March 31, 2019Marissa Schuh, Rachel Stewart, DO, PhD, Riham El Khouli, MD, PhD, Rachel W. Miller, MD, Justine Pickarski, MS, LGC, Eric B. Durbin, DrPH, MS, Susanne Arnold, MD, Jill Kolesar, PharmD, MS
Oncology is unique in that somatic mutations can both drive the development of a tumor and serve as a therapeutic target for treating the cancer. Clinical sequencing of many cancers is now a routine part of care; however, the volume and complexity of sequencing data generated can be overwhelming to practicing oncologists. Molecular tumor boards (MTBs), typically multidisciplinary and disease agnostic, have emerged as a method for analyzing sequencing data and providing clinically relevant recommendations to the treating physician. A number of factors contribute to the effective implementation of an MTB.
MTBs should evaluate their scope by considering the needs of the constituency, the population, and the institution, and the research interests of the team. The focus should be on providing the highest-quality analysis, with broad intellectual support across multiple disciplines. Creating a set of guidance documents and levels of evidence for decision making will place all decisions into context, allowing individual practitioners who receive the MTB reviews to easily understand the data that support recommendations. These measures also give third-party payers and institutions confidence in the decisions of the MTB, and mediate medicolegal risks, while supporting the provision of targeted therapy by insurers.
Members and roles
Identifying the leadership team of an MTB is a critical first step. At our institution, the University of Kentucky Markey Cancer Center, the co-leaders are a clinical pharmacologist and a gynecologic oncologist. The co-leaders have complementary expertise in the clinical care of cancer patients and the molecular pharmacology of anticancer agents, and provide scientific, administrative, and clinical leadership to the MTB.
A pathologist with board certification and/or subspecialty expertise in molecular genetic pathology should be included on an MTB in order to assist with variant interpretation, discussion of clinically actionable variants, and questions regarding test methodology and quality assurance practices. Input from a pathologist can also be useful for prioritizing molecular testing in the setting of small or limited tumor samples. The clinical significance of variants and resulting treatment recommendations are best discussed within the context of the primary site and histopathologic diagnosis. A pathologist with expertise in surgical pathology can add valuable information to the discussion by presenting histopathologic findings, staging information, and interpreting the results of immunohistochemical stains and other ancillary tests.
Patients referred for MTB consultation are typically refractory or relapsing patients who have exhausted all clinical standard of care options, which makes review of imaging a critical component of the process. Board-certified, fellowship-trained radiologists are key members of the MTB and provide expertise regarding disease extent and progression. Careful review and comparison of all prior imaging studies using the standard treatment response metrics—including the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Positron Emission Response Criteria in Solid Tumors (PERCIST 1.0)—is valuable. Additionally, selection of representative images for presentation during the MTB session helps the group understand the disease behavior and the multidisciplinary assessment of each patient.
Our clinical team is composed of physicians, clinical pharmacologists, and genetic counselors. Input from surgical and medical oncologists with broad clinical expertise for the most common tumor types seen by the MTB, and with experience in therapeutic decision making in the era of targeted therapies, is essential. Clinical trialists are also valuable, as they not only review cases for clinical recommendations but also identify potential candidates for clinical trials with biomarker entry criteria. Clinical pharmacologists provide a critical assessment of the drugability of identified mutations, potential treatment strategies, and pharmacological differences within a drug class. A genetics counselor is also present at all MTB meetings to identify candidates for germline testing. Our clinical team reviews the clinical case history, evaluates the targetability of identified mutations, and develops a patient-specific recommendation for either standard of care therapy, off-label therapy, a clinical trial, or additional testing.
The MTB process
The MTB manager oversees all aspects of MTB operations [see flowchart on next page]. The manager uses standard operating procedures to set the meeting agenda, disseminate cases to reviewers, return recommendations to treating physicians, develop documentation, and provide continuing medical education. Guidance documents serve to objectify the decisions of the group, maintain consistency, and provide structure to the review process.
Prior to the initiation of the MTB, we received approval of our initial guidance documents by the university’s policy and administrative bodies. We continuously review the guidance documents as the science changes to incorporate new findings, new technologies, and new therapeutic options for patients. Levels of evidence do not change, however, and that is the context in which we report all results.
MTB data must be properly managed to support clinical decision making, to enable the evaluation of the MTB’s performance, and to support downstream research. At a minimum, an MTB requires the ability to track patients through the MTB process. A data management system should capture patient demographics, consents, details about the cancer diagnosis and stage, prior treatments and responses, and clinically relevant variants, as well as the final recommendations made by the MTB. Information about disease progression and response to treatment post-MTB review are also critical for evaluating the impact of the MTB on patient outcomes. Our center utilizes a clinical trials management system for this purpose.
Molecular data is most useful for analyses and research when integrated with other clinical, biomarker, and multiomics data sources. For example, cancer registry data is often a rich source of standardized clinical, treatment, and long-term outcome information for patients. Our center has partnered with the Kentucky Cancer Registry, a National Cancer Institute Surveillance, Epidemiology and End Results (SEER) registry, to build a Cancer Research Data Commons that integrates data from the MTB, SEER registry, electronic pathology reports, clinical trials, biorepositories, and other multi-omics sources as a resource available to clinicians and researchers. A portal has been developed that allows authorized investigators to review patient populations using a combination of data points from the various sources. This provides an excellent source of preliminary data to further enhance research efforts at our academic medical center.
MTBs are an effective way to interpret and synthesize complex clinical sequencing reports, provide actionable treatment recommendations to treating physicians, and develop a database for ongoing research questions. Implementing an effective MTB requires the input and commitment of a large interdisciplinary team, strong administrative support, adoption of standardized workflows, and incorporation of evidence into clinical decision making.