Cancer Consult. From Prostate Tumors to Myeloid Leukemias, Our Discoveries Are Revolutionizing Patients Risk Assessment and Treatment

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1 Cancer Consult Taussig Cancer Institute Winter 2014 Cancer Genomics: From Prostate Tumors to Myeloid Leukemias, Our Discoveries Are Revolutionizing Patients Risk Assessment and Treatment Also Inside: HDL Cholesterol as a Cancer Fighter Hyperthermia Aids Recurrent Cancer Therapy Highlights from the American Society of Hematology Annual Meeting Ranked as one of the top 10 hospitals in America for cancer care by U.S. News & World Report.

2 CANCER CONSULT WINTER 2014 Dear Colleagues, Welcome to the latest edition of Cleveland Clinic s Cancer Consult. I hope you find this issue informative and inspiring. The history of progress in cancer medicine has been focused in two basic areas: early detection and improved therapeutics. Recently, we have been witnessing an explosion of progress as our knowledge of cancer genomics increases. Genomics is revolutionizing risk assessment, tumor classification and treatment. Our physicians and researchers are involved in several high-profile genomic initiatives. We have initiated a clinical trial to assess the feasibility and clinical utility of next-generation genomic sequencing in 15 solid tumors with historically poor prognosis. Our colleagues at the Glickman Urological & Kidney Institute were instrumental in the research and development of a genetic test Oncotype DX Prostate for prostate cancer, which helps identify men who are good candidates for active surveillance. In an era of personalized cancer care, there is increased focus on defining and treating cancer by its genetic abnormalities. Tumorpromoting enzyme mutations in several cancers have been identified by Cleveland Clinic researchers, including the androgen-synthesizing enzyme 3βHSD1 in castration-resistant prostate cancer, and the SETBP1 gene, which frequently mutates in a subset of leukemias. My goal is that you find the information in these pages useful in your practice. Please do not hesitate to contact me with any questions, concerns or suggestions at or bolwellb@ccf.org. Sincerely, Brian J. Bolwell, MD Chairman, Taussig Cancer Institute Table of Contents First Mutation Identified That Increases DHT Synthesis to Promote Hormone Therapy Resistance...3 Next-Generation Cancer Genomic Testing in a Real-World Setting...4 Genetic Advances Fuel New Hope in Fight Against Myeloid Leukemias...6 Highlights from the ASH Annual Meeting...8 From Bench to Bedside: Genomics for Active Surveillance Now in Clinical Practice...10 Clinical Trials...12 Promising Research Shows HDL, the Carrier of Good Cholesterol, Has Cancer-Fighting Punch...13 Hyperthermia Improves Response Rates in Recurrent Cancers...14 Scoring the Risks: Khorana Score Predicts Risk of Cancer-associated Thrombosis and Mortality...16 New Staff...18 Selected Publications...19 On the cover: Investigators in the lab of Cleveland Clinic researcher Nima Sharifi, MD, have identified the first genetic mutation that helps prostate cancer tumors acquire resistance to hormone therapy.

3 First Mutation Identified That Increases DHT Synthesis to Promote Hormone Therapy Resistance By Nima Sharifi, MD For more information, contact Dr. Sharifi at or For references, please the editor. Nima Sharifi, MD, holds the Kendrick Family Endowed Chair for Prostate Cancer Research in Lerner Research Institute s Department of Cancer Biology, and is an associate staff member of the Department of Solid Tumor Oncology. The development of castration-resistant prostate cancer (CRPC) occurs in large part by tumors acquiring the capability of synthesizing their own supply of 5α-dihydrotestosterone (DHT) from nongonadal sources, particularly from adrenal precursors. The role and requirement for intratumoral DHT synthesis in the development of CRPC is demonstrated by the efficacy of nextgeneration hormone therapies that have entered into clinical practice. This includes abiraterone acetate, which blocks androgen synthesis, and enzalutamide, which is a potent androgen receptor antagonist. Despite the long-recognized phenomenon of elevated androgens in CRPC, no mutation has yet been described that is responsible for increasing DHT synthesis. At Cleveland Clinic, researchers have identified the first such example of a genetic alteration that increases the conversion of precursor steroids to DHT, permitting tumors to grow in the absence of gonadal testosterone. The enzyme 3β-hydroxysteroid dehydrogenaseisoenzyme-1 (3βHSD1) is required for the first and rate-limiting step in the conversion of adrenal dehydroepiandrosterone (DHEA) en route to DHT. A mutation occurs in 3βHSD1 in a subset of human CRPC tumors that blocks degradation of this enzyme, increasing the amount of enzyme available in the cell and resulting in an increase in the flow of precursor steroids to DHT. The essential consequence is that this mutation opens the floodgates to DHT synthesis, permitting tumors to grow in the absence of gonadal testosterone. Nima Sharifi, MD, (left) with Kai-Hsiung Chang, PhD Cleveland Clinic investigators found not only that this mutant 3βHSD1 occurs in human CRPC tumors, but also that it occurs in a mouse model of resistance to abiraterone acetate. Current studies are aimed at determining whether clinical resistance to abiraterone acetate and enzalutamide is attributable in part to 3βHSD1 mutations. In addition to the 3βHSD1 mutation that occurs in tumors with the development of CRPC, the same genetic alteration exists as an inherited germline variant. In this form, it is possible that this germline variant plays a part in upfront resistance to hormonal therapy. Other ongoing studies will identify how germline variant inheritance regulates androgen metabolism in localized prostate cancer. It is conceivable that upfront genetic information on hormone therapy response/resistance may help determine the best treatment modality for a specific patient. 2 3 clevelandclinic.org/cancer

4 CANCER CONSULT WINTER 2014 Next-Generation Cancer Genomic Testing in a Real-World Setting Nearly every major hospital or cancer treatment practice performs specific genomic testing on every cancer patient s tumor sample. Examples include KRAS oncogene analysis for those with colorectal cancer or HER2 analysis in breast cancer. These standard-of-care tests detect a single genetic mutation associated with a patient s tumor type. For more information, contact Dr. Sohal at or sohald@ccf.org. Since August, oncologists at Cleveland Clinic s Taussig Cancer Institute have been enrolling patients in an expanded genomic testing clinical study. Over the next year, 250 patients with a variety of 15 different tumor types will have their tumor sample analyzed for 236 cancer-related genes as part of the investigation. The genes tested have been implicated in cancer, with ramifications for cancer therapeutics. They are all included in the FoundationOne genomics assessment test. For this clinical investigation, Cleveland Clinic has partnered with FoundationOne s developer, Foundation Medicine, a molecular information company specializing in comprehensive genomic analysis of tumors. In the study, each patient s tumor sample is tested with the FoundationOne genomics profile, which detects several types of DNA alterations base substitutions, small insertions/deletions, copy number alterations and gene rearrangements. The test includes those genes that show a high frequency of common alterations but also those on a tail on the curve, such as those mutations occurring at low frequency but across many different tumor types. This type of approach provides a strong rationale for looking broadly rather than just looking with disease-specific genes. Davendra Sohal, MD, MPH, staff physician in the Department of Solid Tumor Oncology

