Lincoln D. Nadauld, MD, PhD, and Derrick S. Haslem, MD
- Clinical implementation of precision cancer medicine and active treatment of patients with targeted therapies continue to be challenges for health care providers.
- Input from a molecular tumor board confers collective insight and experience on treatment decisions and may also provide confidence for physicians who have less experience with interpreting molecular testing results.
- Given the myriad genomic alterations and targeted-therapy combinations in precision oncology, innovative basket and umbrella trial designs, together with large meta-analyses and well-designed retrospective studies, are likely to provide the most clarity about clinical outcomes.
The treatment of cancer historically has relied on the empiric selection of cytotoxic chemotherapeutic regimens that are based on the cancer tissue of origin. Iterative improvements in this approach over 5 decades have yielded the modern chemotherapy of today that can be delivered in the outpatient setting with manageable side-effect profiles and quality clinical outcomes characterized by improved survival and cure rates. The relatively recent advent of novel diagnostic technologies, such as next-generation sequencing, has begun to usher in an era of precision oncology in which the patient and physician use tumor-specific genomic alterations to better inform treatment decisions.
Clinical implementation of precision cancer medicine and active treatment of patients with targeted therapies continue to be challenges for health care providers. Questions about the interpretation of genomic results, costs associated with testing, timing of targeted treatment implementation, and accessibility of therapies suggested by genomic tests remain significant hurdles for providers and patients alike. Although the answers to these questions are available, application of the solutions to enable precision cancer medicine for an entire patient population and implementation of the approach in programmatic fashion remain elusive for many.
To clinically implement precision cancer medicine as a program, we established a personalized medicine clinic as a pilot program. Patients with advanced, refractory cancer were referred to the precision oncology clinic, where they received education and information about cancer genomics and whether it might be appropriate for them. A follow-up visit to the clinic was conducted 2 to 3 weeks later to review genomic testing results and to discuss treatment implications. Patients were referred back to the treating oncologist with an in-depth interpretation of the genomic results and a list of treatment options. Implementation of any targeted treatment options remained solely at the discretion of the primary oncologist. As the program matured, and as referring physicians became increasingly comfortable with genomic testing reports and interpretations, providers began to order and discuss results with patients directly, rather than refer them to the precision oncology clinic. Today, the pilot program has effectively run its course, and providers offer precision oncology approaches to patients with advanced cancer in a programmatic fashion.
A key feature of our precision oncology program (internally dubbed Precision Genomics) has been the input of the molecular tumor board (MTB).1 Modeled after traditional tumor boards, the MTB is composed of clinical experts in cancer genomics and scientists who have an understanding of cancer cell biology and cell signaling. The MTB meets regularly to review and evaluate genomic testing results and to provide a consensus interpretation of the alterations found in a patient’s tumor and of the treatment implications, including clinical trial options, for that patient. For example, a patient with refractory metastatic lung cancer whose tumor harbors KRAS, FGFR1, and CDK6 alterations might be a candidate for several clinical trials, which investigate selective inhibitors of those pathways, or the treating oncologist may wish to employ an approved drug off-label. This scenario illustrates a common challenge in precision medicine: When a tumor harbors multiple actionable mutations, which of the genes or pathways should be targeted? Our MTB generally follows a prioritized algorithm in such cases. Its first priority is to provide patients with on-label treatments or clinical trial enrollment whenever possible, followed by off-label targeted treatments and follow-up testing on new biopsy specimens. The collective experience and insight of an MTB often is the key to determining the best path forward in such cases. The MTB also provides significant confidence for providers who may have less experience with interpretation of molecular testing results.
The MTB at our institution is a multi-institutional effort composed of physicians and scientists with experience in genomics who are from diverse academic institutions and numerous integrated health delivery systems. Our weekly meetings, conducted via videoconference, allow providers to engage the collective expertise of colleagues with specific experience in genomics to whom access might otherwise be limited. The MTB reviews the genomic results of each patient who undergoes testing in the Intermountain Precision Genomics lab and provides a consensus interpretation of the treatment options for the patient. A multi-institutional model provides input from diverse experts and guards against the regionalization of precision oncology that has existed in previous iterations of medical advances.
The question of whether precision oncology positively affects clinical outcomes is the subject of ongoing investigation. Recent studies to evaluate the clinical impact of precision oncology have detected improved survival endpoints and, in some cases, a neutral economic impact.2-5 The prospect of improved survival without increased costs is encouraging for patients, payers, and providers alike. A large meta-analysis of more than 8,000 patients with refractory cancer who received genomics-targeted therapy identified a near doubling of progression-free survival, and prolonged overall survival, compared with patients who received nontargeted therapy.3 Retrospective and case-control trials are accompanied by various caveats, yet they increasingly suggest a survival advantage to genomics-targeted therapies. Demonstration of these outcomes continues to be particularly important for precision oncology, given that the commitment from providers to adopt precision oncology broadly—and the ability of payers to justify payment for this approach—largely hinges on the clinical outcomes associated with this treatment paradigm.
