Cancer Research

Amol Narang MD Radiation Oncology Resident Johns Hopkins MedicineMedicalResearch.com Interview with: Amol Narang MD Radiation Oncology Resident Johns Hopkins Medicine Medical Research: What is the background for this study? What are the main findings? Dr. Narang: The care provided to cancer patients at end-of-life can be intense, including frequent ER visit, hospitalizations, and ICU stays in the last month of life, administration of chemotherapy in last two weeks of life, and late referrals to hospice. Providing high-intensity treatments at end-of-life has been associated with reduced patient quality-of-life and increased caregiver bereavement. Advance care planning represents an opportunity for patients to indicate their preferences for end-of-life care to try to ensure that the care that they receive at end-of-life is consistent with their values, and has been endorsed by oncologic professional societies, such as ASCO and the NCCN. As such, we wanted to assess if oncologists’ long-standing recognition of the merits of advance care planning has translated into increased participation in advance care planning by cancer patients, and to determine which forms of advance care planning are associated with intensity of care given at end-of-life. From 2000-12, we found that the only type of advance care planning that increased was the assignment of a power of attorney (52% in 2000 to 74% in 2012). However, having a power of attorney was not associated with receiving less aggressive end-of-life care. On the other hand, having a living wills and engaging in a discussion with a provider or loved one about preferences for end-of-life care were both associated with reduced treatment intensity. However, the frequency with which cancer patients created a living or discussed their preferences for end-of-life care did not increase over the study period; importantly, 40% of patients dying of cancer never communicated their preferences for care at end-of-life with anyone.

MedicalResearch.com Interview with: Mario Mandalà, MD Department of Oncology and Haematology Papa Giovanni XXIII Hospital Bergamo, Italy Medical Research: What is the background for this study? Dr. Mandalà: In addition to their established molecular mechanism of action, growing evidence suggests that the therapeutic efficacy of BRAFi relies on additional factors that affect the tumor–host interactions, including the enhancement of melanoma antigen expression and the increase in immune response against tumor cells.  Preclinical data show that oncogenic BRAF contributes to immune evasion, and that targeting this mutation may increase the melanoma immunogenicity. Data in vitro or from animal models propose PD-L1 as a potential mechanism that favors BRAFi resistance through the modulation of host immune responses. However, demonstration of this hypothesis in the clinical setting is lacking. Medical Research: What are the main findings? Dr. Mandalà: In the present study, we have evaluated, in a homogeneous series of MMP treated with BRAFi, the association of tumoral PD-L1 IHC expression and the density of TIMC with RR, PFS and OS. Results provide the first proof-of-principle clinical evidence of the predictive and prognostic relevance of PD-L1 IHC expression and density of immune cell infiltration in BRAFV600 mutated MMP receiving BRAFi.

Aung Ko Win, MBBS MPH PhD Research Fellow NHMRC Early Career Clinical Research Fellow Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne VIC 3010 AustraliaMedicalResearch.com Interview with: Aung Ko Win, MBBS MPH PhD Research Fellow NHMRC Early Career Clinical Research Fellow Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne VIC 3010 Australia Medical Research: What is the background for this study? Response: At least 1 in 1,000 people in the population have a mutation in one of the mismatch repair genes that causes Lynch syndrome. These people have a very high risk of bowel cancer (colorectal cancer): if nothing is done, about half would develop the disease. The main risk reduction method for these people is to have regular colonoscopy screening every year. Almost nothing is known whether or not lifestyle factors and medications can modify the risk of bowel cancer for people with Lynch syndrome. A study was conducted to investigate the associations between aspirin and ibuprofen intake and the risk of bowel cancer, by studying 1,858 people with Lynch syndrome who were recruited into the Colon Cancer Family Registry from Australia, New Zealand, Canada and the USA. This is the largest study to date investigating the associations between aspirin, ibuprofen and bowel cancer risk for people with Lynch syndrome.

Aung Ko Win, MBBS MPH PhD Research Fellow NHMRC Early Career Clinical Research Fellow Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne VIC 3010 AustraliaMedicalResearch.com Interview with: Aung Ko Win, MBBS MPH PhD Research Fellow NHMRC Early Career Clinical Research Fellow Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne VIC 3010 Australia Medical Research: What is the background for this study? What are the main findings? Response: About 2-5% of uterine cancer are associated with an underlying genetic condition mainly Lynch syndrome. Lynch syndrome is caused by a mutation in one of the mismatch repair genes. At least 1 in 1000 people in the population have a mutation that causes Lynch syndrome and these people have a very high risk of cancers mainly bowel and uterine cancers. One in three women with a mutation in one of the mismatch repair genes are likely to develop a uterine cancer in their lifetime. The only way to reduce the risk of uterine cancer for these women is to remove the uterus. There is no current recommendation for screening method to detect uterine cancer early. Almost nothing is known about if and how lifestyle factors and hormonal factors can modify their risk of uterine cancer. By studying 1128 women with a mutation that causes Lynch syndrome who were recruited from Australia, New Zealand, Canada and the USA, we found that later age at first menstrual cycle, having one or more live births, and using hormonal contraceptive use for one year or longer were associated with a lower risk of uterine cancer.

