Advances and challenges in cancer immunoprevention and immune interception

*These authors contributed to the devlopment and review of this manuscript but are unable to endorse the request for NIH funding. On Sept. 20, 2011, the American Association for Cancer Research (AACR) released its inaugural AACR Cancer Progress Report to commemorate the

The American Association for Cancer Research (AACR) is the first and largest cancer research organization dedicated to accelerating the conquest of cancer. The stated purpose of the organization when it was founded 115 years ago was “to further the investigation and spread the knowledge of cancer.” Since that time, the AACR has been the driving force to eradicate cancer. Publication of research findings has always been critical to this endeavor, with the 11 founders recognizing the importance of “sharing observations” and the need for a journal to “collect under one cover such contributions as bear in any way upon the general problems of oncology.”The AACR launched its first peer-reviewed scientific journal, The Journal of Cancer Research, in 1916. At the time, it was the only English-language cancer journal in the world. Since then, the AACR portfolio of journals has grown to 10. These journals cover the full spectrum of cancer science and medicine and together, over the years, have published over 100,000 articles and over 130,000 meeting abstracts. This is an immense contribution to the body of knowledge on cancer and has ignited communication among cancer scientists and physicians, helping to catalyze a revolution in the field.We are honored to serve as the current Editors-in-Chief of the AACR journals. Each of the 10 journals was launched by the AACR to meet the scientific information needs of its membership and all those engaged in cancer research. Under our leadership, the journals engage closely and collaboratively with the community to facilitate the presentation and wide dissemination of research findings. Importantly, the AACR is a not-for-profit publisher. This means that any surplus from the AACR journals program is used to help support the cancer research community and the mission of the AACR to prevent and cure all cancers by contributing to funding for AACR grants, scientific conferences, and science policy and advocacy efforts. Here, we highlight the unique roles of our journals within the family of AACR journals and how they serve to advance the mission of the AACR.At the inception of the AACR, there was a clear need for journals focused on cancer research to assemble key studies to help guide the field. Cancer Research was launched in 1941 as the flagship journal of the AACR from a rich ancestry that started with its predecessors: The Journal of Cancer Research (1916–1930) and The American Journal of Cancer Research (1931–1940). From the very beginning, Cancer Research has published landmark papers (https://aacrjournals.org/cancerres/pages/landmark_articles) that have enriched our knowledge of cancer biology and treatment and have provided the foundation upon which major breakthroughs have been built. In the first year of publication, Cancer Research featured seminal studies on the effect of castration on prostate cancer and the mechanism of carcinogenesis that shaped the field (https://www.aacr.org/wp-content/uploads/2019/11/CancerResearch_75Anniversary_1941-2016.pdf). Cancer Research has continued to publish articles that cover the full range of research, spanning from investigations on drug discovery, cancer molecular mechanisms, and the tumor microenvironment to clinical and population studies. As cancer research has evolved over the past century, new AACR journals have emerged to embrace and support expanding fields, providing specialized venues for studies that deepen our understanding of areas that were historically covered by Cancer Research. In this regard, the “pedigree” of AACR journals stemmed from the principles set by Cancer Research, which remains a venue for publishing fundamental studies in all areas of cancer research, including emerging areas such as cancer data science and mathematics. As a society journal, Cancer Research serves the community through its editorial process that is guided by the judgment of international academic editors who provide rich expertise in various areas as practicing researchers. Further, the Journal embraces early career investigators and has recognized these researchers with the prestigious Cancer Research Early Career Award. Guided by its extensive history, Cancer Research hopes to motivate and support the next generation of scientists to lessen the burden of cancer through their innovative research.As cancer science and medicine entered the molecular biology era, it became clear that a communication channel was needed to emphasize basic science studies in oncology—studies that report significant mechanistic findings at the molecular or cellular level. Originally published under the title Cell Growth & Differentiation from 1990 to 2002, Molecular Cancer Research (MCR) was launched as the AACR was beginning to build its now-renowned focus on molecular biology and genetics. The Journal served to help emphasize this focus and attract more scientists into the AACR's membership. As part of this mission, MCR features studies exploring the molecular underpinnings of each of the hallmarks of cancer, with a particular emphasis on studies elucidating oncogenic alterations in metabolism. Cancer metabolism is increasingly recognized as a key vulnerability of tumor biology. MCR is committed to recruiting and disseminating studies featuring novel metabolomic analyses, mass spectrometry, metabolic imaging and tracing, and other approaches that clarify links between metabolism and cancer, with the goal of identifying metabolic vulnerabilities and adding to the armamentarium of anticancer interventions. In addition to publishing impactful basic cancer research studies, the Journal aims to promote diversity of thought and perspective within the basic cancer research community. To achieve this goal, MCR has launched an initiative in which senior investigators are paired with rising stars in their fields to write and edit review articles jointly. This initiative encourages collaboration among researchers by integrating historical perspectives with new directions to provide novel, actionable insights for the field.Cancer Epidemiology, Biomarkers & Prevention (CEBP) is the leading subspecialty journal for fundamental and applied population science research describing the burden of cancer; uncovering possible causes of cancer and its progression; and informing and evaluating strategies for cancer prevention, early detection, cancer survivorship, and closing the cancer disparities gap. CEBP is unique among AACR journals in focusing on populations at risk for cancer, with cancer, and surviving cancer, especially U.S. and global populations who experience health inequities. Among its many contributions, the Journal has advanced the field of molecular epidemiology of cancer by providing expert peer review and a highly regarded publications forum and has helped launch the careers of many investigators who conduct population science research on cancer. CEBP plays an active role in informing public health practice, policy, and recommendations by publishing articles that are cited as part of the evidence base, including by the FDA, the Centers for Disease Control and Prevention, the U.S. Preventive Services Task Force, and the World Health Organization. Recognizing the societal need to enhance the translation of population science evidence for cancer prevention and control today and in the future, the Journal recently expanded its scope to include cancer care delivery and implementation science research. Like the other AACR journals, CEBP serves the research community well through its editorial rigor and publication of innovative and impactful research addressing contemporary and emerging cancer problems.As biologic insights into cancer rapidly accelerated in the decades after the discovery of the structure of DNA and the armamenta­rium of anticancer agents began to expand, the AACR identified the need for a communication outlet focused on the clinical applications of these discoveries; Clinical Cancer Research was launched to provide this much-needed outlet. Early therapeutic development has since transitioned from rigidly divided trial phases into an adaptive process that encompasses investigation of safety, pharmacokinetics, proof of mechanism, and first evidence of clinical activity. These same trials now frequently serve as the basis for first regulatory approval. The Journal bridges the transition from late preclinical development, when a new therapy is being paired with insights into the molecular features that predict responsiveness to therapy, to clinical validation of those hypotheses, and the Journal has evolved into a premier venue for phase I/II trials. As the only AACR journal with clinical research of all types, including clinical trials, as its sole purview, Clinical Cancer Research has taken the charge of being the journal that accounts for what happens to the discoveries described in basic and translational cancer research when they are tested prospectively for their potential impact on the outcomes of patients with cancer. Since its launch, Clinical Cancer Research has also played a distinct educational role among clinical oncology journals, with a robust collection of review articles to benefit basic scientists with clinical interests and clinical investigators studying new agents with unique biologic mechanisms of action. Clinical Cancer Research has also become an important forum for critical discussions in clinical oncology. Field-leading experts are invited to deliberate on the progress made in a given therapeutic area, focusing on the lessons to be learned from recent successes and failures. Authors from the FDA provide detailed insights into the data that drive regulatory decision-making for each successful therapy. Clinical Cancer Research continues to demonstrate the AACR's long-standing commitment to accelerating research that leads to potential interventions for prevention, early detection, and treatment of cancer and particularly to showcasing clinical trials.Improving and expanding the arsenal of anticancer therapies is an essential goal in our shared mission to prevent and cure all cancers. From before the humble beginnings of nitrogen mustards and vinca alkaloids to the advent of immuno-oncology and rationally designed targeted therapy, the last 115 years have seen quantum leaps in therapeutic strategies and clinical options to combat cancer. Molecular Cancer Therapeutics has been at the forefront of this effort for more than 20 years, publishing top-tier science in the design, synthesis, discovery, and preclinical study of novel therapeutic agents for the treatment and prevention of cancer. The Journal's scope covers anticancer therapeutics broadly, including precision medicine therapies of all types: cell therapies, gene therapies, RNA therapeutics, oncolytic viruses, and vaccines in addition to established regimens such as mole­cular and biologic agents, chemotherapy, and radiotherapy. Among these efforts, the Journal provides a specialized venue for the first disclosure of experimental therapeutics advancing toward clinical trials, providing a platform with international reach to authors. The crucial role of Molecular Cancer Therapeutics among the AACR journals—and, indeed, among all oncology journals—cannot be overstated. The Journal's laser focus on disseminating rigorously vetted research with near-term clinical benefit has enormous potential to impact the entire cancer research community and to improve, extend, and defend the lives of patients with cancer. To that end, Molecular Cancer Therapeutics continues to provide a vital forum for the communication of important discoveries in cancer therapeutics research to the global research community.Effective global cancer control must emphasize efforts to reduce cancer incidence rather than concentrating solely