A primary hindrance to the adoption of precision oncology is the ongoing demand by some payers and providers for a prospective, randomized, controlled clinical trial. The request from many payers to review two phase II studies, or one large randomized phase III study, before coverage for a therapy is granted is representative of the outdated payment approval structure that exists in oncology today. Precision oncology, with its myriad genomic alterations and targeted-therapy combinations, cannot be addressed with historical clinical trial designs.6 Instead, innovative basket and umbrella trial designs, in addition to large meta-analyses and well-designed retrospective studies, are likely to provide clarity about precision oncology outcomes.
Two recently launched clinical trials are evaluating the use of precision oncology and its associated clinical outcomes. The Targeted Agent and Profiling Utilization Registry (TAPUR) study, sponsored by ASCO, is a prospective trial that aims to evaluate the safety and efficacy of genomics-targeted therapy. Initially launched at select academic and research-focused community cancer centers, TAPUR enrolls patients with advanced cancer whose tumors harbor a potentially actionable genomic variant to receive a commercially available targeted therapy, regardless of tumor type. A study-sponsored MTB is available for consultation about proposed or alternate treatment options. Plans call for an expansion of the number of participating sites in 2017.
The National Cancer Institute Molecular Analysis for Therapy Choice (MATCH) is another prospective trial that will analyze the use of genomic variants from a patient’s tumor to guide the administration of targeted therapy (NCT02465060). Results from these two trials are likely to provide additional evidence about the outcomes associated with the precision oncology treatment paradigm.
The complexities of precision oncology, characterized by seemingly innumerable biomarker-therapy combinations, suggest that even well-designed basket and umbrella trials may not be capable of definitive determination of the appropriate applications for genomic medicine. Given the significant positive clinical outcome signals associated with the use of targeted therapies that are based on genomic alterations, and given the continued decreases in the cost of genomic testing, it is likely that precision oncology will continue to expand and become standard in many clinical scenarios. The previously referenced trials, and other ongoing research efforts, will provide clarity about the exact clinical applications and uses of the precision oncology paradigm.
When to Implement
At the initiation of our institutional precision oncology program, genomic testing often was obtained late in the disease course, typically when all other treatments had failed. The realities of tumor evolution and tumor heterogeneity were cited as reasons to wait until the disease had become refractory to all other options before genomic testing was ordered. Frankly, providers in our program were largely unfamiliar with the interpretation and implementation of genomic testing, too, so that approach was considered the last resort, if it was considered at all. When we more closely scrutinized the effect of genomic testing, we recognized that testing late in a disease course frequently was accompanied by a decline in the patient’s performance status, which ultimately precluded any clinical trial enrollment or administration of a targeted therapy. Orders for testing late in a disease course rendered the results noncontributory in most cases. It is now clear in our precision oncology program that obtaining genomic testing early in the treatment course of patients with advanced cancer confers the advantage of being able to plan for the timing of enrollment on clinical trials or administration of other targeted therapies. We observed greater utilization of genomic information, measured by management changes and clinical trial enrollment, when genomic testing was obtained early, rather than late, in the disease course.
The Future of Precision Oncology
Precision oncology is a rapidly evolving science. The confluence of cost-effective genomic technologies and the increasing number of targeted therapies have placed clinical cancer care in a unique and enviable position. Providers now have the ability to order comprehensive genomic testing on samples provided by patients, evaluate the identified variants, and select a targeted therapy to treat the cancer. These realities are ushering in an exciting new paradigm in cancer care.
Obstacles to the implementation of precision medicine remain for both the patient and provider: Interpretation of genomic testing is difficult, procurement of targeted therapies for patients with refractory disease can be arduous, and the clinical outcomes that support the broad application of genomic medicine are still maturing. In addition, the complexities of cancer cell biology, including tumor heterogeneity and evolution, and the vast cell-signaling networks affected by various targeted treatments combine to slow our understanding of the impact precision oncology has on the disease itself.
However, in light of the breathtaking responses that can occur, investment in precision oncology continues. Institutions, academic and nonacademic alike, have announced precision medicine centers in diverse locations across the country. Pharmaceutical companies and other industry stakeholders are developing the necessary therapies and diagnostic capabilities to support the widespread adoption of precision medicine.
The coming months and years will yield significant clinical trial data about the impact on outcomes metrics—such as survival and health care–associated costs—that are associated with genomic-guided precision medicine, and the scientific advancements will open additional treatment options. As outcomes data accumulate, and as experience with clinical implementation matures, the precision oncology paradigm may become the standard of care for patients with advanced cancer.
About the Authors: Dr. Nadauld is executive director of Intermountain Precision Genomics at the Intermountain Cancer Center, consulting assistant professor at Stanford School of Medicine, and associate editor for JCO Precision Oncology. Dr. Haslem is director of medical oncology at Intermountain Healthcare.