MedicalResearch.com Interview with: Dr. Jürg Bernhard Ph.D. International Breast Cancer Study Group Coordinating Center and Bern University Hospital, Inselspital, Bern, Switzerland Medical Research: What is the background for this study? What are the main findings? Response: In the combined analysis of the SOFT and TEXT trials, the aromatase inhibitor exemestane was more effective than tamoxifen in preventing breast cancer recurrence in young women (premenopausal) who also receive ovarian function suppression (OFS) as adjuvant (post-surgery) treatment for hormone-sensitive early breast cancer, providing a new treatment option for these women. These trials were conducted by the International Breast Cancer Study Group (IBCSG) and involved more than 4700 patients of over 500 centers in 27 countries. Now we present patient-reported quality of life outcomes from these trials. In the TEXT and SOFT trials, patients assigned exemestane+OFS reported more detrimental effects of bone or joint pain, vaginal dryness, greater loss of sexual interest and difficulties becoming aroused, while patients assigned tamoxifen+OFS were more affected by hot flushes and sweats. Global quality of life domains (mood, ability to cope and physical well-being) were similar between the randomized treatment groups.

Wen-Qing Li Ph.D Department of Dermatology Warren Alpert Medical School Department of Epidemiology, School of Public Health, Brown University, Providence, RIMedicalResearch.com Interview with: Wen-Qing Li Ph.D Department of Dermatology Warren Alpert Medical School Department of Epidemiology, School of Public Health, Brown University, Providence, RI Medical Research: What is the background for this study? Response: Rosacea is a chronic inflammatory cutaneous disorder and may be an end-organ response in a systemic disorder. We systemically examined the association between personal history of rosacea and risk of cancer based on 75088 whites in the Nurses’ Health Study II, during a follow-up of 20 years. Medical Research: What are the main findings? Response: We suggest possible associations between personal history of rosacea and an increased risk of thyroid cancer and Basal Cell Cancer. Analyses did not find significant associations for other individual cancer types. 

MedicalResearch.com Interview with: Dr Ananya Choudhury Consultant and Honorary Senior Clinical Lecturer, Clinical Oncology The Christie NHS Foundation Trust, Wilmslow Road Withington, Manchester, UK Medical Research: What is the background for this study? What are the main findings? Response: Although more than half of newly diagnosed cancer patients are treated with radiotherapy, it is still not possible to select patients who will respond and tolerate radiotherapy compared to those who do not. There has been a lot of work done to try and isolate intrinsic biomarkers which will identify either radio-responsive or radio-resistant disease. We have undertaken a systematic view summarising the evidence for biomarkers as predictors of radiotherapy. Despite identifying more than 500 references during a systematic literature search, we found only twelve studies which fulfilled our inclusion criteria. Important exclusion criteria included pre-clinical studies, studies with no control population and a sample size of less than 100 patients. Only 10 biomarkers were identified as having been evaluated for their radiotherapy-specific predictive value in over 100 patients in a clinical setting, highlighting that despite a rich literature there were few high quality studies suitable for inclusion. The most extensively studied radiotherapy predictive biomarkers were the radiosensitivity index and MRE11; however, neither has been evaluated in a randomised controlled trial.

MedicalResearch.com Interview with: Chao Cheng, Ph.D. Assistant Professor Department of Genetics Institute for Quantitative Biomedical Sciences Geisel School of Medicine at Dartmouth Hanover NH, 03755 Medical Research: What is the background for this study? Dr. Cheng: Bladder cancer is a common tumor type, with non-muscle-invasive bladder cancer (NMIBC) representing the majority of cases. Bacillus Calmette-Guerin (BCG) treatment is an effective immunotherapy that is commonly used to treat cancers of this subtype. However, this treatment fails to suppress tumor recurrence in up to 40% of patients. For this reason, biomarkers that predict the recurrence/progression of bladder cancer and patient response to BCG therapy are needed to tailor treatment strategies to individual patients. Medical Research: What are the main findings? Dr. Cheng: We had previously developed an E2F4 signature that consisted of the E2F4 transcription factor and its target genes identified by ChIP-seq and ChIP-chip experiments. Here, we found that the E2F4 signature is predictive of the progression of both non-muscle-invasive and muscle-invasive bladder cancer. Furthermore, this signature is also predictive of patient responsiveness to intravesical BCG immunotherapy. Our results suggest that patients with positive E2F4 scores (indicating high E2F4 activity) benefit significantly from BCG therapy, while the progression of patients with negative E2F4 scores (indicating low E2F4 activity) does not show significant difference from untreated patients.