on cancer treatment. To help catalyze such efforts, the AACR launched Cancer Prevention Research (CaPR) in 2008 to be devoted excl­usively to cancer prevention research. From its inception, CaPR has endeavored to be a primary resource for original articles, scholarly reviews, and timely perspectives regarding basic, translational, clinical, and population science investigations related to cancer risk reduction. Five years ago, CaPR published the landmark perspective, “Transforming Cancer Prevention through Precision Medicine and Immune-oncology,” which proposed a Pre-Cancer Atlas and recognized unprecedented opportunities to interrogate the biology of premalignancy (1). The subsequent development of the Pre-Cancer Atlas, together with other advances, represents a “moonshot” opportunity for the field of cancer prevention. CaPR will continue to cultivate high-caliber content from pioneers in fields such as carcinogenesis, the biology of premalignancy, cancer risk assessment, screening, and policy implementation that will transform the way we detect and, ultimately, intercept and prevent cancer. The Journal's mission to reflect the current state of cancer prevention and to catalyze the development of the field supports the AACR mission to prevent and cure all cancers. The community of researchers, educators, advocates, and funders that works together under the umbrella of the AACR and its family of journals is a critical part of the cancer prevention ecosystem. Together, we are publishing research that defines the field of cancer prevention, building a translational bridge between bench and community, and developing the next generation of cancer prevention researchers.In 2011, recognizing the cancer research community's need for a journal that published the most impactful research while placing a premium on streamlined editorial processes and service to authors, the AACR launched Cancer Discovery. Bringing together basic scientists with detailed knowledge of cancer biology and physicians at the vanguard of science-driven clinical trial design, Cancer Discovery immediately changed the landscape of scientific publishing in the field, with many other journals now trying to emulate the unique mix of basic, translational, and clinical research that the Journal pioneered. Cancer Discovery has been at the forefront of the most important developments in cancer over the past decade, from targeted therapy and immunotherapy to technological advances in single-cell sequencing and liquid biopsy that have fundamentally changed our understanding of cancer biology and response to treatment. Preclinical and clinical studies published in Cancer Discovery have laid the foundation for numerous FDA approvals within a short period, and influential commentaries and reviews have galvanized the field and guided policy decisions. The unique editorial team consisting of leading researchers and experienced professional editors works collaboratively with the community to quickly publish and disseminate the strongest, immediately impactful science to support the AACR mission to prevent and cure all cancers.The first cancer immunotherapeutic is famously considered to have been administered in 1891 by William B. Coley, one of the 11 founders of the AACR, when he used a mixture of heat-killed bacteria (subsequently known as Coley's toxins) to create an inflammatory response that could treat a patient with sarcoma. However, it took more than 100 years before the field of cancer immunology and immunotherapy research gained meaningful traction among those working in the broader discipline of cancer science and medicine. The rapid expansion of the field began in the early 2000s as a result of increasing evidence linking the immune system with cancer development and demonstrations that the immune system might be harnessed to treat cancer, and it has continued at an even more remarkable pace since the FDA approval of the first immune checkpoint inhibitor, the CTLA4-specific blocking antibody ipilimumab, in 2011. Recognizing the need to further enhance interactions between researchers in the realm of cancer immunology and immunotherapy and those in all other areas of the cancer research community, and to provide a forum for the presentation of advances in the rapidly evolving field of cancer immunology science, the AACR collaborated with the Cancer Research Institute to launch Cancer Immunology Research in 2013. Since its inaugural issue, the Journal has disseminated exciting discoveries and developments in the field of cancer immunology and immunotherapy, and successfully introduced the central principles of immunology to cancer biologists and clinical investigators. As a journal devoted to the science underlying some of the most transformative therapeutics to have entered the clinic for the treatment of cancer in recent years, Cancer Immunology Research has played a unique role in advancing the mission of the AACR.Unprecedented progress in understanding the pathogenesis of hematologic malignancies and in translating these insights into improved clinical outcomes has created a demand for a high-profile outlet for publishing these discoveries. To address this need and to emphasize the AACR's commitment to the prevention and cure of all types of cancer, Blood Cancer Discovery was launched in 2020 to inspire, facilitate, and broadly disseminate important discoveries about hematologic malignancies. The Journal's model of operation replicates Cancer Discovery's success in creating synergies between the expertise of leaders in the field and the dedication of in-house editorial and publishing teams, enabling rigorous, rapid, and transparent editorial processes. Blood Cancer Discovery has published cutting-edge research articles on a broad spectrum of topics encompassing leukemia, lymphoma, myeloma, and other blood cancer subtypes that also have profound implications for our understanding of solid tumors. The Journal has also published all the phases of clinical research: drug development in preclinical disease models, clinical trials, molecular events underlying clinical responses and resistance to therapies, and real-world epidemiology. As a forum for diverse ideas shaping future research directions, Blood Cancer Discovery has published incisive commentaries and has partnered with the AACR's hematologic malignancy-focused Special Conferences, quickly emerging as a thought leader in blood cancer research.The landscape of cancer science and medicine continues to change and accelerate, becoming ever more multifaceted. Launched in October 2021, Cancer Research Communications was designed with these considerations in mind. Most crucially, the Journal is fully open access and boasts the broadest and most flexible scope of any AACR title to date, providing a pathway to publication for authors working within funder mandates or whose work falls outside the scope of other titles in the AACR portfolio. The Journal's nine sections offer a comprehensive view of the spectrum of oncology research. With an editorial ethos centered on accessibility, reproducibility, and value to the field, the Journal is inclusive of a wide variety of important research findings that may be beyond the scope of other journals in the program. Cancer Research Communications is committed to catalyzing the rapid dissemination of rigorously peer-reviewed scientific findings in diversified areas of study, including but not limited to physics, engineering, mathematics, and computational biology. This interdisciplinary approach stimulates the cross-pollination of insight and innovation among cancer researchers. Moreover, the Journal emphasizes flourishing areas of research—such as precision medicine, immuno-oncology, and disparities in cancer health outcomes—that will be foundational to the next 115 years of progress against cancer. As a thoroughly modern platform designed to meet the needs of our authors and readers while complementing the other AACR journals, Cancer Research Communications is poised to stimulate the efficient and dynamic exchange of knowledge, actively sparking new ideas and discoveries to prevent and cure all cancers.Since the very first issue of The Journal of Cancer Research was published in 1916, the AACR journals have been a critical resource for cancer researchers and physicians, providing a forum for disseminating groundbreaking discoveries in cancer science and medicine. As the current Editors-in-Chief of the AACR journals, we are proud that this tradition of publishing seminal, rigorously vetted research that can change the trajectory of the field has established the AACR journals as a trusted partner of the research community. Importantly, we would like to take this opportunity to thank our authors, editorial teams, reviewers, and readers for their invaluable contributions to this endeavor. The tireless efforts of this community provide a beacon of hope to patients and their loved ones.As we look to the future, we continue to collaborate with the research community to ensure that the journals operate with a forward-thinking mentality that adapts to the evolving needs of all stakeholders. In recent years, we have seen critical scientific and technological innovations propel extraordinary progress against cancer. We are confident that this progress will continue, and we remain dedicated to ensuring that the AACR journals continue to provide a platform for the communication of impactful research and support the AACR mission to prevent and cure all cancers.L. Cantley consulted for Petra Pharmaceuticals, Agios Pharmaceuticals, EIP Pharmaceuticals, Volastra, Larkspur, and Cell Signaling Technologies over the past year. He also received grant support from the NIH/NCI, Gray Foundation, The Mark Foundation, the Breast Cancer Research Foundation, and Stand Up To Cancer/American Association for Cancer Research over the past year, and is a stockholder in Agios Pharmaceuticals, EIP Pharmaceuticals, Cell Signaling Technologies, Volastra, and Larkspur. R. Dalla-Favera is a consultant for NeoGenomics and AstraZeneca and receives research funds from AstraZeneca. L.A. Diaz is a member of the board of directors of Jounce Therapeutics and Epitope and is a compensated consultant to PetDx, Innovatus CP, Se'er, Delfi, Blackstone, Kinnate, and Neophore. He is an inventor of multiple licensed patents related to technology for circulating tumor DNA analyses and mismatch repair deficiency for diagnosis and therapy; some of these licenses and relationships are associated with equity or royalty payments directly to the inventors. He holds equity in Epitope, Jounce Therapeutics, PetDx, Se'er, Delfi, Kinnate, and Neophore; he divested his equity in Personal Genome Diagnostics to LabCorp in February 2022 and he divested his equity in Thrive Earlier Detection to Exact Biosciences in January 2021. His spouse holds equity in Amgen. The terms of all these arrangements are being managed by Memorial Sloan Kettering in accordance with their conflict of interest policies. K.T. Flaherty reports personal fees from Clovis Oncology, Checkmate Pharmaceuticals, Strata Oncology, Kinnate Biopharma, Scorpion Therapeutics, PIC Therapeutics, Apricity, Tvardi, ALX Oncology, xCures, Monopteros, Vibliome, Soley Therapeutics, Quanta Therapeutics, Nextech, Takeda, Novartis, OMRx, and Transcode Therapeutics and other support from Roche/Genentech outside the submitted work. P.D. Greenberg reports grants and personal fees from Juno Therapeutics; grants from Lonza; personal fees and other support from Earli, Metagenomi, Elpiscience, Rapt Therapeutics, and and grants, personal and other support from outside the submitted work. reports personal fees from reports personal fees from Oncology, Memorial Sloan Kettering Cancer The Institute for AACR, and Cancer Research grants, personal and support from and grants and personal fees from and Jounce Therapeutics; and personal fees and support from outside the submitted work. reports personal fees from and Therapeutics; grants from Novartis, Therapeutics, and and personal fees and grants from and outside the submitted work. were by the other authors.

