be an important tool for identifying poor outcomes early in the course of treatment. To derive these symptom profiles, we first examined data from 947 depressed subjects treated with selective serotonin reuptake inhibitors (SSRIs) to delineate the heterogeneity of antidepressant response using probabilistic graphical models (PGMs). We then used unsupervised machine learning to identify specific depressive symptoms and thresholds of improvement that were predictive of antidepressant response by 4 weeks for a patient to achieve remission, response, or nonresponse by 8 weeks. Four depressive symptoms (depressed mood, guilt feelings and delusion, work and activities and psychic anxiety) and specific thresholds of change in each at 4 weeks predicted eventual outcome at 8 weeks to SSRI therapy with an average accuracy of 77% (p = 5.5E-08). The same four symptoms and prognostic thresholds derived from patients treated with SSRIs correctly predicted outcomes in 72% (p = 1.25E-05) of 1996 patients treated with other antidepressants in both inpatient and outpatient settings in independent publicly-available datasets. These predictive accuracies were higher than the accuracy of 53% for predicting SSRI response achieved using approaches that (i) incorporated only baseline clinical and sociodemographic factors, or (ii) used 4-week nonresponse status to predict likely outcomes at 8 weeks. The present findings suggest that PGMs providing interpretable predictions have the potential to enhance clinical treatment of depression and reduce the time burden associated with trials of ineffective antidepressants. Prospective trials examining this approach are forthcoming.

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Longitudinal high-dimensional analysis identifies biomarkers of response to anti-PD-1 immunotherapy

10.21203/rs.3.rs-863654/v1 ◽

2021 ◽

Author(s):

Run-Ze Li ◽

Xing-Xing Fan ◽

Ze-Bo Jiang ◽

Jumin Huang ◽

Hu-Dan Pan ◽

...

Keyword(s):

Clinical Response ◽

Mononuclear Cells ◽

Cell Function ◽

Immune Cell ◽

Response To Therapy ◽

High Dimensional ◽

Meso Scale Discovery ◽

Peripheral Blood Mononuclear ◽

Poor Outcomes ◽

Nsclc Patients

Abstract The response to immunotherapy could be better predicted by using a wide set of biomarkers, including serum tumor markers; however, robust immune markers associated with efficacy have yet to be validated. In this study, changes in immune cell subsets from NSCLC patients treated with anti-PD1 therapy were longitudinally monitored by high-dimensional cytometry by time of flight (CyTOF) and Meso Scale Discovery (MSD) multi-cytokines kits. The frequencies of circulating CD8+ and CD8+CD101hiTIM3+ (CCT T) subsets were significantly correlated with clinical response and survival. Enrichment of these populations in peripheral blood mononuclear cells (PBMCs) indicated a poor clinical response to ICB therapy. Cell function assays revealed that these subsets were remarkably impaired, which supported the poor outcomes observed. Additionally, longitudinal analysis showed that KLRG1 expression and cytokines were associated with the response to therapy. Overall, our results provide novel potential biomarkers for guiding the management of NSCLC patients eligible to anti-PD-1 therapy, and contribute insights for new therapeutic strategies.

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SATB1 and Her2 as predictive molecular and immunohistochemical markers for urothelial cell carcinoma of the bladder

Cancer Biomarkers ◽

10.3233/cbm-200072 ◽

2020 ◽

pp. 1-11

Author(s):

Samia Hussein ◽

Anan Fathi ◽

Nehal S. Abouhashem ◽

Samar Amer ◽

Mohamed Hemida ◽

...

Keyword(s):

Bladder Cancer ◽

Prognostic Significance ◽

Immunohistochemical Analysis ◽

Lymph Node Involvement ◽

Genetic Alterations ◽

Response To Therapy ◽

Clinicopathological Parameters ◽

Bladder Tissue ◽

Normal Bladder ◽

Erbb2 Mrna

Studying bladder cancer molecular biology revealed the presence of genetic alterations. So, detection of molecular biomarkers that help in monitoring the disease, evaluating the prognosis of the patients, and their response to therapy is needed. In this study, we investigated the expression and the prognostic significance of SATB-1 and ERBB2 mRNA and protein by quantitative RT-PCR and immunohistochemical analysis in urothelial bladder cancer cases and the surrounding normal bladder tissue. The correlations between the expression of both markers and the clinicopathological parameters were performed with further analysis of the correlation between the expression of SATB-1 and ERBB2. Compared to control, the expression of SATB-1 and ERBB2 mRNA and protein in cancer tissues were significantly up-regulated (p< 0.05). Also, a positive correlation between both markers was found (r= 0.53, p< 0.001). Moreover, elevated levels of both markers were significantly associated with the stage, lymph node involvement at both mRNA and protein levels (p< 0.001). In conclusion, there is a clinical significance of SATB-1 and ERBB2 as potential biomarkers for predicting bladder cancer patients of aggressive behavior and poor prognosis.

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Proteomic signatures of acute myeloid leukemia (AML) distinguishes different outcome groups across cytogenetics and identified potential therapy targets

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.6523 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 6523-6523

Author(s):

R. Tibes ◽

Y. Qiu ◽

K. Coombes ◽

B. Hennessy ◽

H. Kantarjian ◽

...

