By Richard L. Schilsky, MD, FACP, FASCO
ASCO Chief Medical Officer
Personalized cancer care is not a new concept, but its application has been enabled and enhanced by a far greater understanding of the biological underpinnings of cancer than ever existed before. Our deeper understanding of cancer at the genomic level, coupled with the increasingly widespread availability of affordable technologies to interrogate the genome, the transcriptome, the proteome, and other aspects of the tumor and host, is leading to new paradigms of cancer care that rely increasingly on tumor molecular profiling throughout the course of care to inform treatment decisions. More than 30 recently introduced drugs—including both antibodies and small molecules—that target specific molecules and pathways crucial for cancer growth, survival, and spread have revolutionized the treatment of some cancers and given hope to many patients with cancers once considered hopeless. Evidence is building through reports of small research studies and clinical anecdotes to suggest that patient outcomes are improved when a specific targeted agent can be matched to a molecular profile.
Implementing personalized cancer care requires the following: A sound understanding of cancer genomics; an appreciation of the strengths, weaknesses and limitations of the analytical methods available to study cancer; a recognition of the sources of variability in molecular testing; a deep knowledge of the mechanisms of action of targeted drugs; and a way to collect, assimilate and understand complex data sets in the context of a busy clinical oncology practice. With the increasing availability of single-gene and multiplex mutation analysis, large-scale next-generation sequencing, transcriptomic analysis, and other tests now offered by many laboratories, oncologists increasingly struggle with decisions about which tests to order for what purpose, how to understand and interpret the results, and how to convert the information provided by the tests to meaningful clinical decisions that help patients.
To address these many challenges, ASCO has developed a number of guidelines, educational programs, workshops, and research initiatives all aimed at making precision medicine for cancer more easily understood and widely available to oncologists and their patients. The appropriate molecular work-up of common cancers is increasingly complex as new biomarkers are discovered that are associated with sensitivity or resistance to specific treatments. ASCO, working alone or in collaboration with other professional societies, develops and disseminates evidence-based guidelines for cancer molecular diagnosis that include recommended markers, testing platforms, definitions of positive/negative tests, optimal report content, and test limitations or confounders.
ASCO and the College of American Pathologists (CAP) have offered such guidelines for hormone receptor and HER2/neu testing in breast cancer. CAP, the Association of Molecular Pathologists (AMP), and the International Association for the Study of Lung Cancer (IASLC) have collaborated on the publication of ASCO-endorsed guidelines for epidermal growth factor receptor (EGFR) mutation and ALK translocation testing in adenocarcinoma of the lung. ASCO has also issued a provisional clinical opinion on KRAS mutation testing in patients with advanced colorectal cancer testing who are candidates for treatment with anti-epidermal growth factor receptor antibodies; ASCO will soon update this opinion with new information about extended RAS mutation testing. Additional guidelines are in development regarding biomarker testing in other cancer types. ASCO and CAP have also recognized that even standard biomarker testing might not be available in many countries of the world due to limited resources, inadequate equipment or reagents, or lack of qualified professionals and trained staff. A recent workshop on these issues that included oncologists and pathologists from Haiti, Vietnam, and Kenya has begun to identify the magnitude of these problems and potential solutions.
The clinical interpretation of genomic tests is challenging even for experts in the field, and in many cancer centers interpretation is now performed in the context of molecular tumor boards that include clinical oncologists, molecular pathologists, and genomics experts in the traditional multidisciplinary clinical tumor board. Most oncologists have not been well trained in genetics and ASCO now offers comprehensive courses in Cancer Genetics and Tumor Genomics through ASCO University that aim to provide clinical oncologists with essential training in hereditary cancer genetics and somatic genomic alterations, respectively. Although molecular tumor boards have now been organized at many academic medical centers and comprehensive cancer centers, most community oncologists do not have access to such programs. To remedy this situation, ASCO, in collaboration with CAP and AMP, has introduced a Molecular Oncology Tumor Board series on ASCO University. These are monthly, user-driven interactive discussions designed to help cancer care providers interpret and understand molecular profiling tests and their role in patient management. Each case discussion is moderated by a molecular pathologist and a clinical oncologist and incorporates comments, opinion, analysis, and questions from the discussion participants. The cases reviewed so far have included discussions of ROS1 rearrangement in non-small cell lung cancer, PIK3CA mutation in breast cancer, MLL rearrangements in acute myeloid leukemia, and genomic analysis of carcinoma of unknown primary.
For those individuals who are actively engaged in biomarker test development, ASCO also co-sponsors with the National Cancer Institute (NCI) and the European Organization for Research and Treatment of Cancer (EORTC) an annual tutorial on cancer diagnostic development that provides in-depth, case-based training on the scientific and regulatory aspects of biomarker test development.
Clinical trial data have begun to emerge that suggest that patients have better outcomes when their treatment is assigned based on matching drugs to potential genomic targets in their tumor. Such reports have fueled interest among patients and physicians to use genomic profiling as a guide to treatment planning in patients with advanced cancer when standard treatment options have been exhausted. However, access to drugs predicted to be beneficial is often limited. Furthermore, although clinical reports to date suggest that 30% to 70% of advanced solid tumors harbor potentially “actionable” mutations or other gene variants, the outcomes of patients treated based on such tests remain largely anecdotal or unknown. Thus, ASCO is developing the Targeted Agent and Profiling Utilization Registry (TAPUR) study that aims to learn about the effectiveness of marketed, targeted anticancer drugs used outside of their approved indications. The major goals of this study are 1) to facilitate patient access to marketed agents that are predicted to be beneficial based on analysis of patients’ tumor’s genomic profile, and 2) importantly, to then learn which treatments benefit which patients by capturing their outcomes in a prospective database. By providing access to targeted agents—at least those that target common mutations—patients with advanced cancer will have an opportunity to benefit from a treatment that is potentially effective but may not be easily accessible due to cost, coverage, or regulatory obstacles. TAPUR is conceptually similar to both the ongoing AcSé program being conducted by the French National Cancer institute and a major initiative of the U.S. NCI, the Molecular Analysis for Therapy Choice (MATCH) trial.
Precision medicine has begun to transform the lives of many patients with cancer but its application in clinical practice is enormously complex. ASCO, through the variety of its programs summarized here, as well as its annual and thematic meetings and journals (including the new Journal of Global Oncology [JGO]), hopes to contribute to and advance the field by providing oncologists with the training, tools, and data they need to help patients with cancer around the world realize the promise of precision medicine.