Resveratrol, a phytochemical produced by a restricted number of plant species in response to stress, has exerted compelling breast cancer preventive activities in preclinical studies. Resveratrol not only acted as an estrogen receptor agonist/antagonist and inhibited aromatase but also affected multiple carcinogenesis pathways and multiple targets within a pathway. Resveratrol also demonstrated beneficial effects on metabolic disturbances in rodent models for obesity. We conducted an open label, single arm pilot study of resveratrol in postmenopausal women with high body mass index (BMI ≥ 25 kg/m2), a risk factor for breast cancer. The primary objective was to determine the effect of resveratrol on serum estradiol levels with secondary endpoints being measurement of modulation of multiple systemic markers associated with breast cancer risk. Forty eligible subjects were recruited to initiate the resveratrol intervention (1 gm resveratrol daily for 12 weeks) with six withdrawn early due to adverse events. Thirty-four subjects completed 12 weeks of resveratrol intervention. We found that resveratrol intervention did not result in significant changes in serum concentrations of estradiol, estrone, and testosterone in the study cohort but significantly increased serum levels of sex steroid hormone binding globulin (10% increase from baseline, p < 0.01). Resveratrol intervention resulted in a significant increase in urinary 2-hydroxyestrone (2-OHE1) levels (73% increase from baseline, p < 0.01) leading to a favorable change in urinary 2-OHE1/16α-OHE1 ratio (85% increase from baseline, p < 0.01). Serum leptin levels were suppressed significantly (10% decrease from baseline, p < 0.01) following resveratrol intervention whereas serum adiponectin levels were not changed. The most common possibly or probably related adverse events were diarrhea, constipation, and abdominal discomfort. One participant had a possibly related serious grade 4 elevation in hepatic ALT and AST enzymes at the post-intervention visit which resolved after less than 3 months of follow-up. Aside from this event, resveratrol intervention did not result in clinically significant changes in hematology and blood chemistry. We conclude that daily 1 gm dose of resveratrol did not affect the levels of circulating sex steroid hormones in postmenopausal women with high BMI but resulted in favorable changes in serum sex steroid binding globulin and leptin levels and urinary 2-OHE1/16α-OHE1 ratio that may be associated with reduced breast cancer risk. However, the observed adverse effects advocate for the consideration of lower doses for further clinical development of resveratrol for cancer prevention. (supported by a contract, N01-CN-35158, from the National Cancer Institute, Division of Cancer Prevention) Citation Format: H-H. Sherry Chow, Linda L. Garland, Brandy M. Heckman-Stoddard, Chiu-Hsieh Hsu, Valerie D. Butler, Catherine A. Cordova, Wade M. Chew, Terri L. Cornelison. Modulating effects of resveratrol on systemic markers associated with breast cancer risk: a pilot clinical study in postmenopausal women with high adiposity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 159. doi:10.1158/1538-7445.AM2013-159

![Figure][1] On December 31, 2013, the scientific community lost Dr. John A. Milner, an internationally respected scientist known for his work in human nutrition and cancer prevention. John served as Chief of National Cancer Institute's (NCI) Nutritional Science Research Group in the

The essential nutrient selenium appears to have cancer preventive properties that are partly mediated through selenoproteins. This study investigated the role of the 15 kDa selenoprotein (Sep15) in cancer by examining Sep15 knockout in mice. Weanling homozygous Sep15 knockout, heterozygote and wild type littermate controls (N=12/genotype) were given four weekly subcutaneous injections of the known colon carcinogen azoxymethane (10 mg/kg). Sep15 knockout mice developed significantly (p<0.001) fewer aberrant crypt foci (ACF) than controls. Dietary selenium (0, 0.1 or 2.0 μg selenium/g diet) did not significantly affect ACF formation in Sep15 knockout mice. To investigate molecular targets affected by Sep15 knockout, gene expression patterns in colonic mucosal cells of knockout and wild type mice were compared with microarrays and Ingenuity Pathway Analysis. Quantitative PCR and western blot analysis revealed guanylate binding protein-1 (GBP1) mRNA and protein expression to be strongly upregulated in Sep15 knockout mice. Furthermore, serum analysis indicated significant differences in cytokine expression in Sep15 knockout mice. Our results suggest that Sep15 knockout mice are protected against chemically-induced ACF formation possibly through alterations in inflammatory pathways. Funded by NCI Intramural support, the Cancer Prevention Fellowship Program, NIH grants and the Division of Cancer Prevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1868. doi:10.1158/1538-7445.AM2011-1868

