Browsing by Author "Zhu, Jason"
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Item Open Access Acute Myeloid Leukemia After Olaparib Treatment in Metastatic Castration-Resistant Prostate Cancer.(Clinical genitourinary cancer, 2017-12) Zhu, Jason; Tucker, Matthew; Wang, Endi; Grossman, Joel S; Armstrong, Andrew J; George, Daniel J; Zhang, TianItem Open Access Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond.(J Immunother Cancer, 2018-01-25) Zhu, Jason; Armstrong, Andrew J; Friedlander, Terence W; Kim, Won; Pal, Sumanta K; George, Daniel J; Zhang, TianImmune checkpoint inhibitors targeting the PD-1 pathway have greatly changed clinical management of metastatic urothelial carcinoma and metastatic renal cell carcinoma. However, response rates are low, and biomarkers are needed to predict for treatment response. Immunohistochemical quantification of PD-L1 was developed as a promising biomarker in early clinical trials, but many shortcomings of the four different assays (different antibodies, disparate cellular populations, and different thresholds of positivity) have limited its clinical utility. Further limitations include the use of archival specimens to measure this dynamic biomarker. Indeed, until PD-L1 testing is standardized and can consistently predict treatment outcome, the currently available PD-L1 assays are not clinically useful in urothelial and renal cell carcinoma. Other more promising biomarkers include tumor mutational burden, profiles of tumor infiltrating lymphocytes, molecular subtypes, and PD-L2. Potentially, a composite biomarker may be best but will need prospective testing to validate such a biomarker.Item Open Access Clinical applications of liquid biopsies in gastrointestinal oncology.(Journal of gastrointestinal oncology, 2016-10) Zhu, Jason; Strickler, John H"Liquid biopsies" are blood based assays used to detect and analyze circulating tumor products, including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating messenger RNA (mRNA), circulating microRNA (miRNA), circulating exosomes, and tumor educated platelets (TEP). For patients with gastrointestinal (GI) malignancies, blood based biopsies may offer several advantages. First, tumor tissue samples are often challenging to procure, and when obtainable, are often insufficient for genomic profiling. Second, blood based assays offer a real-time overview of the entire tumor burden, and allow anatomically unbiased genomic profiling. Third, given the convenience and relative safety of liquid biopsies, this technology may facilitate identification of genomic alterations that confer sensitivity and resistance to targeted therapeutics. This review will assess the clinical applications of circulating tumor products for patients with GI tumors.Item Open Access Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor response in metastatic renal cell carcinoma.(Journal for immunotherapy of cancer, 2022-10) Brown, Landon C; Zhu, Jason; Desai, Kunal; Kinsey, Emily; Kao, Chester; Lee, Yong Hee; Pabla, Sarabjot; Labriola, Matthew K; Tran, Jennifer; Dragnev, Konstantin H; Tafe, Laura J; Dayyani, Farshid; Gupta, Rajan T; McCall, Shannon; George, Daniel J; Glenn, Sean T; Nesline, Mary K; George, Saby; Zibelman, Matthew; Morrison, Carl; Ornstein, Moshe C; Zhang, TianBackground
Immunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers of response are lacking to predict patients who will have a favorable or unfavorable response to immunotherapy. This study aimed to use the OmniSeq transcriptome-based platform to develop biomarkers of response to immunotherapy.Methods
Two cohorts of patients were retrospectively collected. These included an investigational cohort of patients with mRCC treated with immune checkpoint inhibitor therapy from five institutions, and a subsequent validation cohort of patients with mRCC treated with combination ipilimumab and nivolumab from two institutions (Duke Cancer Institute and Cleveland Clinic Taussig Cancer Center). Tissue-based RNA sequencing was performed using the OmniSeq Immune Report Card on banked specimens to identify gene signatures and immune checkpoints associated with differential clinical outcomes. A 5-gene expression panel was developed based on the investigational cohort and was subsequently evaluated in the validation cohort. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were extracted by retrospective chart review. Objective response rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1.Results
The initial investigation cohort identified 86 patients with mRCC who received nivolumab (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), or pembrolizumab (6%, 5/86). A gene expression score was created using the top five genes found in responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). The ORR in patients with high gene expression (GEhigh) on the 5-gene panel was 29% (14/48), compared with low gene expression (GElow) 3% (1/38, χ2 p=0.001). The validation cohort was comprised of 62 patients who received ipilimumab/nivolumab. There was no difference between GEhigh and GElow in terms of ORR (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 to 3.89), or OS (HR 0.96, 95% CI 0.51 to 1.83). Similarly, no differences in ORR, PFS or OS were observed when patients were stratified by tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) expression by immunohistochemistry or RNA expression, or CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) RNA expression. The International Metastatic RCC Database Consortium (IMDC) risk score was prognostic for OS but not PFS.Conclusion