MedicalResearch.com Interview with: Ashley S. Felix, PhD Bethesda, MD MedicalResearch: What is the background for this study? What are the main findings? Dr. Felix: Endometrial cancer prognosis is strongly affected by disease stage, or the extent of spread from the primary site. Endometrial cancers can spread via the lymph nodes, blood vessels, through the uterine wall, or through the fallopian tube into the peritoneal cavity. The last of these mechanisms is poorly understood, but appears to be a more common mode of spread for aggressive histologic subtypes of endometrial cancer. We hypothesized that women who previously underwent tubal ligation (TL) and later developed endometrial cancer would have lower stage disease, possibly by blocking passage of tumor cells along the fallopian tubes. Further, we hypothesized that TL would be associated with better prognosis, due to its relationship with lower stage. We found that women in our study who previously had tubal ligation were more likely to have lower stage endometrial cancer compared with women who did not report a previous tubal ligation. Specifically, tubal ligation was inversely associated with stage III and stage IV cancer across all subtypes of the disease, including aggressive histologic subtypes. Further, in statistical models of tubal ligation, tumor stage, and mortality, we observed no independent association with improved survival, suggesting that tubal ligation impacts mortality mainly through its effects on stage.

Dr. Janaiah Kota Assistant Professor, Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis, IN,MedicalResearch.com Interview with: Dr. Janaiah Kota Assistant Professor, Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis, IN, Medical Research: What is the background for this study? Dr. Kota: Pancreatic cancer tumors are surrounded by a thick fibrotic shell known as “stroma” which protects the cancer cells from anticancer drugs such as chemotherapy. However, complete depletion of tumor stroma leads to more aggressive disease and decreases survival. The stromal abundance needs to be appropriately moderated (i.e. not too much nor too little) in pancreatic tumors. None of the current anti-stromal therapies have been effective enough to resolve this problem. Unless we understand the molecular signatures associated with tumor stroma, it will be challenging to develop an effective therapeutic strategy. There is a desperate need to develop new therapies for pancreatic cancer as only 7 percent of people with the disease survive more than 5 years after diagnosis. According to the National Cancer Institute, there will be an estimated 48,960 new cases of pancreatic cancer and 40,560 deaths from the disease in 2015. Medical Research: What are the main findings? Dr. Kota: We found that the loss of microRNA-29 (miR-29) is a common phenomenon of pancreatic cancer stromal cells, and that by restoring it, the viability and growth of the cancerous cells and stromal accumulation was reduced. The use of miR-29 as a therapeutic agent may be more effective in targeting reactive stroma, as a single miRNA regulates the expression of several genes associated with disease mechanisms. We expect that this novel approach has the potential to overcome the problems associated with current anti-stromal drugs and could lead to improved therapeutic strategies, enhanced drug delivery to the tumor bed, and, in the future, improved patient survival.

MedicalResearch.com Interview with: Dr Klervi Leuraud, Epidemiologist Institute for Radiological Protection and Nuclear Safety Cedex, France MedicalResearch: What is the background for this study? What are the main findings? Dr. Leuraud: INWORKS was performed to quantify the risk of cancer mortality associated to protracted low doses of ionizing radiation typical of occupational or environmental exposures, as well as of diagnostic medical exposures. While such risks are well known for acute exposures as those experienced by the Japanese survivors of the A-bombs, there is still a lack of information for exposures experienced by the workers and the public. Our study confirms the existence of an association between leukemia mortality and chronic exposure to low doses received by nuclear workers.

Dr. Mitchell Kamrava MD Department of Radiation Oncology University of California Los Angeles Los Angeles, CAMedicalResearch.com Interview with: Dr. Mitchell Kamrava MD Department of Radiation Oncology University of California Los Angeles Los Angeles, CA Medical Research: What is the background for this study? What are the main findings? Dr. Kamrava: Breast conservation (lumpectomy followed by radiation) is known, based on multiple randomized trials with over 20 years of follow-up, to provided equivalent outcomes as mastectomy.  The radiation component of breast conservation has standardly been delivered to the whole breast.  Studies show that the majority of breast recurrences occur near the lumpectomy cavity causing some to ask whether it is necessary to treat the whole breast in order to reduce the risk of a recurrence. Partial breast radiation delivers treatment just to the lumpectomy cavity with a small margin of 1-2 cm.  It’s delivered in a shorter time of 1 week compared with about 6 weeks for standard whole breast radiation and 3-4 weeks for hypofractionated whole breast radiation. The original method developed to deliver partial breast radiation is interstitial tube and button brachytherapy.  This uses multiple small little tubes that are placed through the lumpectomy cavity to encompass the area at risk.  One end of these tubes can be connected to a high dose rate brachytherapy machine that allows a motorized cable with a very small radiation source welded to the end of it to be temporarily pushed in and out of each of the tubes so that the patient can be treated from “inside out”.  This helps concentrate the radiation to the area of the lumpectomy cavity while limiting exposure to normal tissues.  This treatment is most commonly delivered as an out-patient two times per day for a total of 10 treatments. The main finding from our paper is that in reviewing the outcomes on over 1,000 women treated with this technique with an average follow-up of 6.9 years that the 10 year actuarial local recurrence rate was 7.6% and in women with more than 5 years of follow-up physician reported cosmetic outcomes were excellent/good in 84% of cases.