5 CLEVELAND CLINIC TAUSSIG CANCER INSTITUTE CANCER CONSULT There is an opportunity to make a difference for people if we can apply the existing knowledge about cancer mutations to making useful treatment decisions. Brian J. Bolwell MD, Chairman, Taussig Cancer Institute We have chosen a variety of cancers that includes the most common cancers, says Davendra Sohal, MD, MPH, staff physician in the Department of Solid Tumor Oncology and principal investigator of the study. The goal is to see if this type of expanded genomic testing can impact clinical outcomes in a meaningful way. We understand the importance of genomic testing in a broad fashion and are investing heavily in this, adds Brian J. Bolwell, MD, FACP, chairman of Cleveland Clinic s Taussig Cancer Institute. The target population for the study includes patients lacking good treatment options, such as those with metastatic disease or whose cancer has progressed despite one or two rounds of standard chemotherapy. There is an opportunity to make a difference for these people if we can apply the existing knowledge about cancer mutations to making useful treatment decisions. Feasibility and Utility One of the trial s goals is to study the feasibility of doing genomic analyses in a real-world setting. We want to see how well tests like FoundationOne can be performed in a real-world setting in a variety of tumors, comments Dr. Sohal. Questions to be answered include: How long does it take for a patient to be consented to receive this testing? How long does it take to process the test and for doctors at Cleveland Clinic to get the result? How long does it take for the patient to learn the result and get recommendations for treatment? The ultimate goal is to probe the clinical usefulness of expanded genomic testing. Every test result includes molecular details about a patient s tumor along with supporting data suggesting a particular targeted therapy. This information is provided to a panel of oncologists within Taussig Cancer Institute. This Genomics Tumor Board meets weekly to review each result independently and make recommendations for treatment whether with approved drugs or as part of clinical trials in and around Cleveland. These recommendations are transmitted to the primary oncologist, who makes final personalized recommendations to the patient. If many patients can get to useful treatments whether FDA-approved or off-label, or under a clinical trial of a targeted therapy then it can make a real difference, says Dr. Sohal. Because the science behind genomic testing is evolving rapidly, new genetic mutations are rapidly emerging. Cleveland Clinic has chosen to partner with Foundation Medicine as the company continually updates its testing panel to keep current with the latest research in cancer-related genetics. 4 5 clevelandclinic.org/cancer

6 CANCER CONSULT WINTER 2014 Genetic Advances Fuel New Hope in Fight Against Myeloid Leukemias Driven by leading-edge genetic discoveries that reveal how myeloid leukemias and myelodysplastic syndrome acquire specific genetic mutations that can help predict the clinical behavior of these diseases, researchers at Cleveland Clinic s Taussig Cancer Institute continue to lead as the focus shifts to translating this research. They now are moving from a discovery phase into clinical application and innovative diagnostic, individualized therapies. For more information, contact Dr. Maciejewski at or maciejj@ccf.org. We are on the forefront with the new, incredibly efficient genomic technologies that exponentially increase our ability to characterize genomic defects leading to leukemia. Our team has discovered multiple new mutations, including those in the SETBP1 gene, which frequently mutate in a subset of leukemias, says Jaroslaw Maciejewski, MD, PhD, Chairman of the Department of Translational Hematology and Oncology Research. Now we are moving into the clinical application of these technologies to generate comprehensive testing panels for the most commonly occurring mutations. Dr. Maciejewski says SETBP1 mutations hold great promise as a novel therapeutic target. SETBP1 mutations ramp up evolution of myeloid leukemia. Conceptually, development of a drug to turn off or silence an overactive gene mutation is easier, he explains, compared with devising a strategy to turn on an essential gene switched off or damaged by a cancer. We ve discovered a very important mutation, a somatic mutation, in a subset of leukemia patients that can be targeted with drugs, says Dr. Maciejewski, who is also Professor of Medicine at Cleveland Clinic Lerner College of Medicine. The implications go beyond identification of specific mutations to aid the approximately 10 percent of leukemia or myelodysplastic syndrome patients who carry SETBP1 mutations. These innovations coming out of Cleveland Clinic will usher in a new era of individualized medicine for patients fighting these cancers. That s the big picture, Dr. Maciejewski says. The genetic profile of individual lesions can help clinicians identify which patients are likely or unlikely to respond to individualized therapy. Many of the drugs we have now work very well but they are not very targeted, so we don t know who will respond, Dr. Maciejewski says. By targeting therapy to a specific genomic lesion, we avoid WT 1871T D868N Two leukemia-specific mutations in the SETBP1 gene (middle and right panel) were introduced into normal stem cells (left panel). The mutant genes prevented cells from maturing and rendered them immortal.

7 CLEVELAND CLINIC TAUSSIG CANCER INSTITUTE CANCER CONSULT By targeting therapy to a specific genomic lesion, we avoid potentially toxic and futile therapies for patients who do not have the lesion and we maximize response among those who do. Jaroslaw Maciejewski, MD, PhD, Chairman, Department of Translational Hematology and Oncology Research potentially toxic and futile therapies for patients who do not have the lesion and we maximize response among those who do. Without such knowledge, administration of an agent that effectively shuts down the SETBP1 mutation and its promotion of cancer progression would work in only about 10 percent of leukemia patients. Dr. Maciejewski says, But if you only treat the 10 percent of patients who have the mutations, your response rate in this subgroup of patients will be very, very high. Thus we can provide effective therapy to a subset of patients while working on drugs for the next variant of leukemia. Discovery of the surprising role of SETBP1 somatic mutations in fostering leukemias and myelodysplastic disease is the latest in a series of important advances to emerge from Cleveland Clinic. The findings were simultaneously published in two studies in the August 2013 Nature Genetics by Dr. Maciejewski and colleagues. The studies outline the promise of SETBP1 findings for a subset of adults fighting these cancers (2013;45(8): ) as well as for children combating chronic juvenile myelomonocytic leukemia (2013;45(8): ). The SETBP1 research was one of only five studies highlighted during the plenary session at the 2012 American Society of Hematology Annual Meeting in Atlanta. All these advances in understanding the genetic framework behind myeloid leukemias and myelodysplastic syndrome are a reality due to rapid developments in next-generation genetic sequencing and high-throughput genetic arrays. These technologies have led to a realization and appreciation of the great diversity of these cancers. These mutations, or combinations of these mutations, are individual to each patient, Dr. Maciejewski says. Previously, SETBP1 mutations primarily were associated with Schinzel-Giedion syndrome. Notably, children with this rare congenital condition and its characteristic physical malformations inherit the genetic abnormality. In contrast, the new discoveries at Cleveland Clinic show that the SETBP1 mutations are acquired during the cancer development process. These research findings exemplify our Cancer Institute s strengths. We are on the forefront of driving discoveries with this set of diseases, and we hope to translate these discoveries into the development of individualized therapies, Dr. Maciejewski says. 6 7 clevelandclinic.org/cancer