Keyword(s):

Transcriptional Profiling ◽

Initial Response ◽

Response To Therapy ◽

Specific Expression ◽

Therapy Targets ◽

Class 1 ◽

Marker Distribution ◽

Large Clusters ◽

Subsequent Relapse ◽

Risk Of Relapse

6523 Background: Cytogenetics (CG) guide AML treatment but reliable markers predicting response and relapse within CG groups are missing. We therefore determined whether functional proteomic signatures can classify AML into groups with different outcomes and risk of relapse. Method: Using Reverse Phase Protein Array, total and phospho-site specific expression of 37 proteins in 73 primary AML was measured. Outcomes in the set were comprised equally of primary refractory (PR), relapsed (Rel) and continuous complete remission (CCR) patients. Cell lysates were spotted on nitrocellulose coated slides, probed with validated antibodies, expression intensities were quantified, data was standardized and analyzed for correlations using different clustering approaches. Results: Unsupervised hierarchical clustering based on Pearsons’ correlation distance yielded 4 large clusters. Subsequent perturbation bootstrap re-sampling arranged samples into four classes that correlated with initial response to therapy and risk of relapse (see Table ). Protein profiles in each of he 4 classes differed. Cytogenetic marker distribution were similar across the 4 clusters. Class 1 and 4 demonstrated a similar predictive value of patient outcome as cytogenetics. In classes at highest risk of relapse (2, 3) different proteins were predictive of response. In class 2, the most discriminatory proteins predicting CCR were elevated AMPK, p27, 4-EBP1, BclXL. In class 3, relapsed patients had elevated PTEN, phospho-Stat3, total Stat3, and phospho-PKCα compared to CCR patients. Conclusion: Pretreatment protein expression signatures divide AML into classes that predict for initial achievement of CR and subsequent relapse independent of CG. Poteomic profiling may suggest potential therapy targets as opposed to CG or transcriptional profiling. These preliminary results need to be confirmed in formal training and test sets prior to changing patient management. [Table: see text] No significant financial relationships to disclose.

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Expression of caveolin-1 in renal neoplasms

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.14509 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 14509-14509

Author(s):

M. Zhou ◽

I. Tamaskar ◽

L. Sercia ◽

B. I. Rini ◽

R. M. Bukowski

Keyword(s):

Renal Cell ◽

Vascular Endothelial Cells ◽

Pearson Correlation ◽

Positive Control ◽

Renal Tumors ◽

Renal Cell Carcinomas ◽

Cell Renal Cell Carcinoma ◽

Growth And Survival ◽

Caveolin 1 ◽

Poor Outcomes

14509 Background: Caveolin-1 is the major structural and functional component of caveolae, which are specialized lipid raft microdomains on cell membrane important for signaling pathways related to cell adhesion, growth and survival. Studies have shown that clear cell renal cell carcinoma (CCRCC) expressed caveolin-1 and that the over-expression correlated with adverse pathological findings and poor outcomes. The expression of caveolin-1 in other types of renal tumors has not been studied. Methods: A tissue microarray (TMA) was constructed from 60 normal kidneys, 22 CCRCC, 20 papillary renal cell carcinomas (PRCC), 16 chromophobe renal cell carcinomas (ChRCC), and 19 oncocytomas (ONC). The TMA was immunostained for caveolin-1 protein. Membranous caveolin-1 expression was scored using the internal vascular endothelial cells as positive control. Results: Membranous caveolin-1 expression was detected in 19/22 (86.4%) CCRCC, in 1/20 (5%) PRCC, 0/16 (0%) ChRCC, and 1/19 (5.3%) ONC. Cytoplasmic caveolin-1 was detected in 16/22 (72.7%) CCRCC, 13/20 (65%) PRCC, 8/16 (50%) ChRCC and 13/19 (68.4%) ONC. Membranous caveolin-1 expression correlated with tumor size (Pearson correlation = 0.266, p = 0.043). There was no correlation between membranous or cytoplasmic caveolin-1 expression and other pathological parameters, including Fuhrman nuclear grade, or TNM stage. Conclusion: Caveolin-1 exhibits distinct subcellular localization in different renal tumors. Membranous caveolin-1 is most commonly detected in CCRCC, rarely found in PRCC and ONC, and is absent in ChRCC. This finding suggests that caveolin-1 may play an important role in the pathogenesis of CCRCC. [Table: see text]

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Modulation of soluble c-Met, bone turnover markers, angiogenic factors, and c-Met in men with mCRPC treated with cabozantinib.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.58 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 58-58 ◽

Cited By ~ 2

Author(s):

Paul G. Corn ◽

Andreas Varkaris ◽

Elsa M. Li Ning Tapia ◽

John C. Araujo ◽

Ana Aparicio ◽

...