Hui Zhu, MD, ScD Section Chief, Urology Section Louis Stokes Cleveland Veterans Affairs Medical Center and Staff, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation Cleveland, Ohio MedicalResearch.com Interview with: Hui Zhu, MD, ScD Section Chief, Urology Section Louis Stokes Cleveland Veterans Affairs Medical Center and Staff, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation Cleveland, Ohio MedicalResearch: Tell me a little bit about the impetus for this study. What gap in knowledge were you trying to fill?  Dr. Zhu: Prostate cancer is a very challenging disease to understand and manage. For the minority of men, prostate cancer is a lethal disease, and in fact, it is the second leading cause of cancer death in American men, behind only lung cancer. However, for the majority of men, prostate cancer poses little risk of death. In fact, about 1 man in 7 will be diagnosed with prostate cancer during his lifetime, but only 1 man in 38 will die from prostate cancer. In an effort to avoid suffering and death from prostate cancer for those men with the lethal form, the early detection of prostate cancer (before the disease has reached a stage when it is no longer curable) through widespread prostate cancer screening was instituted in the late 1980s and early 1990s. As a result, prostate cancer diagnosis increased substantially, and most prostate cancers were detected at an early, treatable stage. Screening successfully reduced the risk of death from prostate cancer by 20%. Unfortunately, our best available screening tests, i.e. prostate-specific antigen (PSA) testing and the digital rectal exam, do not differentiate well between lethal and nonlethal prostate cancer. Consequently, screening is associated with a high risk of overdiagnosis of nonlethal prostate cancer. As a result, about 800 men must be screened and about 30 men must be diagnosed and treated to avoid one death from the prostate cancer, according to recent results from the largest prostate cancer screening trial. Since the natural history of newly diagnosed screen-detected prostate cancer is difficult to predict (i.e. lethal or nonlethal), most prostate cancers have been treated aggressively, leading to overtreatment of many nonlethal cancers. Aside from receiving unnecessary treatment, these men are exposed to the potential side effects and complications of treatment, including erectile dysfunction and urinary incontinence. In response to the harms associated with screening and treatment, the US Preventative Services Task Force issued a statement in 2011 (formalized in 2012) recommending against prostate cancer screening in all men. Unfortunately, while minimizing the risks of overdiagnosis and overtreatment for men with nonlethal prostate cancer, this solution eliminates any of the potential benefits of screening for those men with the lethal form of the disease. As urologists, our solution is different. Rather than throw the baby out with the bathwater, we prefer to preserve PSA screening and its benefits by addressing and hopefully minimizing its associated risks. To achieve this, our goal is to better distinguish between those men who have lethal vs. nonlethal prostate cancer, limiting treatment only to those men who have the lethal form of the disease at an early stage when it is still curable. The dilemma is that our currently available diagnostic tests are unable to accurately differentiate lethal from nonlethal prostate cancer with 100% certainty at the time of initial diagnosis. The solution, or at least part of the solution, is active surveillance. In men who appear to have nonlethal (“low risk”) cancer at the time of diagnosis, it now appears to be safe to observe these cancers, at least initially. This is the concept behind active surveillance. Active surveillance entails carefully monitoring men with low-risk prostate cancer using serial testing and reserving the option of treatment for those men with prostate cancers that exhibit lethal characteristics. In this way, active surveillance preserves the benefits of screening while minimizing the harms of overdiagnosis and overtreatment. Active surveillance was first introduced in the early 2000s, but its efficacy and safety have only been elucidated recently over the last 5 years. Given that active surveillance may be one solution to the screening dilemma, we wanted to evaluate contemporary active surveillance utilization, which is the impetus for our study. Based on the most recent data available to us, we chose the years 2010-2011, which coincide to the time immediately before and during the release of the US Preventative Services Task Force statement against PSA screening.

Timothy P. Padera, PhD Edwin L. Steele Laboratories Department of Radiation Oncology MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts 02114MedicalResearch.com Interview with: Timothy P. Padera, PhD Edwin L. Steele Laboratories Department of Radiation Oncology MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts 02114 MedicalResearch: What is the background for this study? What are the main findings? Dr. Padera: Systemic therapy benefits cancer patients with lymph node metastases; however all phase III clinical trials to date of antiangiogenic therapy have failed in the adjuvant setting. We have previously reported the lack of efficacy of antiangiogenic therapies in pre-clinical models of spontaneous lymphatic metastasis, however there were no mechanistic data to explain these observations. Here, we developed a novel chronic lymph node window model to facilitate new discoveries in the mechanisms of growth and spread of lymph node metastases. Our new data provide pre-clinical evidence along with supporting clinical evidence that angiogenesis does not occur in the growth of metastatic lesions in the lymph node. These results reveal a mechanism of treatment resistance to antiangiogenic therapy in adjuvant setting, particularly those involving lymph node metastases.