8 HIGHLIGHTS from the A SH ANNUAL MEETING Physicians and investigators from Cleveland Clinic s Taussig Cancer Institute made major contributions to the American Society of Hematology (ASH) 2013 Annual Meeting in New Orleans, describing their research in more than 30 oral presentations and more than 60 poster presentations. Here we feature condensed abstracts from five of the presented research papers (Cleveland Clinic authors are listed in bold). For complete abstracts, see Inhibition of JAK-STAT Pathway as a Therapeutic Option for Myelofibrosis Associated Pulmonary Hypertension Ali Tabarroki, MD, Daniel Lindner, MD, PhD, Valeria Visconte, PhD, Li Zhang, PhD, Edy Hasrouni, Yvonne Parker, Heesun J. Rogers, MD, PhD, Tracy Cinalli, RN, Kristin Dodd, RN, Gina Rupp, RN, Hien Kim Duong, MD, Alan E. Lichtin, MD, Matt Kalaycio, MD, Mikkael A. Sekeres, MD, MS, Anjali S. Advani, MD, Betty K. Hamilton, MD, Sudipto Mukherjee, MD, PhD, MPH, Yogen Saunthararajah, MD, Stavros E. Mountantonakis, MD, Gustavo A. Heresi, MD, and Ramon V. Tiu, MD Background: Pulmonary hypertension (PH) is an under-recognized complication of myelofibrosis (MF), occurring in 30 percent of MF patients and associated with poor survival. The pathophysiology of PH in MF has not been elucidated, although in idiopathic PH, the proliferation of pulmonary artery endothelial cells has been linked to activation of the STAT3 pathway. Dysregulation of the JAK-STAT pathway has been implicated in the pathogenesis of MF. Ruxolitinib, a JAK1/2 inhibitor, was approved for management of splenomegaly and cytokine-mediated symptoms in MF. No specific therapy in the management of MF-associated PH has been established. Given the association between MF and PH and the possible pathophysiologic link mediated by JAK signaling, we prospectively followed 19 patients with MF-associated PH and compared their echocardiographic findings and PH-relevant serum biomarker levels pre- and post-ruxolitinib therapy. Results: Nitric oxide (NO), a primary regulator of vascular endothelial function, is reduced in MF patients with PH compared to normal individuals. Treatment with ruxolitinib resulted in marked increase in NO levels compared to baseline, while no changes in NO levels were observed after treatment with hydroxyurea and lenalidomide. Treatment with ruxolitinib also resulted in reduction of key cytokines that inhibit NO production and induction of cytokines that lead to increase in NO synthesis, supporting the role of cytokines in PH pathogenesis in MF. Conclusion: Aberrant JAK-STAT signaling in MF mediates PH by dysregulation of NO and cytokine levels, which can be restored by therapy with JAK inhibitors. This suggests that inhibition of the JAK- STAT signaling pathway is a novel, viable target for the management of patients with MF-associated PH. Differences in Perceptions of Disease and Treatment Effectiveness and Adherence Between Physicians and Patients with Myelodysplastic Syndromes (MDS) David P. Steensma, MD, Richard M. Stone, MD, John Huber, MS, Betsy Dennison, MS, RN and Mikkael A. Sekeres, MD, MS Background and Methods: MDS are complex conditions, described with sometimes confusing terminology. Contemporary drug therapies (tx) for MDS require repeated treatment administration cycles to achieve clinical effect. Lack of disease understanding or premature discontinuation of tx may result in poorer outcomes for patients (pts). To better understand physician (MD) and pt perceptions about MDS and tx decisions, we conducted two online surveys: one for MDS pts and one for healthcare providers (HCP). Pt and HCP surveys assessed understanding of MDS, perceptions of specific tx, barriers to tx adherence, and overall tx experience. Results: Of 4,039 pts invited to participate, 477 (12%) complete responses were received. Of 4,594 HCPs invited to participate, 120 (3%) complete responses were received. Because of low participation among other HCP groups, only MD responses were examined. Only 10% of pts reported MDS (p <.001) was described to them as cancer compared to how it was described by 59% of MDs. Only 29% of pts reported that MDS was curable, compared to 52% of MDs (p <.001). Forty-two percent of pts had received at least one diseasemodifying tx. MD and pt perceptions of active tx were significantly different, with MDs overestimating quality of life (QOL) benefits for drugs and underestimating the negative impact of tx on pt activities for hypomethylating agents. MDs interpreted the benefit of active tx significantly higher than pts; however, pts perceived the actual tx experience more positively than MDs. Most pts (81%) reported the MD had the most influence on their decision to stop tx, correlating to 69% of MDs who reported recommending stopping tx prior to the completion of tx regimen. Reported reasons diverged significantly between MD and pt, and included the burden of tx exceeding benefit to the pt, as well as perceptions that the impact on the pt and family was too great. Conclusion: Physicians and MDS pts have distinct views of the value of tx for MDS, with MDs underestimating the impact of tx on QOL, but overestimating it as a justification for stopping tx. Improved communication may improve understanding of MDS and the impact of active treatment to achieve better tx adherence and ultimately response. Prospective Study of an Emergency Department Febrile Neutropenia Pathway in Patients with Hematologic Malignancies Michael K. Keng, MD, Elaine Thallner, MD, MS, Paul Elson, ScD, Christine Zayac, MA, Jennifer Sekeres, PharmD, BCPS, Candice M. Wenzell, PharmD, BCOP, Erika M. Gallagher, PharmD, BCOP, Catherine M. Weber, PharmD, BCOP, Marc A. Earl, PharmD, BCOP, Sudipto Mukherjee, MD, PhD, MPH, David J. Seastone, DO, PhD, Brad Pohlman, MD, Eric Cober, MD, Beth Rodgers, RN, MSN, CEN, Virginia B. Foster, PhD, MPH, Joy Yuhas, RN, MSN, Matt E. Kalaycio, MD, Brian J. Bolwell, MD, and Mikkael A. Sekeres, MD, MS Background: Febrile neutropenia (FN) is an oncologic emergency associated with high morbidity and mortality, particularly in patients (pts) with hematologic malignancies. Delays in antibiotic administration, which can occur in busy emergency departments (EDs), lead to worse outcomes. We instituted an FN pathway (FNP) in Cleveland Clinic s (CC) ED to reduce antibiotic delays. Methods: We compared patients from 06/2012 to 06/2013 to historical pts from 02/2010 to 05/2012. Fever was defined as temperature 38 C, while neutropenia as absolute neutrophil count < 0.5 x 10 9 /L. All CC cancer pts received a special Neutropenic Risk Hospital Medical Alert Card, which they presented upon CC ED registration with fever. The pathway formally recognized fever with a history of cancer as a distinct chief complaint and categorized FN as Emergency Severity Index level 2 (equivalent to stroke or myocardial infarction) for immediate triage and care. ED-specific electronic FN order sets were created to facilitate antibiotic, laboratory, and blood culture ordering, with antibiotics administered prior to return of neutrophil count. The primary goal of the FNP is administration of empiric broad-spectrum antibiotics within 120 minutes of ED presentation, per Infectious Diseases Society of America