In recent years, there has been a growing interest in incorporating patients’ perspectives when measuring and interpreting the clinical benefit of cancer therapies. Patient-reported outcomes (PROs) are used in a variety of cancer clinical trials. These studies range from using PROs to better understand the burden of cancer and the adverse effects of cancer therapy (such as pain), to studies that use PROs as the primary end point of the clinical trial, such as reducing symptoms like nausea or fatigue that can be caused by certain cancer therapies. The evolution of PROs in cancer trials has been recently documented by the National Cancer Institute (NCI)–supported Cancer Outcomes Measurement Working Group and by the US Food and Drug Administration’s recent guidance for the use of PROs in product labeling. PRO research also has been recognized as an important element in the NCI strategic planning process. A major NCI goal is to support research that enhances our understanding of the burden of disease among patients with cancer and cancer survivors, and reduces the sequellae of cancer throughout the continuum of care. NCI has taken an important role in developing new ways to measure patient-reported symptoms such as pain and fatigue, and aspects of health-related quality of life across a wide range of cancers and other diseases, through the Patient Reported Outcomes Measurement Information System (PROMIS). As a National Institutes of Health Roadmap initiative, PROMIS will provide clinical research communities with a reliable, valid, and standardized approach to capture these clinically relevant, but subjective and difficult-to-measure outcomes in clinical trials. Standardization of these data will provide additional benefits to the cancer clinical trial enterprise because it will eventually facilitate their incorporation into the cancer bioinformatics grid (ca-BIG), thereby making PROs available to all researchers who participate in and use the grid to support correlative research studies in connection with clinical trials. Through the NCI Clinical Trials Working Group (CTWG), NCI also has undertaken a major reassessment of the design, review, funding, and implementation of cancer clinical treatment trials and symptom management trials. Among the many recommendations contained in the CTWG report are ones to establish a new funding mechanism and prioritization process for supporting correlative science and quality-of-life studies using PROs, that can be initiated in association with clinical trials. As part of the CTWG process, NCI recently created a Symptom Management and Health-Related Quality of Life (SxQOL) Steering Committee to prioritize and review studies that include PROs as primary end points in symptom management clinical trials, and PROs as secondary end points in phase III Cooperative Group cancer treatment trials sponsored by the NCI. In addition, the SxQOL committee will provide guidance on how to improve the utility of PROs in cancer treatment trials and in symptom management trials. Although PRO data have potential utility for a variety of analyses in cancer clinical trials, the issues surrounding their appropriate and effective application are complex. In September 2006, the NCI convened a 2-day conference entitled “PatientReported Outcomes Assessment in Cancer Trials (PROACT): Evaluating and Enhancing the Payoff to Decision-Making.” This conference was cosponsored by the American Cancer Society and represented a collaborative effort among the leadership from all major NCI extramural divisions involved with clinical trials—the Division of Cancer Treatment and Diagnosis, the Division of Cancer Prevention, and the Division of Cancer Control and Population Sciences. The goal of the PROACT conference was to bring together scientists working in this area to inform NCI and the broader cancer research and policy community on how the NCI clinical trial infrastructure is currently organized to support PRO research in clinical trials, and to identify the issues and lessons learned from the experiences of NCI-sponsored cooperative groups and Community Cancer Oncology Programs; other national and international researchers; and US pharmaceutical industry experts in using PROs in phase II and III cancer treatment trials, as well as in symptom management trials. Before the conference, NCI charged a multidisciplinary Scientific Program Committee of internationally recognized experts to identify key determinants of the successful application of PROs in JOURNAL OF CLINICAL ONCOLOGY O V E R V I E W VOLUME 25 NUMBER 32 NOVEMBER 1

Pivotal presentations from the 100th Annual Meeting 2009 of the American Association for Cancer Research (AACR) are reviewed in this article, along with discussion of scientific findings and their impact on clinical practices and ongoing clinical trials. Among these presentations, the report on predictive biomarkers for targeted therapies may lead to the possibility of selection of the right drug for the right patient. The results of cancer genomic researches has started to yield surprising insights into the pathogenesis of a range of different cancers, with analyses of somatic copy number alterations, genomic rearrangements and sequence mutations. Cancer stem cells have again been confirmed to play an important role in therapeutic resistance, promoting angiogenesis and metastasis. A diversity of viewpoints from different cancer types regarding the current understanding of cancer stem cell biology was introduced. MicroRNA alterations were also investigated and findings of recent studies were summarized. Apart from cancer cells, researchers have begun to examine the communication between the tumor cells and its surroundings. Novel findings on tumor microenvironment and inflammation were introduced. The latest developments of nanotechnology and biomarker discoveries were also presented. In addition, there were clinical trials supporting the use of new targeted therapies, while other researchers focused on cancer prevention using existing agents and approaches. These and other important presentations from the AACR Annual Meeting 2009 are discussed in this article, which intends to provide updates on the cancer research presented in the most important cancer research meeting in the world.