Nishant Agrawal M.D. Associate Professor of Otolaryngology Johns Hopkins University School of MedicineMedicalResearch.com Interview with: Nishant Agrawal M.D. Associate Professor of Otolaryngology Johns Hopkins University School of Medicine Medical Research: What is the background for this study? What are the main findings? Dr. Agrawal: The idea of the study really arose from the specificity of genetic changes that characterize and are the hallmark of cancer cells.  Only cancer cells contain these mutations so their detection in bodily fluids was a reasonable expectation.  The current study builds on previous work from our group that tumor DNA can be detected in the bodily fluids of patients with many different types of solid malignancies.  The main findings of the study are that tumor DNA in saliva and plasma provides a non-invasive biomarker for head and neck cancer.  The take home message is that tumor DNA has potential to be used as a biomarker for screening, early detection, monitoring during treatment, and surveillance after cancer treatment is completed.

Michael B. Burns, Ph.D. HHMI Post-Doctoral Fellow Dept. of Genetics, Cell Biology and Development Dept. of Ecology, Evolution, and Behavior Masonic Cancer Center Dept. of Biology Teaching and Learning University of Minnesota, Twin Cities St. Paul, MN 55108MedicalResearch.com Interview with: Michael B. Burns, Ph.D. HHMI Post-Doctoral Fellow Dept. of Genetics, Cell Biology and Development Dept. of Ecology, Evolution, and Behavior Masonic Cancer Center Dept. of Biology Teaching and Learning University of Minnesota Twin Cities St. Paul, MN 55108 Medical Research: What is the background for this study? Dr. Burns: Recent technological advances have made it possible to survey all the of microbes that are in, on, and around us. One of the surprising things is the sheer quantity and diversity of the bacteria in our environments and our microbiomes. Many researchers have begun the systematic characterization of the microbes that are associated with specific disease states, including cancer. With regard to colorectal cancer, there have been numerous studies that have identified specific bacteria that are linked to the presence of the disease. There have been many reports that have identified particular potentially important microbes that may be causing the cancer, driving the cancer, or some combination of the two. Among these microbes, one of the best studied so far is a group of bacteria called Fusobacterium. Medical Research: What are the main findings? Dr. Burns: In our work, we set out to perform another characterization of the bacteria in the gut microbiome that are specifically associated with colorectal tumors. We used samples of normal colon tissue from the same individuals as controls, which allowed us to account for much of the variability in the different bacteria we found that might have been simply the result of, for instance, diet. In our analysis, we confirmed the previous results related to Fusobacterium, and additionally discovered a new potential culprit in colorectal cancer, a group of bacteria named Providencia. The finding of another new set of microbes that might be causing or driving cancer is not surprising. As indicated above, there are many groups who have found other potential candidate microbes that could be implicated in the disease. Our next question was to determine if there was some reason why there might be so many different bacteria that are linked with the disease and what it might be able to tell us about what these bacteria are doing. To that end, we used computational approaches to assess what these two groups of bacteria might be doing at a functional level and if there were any similarities. We found that there was a great deal in common between Fusobacterium and Providencia, including a finding that one of the common functions was related to a large group of virulence genes.

Mitchell S. Stark Senior Research Assistant/PhD Student Oncogenomics Group QIMR Berghofer Medical Research Institute Herston, Brisbane, AustraliaMedicalResearch.com Interview with: Mitchell S. Stark Senior Research Assistant/PhD Student Oncogenomics Group QIMR Berghofer Medical Research Institute Herston, Brisbane, Australia Medical Research: What is the background for this study? What are the main findings? Response: Melanomas are among the most commonly occurring cancers with the number of new cases rising each year. Melanoma is currently is listed as the 4th and 6th most common cancer in Australia and the USA with >11,000 and >76,000 news diagnoses each year.  The overall 5-year survival for melanoma is 91%, which is largely due to curative surgery for early stage disease. However, cure rates are <15% if distant metastasis occurs (stage IV). We now have evidence that current therapeutic options for late stage disease are more effective if the disease is treated with a lower disease burden.  2010). Hence, melanoma must be treated in earlier stages to maximize the chances of patient survival. Therefore, the ability to identify signs of melanoma progression sooner would be a valuable clinical tool. The use of melanoma progression markers have been used for many years however it is clear from the survival rates that melanoma must be detected before disease progresses thus highlighting that the current methods of progression detection are inadequate. We have identified a seven-microRNA panel (MELmiR-7) that has the ability to detect the presence of melanoma with high sensitivity and specificity which is superior to currently used markers for melanoma progression, recurrence, and survival. This panel may enable more precise measurement of disease progression and may herald an increase in overall survival.

Dr. Ayalew Tefferi, M.D.Department of Medicine, Mayo Clinic Rochester, Minnesota MedicalResearch.com Interview with: Dr. Ayalew Tefferi, M.D. Department of Medicine, Mayo Clinic Rochester, Minnesota MedicalResearch: What is the background for this study? What are the main findings? Dr. Tefferi: William Vainchenker discovered and reported an activating JAK2 mutation (JAK2V617F) in myelofibrosis and related myeloproliferative neoplasms in 2005 (Nature. 2005;434:1144-1148). This seminal observation led to the recognition of activated JAK-STAT as the potential disease-driving pathway in myeloproliferative neoplasms and development of several JAK inhibitors, including fedratinib, ruxolitinib and momelotinib, for treatment of myelofibrosis. In phase 2 studies, these JAK inhibitors showed similar activity in alleviating constitutional symptoms and reducing spleen size. However, none of them were able to induce complete or partial remissions or reversal of bone marrow fibrosis or significant lowering of JAK2 mutant allele burden. A subsequent phase 3 study provided the information required for FDA approval of ruxolitinib and the current phase 3 study was meant to do the same for fedratinib.