A 5-gene panel that was associated with improved ORR in a predominantly nivolumab monotherapy population of patients with mRCC was not predictive for radiographic response, PFS, or OS among patients with mRCC treated with ipilimumab and nivolumab.Item Open Access LRP1B mutations are associated with favorable outcomes to immune checkpoint inhibitors across multiple cancer types.(Journal for immunotherapy of cancer, 2021-03) Brown, Landon C; Tucker, Matthew D; Sedhom, Ramy; Schwartz, Eric B; Zhu, Jason; Kao, Chester; Labriola, Matthew K; Gupta, Rajan T; Marin, Daniele; Wu, Yuan; Gupta, Santosh; Zhang, Tian; Harrison, Michael R; George, Daniel J; Alva, Ajjai; Antonarakis, Emmanuel S; Armstrong, Andrew JBackground
Low-density lipoprotein receptor-related protein 1b (encoded by LRP1B) is a putative tumor suppressor, and preliminary evidence suggests LRP1B-mutated cancers may have improved outcomes with immune checkpoint inhibitors (ICI).Methods
We conducted a multicenter, retrospective pan-cancer analysis of patients with LRP1B alterations treated with ICI at Duke University, Johns Hopkins University (JHU) and University of Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) to ICI and pathogenic or likely pathogenic (P/LP) LRP1B alterations compared with LRP1B variants of unknown significance (VUS). Secondary outcomes were the associations with progression-free survival (PFS) and overall survival (OS) by LRP1B status.Results
We identified 101 patients (44 Duke, 35 JHU, 22 UM) with LRP1B alterations who were treated with ICI. The most common tumor types by alteration (P/LP vs VUS%) were lung (36% vs 49%), prostate (9% vs 7%), sarcoma (5% vs 7%), melanoma (9% vs 0%) and breast cancer (3% vs 7%). The ORR for patients with LRP1B P/LP versus VUS alterations was 54% and 13%, respectively (OR 7.5, 95% CI 2.9 to 22.3, p=0.0009). P/LP LRP1B alterations were associated with longer PFS (HR 0.42, 95% CI 0.26 to 0.68, p=0.0003) and OS (HR 0.62, 95% CI 0.39 to 1.01, p=0.053). These results remained consistent when excluding patients harboring microsatellite instability (MSI) and controlling for tumor mutational burden (TMB).Conclusions
This multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUS LRP1B alterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted.Item Open Access Predictors of survival in 211 patients with stage IV pulmonary and gastroenteropancreatic mIBG positive neuroendocrine tumors treated with I-131 mIBG.(Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2018-05-18) Kane, Ari; Thorpe, Matthew P; Morse, Michael A; Howard, Brandon A; Oldan, Jorge D; Zhu, Jason; Wong, Terence Z; Petry, Neil A; Reiman, Robert; Borges-Neto, SalvadorPurpose: This retrospective analysis identifies predictors of survival in a cohort of patients with mIBG positive stage IV pulmonary and gastroenteropancreatic neuroendocrine tumor (P/GEP-NET) treated with I-131 mIBG therapy, in order to inform treatment selection and post-treatment monitoring. Methods: Survival, symptoms, imaging, and biochemical response were extracted via chart review from n = 211 P/GEP-NET patients treated with mIBG between 1991-2014. For patients with computed tomography (CT) follow up (n = 125), imaging response was assessed by Response Evaluation Criteria on Solid Tumors (RECIST) 1.1 where images were available (n = 76) or by chart review of the radiology report where images could not be reviewed (n = 49). Kaplan Meier analysis and Cox multivariate regression estimated survival and progression free survival benefits predicted by initial imaging, biochemical and symptomatic response. Results: All patients had stage IV disease at time of treatment. Median survival was 29 months from time of treatment. 71% of patients demonstrated symptomatic response with median duration of symptomatic relief of 12 months. Symptomatic response at first follow-up predicted a survival benefit of 30 months (p<0.001). Biochemical response at first clinical follow up was seen in 34% of patients with stability of labs in 48%; response/stability vs. progression extended survival 40 months (p<0.03). Imaging response (20% of patients) or stability (60%) at initial 3 month follow up imaging extended survival 32 months (p<0.001). Additionally, multiple mIBG treatments was associated with 24 months additional survival (p<0.05). Conclusion: Therapeutic I-131-mIBG for metastatic pulmonary or gastroenteropancreatic neuroendocrine tumors appears to be an effective means of symptom palliation. Imaging, biochemical, and symptomatic follow-up each help prognosticate expected survival following mIBG therapy. Multiple rounds of mIBG are associated with prolonged survival; it is unclear whether this represents cause or effect.