Current Opinion in Pediatrics was launched in 1989. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The fields of pediatrics are divided into 18 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Editor and Section Editors for this issue. EDITOR Philip A. PizzoPhilip A. PizzoPhilip A. Pizzo, MD, is the David and Susan Heckerman Professor and Founding Director of the Stanford Distinguished Careers Institute, USA. Dr Pizzo served as Dean of the Stanford School of Medicine from April 2001 to December 2012, where he was also the Carl and Elizabeth Naumann Professor of Pediatrics and of Microbiology and Immunology. Dr Pizzo has devoted much of his distinguished medical career to the diagnosis, management, prevention and treatment of childhood cancers and the infectious complications that occur in children whose immune systems are compromised by cancer and AIDS. He has also been a leader in academic medicine, championing programs and policies to improve the future of science, education and healthcare in the US and beyond. Dr Pizzo received his MD degree with Honors and Distinction in Research from the University of Rochester, USA in 1970, and completed an internship and residency at Children's Hospital Medical Center in Boston, USA, a teaching fellowship at Harvard Medical School, USA, and a clinical and research fellowship in pediatric oncology at the National Cancer Institute. Pizzo served as Head of the Institute's Infectious Disease Section, Chief of the NCI's Pediatric Department, and Acting Scientific Director for NCI's Division of Clinical Sciences between 1973 and 1996. Before joining Stanford in 2001, he was the Physician-in-Chief of Children's Hospital in Boston and Chair of the Department of Pediatrics at Harvard Medical School, where he was also the Thomas Morgan Rotch Professor of Pediatrics. Dr Pizzo is the author of more than 615 scientific articles and 16 books and monographs, including Principles and Practice of Pediatric Oncology, the Seventh Edition of which was published in 2015. He co-led a multidisciplinary committee for the Institute of Medicine (IOM) that resulted in the 2011 report Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education and Research; he also co-chaired the IOM report Dying in America: Improving Quality and Honoring Individual Preferences at the End of Life, which was published in 2015. Dr Pizzo has received numerous awards and honors, among them the Public Health Service Outstanding Service Medal in 1995, the Barbara Bohen Pfiefer Award for Scientific Excellence in 1991, the Elizabeth Kubler-Ross Award in 2008, the Ronald McDonald Charities Award of Excellence in 2009, and the John and Emma Bonica Public Service Award in 2013. He is the 2012 recipient of the John Howland Award, the highest honor for lifetime achievement bestowed by the American Pediatric Society. He has been elected to a number of prestigious organizations and societies, including the Association of American Physicians, the American Society of Clinical Investigation, the American Pediatric Society and the Institute of Medicine of the National Academy of Sciences, where he was also elected to the Governing Council. The IOM became the National Academy of Medicine in 2015. Dr Pizzo has served as Chair of the Association of Academic Health Centers, and Chair of the Council of Deans of the Association of American Medical Colleges, and was elected to the Board of Directors of the American Society for Clinical Oncology and the Infectious Diseases Society of America. He was President of the International Immunocompromised Host Society (1998–2011). He served on the Governing Board for the California Institute of Regenerative Medicine from 2004–2012. In 2009 he was elected to the Board of Trustees of the University of Rochester and the Board of Overseers of Koc University in Istanbul, Turkey. He is also a member of the Board of Directors of MRI Interventions and the Academic Advisory Council for Merritt Hawkins. In 2014 he was elected to the Board of Directors of the Ludwig Institute for Cancer Research and in 2015 he was elected to the Board of Directors of Global Blood Therapeutics. SECTION EDITORS Susan M. BlaneySusan M. BlaneySusan M. Blaney, MD, is a Professor and Executive Vice Chair for the Department of Pediatrics at Baylor College of Medicine, USA and the Director of Texas Children's Cancer Center at Texas Children's Hospital, USA. She is a board-certified pediatric oncologist whose career over the past 25 years has focused on the development of new agents and therapeutic strategies for children with recurrent or refractory cancer, particularly for those with malignancies of the central nervous system. She has extensive experience in clinical translational research and currently serves as the Vice Chair for the Children's Oncology Group (COG), an NCI-funded cooperative effort of 200 leading children's hospitals across North America. Dr Blaney has played a leadership role in the development of numerous early phase clinical trials of novel agents for the treatment of childhood cancer over the course of her career. Dr Blaney has also served as a mentor to many pediatric medical students, residents, fellows and faculty who are current or developing leaders in the field of pediatric oncology. Her influence in the field also extends to numerous advisory roles that she has held including an service on the National Cancer Institute's Clinical Trial Advisory Committee, as a member of the Investigational Drug Steering Committee for the National Cancer Institute, as a regular consultant for the FDA's Pediatric Oncology Drug Advisory Committee, as well as for other leading cancer organizations such as the American Association for Cancer Research and the American Society of Clinical Oncology. She also directs or has served on the scientific advisory boards for many not-for-profit foundations for childhood cancer research. Dr Blaney has published more than 200 articles in peer-reviewed journals, has authored numerous book chapters, and is an editor for Rudolph's Pediatrics as well as an Associate editor for Pizzo and Poplack's Principles and Practice of Pediatric Oncology, the leading textbook in the field of pediatric oncology. Daniel W. GreenDaniel W. GreenDr Daniel W. Green has been practicing at the Hospital for Special Surgery, USA since 1998 and is currently the Director of the Pediatric Sports Program for the Division of Pediatric Orthopedic Surgery. While he thoroughly enjoys caring for patients from birth into early adulthood, he has a special interest in pediatric sports injuries and pediatric knee injuries, in addition to pediatric orthopedic trauma. He provides emergency treatment for pediatric fractures and other orthopedic emergencies at New York Presbyterian Hospital-Manhattan, USA and the Hospital for Special Surgery. His focus is to provide the finest, most advanced orthopedic care available and is devoted to advancing treatments in order to improve patient outcomes and the overall patient experience. His research focuses on pediatric knee surgery, cartilage repair and restoration, pediatric ACL surgery, pediatric growth plate surgery, pediatric fracture care, and osteogenesis imperfecta. He has extensively studied the surgical options for patellar dislocations, evaluating both conservative and surgical approaches to stabilizing the patella. He has also investigated surgical techniques for ACL reconstruction in the skeletally immature. Dr Green is a clinical professor of orthopedic surgery at the Weill Cornell Medical College, USA. Yvonne J. BrysonYvonne J. BrysonDr Yvonne J. Bryson is a Distinguished Professor and recent past Chief of Global Pediatrics Infectious Diseases at David Geffen School of Medicine at UCLA, Mattel Children's, USA. She is a world-renowned leader, researcher, virologist and clinician in the field of HIV pathogenesis, prevention, and treatment of maternal-fetal and pediatric HIV-1, and is an active member of the HIV CURE Scientific Committee of International Maternal Pediatric and Adolescent AIDS Clinical trials network (IMPAACT) and the Adolescent trials network for identification and treatment of HIV acute infection. She is past Chair of the NIH Network IMPAACT PMTCT Committee (Prevention of Mother-to-Child Transmission of HIV) as well as a previous past chair. She has served a national and international leadership role for the past 25 years in studies of prevention and treatment of pediatric HIV. She has served on the HIV Therapeutics Trans NIH panel to set the NIH agenda for the past eleven years. Dr Bryson was influential in the development of CDC and Public Health guidelines for the diagnosis and treatment of HIV-infected pregnant women and has been involved in the planning and execution of national cooperative studies of maternal-fetal HIV transmission. She has made significant contributions to the development of the original studies of the use of Zidovudine and Nevirapine for the prevention of perinatal HIV. She published studies of maternal risk factors for vertical transmission of HIV including viral load and autologous neutralizing antibody, as well as advances in the early diagnosis of HIV in newborns. Her research at UCLA has been funded by NIH for over twenty-five years. She has over 190 original peer-reviewed publications and is a sought-after lecturer and reviewer. She was founding advisor and one of the original health board advisors of the Elizabeth Glaser Pediatric AIDS Foundation, with co-founders Elizabeth Glazer, Susie Zeegan and Susan Delorentis, and colleagues Dr Richard Stiehm and Phil Pizzo. She participated and helped plan the EGPAF thinktanks, the Ariel Project, the Elizabeth Glazer Scientist Award, and fundraising strategies for the foundation and the role of NIH in promoting new investigators in the field. She also was involved in political activism in Washington DC and California with Elizabeth and cofounders to focus attention on children. Dr Bryson has served on numerous NIH study section reviews and panels. She had significant experience in global health issues related to reduction of maternal infant mortality and morbidity and meeting the millennium goals. Dr Bryson has had significant leadership and field experience setting up NIH funded clinical trials, laboratories and infrastructure in Brazil over the past 13 years. She has trained a large number of students and post-doctoral MD, PhD scholars and junior faculty who are now national and international leaders as academic faculty or public health professionals in the US and around the world. Dr Bryson is a strong advocate for mothers and children for the prevention and treatment of infectious disease and is now committed to the CURE for HIV. She still has active NIH RO1 grants for studies of HIV remission and cure in infants and children, collaboration on an infant maque monkey model, and most recently, studies in adolescents in Los Angeles and New Orleans. She is an expert in perinatal infections, pediatric infectious disease, antivirals herpes infections, and other viral, bacterial, and opportunistic infections, and serves as a pediatric infectious disease consultant. Henry H. BernsteinHenry H. BernsteinDr Bernstein is a Professor of Pediatrics at Hofstra Northwell School of Medicine in New York, USA. He taps into his extensive 32-year experience as a general pediatrician in private practice and in academia at urban, suburban, and rural children's hospitals to promote the health and wellbeing of children, their families, and their communities. His private, community-based primary care (generalist) experiences in combination with academic experiences have provided him with a value-added, translational science perspective, unique from many others in academia. This tacit knowledge enables him to fulfill a lifelong passion of communicating, educating, and translating science into clinical settings, educational venues, policy-making, and media interactions to advance the health of children. Research is consistently woven into the fabric of Dr Bernstein's clinical practice, which has served as a “laboratory” for his active studies. His research and quality improvement initiatives focus on issues important to Academic General Pediatrics and community-based practice, including immunizations, postpartum newborn discharge, childhood obesity, breastfeeding, health promotion, preventive health screening in primary care, technology, and medical education. His commitment, innovative spirit, and enthusiasm also encompass many facets of medical education along the continuum, from training and mentoring future physicians to fostering lifelong learning, to supporting the continuous professional development of practicing pediatricians. Hank is an ex-officio member of the American Academy of Pediatrics’ Committee on Infectious Diseases (Red Book Committee), Associate Editor of Red Book Online, and AAP liaison to the CDC Advisory Committee on Immunization Practices’ Influenza Workgroup, spearheading both seasonal and pandemic influenza preparedness and policy for children. In addition, he is Editor-in-Chief Emeritus of PediaLink, the AAP's online home for lifelong learning and chair of the interdisciplinary Bright Futures Health Promotion Workgroup, which has created a distinctive health promotion curriculum, videos, and a companion educational website (www.pediatricsinpractice.org). He regularly shares his knowledge and expertise by educating the public, writing for health information websites, and participating in media interviews on a variety of pediatric health care issues including immunization, diagnosis and treatment of common childhood infectious diseases and illnesses, and practical information for parents, teachers and caregivers. In the spirit of lifelong learning, Hank earned a masters in healthcare management at Harvard School of Public Health, USA, in 2013. He actively maintains his certification by the American Board of Pediatrics. He completed his residency training in pediatrics at St Christopher's Hospital for Children in Philadelphia, USA, after earning his medical degree from the University of Medicine and Dentistry of New Jersey - School of Osteopathic Medicine, USA. Hank and his wife, Sophie, have been married for 36 years and are extremely proud of their 31-year-old daughter, Lauren, and 26-year-old son, David.