Keyword(s):

Soft Tissue ◽

Bone Turnover ◽

Cell Function ◽

Angiogenic Factors ◽

Response To Therapy ◽

Specific Expression ◽

Bone Marrow Biopsies ◽

Bone Specific Alkaline Phosphatase ◽

Median Reduction ◽

Soluble C

58 Background: Cabozantinib (cabo) is a multi-TKI against c-Met and VEGFR2. Cabo elicits striking changes in bone scans (BS), reductions in soft-tissue mets, and improves bone pain in mCRPC. This unique response is unlinked from PSA and suggests that targets of Cabo reside in the bone microenvironment. To explore the underlying mechanisms of Cabo activity, we examined changes in soluble c-Met, angiogenic factors, bone specific alkaline phosphatase (BAP), and tumor specific c-Met signaling in men on Cabo. Methods: A phase II cohort of docetaxel pretreated men with mCRPC received Cabo. Response was assessed q6 wks by BS and CT scan. Blood and trans-iliac bone marrow biopsies (BMs) were collected pretreatment and at wk 6. Soluble c-Met was measured by ELISA, angiogenic factors by multiplex immunoassay, and tumor c-Met/phospho c-Met expression by IHC. Results: 21 patients with bony mets were evaluated; 38% also had soft tissue mets. 13/21 (62%) pts experienced an improvement (PRs + CRs) in BS and 2/8 (25%) achieved a PR in soft tissue mets. 12/20 (60%) pts had reductions in BAP on therapy (median reduction 48.5%). VEGFR2 levels decreased in response to therapy (p<0.0001) and VEGF levels increased (p<0.085). Soluble c-Met levels increased on therapy (p<0.009). Pretreatment BMs containing >5% tumor involvement (median 80%) were evaluable for 10 patients, 9 of whom also had a 6 wk BM. High intensity, tumor-specific expression of c-Met was detectable in 8/10 (80%) of pretreatment tumors (median involvement 60%) and increased in 4/9 (45%) pts at 6 wks (median increase 30%). Activated phospho c-Met was detectable in 9/10 (90%) of pretreatment tumors (median involvement 80%) and decreased in 5/9 (56%) pts (median reduction 30%) at 6 wks. Conclusions: The results of our study suggest that changes in soluble markers of c-Met, bone turnover, and angiogenesis are linked to Cabo activity. Analyses of BMs demonstrate high c-Met activation in pretreatment mets and suggest Cabo-mediated inhibition at 6 wks. These data support the hypothesis that c-Met contributes to “driver” signaling networks in mCRPC and suggest that biomarkers of stromal cell function should be prioritized for further study.

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Association of cfDNA androgen receptor amplifications with BRAF alterations in mCRPC.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.234 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 234-234

Author(s):

Elisa M. Ledet ◽

Joshua Schiff ◽

Patrick Cotogno ◽

Charlotte Manogue ◽

Emma M. Ernst ◽

...

Keyword(s):

Point Mutations ◽

Response To Therapy ◽

Cancer Center ◽

Therapeutic Implications ◽

Heterogenous Group ◽

Somatic Alterations ◽

The Common ◽

The Relationship ◽

Larger Sample ◽

Redwood City

234 Background: Cell free DNA (cfDNA) present in plasma of cancer pts can reflect tumoral alterations. Genomic alterations in cfDNA alter prognosis and abiraterone/enzalutamide resistance in mCRPC. The goal of this evaluation was to characterize AR amplifications (Amps) and various somatic point mutations (Muts) detected in mCRPC cfDNA and to relate those changes to other common alterations in the cfDNA landscape. Methods: A heterogenous group of 46 mCRPC patients (pts) with evidence of clinical progression from Tulane Cancer Center underwent cfDNA analysis using Guardant360 test (Guardant Health, Redwood City, CA). This evaluation included full exonic coverage of 70 genes and amplifications in 18 genes. Mutations reported herein include both known pathogenic mutations as well as mutations uncharacterized for functional importance. Results: 69.5% (n = 32) of the mCRPC pts evaluated had an AR alteration. Of the pts with AR alterations, 46.8% (n = 16) had AR Amps, 43.7% (n = 14) had AR Muts, and only 6.25% (n = 2) had both. In this cohort, AR alterations were the most commonly observed aberration. In addition to amplifications, 12 different AR Muts were detected. AR Muts included: T878A (n = 9), H875Y (n = 5), W742C (n = 4), AR L702H (n = 3), and others. To better understand the relationship between AR alteration and other commonly detected cfDNA aberrations, association between BRAF (35.5%), TP53 (46.7%), and MYC (22.2%) alterations and AR were assessed. Among these genes, TP53 alterations were all Muts and MYC alterations were all Amps. BRAF alterations were predominantly Amps (N = 15) though Muts were also detected (N = 6). Neither TP53 Muts or MYC Amps were significantly associated with AR alterations. On the other hand, BRAF alterations were significantly associated with AR Amps (p = 0.041); 60% (9/15) pts with AR Amps also had BRAF alteration (Odds ratio = 7.71, 95% CI 1.284- 46.366). Conclusions: AR alterations in cfDNA impact both disease progression and response to therapy. Co-segregation of AR and BRAF alterations may have significant prognostic and therapeutic implications. Further research and larger sample size is needed to further elucidate associations between the common somatic alterations detected in mCRPC.

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