Dr. Stacy Loeb, MD, MScDepartment of Urology, Population Health, and Laura and Isaac Perlmutter Cancer CenterNew York University, New York MedicalResearch.com Interview with: Dr. Stacy Loeb, MD, MSc Department of Urology, Population Health, and Laura and Isaac Perlmutter Cancer Center New York University, New York Medical Research: What is the background for this study? Dr. Loeb: A paper published last year suggested a relationship between use of (Viagra) and melanoma.  That study had only 142 cases of melanoma, and of these men 14 had used sildenafil.  This study got a lot of publicity leading numerous patients to express concern over whether erectile dysfunction drugs could cause melanoma. Our goal was to look more closely at this issue in a larger population from Sweden (including 4065 melanoma cases of whom 435 used any type of erectile dysfunction drug- Viagra, as well as Levitra and Cialis).  Sweden has a national health system so we were able to access prescription records for men across the entire country, which we linked to the national registries for melanoma and basal cell skin cancer.  

MedicalResearch.com Interview with: Keiran Smalley, PhD. Scientific Director The Comprehensive Melanoma Research Center Associate Professor The Moffitt Cancer Center & Research Institute, Tampa, FL Medical Research: What is the background for this study? What are the main findings? Dr. Smalley: The major finding of this study is that some melanomas (those which are BRAF mutant and PTEN null)...

MedicalResearch.com Interview with: Vinay Prasad, MD, MPH Medical Oncology Service, National Cancer Institute National Institutes of Health Bethesda, Maryland MedicalResearch: What is the background for this study? What are the main findings? Dr. Prasad: In medicine, there are two types of endpoints:  clinical endpoints and surrogate endpoints. Clinical endpoints, such as survival or quality of life, measure how a patient, feels, functions or lives.  In contrast, a surrogate endpoint is not a measure of patient benefit. Instead, it is merely hoped to correlate with one.  LDL levels are a surrogate for cardiovascular risk, for instance. Oncologists use and trust surrogate endpoints, such as response rate, progression free survival and disease free survival.  The majority of drug approvals and many guideline recommendations are based on improvements in surrogates.  Surrogates are assumed to correlate with overall survival, but we wanted to know if this was true, and under what circumstances. We reviewed all well done studies of surrogate-survival association.  We found that the majority--especially in the setting of metastatic disease--found a poor correlation between a surrogate and survival.  In fact, correlations were strong in only a handful of settings, such as adjuvant colorectal cancer.  Moreover, we found that correlations were always based on a subset of potentially informative literature, even when authors surveyed unpublished trials.  Missing data in these association studies raises the concern that correlations would be different if all data had been considered. Our overall conclusion was that most surrogate-survival correlations in oncology are based on weak evidence and are poor.

MedicalResearch.com Interview with: Kristian Pietras, Ph.D. Göran & Birgitta Grosskopf Professor of Molecular Medicine Strategic Director of Cancer Research Lund University Dept of Laboratory Medicine Lund Div of Translational Cancer Research Lund, Sweden Medical Research: What is the background for this study? What are the main findings? Dr. Pietras: Breast cancer is the largest malignant disease among women with 1.7 million new cases worldwide each year (25% of all new cancer cases for women). The prognosis for breast cancer patients is relatively good when the disease is detected at early stages (close to 90% of patients are still alive 5 years after diagnosis). Nevertheless, metastatic disease is the cause of 90% of all cancer-related deaths. Thus, learning more about the metastatic process and finding new cures for widespread disease is justifiably at the center of clinical attention. The current study is part of our ongoing efforts to map support functions performed by the various cell types comprising the tumor stroma with the premise that decisive treatment benefit can only be achieved by targeting multiple, but distinct, cell types and pathways that collectively sustain the growth of tumors. The development of a rich vascular supply  is recognized as a key hallmark of a growing tumor necessary for the development into a clinically relevant disease. Our focus is the role of the tumor vasculature in preventing or promoting metastatic dissemination from the primary tumor. For a metastasis to form, a cancer cell must, 1) detach from its neighboring cells in the mother tumor, 2) traverse the vascular wall to escape into the blood stream, 3) exit the vasculature to enter the metastatic site, and 4) colonize the metastatic site. Recent evidence points to that the transmigration into and out of the vasculature is a regulated process of previously unrecognized importance for the metastatic process. Importantly, the fact that the process of escape into/from the vasculature is regulated also implies that it is possible to use drugs to block this process. In the present study, we have combined functional studies in advanced models of cancer and computational biology approaches to investigate the specific contribution to the metastatic process of a molecular signaling pathway emanating from the ALK1 protein expressed by endothelial cells in the vasculature. Using information from 2 different patient cohorts including a total of  nearly 2000 breast tumors, we found that patients specifically having high levels of ALK1 in the vasculature of their tumor were much more likely to develop metastatic/recurrent disease. Accordingly, therapeutic administration of a drug (dalantercept) blocking the action of ALK1 prevented metastatic dissemination in multiple mouse models of breast cancer to a large degree. In addition, combination therapy of dalantercept and a commonly used chemotherapeutic drug (docetaxel) was exceedingly effective in preventing spread of the primary tumor to the lungs. Our results suggest that the molecular features of the tumor vasculature are important to consider as potential determinants of breast cancer dissemination and that metastatic spread can be delayed by targeting the tumor vasculature.