The AACR 2013 in Washington D.C.

RÉSUMÉ: Cette thèse porte sur une nouvelle technique d'imagerie médicale qui permet de déterminer la distribution de conductivité électrique des tissus d'une région du corps avec une résolution comparable à celle de techniques courantes d'imagerie par ultrasons. Cette nouvelle technique, appelée imagerie par « modulation acoustique de conductivité électrique » (MACE), est basée sur l'interaction entre une onde acoustique et un champ électrique. Dans sa réalisation expérimentale la plus simple, quatre électrodes placées à proximité de la région à imager appliquent un courant électrique de faible amplitude et mesurent la différence de potentiel résultant du passage du courant dans les tissus. Un transducteur ultrasonore focalisé vient insonifier un voxel de la région d'intérêt, modifiant la distribution de conductivité et, ce faisant, l'amplitude du potentiel mesuré par les électrodes. Une image de la distribution de conductivité peut être obtenue en déplaçant l'ensemble capteur-électrodes pour balayer la région d'intérêt ; l'onde acoustique sert alors d'agent de localisation, tandis que la mesure de potentiel quantifie la variation de conductivité dans chaque voxel insonifié. L'imagerie par MACE présente de nombreux avantages mais aussi des défis importants de mise en œuvre. Puisque ces avantages et défis dépendent de l'application visée, notre démarche a été orientée vers un objectif particulier, soit l'application de l'imagerie par MACE au diagnostic du cancer du sein. Ce choix est justifié par le potentiel que présente cette technique pour discriminer une tumeur maligne des autres tissus mammaires. En effet, des études expérimentales sur des tissus excisés réalisées durant près d'un siècle ainsi que l'apport plus récent des techniques de mesure d'impédance confirment qu'il existe une différence significative dans les spectres fréquentiels de conductivité électrique des tissus cancéreux et sains. Le développement de systèmes de tomographie d'impédance électrique (TIE) orientés vers l'imagerie du sein ne semble pas pouvoir réaliser ce potentiel, principalement parce que la résolution spatiale de la TIE est insuffisante pour détecter les tumeurs à un stade précoce. L'imagerie par MACE pourrait contourner cette limite fondamentale de la TIE. Deux modèles sont proposés dans cette thèse pour réaliser l'imagerie par MACE. ABSTRACT: This thesis describes a new medical imaging technique for determining the electrical conductivity distribution of tissues in a body region with a resolution comparable to that of current ultrasound techniques. The new technique, henceforth referred to as "Acousto-Electric Conductivity Modulation" (AECM) imaging, is based on the interaction of a sound wave with an electrical field. In its simplest form, four electrodes located near the region to be imaged apply a low-amplitude electrical current and measure the potential difference arising from current flow in the tissues. A focused ultrasound transducer directs a pressure wave to a voxel of the region of interest, modifying its conductivity distribution and, as a result, the amplitude of the potential measured by the electrodes. An image of the conductivity distribution can thus be constructed point-by-point by moving the electrodes and transducer to scan the object. In this context, the acoustic wave acts as the localization agent while the electrical potential provides a measure of the local conductivity change that occurs in the voxel.AECM imaging presents several advantages but also implies addressing significant difficulties in its deployment. Since the advantages and implementation difficulties depend on the intended application, we have focused on achieving a specific objective: applying AECM imaging to the diagnosis of breast cancer. The rationale for this choice is the potential presented by AECM imaging for discriminating cancerous tumors from healthy breast tissue. Indeed, experimental studies on excised tissues carried out over nearly a century, supported by more recent wideband tissue impedance measurements, have shown that there are significant differences in the electrical conductivity spectra of cancerous and normal tissues. Yet electrical impedance tomography (EIT) systems specifically designed for breast imaging do not seem to be capable of providing the required tissue discrimination characteristics, mainly because the low spatial resolution of EIT prevents detecting tumors at an early stage. AECM imaging could overcome this inherent limitation of EIT.Two models are proposed in this thesis for implementing AECM imaging. Formulations for the forward and inverse problems are provided for both models. The forward problem involves computing the AECM signals given the electrical conductivity distribution of the medium and the data acquisition protocol.

PD-L1 (programmed cell death ligand 1) immunohistochemistry (IHC), tumor mutational burden (TMB), gene expression profiling (GEP), and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) assays have been used to assess pretreatment tumor tissue to predict response to anti-PD-1/PD-L1 therapies. However, the relative diagnostic performance of these modalities has yet to be established. To compare studies that assessed the diagnostic accuracy of PD-L1 IHC, TMB, GEP, and mIHC/IF in predicting response to anti-PD-1/PD-L1 therapy. A search of PubMed (from inception to June 2018) and 2013 to 2018 annual meeting abstracts from the American Association for Cancer Research, American Society of Clinical Oncology, European Society for Medical Oncology, and Society for Immunotherapy of Cancer was conducted to identify studies that examined the use of PD-L1 IHC, TMB, GEP, and mIHC/IF assays to determine objective response to anti-PD-1/PD-L1 therapy. For PD-L1 IHC, only clinical trials that resulted in US Food and Drug Administration approval of indications for anti-PD-1/PD-L1 were included. Studies combining more than 1 modality were also included. Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were followed. Two reviewers independently extracted the clinical outcomes and test results for each individual study. Summary receiver operating characteristic (sROC) curves; their associated area under the curve (AUC); and pooled sensitivity, specificity, positive and negative predictive values (PPV, NPV), and positive and negative likelihood ratios (LR+ and LR-) for each assay modality. Tumor specimens representing over 10 different solid tumor types in 8135 patients were assayed, and the results were correlated with anti-PD-1/PD-L1 response. When each modality was evaluated with sROC curves, mIHC/IF had a significantly higher AUC (0.79) compared with PD-L1 IHC (AUC, 0.65, P < .001), GEP (AUC, 0.65, P = .003), and TMB (AUC, 0.69, P = .049). When multiple different modalities were combined such as PD-L1 IHC and/or GEP + TMB, the AUC drew nearer to that of mIHC/IF (0.74). All modalities demonstrated comparable NPV and LR-, whereas mIHC/IF demonstrated higher PPV (0.63) and LR+ (2.86) than the other approaches. In this meta-analysis, tumor mutational burden, PD-L1 IHC, and GEP demonstrated comparable AUCs in predicting response to anti-PD-1/PD-L1 treatment. Multiplex immunohistochemistry/IF and multimodality biomarker strategies appear to be associated with improved performance over PD-L1 IHC, TMB, or GEP alone. Further studies with mIHC/IF and composite approaches with a larger number of patients will be required to confirm these findings. Additional study is also required to determine the most predictive analyte combinations and to determine whether biomarker modality performance varies by tumor type.

