Jeremy C. Durack

Integrative clinical genomics of advanced prostate cancer

Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.

Percutaneous Ablation of Peribiliary Tumors with Irreversible Electroporation

PURPOSE To assess biliary complications after irreversible electroporation (IRE) ablation of hepatic tumors located < 1 cm from major bile ducts. MATERIALS AND METHODS A retrospective review was conducted of all percutaneous IRE ablations of hepatic tumors within 1 cm of the common, left, or right hepatic ducts at a single institution from January 2011 to September 2012. Computed tomography imaging performed before and after treatment was examined for evidence of bile duct dilatation, stricture, or leakage. Serum bilirubin and alkaline phosphatase levels were analyzed for evidence of biliary injury. RESULTS There were 22 hepatic metastases in 11 patients with at least one tumor within 1 cm of the common, left, or right hepatic duct that were treated with IRE ablations in 15 sessions. Median tumor size treated was 3.0 cm (mean, 2.8 cm ± 1.2, range, 1.0-4.7 cm). Laboratory values obtained after IRE were considered abnormal after four treatment sessions in three patients (bilirubin, 2.6-17.6 mg/dL; alkaline phosphatase, 130-1,035 U/L); these abnormal values were transient in two sessions. Two patients had prolonged elevation of values, and one required stent placement; both of these conditions appeared to be secondary to tumor progression rather than bile duct injury. CONCLUSIONS This clinical experience suggests that IRE may be a treatment option for centrally located liver tumors with margins adjacent to major bile ducts where thermal ablation techniques are contraindicated. Further studies with extended follow-up periods are necessary to establish the safety profile of IRE in this setting.

Percutaneous Radiofrequency Ablation of Colorectal Cancer Liver Metastases: Factors Affecting Outcomes—A 10-year Experience at a Single Center

PURPOSE To identify predictors of oncologic outcomes after percutaneous radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLMs) and to describe and evaluate a modified clinical risk score (CRS) adapted for ablation as a patient stratification and prognostic tool. MATERIALS AND METHODS This study consisted of a HIPAA-compliant institutional review board-approved retrospective review of data in 162 patients with 233 CLMs treated with percutaneous RFA between December 2002 and December 2012. Contrast material-enhanced CT was used to assess technique effectiveness 4-8 weeks after RFA. Patients were followed up with contrast-enhanced CT every 2-4 months. Overall survival (OS) and local tumor progression-free survival (LTPFS) were calculated from the time of RFA by using the Kaplan-Meier method. Log-rank tests and Cox regression models were used for univariate and multivariate analysis to identify predictors of outcomes. RESULTS Technique effectiveness was 94% (218 of 233). Median LTPFS was 26 months. At univariate analysis, predictors of shorter LTPFS were tumor size greater than 3 cm (P < .001), ablation margin size of 5 mm or less (P < .001), high modified CRS (P = .009), male sex (P = .03), and no history of prior hepatectomy (P = .04) or hepatic arterial infusion chemotherapy (P = .01). At multivariate analysis, only tumor size greater than 3 cm (P = .01) and margin size of 5 mm or less (P < .001) were independent predictors of shorter LTPFS. Median and 5-year OS were 36 months and 31%. At univariate analysis, predictors of shorter OS were tumor size larger than 3 cm (P = .005), carcinoembryonic antigen level greater than 30 ng/mL (P = .003), high modified CRS (P = .02), and extrahepatic disease (EHD) (P < .001). At multivariate analysis, tumor size greater than 3 cm (P = .006) and more than one site of EHD (P < .001) were independent predictors of shorter OS. CONCLUSION Tumor size of less than 3 cm and ablation margins greater than 5 mm are essential for satisfactory local tumor control. Tumor size of more than 3 cm and the presence of more than one site of EHD are associated with shorter OS.