Isabelle Bedrosian, M.D., F.A.C.S. Associate Professor, Department of Surgical Oncology, Division of Surgery, Medical Director, Nellie B. Connelly Breast Center The University of Texas MD Anderson Cancer Center, Houston, TXMedicalResearch.com Interview with: Isabelle Bedrosian, M.D., F.A.C.S. Associate Professor, Department of Surgical Oncology, Division of Surgery, Medical Director, Nellie B. Connelly Breast Center The University of Texas MD Anderson Cancer Center, Houston, TX Medical Research: What is the background for this study? What are the main findings? Dr. Bedrosian: There have been a number of reports on the rates of Breast Conserving Therapy (BCT) and mastectomy among women with early stage breast cancer. These reports have been discordant, with some suggesting that index mastectomy rates have increased and others suggestion Breast Conserving Therapy rates have actually increased. We hypothesized that these differences in reporting may be due to data source (ie tertiary referral centers vs population based studies) and turned to the NCDB, which captures 70% of cancer cases in the US and as such provides us with the most comprehensive overview on patient treatment patterns.

MedicalResearch.com Interview with: Chiara Martinoli, PhD Medical Oncology of Melanoma European Institute of Oncology Milan, Italy MedicalResearch: What is the background for this study? What are the main findings? Dr. Martinoli: The recent advent of new immunomodulatory drugs and targeted therapies is changing the therapeutic algorithm for metastatic melanoma patients. Immunomodulation with the anti-CTLA-4 antibody ipilimumab improves survival but is not devoid of potential risks. There is an urgent need for biomarkers to identify patients best suited to receive this therapy, in order to maximize treatment benefit and spare toxicities. In this study, by analyzing pre-therapy hematological parameters of a large group of metastatic melanoma patients treated with ipilimumab, we showed that neutrophil-to-lymphocyte ratio is strongly and independently associated to patient outcome. Patients with a low baseline neutrophil-to-lymphocyte ratio had a double-reduced risk of disease progression and a two-to-four-fold reduced risk of death, regardless of age, sex and LDH.

MedicalResearch.com Interview with: Ann Goding Sauer Epidemiologist, American Cancer Society, Inc. Atlanta, GA 30303 MedicalResearch: What is the background for this study? Response: Among US women, a positive association between Pap test uptake and HPV vaccination has been shown, though potential variation of the association by race/ethnicity had not been explored previously. The prevalence of some HPV types varies across different racial/ethnic groups so it is important to explore the association between Pap test uptake and HPV vaccination in detail. MedicalResearch: What are the main findings? Response: Pap test uptake was significantly lower among those who had not initiated HPV vaccination (81.0%) compared to women who had initiated vaccination (90.5%) (adjusted prevalence ratio = 0.93, 95% CI: 0.90–0.96). This result was seen across most of the sociodemographic factors examined, though not statistically significant for non-Hispanic blacks, Hispanics, those with lower levels of education, or those with higher levels of income.

Eric Jonasch, MD Associate Professor Department of Genitourinary Medical Oncology University of Texas MD Anderson Cancer Center Houston, TXMedicalResearch.com Interview with: Eric Jonasch, MD Associate Professor Department of Genitourinary Medical Oncology University of Texas MD Anderson Cancer Center Houston, TX and Dr. Thai H. Ho, MD Ph.D. Department of Oncology Mayo Clinic Scottsdale ArizonaDr. Thai H. Ho, MD Ph.D. Department of Oncology Mayo Clinic Scottsdale Arizona Medical Research: What is the background for this study? What are the main findings? Response: The blueprints of a cell are encoded in DNA strands (its genome) which are highly compressed in order to fit into a tiny cell. The reading (called the epigenome) of these DNA ‘blueprints’ determines whether that cell will develop into a kidney cell or another type of cell. However, in cancer, errors occur either in the blueprints themselves or the cell makes mistakes in reading the blueprints. Cancers of the kidney affect more than 61,000 patients annually and over 13,000 patients die annually, making it one of the top 10 leading causes of cancer deaths. Studies have revealed that mutations occur in genes that regulate how our DNA ‘blueprints’ are compacted in greater than >50% of kidney cancers, making these genes as a group the most frequently mutated. In our study, we identified that these errors that initially arise in an early kidney cancer lead to propagation of these same errors in metastases, a phenomenon in which the cancer has spread to another organ and is a major cause of death. Furthermore, we generated a detailed map of these epigenomic changes in patient-derived tumors.