Background: Understanding the ability of chemopreventive agent efficacy in morphologic (in vitro/in vivo) assays to predict efficacy in animal (mouse and rat) in vivo tumor assays has not been well studied. The Chemopreventive Agent Development Research Group (CADRG) in the U.S. NCI's Division of Cancer Prevention has, over 25 years, tested approximately 800 agents for potential chemopreventive activity. Of these agents, a subset of 146 that were tested in both morphologic and mammary gland tumor assays constitutes the focus of our current project. Our goal is to gain deeper insight into the relevant predictive values. Materials and Methods: Two critical steps are involved in the early stages of the CADRG testing pathway: (1) in vitro/in vivo morphologic assays and, for agents successful in these, (2) testing for tumor prevention (measured in terms of tumor incidence and multiplicity reduction) in animal tumor assays. Ultimately, our goal is to test agents that successfully decrease tumor incidence and multiplicity in animal tumor assays in humans. In the project presented here, we evaluated the predictive values of earlier-stage (morphologic) assays for efficacy in later-stage (animal tumor, specifically mammary tumor) assays. We used statistical modeling to determine how well the six most commonly used morphologic assays predicted efficacy of the 146 tested agents in mouse and rat mammary gland tumor assays. For this purpose multimodel inference was applied to ordinal logistic regression. Results: We evaluated the ability of the six morphologic assays to predict tumor outcomes in the mouse and rat mammary gland cancer assays. In our statistical modeling approach, each morphologic assay was assigned a value describing how strongly it predicted outcomes in the mammary gland tumor assays. Specific morphologic assays (mouse mammary organ culture/MMOC and human foreskin epithelial cell/HFE morphologic assays) in combination yielded predictive values that are reasonably suggestive of the efficacy demonstrated by chemopreventive agents in the mouse and rat mammary gland tumor assays. Conclusions: Predictive models such as these should prove useful in guiding future decision-making regarding agent selection and morphologic and animal tumor assay use. Our current strategy is to gain insight into the Predictive Value approach by: (1) identifying the mammary gland tumor assays that best reflect anti-tumor efficacy in animals; (2) teasing apart those classes of agents that exhibit the highest predictive values overall; and (3) examining those classes of agents that exhibit the highest efficacy in specific mammary gland tumor assays. Citation Format: Barbara K. Dunn, Vernon E. Steele, Richard M. Fagerstrom, Carol F. Topp, Barnett S. Kramer. Chemoprevention of mammary cancer: Modeling predictive values of short-term morphologic assays for efficacy in animal tumor assays. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2813. doi:10.1158/1538-7445.AM2015-2813

When Leslie Bernstein, PhD, joined the faculty of City of Hope at the age of 67, she told the institution's leaders that she would stay for no more than a decade. After all, she had just spent 25 years at the University of Southern California (USC) in Los Angeles, serving as a professor in the department of preventive medicine, the medical school dean for faculty affairs, and the university vice provost for medical affairs. However, some 13 years after her pronouncement—with a move across the country to be closer to her daughter in New Jersey thrown in—Dr. Bernstein continues to work with the center remotely, publishing research and mentoring younger colleagues. “I'm hoping to retire soon, but so far the answer has been, ‘We'd rather you stay on,’” she says. It is easy to understand why the leaders of City of Hope, a National Cancer Institute-Designated Comprehensive Cancer Center in Duarte, California, are reluctant to let Dr. Bernstein go. As a professor in its division of biomarkers of early detection and prevention, she has conducted landmark studies in breast cancer risk and prevention and has been instrumental in leading other key research in cancer epidemiology. “Very few investigators can point to groundbreaking work that has actually led to changes in practice and impacted the ways that scientists and clinicians think about breast cancer like she can,” says her colleague and former student, Jonine Bernstein, PhD, (no relation), an epidemiologist and coleader of the Population Sciences Research Program at Memorial Sloan Kettering Cancer Center in New York City. “And she's passionate about every aspect of her work—she's one of these researchers who's in it for the people affected as well as for the intellectual challenge.” As a result, many in the oncology world look to involve Dr. Bernstein, in some capacity, with their work, whether it is as a collaborator, advisor, or member of their board or advocacy group. “She sits on every important advisory committee in our field,” Dr. Jonine Bernstein says. Dr. Jonine Bernstein has long relied on Dr. Leslie Bernstein's expertise herself. The 2 researchers have worked together for more than 20 years on the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study, an international research project funded by the National Institutes of Health that explores genetic susceptibility and the effects of radiation treatment on contralateral breast cancer risk. Together, they designed, conducted, supported, and analyzed the research, which remains the largest study of second primary breast cancer with direct patient interviews, biospecimens, and detailed patient information. “She's had such an incredible influence on me and my career path,” Dr. Jonine Bernstein says. “She's an educator, mentor, colleague, and a dear friend.” Among her many contributions to the field, Dr. Bernstein cofounded the California Teachers Study, along with several cancer epidemiology colleagues. The closed cohort study, launched in 1995, included a total of 133,479 female active or retired public school professionals, primarily teachers and administrators, who completed questionnaires regarding their health behaviors. Participants have been followed in the decades since and monitored for disease development and other health outcomes. Although originally created to study breast cancer, the study also has yielded important findings regarding other cancers and diseases. Indeed, Dr. Bernstein and her colleagues continue to use data from the study, which has led to more than 140 articles, she says. Because the California Teachers Study did not have biospecimens at its outset, Dr. Bernstein launched a large case-control study and collected samples from study participants who had been diagnosed with breast cancer after they had enrolled, as well as nonparticipants. Those original 13,000 specimens were supplemented by a focused specimen collection effort that more than doubled the California Teachers Study biospecimen repository, thereby enabling investigators to conduct genetics research. In addition, pooling data from the California Teachers Study with other cohorts, including those from cancer prevention studies by the American Cancer Society, the Nurses' Health Study, and the USC Multiethnic Cohort Study, has generated more studies with much larger data sets, adding to the strength of their findings. Researchers from these and other large cohort studies are members of the National Cancer Institute Cohort Consortium, which encourages large-scale collaborations to pool data and biospecimens. Another important contribution to the field made by Dr. Bernstein was her 1994 publication of what is believed to be the first definitive research article linking physical activity and breast cancer risk.1 Prior to that, she had conducted a number of studies concerning the menstrual cycle and hormones, including one study of nuns who had never given birth and their parous sisters that indicated a hormonal link between pregnancy and breast cancer risk. When Dr. Bernstein and her colleagues began examining the connection between physical activity and breast cancer risk, she says, “we knew that when a woman had her first child and when she had her first and last menstrual periods had an effect on risk, but we had nothing we could tell women they could do to lower their risk.” She did, however, have a theory. Having trained as a competitive swimmer (as a teenager, Dr. Bernstein had narrowly missed making the Olympic team), she knew that intense physical activity interfered with the menstrual cycle, which led to reduced exposure to the hormones estradiol and progesterone. Understanding the causal connection between these hormones and breast cancer, she reasoned that exercise could potentially reduce a woman's risk of developing the disease. “Very few investigators can point to groundbreaking work that has actually led to changes in practice and impacted the ways that scientists and clinicians think about breast cancer like she can.” —Jonine Bernstein, PhD More recently, Dr. Bernstein has explored the role of low-dose aspirin in reducing breast cancer risk. In 2017, she published research that found an overall 16% lower risk of breast cancer among women in the California Teachers Study who reported using low-dose aspirin at least 3 times per week.2 The risk reduction was even higher, at 20%, for the most common breast cancer subtype, estrogen receptor–positive or progesterone receptor–positive, human epidermal growth factor receptor 2–negative disease. In 2018, Dr. Bernstein received the American Association for Cancer Research and the American Cancer Society Award for Research Excellence in Cancer Epidemiology and Prevention. She was only the third woman to receive it. Dr. Bernstein's father was diagnosed with metastatic melanoma when she was 11 years old. He even taught her how to drive at that young age so there would be 2 drivers in the family in the event of an emergency (“It was the 1950s, and things were different then,” she recalls). Dr. Bernstein has had a lifelong passion for math, and she says it was her love for the subject that eventually drove her toward epidemiology. She traces the roots of her fascination with numbers back to her father. “My dad played math games with me from the time I was 2,” she says. By age 16, she was a bona fide math whiz and was accepted into the University of California at Los Angeles. She worked full time to afford the tuition. Shortly after, she began dating a fellow competitive swimmer, Saul Bernstein, whom she married when she was 18. “He had always dreamed of being a physician, but he was majoring in physical education in college,” she says. No one else in his poor, immigrant family had received a formal education, and “he didn't know how to go about it,” she explains. However, with her help, Saul not only began to excel in his college courses but applied to and was accepted into medical school, eventually becoming a highly regarded pediatric orthopedic surgeon. However, when Dr. Bernstein became pregnant at age 19 years, the couple soon realized that they could only afford 1 education at a time, and she left college. She completed her bachelor's degree in mathematics several years later while her husband was an orthopedic resident. After Saul Bernstein was drafted during the Vietnam War, he was stationed at US military bases in Kansas and Georgia to care for returning wounded soldiers. Later, the family moved to England, where Saul completed his fellowship. By then a mother of 3, Dr. Bernstein never gave up on her dreams of furthering her education. At age 37, she returned to graduate school at USC, and completed a master's degree in gerontology in 1978 and a PhD in biometry (biostatistics) in 1981. “I've been working ever since,” she says. In reflecting on the state of the cancer research field, Dr. Bernstein says she and other colleagues have felt that too much focus has been placed on genome-wide association type studies and too little on understanding mechanisms that will lead to prevention efforts. “For example, we've never done a clinical trial of exercise and breast cancer risk, because it's really difficult to do,” she says. “What we need instead are smaller studies to nail down the mechanisms involved so we can answer questions like what type of exercise is best and at which ages during a woman's lifetime is it most important to exercise.” In addition to her work, Dr. Bernstein is the proud grandmother of 11 grandchildren, whose list of accomplishments is growing, with one about to receive her PhD, another conducting HIV research in South Africa, and a third applying to medical school. The remaining grandchildren are still in college. “I spend a lot of time with them—guiding them and answering their questions,” she says. She offers those in the field a similar gift, Dr. Jonine Bernstein says. “She's so thoughtful and incredibly humble—she takes great joy in having people around her succeed. Everyone should be so lucky as to work with and be supported by a Leslie Bernstein in their life.”