9 guidelines. The primary outcomes measured were time intervals related to it, e.g. time to blood draw, physician assessment, and antibiotic order/ administration. All reported times were from ED registration. Results: FNP study pts had significantly shorter time to having blood drawn (median 38.5 vs. 70 minutes, p < ), seeing a doctor (median 44 vs. 71 minutes, p = ) and to receiving antibiotics (median 79 vs. 228 minutes, p < ). Time to admission was also shorter for FNP study pts, though study pts (4.2 vs. 6.0 hours, p < ) were less likely to be admitted than historical controls (83% vs. 97%, p = 0.005), p < ). For FNP pts admitted to the hospital, there was a non-significant decrease in length of stay, ICU admission and length of ICU stay compared to historical controls. Comparing the two FNP groups treated or not treated per the order set, those treated using the order set had shorter times to antibiotics being ordered (median 28.0 vs minutes, p < ) and administered (100% vs. 90%, p = 0.02). ED order set pts also had a higher rate of antibiotic use. Correct antibiotic use, antibiotic overuse, hospital and ICU admission rates, time to hospital admission, and length of hospital stay were all similar between the two groups (all p 0.28). Conclusion: The FNP significantly decreased time from ED registration to all set time-points, including time to antibiotics by almost threefold, compared to historical controls in pts with hematologic malignancies. Rate of hospitalization was significantly lower, and ICU and length of stay numerically lower. The FNP is an effective clinical tool to provide prompt antibiotic administration to FN pts and likely represents a significant mechanism for improved outcomes and cost savings to patients with hematologic malignancies presenting with FN. Distinct Pattern of Genomic Changes Associated with Smoking in Patients with Myelodysplastic Syndromes (MDS) David J. Seastone, DO, PhD, Sudipto Mukherjee, MD, PhD, MPH, Zaher K. Otrock, MD, Paul Elson, ScD, Michael K. Keng, MD, Bartlomiej Przychodzen, PhD, Hideki Makishima, MD, PhD, Brittney Dienes, Sean Hobson, Kristin Dodd, RN, Tracy Cinalli, RN, Ramon V. Tiu, MD, Yogen Saunthararajah, MD, Jaroslaw P. Maciejewski, MD, PhD, FACP and Mikkael A. Sekeres, MD, MS Background: Smoking is a risk factor for development of MDS and for overall survival. The pathogenesis of MDS is a multistep process with environmental and genetic influences. The link between smoking and MDS is thought to be mediated by organic solvents in tobacco. We identified specific molecular abnormalities associated with smoking exposure in MDS patients (pts). Methods: 151 MDS pts seen from 2000 to 2012 with complete smoking and molecular data were included. We assessed associations between the number of mutations present and demographic and clinical factors. Analysis was performed using next-generation targeted deep gene sequencing with 22 common gene mutations, selected based on the frequency observed in a cohort of MDS patients analyzed by whole exome sequencing. Mutations were considered individually and in functional groups: methylation (TET2, IDH1, IDH2), histone modification (ASXL1, EZH2), and gene splicing (SRSF2, U2AF1, SF3B1). Results: Overall 68% of pts had at least one mutation of the 22 screened mutations: 32% had a single mutation, 22% had 2, and 13% had 3 to 6 mutations. The most common mutations were in TET2, SF3B1, ASXL1, DNMT3A and U2AF1; 32% of pts had one or more mutation in genes involved in methylation, 19% in histone modification, and 32% with splicing. In univariable analyses, current/ex-smokers were more likely to have at least one of the common mutations than never smokers. The number of mutations increased with smoking exposure, particularly with genes involved with histone modification. Certain mutations increased in prevalence with age, e.g.: pts < 60 had fewer mutations overall than pts 60, and in particular fewer mutations in methylationassociated genes. Older age and greater smoking history/exposure were both associated with more mutations. Current and ex-smokers and heavier smoking exposure (> 20 pack years) were also associated with worse survival, though current or ex-smokers with < 20 pack years had similar survival to never smokers. Multivariable analyses confirmed smoking as a risk factor for survival. Conclusion: Smoking is associated with a greater number of molecular abnormalities in MDS pts, and may generate a distinct mutational signature pattern, particularly along histone acetylation pathways. This study identifies specific environmentally mediated pathways in the multistep pathogenesis of MDS. Somatic Mutational Screen for Improved Prediction of the Outcomes of Epigenetic Therapy in Myelodysplastic Syndromes (MDS) Swapna Thota, MD, Paul Lakin, Holleh Husseinzadeh, MD, Hideki Makishima, MD, PhD, Bartlomiej P. Przychodzen, PhD, Brittney Dienes, Kathryn M. Guinta, Naoko Hosono, MD, PhD, Tomas Radivoyevitch, PhD, Mikkael A. Sekeres, MD, MS, Yogen Saunthararajah, MD and Jaroslaw P. Maciejewski, MD, PhD Background: Hypomethylating agents decitabine and azacitidine are standard treatments for MDS. However, individual treatment responses vary from complete remissions (CR) to complete refractoriness. In general, at least months of therapy are needed prior to assessing response. Thus, patients may be subjected to prolonged exposure to ineffective therapy, suffering toxicities without clinical benefit, while potentially more effective alternative treatments are delayed. Currently, there are no reliable phenotypic or mutational markers for predicting response to hypomethylating agents. With the availability of whole exome sequencing (WES) for more routine analysis, we theorized that somatic mutational patterns may help identify patients who would most benefit from these drugs, thereby maximizing response rate by rational patient selection. Methods: We screened 168 patients with MDS who received either azacitidine or decitabine for the presence of somatic mutations. Only those who received sufficient therapy, i.e., completed at least 4 cycles, were selected for outcome analysis. WES and targeted deep nextgeneration sequencing for a subset of 60 genes most frequently affected by somatic mutations in MDS was applied to 94 evaluable patients. Overall, the most frequently mutated genes include: TET2, IDH1/IDH2, SRSF2, ASXL1, SF3B1, RUNX1, EZH2/EED/SUZ12, SETBP1, CBL and PPFIA2. For some analyses we also divided mutations into functional gene families; e.g., DNMT family (DNMT1, DNMT3A, DNMT3B), PRC2 family (EZH2, EED, SUZ12, JARID2, RBBP4, PHF1), IDH family (IDH1, IDH2), CBL family (CBL, CBLB), and RAS family (NRAS, KRAS, HRAS, NF1, NF2, RIT1, PTPN11), among others. Results: The most common molecular abnormalities in responders included the presence of complex karyotype, del7q/-7, del5q and mutations in DNMT3, ASXL1 and others. Similarly, the most common defects found in refractory included the U2AF1/2 family of genes. When compared and selected by the lowest p value, the top mutations in terms of predicting response were SRSF2 (OR 2.4), cohesin (5.1), ATM (OR 5.6) and PHF6 (OR 4.22). Mutations predicting non-response include RAS (OR 0.3), U2AF1/2 (OR 0.4) and LUC7L defects (OR 0.53). To generate better predictors, we combined mutations in either/or fashion. For instance, the presence of either SRSF2 and cohesin, or cohesin and PHF6 mutations, will be considered predictors of response, and the presence of either RAS/U2AF1 and/or cohesin/atm and SRSF2 are predictors of refractoriness. Conclusions: Mutational patterns may be helpful in identifying patients who may benefit from hypomethylating therapies. Identification of the most predictive genes could guide development of molecular markerbased selection of patients for hypomethylating agent therapy, but will require ongoing analysis and additional prospective testing for validation. 8 9 clevelandclinic.org/cancer