Susan Schwab, PhD Assistant professor at NYU Langone Skirball Institute of Biomolecular Medicine MedicalResearch.com Interview with: Susan Schwab, PhD Assistant professor at NYU Langone Skirball Institute of Biomolecular Medicine Medical Research: What is the background for this study? What are the main findings? Dr. Schwab:  T cell acute lymphoblastic leukemia (T-ALL) remains a devastating pediatric disease.  Roughly 20% of children do not respond to current therapies.  Furthermore, metastasis to the central nervous system is common in T-ALL, and intrathecal chemotherapy, even when successful at eradicating the cancer, causes serious long-term cognitive side-effects. Here we report that the chemokine receptor CXCR4 is essential for T cell acute lymphoblastic leukemia progression in both mouse and human xenograft models of disease.  Consistent with sustained disease remission in the absence of CXCR4, loss of CXCR4 signaling results in decreased levels of c-Myc, which is required for leukemia initiating cell activity.   T-ALL cells reside near cells generating the CXCR4 ligand CXCL12 in the bone marrow, and our data suggest that vascular endothelial cells may be an important part of the T-ALL niche.

MedicalResearch.com Interview with: Prof. Catherine Quantin Teaching Hospital, Department of Biostatistics and Medical Informatics France; Dijon University Hospital, Clinical Investigation Center, Clinical Epidemiology/Clinical Trials Unit, Dijon, France and Dr Michal Abrahamowicz Ph.D Department of Epidemiology, Biostatistics and Occupational Health McGill University, Montreal, Canada Medical Research: What is the background for this study? Response: One difficulty, common to prognostic studies of cancer, concerns the need to separate the effects of prognostic factors on different clinical endpoints, such as disease recurrence vs recurrence-free death. Some published prognostic studies used a Cox regression model that included recurrence as a time-dependent covariate, to assess the impact of recurrence on mortality, and to adjust for recurrence when estimating the effects of other prognostic factors on mortality. However, the Cox model is limited to the assessment of the effects of covariates on a single endpoint, such as death. This limitation is overcome by multi-state models, that make it possible to model alternative pathways of disease progression and to assess the impact of prognostic factors on both recurrence-free death vs death after recurrence, and recurrence followed by death. Another difficulty, is that the cause of death is not available or not accurately coded. Yet, some patients are likely to die of causes not related to the disease of primary interest, especially in cancers with longer survival and in those that affect older subjects. The effects of prognostic factors estimated with Cox model, or classic multi-state models, are not able to discriminate between their effects on the mortality due to cancer of primary interest vs natural mortality. However, age is a very strong predictor of overall mortality, but is not systematically associated with higher cancer-specific mortality. To deal with this difficulty, many prognostic studies use relative survival methods. The general idea is to use the mortality tables for the relevant general population to estimate survival corrected for the expected natural mortality, due to other causes of death.

MedicalResearch.com Interview with: Prajakta Adsul, MBBS, MPH, PhD; Ricardo Wray, PhD, and Sameer Siddiqui, MD Center for Cancer Prevention, Research and Outreach Saint Louis University MedicalResearch: What is the background for this study? What are the main findings? Response: Patient decision aids are interventions designed to help patients engage in shared decision making with their providers when multiple choices with more or less equivalent efficacy are available for a particular medical decision. Several patient decision aids exists for numerous medical conditions and previous research has demonstrated them to be effective in improving the patient's knowledge and understanding of treatment options and their relative efficacy and side-effects and resulting in a higher proportion of decision that are consistent with patient's values and personal preferences. In the context of prostate cancer treatment, the practice of shared decision making is vital as highlighted by recent calls from the American Urological Association and the American Cancer Society. To aid with this process, several patient decision aids exist. However, the content presented, the format and presentation styles of decision aids can be variable and can have an influence on the choice made by the patients. The purpose of this study was to assess the characteristics of the patient decision aids designed for men facing prostate cancer treatment. We used the widely accepted International Patient Decision Aids Standards (IPDAS) for the assessment, supplemented with implementation criteria to strategize successful future improvement and promotion of decision aids in routine urological practice. The main findings of the review were that none of the decision aids reviewed met all standards. The aids had variable content, format and presentation of prostate cancer treatment information. Several decision aids were outdated and critical issues such as the risk of overtreatment and active surveillance as a treatment option for prostate cancer were not always covered in decision aids.

Michaela Dinan, Ph.D. Duke Clinical Research Institute and Duke Cancer Institute Department of Medicine Duke University School of Medicine Durham, North CarolinaMedicalResearch.com Interview with: Michaela Dinan, Ph.D. Duke Clinical Research Institute and Duke Cancer Institute Department of Medicine Duke University School of Medicine Durham, North Carolina Medical Research: What is the background for this study? What are the main findings? Response: I think it will be critical to further explore the implications of Oncotype DX breast cancer assay (ODX testing) in women with breast cancer.  The ODX test helps predict which cancers will be more aggressive as well as guide recommendations as to which patients would most likely benefit from chemotherapy. I think we should look to see what impact this test is really having on the use of chemotherapy and its associated costs and outcomes for real-world breast cancer patients.