Our previous studies have shown that the cancer-preventive actions of selenium may be negated by an over-expression of selenoprotein thioredoxin reductase (TR). This reductase reverses selenocompound-induced sulfhydryl redox inactivation of protein kinase C (PKC), a step which is intimately involved in the cancer-preventive actions of selenium. Consistent with this observation, the TR-specific inhibitor auranofin increases the sensitivity of prostate cancer cells to methylseleninic acid (MSA). This is particularly significant for advanced prostate cancer cells which require higher concentrations of MSA than early stage cancer cells. Selenium prevents cancer in some cases but fails to do so in others. Selenium's failure in this respect may be due to the development of TR-mediated resistance to its chemopreventive actions. Therefore, there is a potential role for agents that inhibit TR and thereby sensitize cancer cells to selenium. Several studies have shown that cancer prevention by a single agent may be less effective than multiple agents administered simultaneously. Here we report that curcumin, another cancer -preventive agent, at 5 to 10 μM concentrations potentiates the action of MSA in inhibiting growth and inducing apoptosis of both androgen-dependent LNCaP cells and androgen-independent DU145 cells. Nearly 2- to 4-fold lower concentrations of MSA were needed for 50% inhibition of cell growth in the presence of curcumin than in its absence. Under these conditions, curcumin inactivated TR in these cell types. There was also a concomitant increase in MSA-induced sulfhydryl oxidative inactivation of PKC. Furthermore, we found a correlation between curcumin-induced inactivation of TR and curcumin-induced potentiation of MSA-associated growth inhibition and apoptosis. These results suggest TR may be a molecular target for cancer prevention. While auranofin, the prototypical TR inhibitor, is toxic, curcumin appears to be a safe alternative. Our results provide a mechanistic rationale to the combination of selenium and curcumin for cancer prevention. Just as resistance develops to cancer chemotherapy, cancer prevention may also be counteracted by resistance mechanisms. Similarly, a combination of agents may prevent the development of resistance in cancer prevention just as it does in chemotherapy. Instead of the random mixing of agents in an empiric manner, a mechanistically informed choice of agents as has been proposed here is a more rational approach to identify effective combination of agents for cancer prevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1889.

We have shown previously that phenethyl isothiocyanate (PEITC), which is a highly promising cancer chemopreventive constituent of edible cruciferous vegetables (e.g., watercress), inhibits growth of cultured breast cancer cells in association with apoptosis induction. The present study was undertaken to determine the efficacy of PEITC for prevention of breast cancer using MMTV-neu mouse model. PEITC administration in the diet (3 mmol PEITC/kg AIN76A diet) for 29 weeks caused an approximate 27% decrease in incidence of mammary hyperplasia compared with control, but the difference between control and PEITC treatment groups did not reach statistical significance. On the other hand, incidence of palpable tumors was reduced by about 53% by PEITC administration (P= 0.07 by two-sided Fisher's exact test). Moreover, size of microscopic carcinoma lesions was significantly lower in mice fed PEITC-supplemented diet compared with those fed basal diet (P= 0.05 by two-sided Fisher's exact test). Average body weight of the PEITC-fed mice was modestly but significantly higher than that of control mice at earlier time points (weeks 1-7) but this differential was not observed at later time points (weeks 8-29). Diet consumption was comparable for mice placed on basal diet and PEITC-supplemented diet. Mean PEITC concentration in the plasma and tumor tissue was 901 nM (95% confidence interval- 741-1060 nM) and 87 nmol/kg (95% confidence interval- 67-107 nmol/kg), respectively. Expression of HER-2 oncoprotein as well as number of CD31-positive blood vessels in the tumor did not differ between control and PEITC treatment groups. On the other hand, tumors from PEITC treatment group exhibited about 46% decrease in Ki-67 expression in comparison with control (P= 0.01). Consistent with cellular observations, number of TUNEL-positive apoptotic bodies was about 4.4-fold higher in the tumors of PEITC-fed mice as compared with controls (P= 0.01). Pulmonary metastasis was evident in 3/35 control mice but only 1/32 mice placed on PEITC-supplemented diet exhibited microscopic evidence of metastasis. Size of pulmonary metastasis was also smaller in the PEITC treatment group compared with control. The results indicate that PEITC administration in the diet inhibits carcinoma development in MMTV-neu mice without any signs of overt toxicity. This investigation was supported in part by the US PHS grants CA101753 and CA129347 awarded by the National Cancer Institute. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 563. doi:1538-7445.AM2012-563