10 CANCER CONSULT WINTER 2014 Cancer Consult provides information from Cleveland Clinic Taussig Cancer Institute specialists about innovative research and diagnostic and management techniques. Please direct correspondence to Taussig Cancer Institute/R35 Cleveland Clinic 9500 Euclid Ave. Cleveland, OH Cleveland Clinic Taussig Cancer Institute annually serves more than 28,000 cancer patients. More than 250 cancer specialists are committed to researching and applying the latest, most effective techniques for diagnosis and treatment to achieve long-term survival and improved quality of life for all cancer patients. Taussig Cancer Institute is part of Cleveland Clinic, an independent, nonprofit, multispecialty academic medical center. Cancer Consult Medical Editor Brian Rini, MD Solid Tumor Oncology Cancer Consult Editorial Board Brian J. Bolwell, MD, Chairman, Taussig Cancer Institute From Bench to Bedside: Genomics for Active Surveillance Now in Clinical Practice By Eric A. Klein, MD Dr. Klein is chairman of Cleveland Clinic s Glickman Urological & Kidney Institute. For more information, contact him at or kleine@ccf.org. For references, please the editor. A presentation at the American Urological Association in San Diego on May 8, 2013, marked a watershed moment for patients with early-stage prostate cancer considering active surveillance. That morning, the results of a validation study performed at the University of California at San Francisco (UCSF) that was based on developmental work undertaken at Cleveland Clinic showed that a 17-gene signature (Figure 2) performed on prostate biopsies could accurately predict the presence or absence of adverse pathology on radical prostatectomy specimens. The signature, called the Genomic Prostate Score (GPS) and marketed by Genomic Health Inc. as the Oncotype DX Prostate, helps identify men who are good candidates for active surveillance. The commercialization of GPS represented the culmination of seven years of developmental work and clinical validation studies. Robert Dreicer, MD, Chairman, Solid Tumor Oncology Timothy Spiro, MD, Chairman, Regional Oncology John Suh, MD, Chairman, Radiation Oncology Gene Barnett, MD, Director, Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center Eric Klein, MD, Chairman, Glickman Urological & Kidney Institute Managing Editor John Mangels mangelj@ccf.org Designer Amy Buskey-Wood Photography Russell Lee Clinical Risk Groups Very Low Low Intermediate Low GPS Favorable Biology Very Low Risk Individual Risk High GPS Unfavorable Biology Intermediate Risk Cancer Consult is written for physicians and should be relied on for medical education purposes only. It does not provide a complete overview of the topics covered and should not replace the independent judgment of a physician about the appropriateness or risks of a procedure for a given patient. Figure 1 A patient s Genomic Prostate Score (GPS) helps distinguish individual risk of unfavorable pathology across a spectrum of clinical disease categories The Cleveland Clinic Foundation

11 CLEVELAND CLINIC TAUSSIG CANCER INSTITUTE CANCER CONSULT Androgen Signaling AZGP1 One major barrier to more widespread adoption of active surveillance is uncertainty on the part of both patients and physicians as to whether a biopsy showing low-volume Gleason 6 cancer is reflective of the biology of the entire prostate. Current clinical practice is typically to perform a repeat biopsy soon after initial diagnosis, and at some centers to perform a prostate MRI, but neither of these methods has been sufficiently clinically validated to completely assuage concerns about undergrading or understaging. GPS was specifically designed to address this issue. In the initial development study, the primary and highest Gleason pattern tumors contained in radical prostatectomy specimens were microdissected, and gene expression signatures were measured independently in each tumor. The results showed that a subset of genes could predict clinical outcomes regardless of whether they were measured in the primary or highest grade. This suggests that if expression of the same genes was measured in a prostate biopsy, the result would be informative about the biology of the entire prostate. Two subsequent studies, one at Cleveland Clinic and the one at UCSF previously mentioned, demonstrated that gene expression on biopsy could predict for the presence of a dominant pattern 4 cancer or extracapsular disease, both of which are features that are desirably avoided in men managed by surveillance. The clinically available GPS is derived from biopsy material from an individual patient and is reported on a scale of 0 to 100. Lower scores are indicative of a higher likelihood of having favorable pathology (i.e., absence of dominant pattern 4 disease and absence of extracapsular disease), which helps discriminate individual risk in men categorized with National Comprehensive Cancer Network very low-, low- or intermediaterisk disease (Figure 1). The overdiagnosis of nonlethal prostate cancer by PSA screening has resulted in a paradigm shift in FAM13C KLK2 SRD5A2 Stromal Response BGN COL1A1 SFRP4 Proliferation TPX2 Cellular Organization FLNC GSN GSTM2 TPM2 Reference ARF1 ATP5E CLTC GPS1 PGK1 Figure 2 The 17 genes comprising the Genomic Prostate Score the management of newly diagnosed disease. The main question men should ask is no longer What is the best treatment for my cancer?, but rather, Does my cancer need to be treated at all? The development of the GPS helps usher in an era of precision medicine, where the correct answer to the question on need for treatment is less a clinical judgment than a decision informed by an individual s tumor biology clevelandclinic.org/cancer

12 Clinical Trials At any given time, Taussig Cancer Institute has more than 100 cancer clinical trials underway on the main campus and at some Cleveland Clinic community facilities. Here is a representative sample of trials that are currently accepting patients: Get the Latest on Cancer Trials with Our New Mobile App Stay up to date on Cleveland Clinic s more than 100 active clinical trials for cancer patients. Our free Cancer Clinical Trials app available for iphone, ipad, Android TM phone and Android tablet makes it easy. With this app, you can: Search the database of open clinical trials by disease, phase, physician or location. Browse real-time information on each trial s objective, eligibility criteria, stage(s) and more. Connect to our Cancer Answer Line for more information about a trial or to enroll patients. Making clinical trials accessible offers patients important treatment options, says Brian Rini, MD, a staff member in Solid Tumor Oncology. This app is one more way for doctors to know what trials are available, in real time. To download, go to clevelandclinic.org/cancertrialapp. GLIOBLASTOMA CCF IRB Phase II study of TKI258 (dovitinib) in patients with recurrent or progressive glioblastoma who have progressed with or without anti-angiogenic therapy (including anti-vegf therapy) CCF IRB Phase II Evaluation of TRC105 in combination with bevacizumab for the treatment of recurrent or progressive glioblastoma that has progressed on bevacizumab CCF IRB Prospective Phase II trial of NovoTTF- 100A with bevacizumab (Avastin ) in patients with recurrent glioblastoma LYMPHOMA CCF IRB Phase II study of radioimmunotherapy with Zevalin (ibritumomab tiuxetan) therapy for patients with refractory or relapsed primary central nervous system lymphoma (PCNSL) MESOTHELIOMA VERA 1513 / Phase II randomized double-blind, placebo-controlled, multicenter study of VS-6063 in subjects with malignant pleural mesothelioma (Verastem Inc) New: SARCOMA THRS 1711 Randomized Phase III, multicenter, open-label study comparing TH-302 in combination with doxorubicin vs. doxorubicin alone in subjects with locally advanced unresectable or metastatic soft tissue sarcoma. MYELOMA CASE1A09 / CC-902 Azacitidine with lenalidomide and dexamethasone for relapsed/refractory myeloma CASE2A10 / CC Placebo-controlled trial to assess efficacy of glutamine in prevention of bortezomib-induced neuropathy CASE1A13 / Mini allogeneic stem cell transplant with bortezomib as graft-vs.-host disease prophylaxis and delayed low-dose lenalidomide maintenance with the goal to maximize graft versus myeloma effects SWOG1211 / The antics-1 antibody elotuzumab together with bortezomib, lenalidomide and dexamethasone for high-risk multiple myeloma RENAL GENE 1813 Phase II randomized study of MPDL3280A administered as monotherapy or in combination with bevacizumab vs. sunitinib in patients with untreated advanced renal cell carcinoma clevelandclinic.org/cancer For information about clinical trials, call the Cancer Answer Line at To search the database, visit clevelandclinic.org/cancerclinicaltrials.