A Phase I/II Study for Analytic Validation of 89Zr-J591 ImmunoPET as a Molecular Imaging Agent for Metastatic Prostate Cancer

Purpose: Standard imaging for assessing osseous metastases in advanced prostate cancer remains focused on altered bone metabolism and is inadequate for diagnostic, prognostic, or predictive purposes. We performed a first-in-human phase I/II study of 89Zr-DFO-huJ591 (89Zr-J591) PET/CT immunoscintigraphy to assess performance characteristics for detecting metastases compared with conventional imaging modalities (CIM) and pathology. Experimental Design: Fifty patients with progressive metastatic castration-resistant prostate cancers were injected with 5 mCi of 89Zr-J591. Whole-body PET/CT scans were obtained, and images were analyzed for tumor visualization. Comparison was made to contemporaneously obtained bone scintigraphy and cross-sectional imaging on a lesion-by-lesion basis and with biopsies of metastatic sites. Results: Median standardized uptake value for 89Zr-J591–positive bone lesions (n = 491) was 8.9 and for soft-tissue lesions (n = 90), it was 4.8 (P < 0.00003). 89Zr-J591 detected 491 osseous sites compared with 339 by MDP and 90 soft-tissue lesions compared with 124 by computed tomography (CT). Compared with all CIMs combined, 89Zr-J591 detected an additional 99 osseous sites. Forty-six lesions (21 bone and 25 soft tissue) were biopsied in 34 patients; 18 of 19 89Zr-J591–positive osseous sites and 14 of 16 89Zr-J591–positive soft tissue sites were positive for prostate cancer. The overall accuracy of 89Zr-J591 was 95.2% (20 of 21) for osseous lesions and 60% (15 of 25) for soft-tissue lesions. Conclusions: 89Zr-J591 imaging demonstrated superior targeting of bone lesions relative to CIMs. Targeting soft-tissue lesions was less optimal, although 89Zr-J591 had similar accuracy as individual CIMs. This study will provide benchmark data for comparing performance of proposed prostate-specific membrane antigen (PSMA) targeting agents for prostate cancer. Clin Cancer Res; 21(23); 5277–85. ©2015 AACR.

Comparison of traditional methods with 3D computer models in the instruction of hepatobiliary anatomy

This study was designed to determine whether an interactive three‐dimensional presentation depicting liver and biliary anatomy is more effective for teaching medical students than a traditional textbook format presentation of the same material. Forty‐six medical students volunteered for participation in this study. Baseline demographic information, spatial ability, and knowledge of relevant anatomy were measured. Participants were randomized into two groups and presented with a computer‐based interactive learning module comprised of animations and still images to highlight various anatomical structures (3D group), or a computer‐based text document containing the same images and text without animation or interactive features (2D group). Following each teaching module, students completed a satisfaction survey and nine‐item anatomic knowledge post‐test. The 3D group scored higher on the post‐test than the 2D group, with a mean score of 74% and 64%, respectively; however, when baseline differences in pretest scores were accounted for, this difference was not statistically significant (P = 0.33). Spatial ability did not statistically significantly correlate with post‐test scores for the 3D group or the 2D group. In the post‐test satisfaction survey the 3D group expressed a statistically significantly higher overall satisfaction rating compared to students in the 2D control group (4.5 versus 3.7 out of 5, P = 0.02). While the interactive 3D multimedia module received higher satisfaction ratings from students, it neither enhanced nor inhibited learning of complex hepatobiliary anatomy compared to an informationally equivalent traditional textbook style approach. Anat Sci Educ 4: 84–91, 2011.

Management of Small Renal Masses: American Society of Clinical Oncology Clinical Practice Guideline

Purpose To provide recommendations for the management options for patients with small renal masses (SRMs). Methods By using a literature search and prospectively defined study selection, we sought systematic reviews, meta-analyses, randomized clinical trials, prospective comparative observational studies, and retrospective studies published from 2000 through 2015. Outcomes included recurrence-free survival, disease-specific survival, and overall survival. Results Eighty-three studies, including 20 systematic reviews and 63 primary studies, met the eligibility criteria and form the evidentiary basis for the guideline recommendations. Recommendations On the basis of tumor-specific findings and competing risks of mortality, all patients with an SRM should be considered for a biopsy when the results may alter management. Active surveillance should be an initial management option for patients who have significant comorbidities and limited life expectancy. Partial nephrectomy (PN) for SRMs is the standard treatment that should be offered to all patients for whom an intervention is indicated and who possess a tumor that is amenable to this approach. Percutaneous thermal ablation should be considered an option if complete ablation can reliably be achieved. Radical nephrectomy for SRMs should only be reserved for patients who possess a tumor of significant complexity that is not amenable to PN or for whom PN may result in unacceptable morbidity even when performed at centers with expertise. Referral to a nephrologist should be considered if chronic kidney disease (estimated glomerular filtration rate < 45 mL/min/1.73 m2) or progressive chronic kidney disease occurs after treatment, especially if associated with proteinuria.

Selective Arterial Embolization of Angiomyolipomas: A Comparison of Smaller and Larger Embolic Agents

PURPOSE Selective transarterial embolization for renal angiomyolipomas is effective in preventing or limiting hemorrhage and preserving normal parenchyma. Data are insufficient regarding the safety and efficacy of embolic agents. We compared transarterial embolization of angiomyolipomas using embolic agents of different sizes. MATERIALS AND METHODS We performed a retrospective review of all transarterial angiomyolipoma embolizations from 1999 to 2010, and evaluated demographics, procedural data, embolization response and outcomes comparing smaller (less than 150 microns) and larger (more than 150 microns) embolic agents. RESULTS Overall 48 patients underwent 66 embolization procedures for 72 angiomyolipomas. Smaller agents were used more commonly (58%). Age, gender, indications, pre-embolization angiomyolipoma size and prevalence of tuberous sclerosis were similar between the groups. Angiomyolipomas decreased a mean±SD 25%±18% after embolization with no differences between the groups (p=0.24). There were 10 angiomyolipomas that required 14 repeat embolizations (median 14 months). Repeat embolization of the same mass was almost sixfold more likely in those embolized with smaller agents (OR 5.88, 95% CI 1.64-20.8, p=0.002). Complications were similar between the groups, although 2 of 3 patients with acute respiratory distress underwent embolization with smaller agents. Patients with tuberous sclerosis had similar angiomyolipoma size, decrease in angiomyolipoma size, followup, complications and need for repeat embolization. Practice patterns changed regarding embolization agent size during the study period. CONCLUSIONS Angioembolization with larger embolic agents is associated with higher long-term efficacy compared to smaller agents. Due to concerns for serious pulmonary complications, we no longer use agents smaller than 150 microns. Prospective studies are necessary to evaluate the optimal embolization technique to achieve durable outcomes without increasing patient morbidity.

A Pilot Study of Preoperative Single-Dose Ipilimumab and/or Cryoablation in Women with Early-Stage Breast Cancer with Comprehensive Immune Profiling

Purpose: To assess the safety and tolerability of preoperative cryoablation-mediated tumor antigen presentation and/or ipilimumab-mediated immune modulation in women with operable breast cancer. Experimental Design: In this pilot study, 19 women with breast cancer for whom mastectomy was planned were treated with preoperative tumor cryoablation (n = 7), single-dose ipilimumab at 10 mg/kg (n = 6), or both (n = 6). The primary outcome for this pilot study was safety/tolerability as defined as freedom from delays in pre-planned, curative-intent mastectomy. Exploratory studies of immune activation were performed on peripheral blood and tumor. Results: Preoperative cryoablation and/or ipilimumab were safe and tolerable, with no delays in pre-planned surgery. Grade III toxicity was seen in 1 of 19 (unrelated rash after ipilimumab). Combination therapy was associated with sustained peripheral elevations in: Th1-type cytokines, activated (ICOS+) and proliferating (Ki67+) CD4+ and CD8+ T cells, and posttreatment proliferative T-effector cells relative to T-regulatory cells within tumor. Conclusions: Preoperative cryoablation and single-dose ipilimumab are safe alone or in combination with no surgical delays incurred. Potentially favorable intratumoral and systemic immunologic effects were observed with the combination, suggesting the possibility for induced and synergistic antitumor immunity with this strategy. Clin Cancer Res; 22(23); 5729–37. ©2016 AACR.