13 apoa1 Promising Research Shows HDL, the Carrier of Good Cholesterol, Has Cancer-Fighting Punch It may be time to add potential cancer fighter to the list of promising benefits of HDL, the carrier of good cholesterol, according to cutting-edge research emerging from Cleveland Clinic s Lerner Research Institute. In a series of innovative experiments, Stanley Hazen, MD, PhD, and his team determined that apolipoprotein A1 (apoa1), or the major cardioprotective protein component of high-density lipoprotein (HDL), combats metastatic malignant melanoma and lung cancer through multiple pathways. ApoA1 injections not only inhibited tumor growth and progression in experiments with mice, but actually spurred tumor and metastases regression. Researchers at Cleveland Clinic, including Dr. Hazen; Joseph DiDonato, PhD; Maryam Zamanian- Daryoush, PhD; and Daniel Lindner, MD, PhD, are now poised to translate these advances to therapeutic strategies for the clinical setting. The apoa1 findings are a prime example of new advances coming from the evolving field of cardiooncology. Cardiovascular disease and cancer are not so disparate in the sense that there are major contributing pathways that operate in concert in both diseases, says Dr. Hazen, Chair of Cellular and Molecular Medicine, the Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis, and the Leonard Krieger Chair in Preventive Cardiology at Cleveland Clinic. In apoa1, we may have identified an important central player nexus and a possible intervention that works positively to combat both diseases. Interestingly, after in vitro studies ruled out a direct effect of apoa1 on tumor cells, the Cleveland Clinic team determined apoa1 instead modulates innate and adaptive immune systems in the host in multiple ways to create a micro-environment that works against cancer development. For example, they demonstrated apoa1 can actually switch tumor-associated macrophages from an M2 phenotype to a more beneficial M1; can decrease tumor angiogenesis independent of vascular endothelial growth factor pathways; and can increase levels of tumor-killing CD8 T cells circulating in and around a tumor. Although complexity usually works in cancer s favor, here it may be a distinct disadvantage. The simple elegance of a multipronged approach is that the tumor cell should have a very difficult time in coming up with a solution to negate apoa1 effects, says Dr. DiDonato, Supervisor of the Cellular and Molecular Medicine Laboratory at Cleveland Clinic. If apoa1 had a direct effect on the tumor, the tumor could mutate to circumvent apoa1 s direct effect, much like tumors do in response to chemotherapeutic agents that target a single pathway or protein in the tumor cell. Dr. Hazen says, In contrast to most chemotherapies, which weaken the immune system and have infection risk as a side effect, apoa1 therapy for these tumors augments the immune system s functions, harnessing the body s natural tumor-fighting potential to promote tumor and metastases regression it s exciting. The investigators observed zero to very limited metastatic melanoma tumor growth in transgenic animals overexpressing apoa1 at approximately twice the normal circulating levels. In further experiments, Dr. Hazen, Dr. DiDonato and their colleagues found palpable tumors regressed 50 percent from their peak volume within one week among animals injected with apoa1, a beneficial result maintained over time. It remains unknown if apoa1 s anti-inflammatory action is the shared underlying etiology between the benefits of HDL seen in cardiology and potentially now also observed in oncology. That is the $64,000 question, Dr. DiDonato says. What we do know is that inflammation plays a major role, not only in the initiation or establishment of the tumor, but also in the propagation and migration or metastasis of the tumor cells. For more information, contact Dr. Hazen at or hazens@ccf.org. Dr. DiDonato can be reached at or didonaj@ccf.org clevelandclinic.org/cancer

14 CANCER CONSULT WINTER 2014 Hyperthermia Improves Response Rates in Recurrent Cancers A large number of clinical studies show that treatment with hyperthermia in combination with radiation leads to a better response than radiation alone in a variety of cancers, particularly for superficial cancers. Wellcontrolled studies show that the combination treatment can increase complete response rates in patients with recurrent breast cancer compared with radiation alone, particularly for those patients who have had prior radiation. Yet despite these benefits, the treatment is not widely available. Cleveland Clinic s Taussig Cancer Institute is the only cancer program in Ohio and one of the few in the United States to offer hyperthermia. For more information, contact Dr. Yu at or yuj2@ccf.org Hyperthermia is a noninvasive method of increasing tumor temperature that makes it more sensitive to the effects of radiation. Our group has shown that the addition of hypothermia to radiation can sensitize cancer stem cells which are fairly resistant to radiation and to chemotherapy alone to subsequent radiation treatment, says Jennifer Yu, MD, PhD, radiation oncologist at Taussig Cancer Institute, and a cancer researcher in Stem Cell Biology and Regenerative Medicine at Lerner Research Institute. Hyperthermia makes radiation much more efficacious, she says. The combination of hyperthermia and radiation in particular is a great treatment for patients who have failed prior chemotherapy and failed prior radiation therapy. Taussig Cancer Institute houses a hyperthermia unit that is primarily used for treating superficial cancers. Within the past 18 months, more than 20 patients have received this treatment. Most patients seen have recurrent breast cancers and some patients have unresectable melanoma and recurrent vulvar cancers that previously had been irradiated. We have the capacity to treat deeper tumors as well, such as advanced cervical cancer, Dr. Yu adds. Hyperthermia helps address the limitations of repeat radiation for many patients by effectively increasing the radiation dose without substantially increasing side effects. With the addition of hyperthermia we are able to use lower radiation doses and yet have comparable results seen with higher doses, says Dr. Yu. She explains that hyperthermia effectively increases the amount of radiation a patient receives by about 50 percent.

15 CLEVELAND CLINIC TAUSSIG CANCER INSTITUTE CANCER CONSULT The combination of hyperthermia and radiation in particular is a great treatment for patients who have failed prior chemotherapy and failed prior radiation therapy. Jennifer Yu, MD PhD, Radiation Oncologist Proven Protocols Hyperthermia is done prior to each radiation treatment. For recurrent breast cancer, treatment requires about 60 minutes of hyperthermia followed by radiation. During the treatment, a heated water bolus is placed on the area to be treated, which is the tumor plus a small area around it. A microwave unit is added on top that heats the treatment area to 109 to 110 degrees Fahrenheit. Physicians use thermistors to measure temperature in real time to make sure the tumor is receiving adequate heating, not over- or underheating. The hyperthermia we use involves mild but effective temperatures, adds Dr. Yu. It is not so high that the tumor is destroyed, such as with thermal ablation. After the procedure, some patients may feel mild to moderate pain; others just feel warm. Most patients do not require pain medications. Many patients are sufficiently relaxed that they fall asleep during the hyperthermia treatment. Patients typically receive hyperthermia/radiation treatment twice a week, but it may vary due to the radiation protocol prescribed. Each hyperthermia session must be accompanied by radiation or, in some cases, chemotherapy. Hyperthermia is generally well-tolerated. A minority of patients develop skin blistering or ulceration that typically heals with conservative measures. Most patients referred to Taussig Cancer Institute s hyperthermia unit are sent by medical oncologists who have tried multiple types of chemotherapy, or radiation oncologists who are aware of the benefits of hyperthermia and radiation clevelandclinic.org/cancer

16 CANCER CONSULT WINTER 2014 Scoring the Risks: Khorana Score Predicts Risk of Cancer-associated Thrombosis and Mortality Thrombosis and cancer are integrally linked. Patients with cancer carry a fourfold increase in thrombosis risk, with chemotherapy elevating the risk even higher. For more information, contact Dr. Khorana at or khorana@ccf.org For the past eight years, Alok Khorana, MD, Director of the Gastrointestinal Malignancies Program at Cleveland Clinic s Taussig Cancer Institute since April 2013, has been studying this link. In 2008, he published what has become a seminal paper in the field of thrombosis and cancer, detailing a risk score protocol that helps predict a cancer patient s risk of venous thromboembolism (VTE). The Khorana score, as it known, predicts thrombosis risk based on a collection of simple variables type of cancer, body mass index (BMI) and complete blood count (platelet, leukocyte, hemoglobin). Not only is the score effective for assessing risk, but it is also easy to use because expensive tests are not required, says Dr. Khorana. It is data everyone already has for their patients. Each variable in the score is assigned a value. Elevated pre-chemotherapy platelet counts over 350,000/mcL, BMI of at least 35 kg/m 2, and cancer types such as stomach and pancreas cancer each raise the risk, for example. Cancer patients with a Khorana score of 3 or greater are at high risk for developing blood clots. Our initial study of 4,000 patients also showed that patients who are at high risk of developing clots experience shorter progression-free survival and early mortality, he adds. Today, nearly 10,000 patients in the United States and Europe have been part of clinical studies assessing the effectiveness of the Khorana score in predicting the risk of cancer-associated thrombosis. Since our first study, multiple institutions have validated the score in predicting blood clot risk, he adds. All of the studies show it works exceedingly well. In June 2013, the American Society of Clinical Oncology (ASCO) issued guidelines affirming the use of a slightly modified Khorana score as a well-established risk calculator for thromboembolism. Specifically, new ASCO guidelines recommend that patients with cancer be assessed for VTE risk at the time of chemotherapy initiation and periodically thereafter. The guidelines also suggest that physicians consider using the score when deciding if VTE prophylaxis is an appropriate intervention for a particular patient. This is an important recommendation because several randomized clinical trials, including the Prophylaxis of Thromboembolism During Chemotherapy Trial (PROTECHT) study and the SAVE-ONCO investigation, the largest thromboprophylaxis study ever conducted in cancer patients, have recently demonstrated that outpatient anti-coagulation prophylaxis is feasible, safe and effective. But it remains unclear which cancer patients should be selected for VTE prophylaxis. The ASCO guidelines suggest that only those ambulatory cancer patients at high risk for VTE receive anti-coagulation therapy on a prophylactic basis.

17 CLEVELAND CLINIC TAUSSIG CANCER INSTITUTE CANCER CONSULT Predicts Mortality in Cancer The main use of the score is to assess risk of blood clots and to inform a recommendation for anticoagulation prophylaxis. The new use of the score is that it is predictive of mortality, explains Dr. Khorana. A European analysis of more than 1,500 patients with a variety of cancers determined that higher Khorana scores correlate with higher mortality rates independent of the presence of blood clots. After two years of follow-up, patients with a Khorana score of 0 had a 27 percent mortality rate; those with a Khorana score of 3 or more had a 63 percent mortality rate, a fourfoldhigher mortality rate after adjustment compared with patients with a score of 0. While this study based in Vienna, Austria, was performed in patients with several types of cancers, Dr. Khorana and others are conducting other investigations in specific cancer types to validate the score s efficacy and usefulness in those patient populations. His research group has already performed two studies using the score in patients with gastrointestinal cancers. While the results are pending publication, Dr. Khorana explains that when we look purely at colorectal cancer patients, which are the patients I treat personally, it appears highly effective in predicting mortality in that population clevelandclinic.org/cancer

18 CANCER CONSULT WINTER 2014 New Staff Mohamed Abazeed, MD, PhD Specialty: Translational Hematology Oncology Research Office: Lanea Keller, MD Specialty: Radiation Oncology Office: Alberto Montero, MD Specialty: Breast Oncology Office: Nima Sharifi, MD Specialty: Prostate Cancer Office: Qing Yi, MD, PHD Department Chair, Cancer Biology Specialty: Cancer Biology Office: Jame Abraham, MD, has been named director of the Breast Oncology Program at Cleveland Clinic Taussig Cancer Institute. Previously he was the first Bonnie Wells Wilson Distinguished Professor and Eminent Scholar in breast cancer research at West Virginia University s Mary Babb Randolph Cancer Center, where he also served as Medical Director of the Cancer Service Line and Chief of Hematology/Oncology. Dr. Abraham is the founding editor of the Bethesda Handbook of Clinical Oncology, as well as the chief editor of Emerging Cancer Therapeutics. He is a member of the NSABP Breast Cancer Working Group, and for four years was a member of the American Cancer Society s Board of Directors. Among Dr. Abraham s honors are the Dean s Award for Excellence in Clinical Medicine from the West Virginia University School of Medicine, and a 2010 award from the president of India for contributions to medicine. In this day and age, breast cancer treatment should be delivered by a team of experts, Dr. Abraham says. Fortunately at Cleveland Clinic, we have an excellent breast cancer team. My goal is to work with our outstanding team members to operate one of the best patient-centered breast cancer programs in the country. That means continuing to provide excellent patient care; offering innovative, pathway-driven, novel treatment approaches through clinical trials; and, above all, making sure that every patient receives the highest quality of care, delivered in a coordinated way. Dr. Abraham earned his medical degree from India s Calicut Medical College. He completed his internal medicine residency at the University of Connecticut, and a hematology fellowship at the National Heart, Lung, and Blood Institute. He was a Senior Fellow at the National Cancer Institute, and took part in the Leadership for Development of Physicians in Academic Health Centers program at Harvard University s School of Public Health. Office: Navneet Majhail, MD, MS, has joined Cleveland Clinic Taussig Cancer Institute as director of the Blood and Marrow Transplant Program. He also serves as a staff physician in the Department of Hematologic Oncology and Blood Disorders. Previously, Dr. Majhail was an adjunct associate professor in the University of Minnesota s Blood and Marrow Transplant Program, and Medical Director of Health Services Research at the National Marrow Donor Program in Minneapolis. Dr. Majhail s research involves prevention and management of complications of blood and marrow transplantation. He also focuses on health policy issues such as healthcare disparities, quality of care, survivorship and economic issues related to transplant. He holds leadership positions with the Center for International Blood and Marrow Transplant Research, where he is the scientific director for the Late Effects and Health Policy Working Committees and their Health Services Research Program. Cleveland Clinic s Blood and Marrow Transplant Program is a national leader in providing patient-centered, high-quality and cutting-edge care to transplant patients, says Dr. Majhail. I am committed to continuing and building on this legacy. It takes a village to take care of a transplant patient, and the excellent team of providers that we have in our program was an important factor in my decision to come here. I look forward to increasing collaboration with our internationally recognized hematologic malignancy programs, and to further building our portfolio of clinical trials so that we can continue to provide highly innovative, leading-edge treatments to our patients. Dr. Majhail earned his medical degree from India s Government Medical College in Chandigarh, India. He completed his internal medicine residency at Cleveland Clinic and a hematology/oncology fellowship at the University of Minnesota. Office:

19 Selected PUBLICATIONS CLEVELAND CLINIC TAUSSIG CANCER INSTITUTE CANCER CONSULT Sohal DPS, Metz JM, Sun W, Giantonio BJ, Plastaras JP, Ginsberg G, Kochman ML, Teitelbaum UR, Harlacker K, Heitjan DF, Feldman MD, Drebin JA, O Dwyer PJ. Toxicity study of gemcitabine, oxaliplatin, and bevacizumab, followed by 5-fluorouracil, oxaliplatin, bevacizumab, and radiotherapy, in patients with locally advanced pancreatic cancer. Cancer Chemother Pharmacol Jun;71(6): Lane BR, Campbell SC, Gill IS. 10-year oncologic outcomes after laparoscopic and open partial nephrectomy. J Urol Jul;190(1): Przybycin CG, Magi-Galluzzi C, McKenney JK. Hereditary syndromes with associated renal neoplasia: a practical guide to histologic recognition in renal tumor resection specimens. Adv Anat Pathol Jul;20(4): Sloan AE, Ahluwalia MS, Valerio-Pascua J, Manjila S, Torchia MG, Jones SE, Sunshine JL, Phillips M, Griswold MA, Clampitt M, Brewer C, Jochum J, McGraw MV, Diorio D, Ditz G, Barnett GH. Results of the NeuroBlate System first-in-humans Phase I clinical trial for recurrent glioblastoma. J Neurosurg Jun;118(6): Smith MR, Joshi I, Pei J, Slifker M, Jin F, Testa JR, Al-Saleem T. Murine mantle cell lymphoma model cell line. Leukemia Jul;27(7): Dreicer R, Garcia J, Rini B, Vogelzang N, Srinivas S, Somer B, Shi P, Kania M, Raghavan D. A randomized, double-blind, placebo-controlled, Phase II study with and without enzastaurin in combination with docetaxel-based chemotherapy in patients with castration-resistant metastatic prostate cancer. Invest New Drugs Aug;31(4): Estfan B, Byrne M, Kim R. Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy. Am J Clin Oncol Aug;36(4): Makishima H, Yoshida K, Nguyen N, Przychodzen B, Sanada M, Okuno Y, Ng KP, Gudmundsson KO, Vishwakarma BA, Jerez A, Gomez-Segui I, Takahashi M, Shiraishi Y, Nagata Y, Guinta K, Mori H, Sekeres MA, Chiba K, Tanaka H, Muramatsu H, Sakaguchi H, Paquette RL, McDevitt MA, Kojima S, Saunthararajah Y, Miyano S, Shih LY, Du Y, Ogawa S, Maciejewski JP. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet Aug;45(8): Rajala HLM, Eldfors S, Kuusanmaki H, van Adrichem AJ, Olson T, Lagstrom S, Andersson EI, Jerez A, Clemente MJ, Yan Y, Zhang D, Awwad A, Ellonen P, Kallioniemi O, Wennerberg K, Porkka K, Maciejewski JP, Loughran TP, Jr., Heckman C, Mustjoki S. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood May 30;121(22): Finke JH, Rayman PA, Ko JS, Bradley JM, Gendler SJ, Cohen PA. Modification of the tumor microenvironment as a novel target of renal cell carcinoma therapeutics. Cancer J Jul;19(4): Herts BR, Baker ME, Obuchowski N, Primak A, Schneider E, Rhana H, Dong F. Dose reduction for abdominal and pelvic MDCT after change to graduated weight-based protocol for selecting quality reference tube current, peak kilovoltage, and slice collimation. AJR Am J Roentgenol Jun;200(6): Jagadeesh D, Smith MR. Novel targeted therapies in peripheral T cell lymphoma. Discov Med Jun;15(85): ABSTRACTS Koyfman SA, Agre P, Carlisle R, Classen L, Cheatham C, Finley JP, Kuhrik N, Kuhrik M, Mangskau TK, O Neill J, Reddy CP, Kodish E, McCabe MS. Consent form heterogeneity in cancer trials: The cooperative group and institutional review board gap. J Natl Cancer Inst Jul 3;105(13): Cooperative group (CG) provided consent forms (CGP-CFs) undergo re-review and revision by local institutional review boards (IRB) before institutional approval. We compared the relative readability and length of IRB-approved consent forms (IRB-CFs) used at seven academic institutions with their corresponding CGP-CFs. We also assessed the variability of these metrics across our institutions. This study included 197 consent forms (CFs) from 56 CG trials that were open in at least two of the participating institutions. The Flesch Reading Ease Score (FRES), the Flesch-Kincaid Grade Level (FKGL), and document length were collected on all CFs. Unpaired t test was used to compare length and readability of CGP-CF with the IRB-CF. Analysis of variance and Bonferroni-Dunn tests were used to assess interinstitutional variability in readability for all IRB-CFs. All statistical tests were two-sided. IRB-CFs were statistically significantly longer than CGP-CFs (mean number of pages = 17 vs 13; p <.001). Mean FKGLs were higher (10.3 vs 9.4; p <.0001) and the mean FRESs were lower (53.1 vs 57.1; p <.0001) for IRB-CFs compared with CGP-CFs. Readability varied statistically significantly between institutions for all sections of the IRB-CF (p <.0001). Finalized IRB-CFs for identical clinical trials at different institutions demonstrated substantial heterogeneity of readability and length. As CFs progress from National Cancer Institute (NCI)-sponsored CGs to local IRBs, they seem to become longer and less readable. Interinstitutional heterogeneity in CF readability is substantial and widespread. More consistent adherence to CGP-CFs based on the newly revised NCI CF template with minimal modification by local IRBs should help simplify and standardize CFs used in cancer clinical trials Chang KH, Li R, Kuri B, Lotan Y, Roehrborn CG, Liu J, Vessella R, Nelson PS, Kapur P, Guo X, Mirzaei H, Auchus RJ, Sharifi N. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell Aug 29;154(5): Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation that leads to a gain-of-function in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3βHSD1 is a valid target for the treatment of CRPC clevelandclinic.org/cancer

20 The Cleveland Clinic Foundation Taussig Cancer Institute 9500 Euclid Ave. / AC311 Cleveland, OH The Cleveland Clinic Way By Toby Cosgrove, MD, CEO and President of Cleveland Clinic Great things happen when a medical center puts patients first. Visit clevelandclinic.org/clevelandclinicway for details or to order a copy. Resources for Physicians Physician Directory View all Cleveland Clinic staff online at clevelandclinic.org/staff. Same-Day Appointments Cleveland Clinic offers same-day appointments to help your patients get the care they need, right away. Have your patients call our sameday appointment line, CARE (2273) or CARE (2273). Track Your Patients Care Online Establish a secure online DrConnect account for real-time information about your patients treatment at Cleveland Clinic at clevelandclinic.org/drconnect. Critical Care Transport Worldwide To arrange for a critical care transfer, call or Visit clevelandclinic.org/criticalcaretransport to learn more. CME Opportunities: Live and Online Visit ccfcme.org to learn about the Cleveland Clinic Center for Continuing Education s convenient, complimentary learning opportunities. 24/7 Referrals Referring Physician Hotline 855.REFER.123 ( ) Hospital Transfers On the Web at: clevelandclinic.org/refer123 Stay connected with us on Outcomes Data View Outcomes books at clevelandclinic.org/outcomes. Clinical Trials We offer thousands of clinical trials for qualifying patients. Visit clevelandclinic.org/clinicaltrials. Executive Education Learn about our Executive Visitors Program and two-week Samson Global Leadership Academy immersion program at clevelandclinic.org/executiveeducation. Download Our New Physician Referral App! Contacting us is now easier than ever. With our free Physician Referral App, you can view all our specialists and get in touch immediately with one click of your iphone, ipad, or Android phone or tablet. Download today at the App Store or Google Play. Cleveland Clinic is an integrated healthcare delivery system with local, national and international reach. At Cleveland Clinic, more than 3,000 physicians and scientists represent 120 medical specialties and subspecialties. We are a main campus, 18 family health centers, eight community hospitals, Cleveland Clinic Florida, the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Cleveland Clinic Canada, Sheikh Khalifa Medical City, and Cleveland Clinic Abu Dhabi. In 2013, Cleveland Clinic was ranked one of America s top four hospitals in U.S. News & World Report s annual America s Best Hospitals survey. The survey ranks Cleveland Clinic among the nation s top 10 hospitals in 14 specialty areas, and the top hospital in three of those areas. 13-CNR-909