Erratum: Integrative Clinical Genomics of Advanced Prostate Cancer

Dan Robinson, Eliezer M. Van Allen, Yi-Mi Wu, Nikolaus Schultz, Robert J. Lonigro, Juan-Miguel Mosquera, Bruce Montgomery, Mary-Ellen Taplin, Colin C. Pritchard, Gerhardt Attard, Himisha Beltran, Wassim Abida, Robert K. Bradley, Jake Vinson, Xuhong Cao, Pankaj Vats, Lakshmi P. Kunju, Maha Hussain, Felix Y. Feng, Scott A. Tomlins, Kathleen A. Cooney, David C. Smith, Christine Brennan, Javed Siddiqui, Rohit Mehra, Yu Chen, Dana E. Rathkopf, Michael J. Morris, Stephen B. Solomon, Jeremy C. Durack, Victor E. Reuter, Anuradha Gopalan, Jianjiong Gao, Massimo Loda, Rosina T. Lis, Michaela Bowden, Stephen P. Balk, Glenn Gaviola, Carrie Sougnez, Manaswi Gupta, Evan Y. Yu, Elahe A. Mostaghel, Heather H. Cheng, Hyojeong Mulcahy, Lawrence D. True, Stephen R. Plymate, Heidi Dvinge, Roberta Ferraldeschi, Penny Flohr, Susana Miranda, Zafeiris Zafeiriou, Nina Tunariu, Joaquin Mateo, Raquel Perez-Lopez, Francesca Demichelis, Brian D. Robinson, Andrea Sboner, Marc Schiffman, David M. Nanus, Scott T. Tagawa, Alexandros Sigaras, Kenneth W. Eng, Olivier Elemento, Andrea Sboner, Elisabeth I. Heath, Howard I. Scher, Kenneth J. Pienta, Philip Kantoff, Johann S. de Bono, Mark A. Rubin, Peter S. Nelson, Levi A. Garraway, Charles L. Sawyers,* and Arul M. Chinnaiyan* *Correspondence: sawyersc@mskcc.org (C.L.S.), arul@umich.edu (A.M.C.) http://dx.doi.org/10.1016/j.cell.2015.06.053

Deep Sequencing of T-Cell Receptor DNA as a biomarker of clonally expanded TILs in breast cancer after immunotherapy

Tumor cryoablation plus immune checkpoint blockade facilitates antitumor T-cell responses (TCRs) and improves survival in mice. Deep sequencing of TCRs in human early-stage breast cancer tumors revealed T-cell clonality and density and served as a biomarker after cryo-immunotherapy. In early-stage breast cancer, the degree of tumor-infiltrating lymphocytes (TIL) predicts response to chemotherapy and overall survival. Combination immunotherapy with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA sequencing to evaluate both the effect of cryoimmunotherapy in humans and the feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical trial, 18 women with early-stage breast cancer were treated preoperatively with cryoablation, single-dose anti–CTLA-4 (ipilimumab), or cryoablation + ipilimumab. TCRs within serially collected peripheral blood and tumor tissue were sequenced. In baseline tumor tissues, T-cell density as measured by TCR sequencing correlated with TIL scores obtained by hematoxylin and eosin (H&E) staining. However, tumors with little or no lymphocytes by H&E contained up to 3.6 × 106 TCR DNA sequences, highlighting the sensitivity of the ImmunoSEQ platform. In this dataset, ipilimumab increased intratumoral T-cell density over time, whereas cryoablation ± ipilimumab diversified and remodeled the intratumoral T-cell clonal repertoire. Compared with monotherapy, cryoablation plus ipilimumab was associated with numerically greater numbers of peripheral blood and intratumoral T-cell clones expanding robustly following therapy. In conclusion, TCR sequencing correlates with H&E lymphocyte scoring and provides additional information on clonal diversity. These findings support further study of the use of TCR sequencing as a biomarker for T-cell responses to therapy and for the study of cryoimmunotherapy in early-stage breast cancer. Cancer Immunol Res; 4(10); 835–44. ©2016 AACR.