A multidisciplinary process sets a model for developing future guidelines
Interview by Steve Halasey
On April 22, the American Society for Clinical Pathology (ASCP), the College of American Pathologists (CAP), the Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO) closed the public comment period on their draft of a clinical practice guideline for the use of molecular marker testing for patients with primary or metastatic colorectal carcinoma.
A product of more than 2 years of coordinated effort by the sponsoring associations, the “Guideline on the Evaluation of Molecular Markers for Colorectal Cancer” is intended to help establish standard molecular marker testing, guide targeted therapies, and advance personalized care for colorectal cancer patients. Taking a multidisciplinary approach to the work, the sponsors sought to create a document suited for the full continuum of care, from specimen collection to treatment follow-up.
“This guideline addresses all current molecular markers that can impact treatment decisions for patients with colorectal cancer,” says Stanley R. Hamilton, MD, FCAP, AGAF, head of the division of pathology and lab medicine at the University of Texas MD Anderson Cancer Center, and project cochair on behalf of CAP. “To date, there isn’t an evidence-based guideline that’s quite as all-encompassing and patient-centered as this one.”
Publication of the final guideline is anticipated later this year. To find out more about the guideline and how it came into being, CLP recently spoke with one of the four cochairs directing the project, Antonia R. Sepulveda, MD, PhD, FASCP, FCAP, a professor of pathology and cell biology, vice chair for translational research, and director of the division of gastrointestinal pathology at Columbia University; and project cochair on behalf of AMP.
CLP: What was the trigger that set in motion the process of compiling these guidelines on molecular marker testing in colorectal cancer?
Antonia R. Sepulveda, MD, PhD: It is a lengthy process when guidelines are put together for the first time, because it involves a very extensive systematic review of the literature. The literature search for these guidelines was conducted from 2008 to 2015, and involved the review of several thousand studies.
The process of actually reviewing the literature and compiling the evidence-based guidelines started about 2 years ago, and was initiated by the leading pathology societies. We realized that it would be quite important to have clinical input and insight into the guidelines, so we were pleased to have ASCO join our efforts. I think ASCO’s participation has made the guidelines even stronger.
At the time—and it continues to be a timely reason—there was a lack of published, comprehensive, and updated guidelines on molecular testing for selecting colorectal cancer patients for targeted and conventional therapies. So this project was started to address that perceived gap in clinical practice.
CLP: What issues related to colorectal cancer can guidelines address now that might not have been possible a decade ago?
Sepulveda: For many cancers, including colorectal cancer, we have recently witnessed a proliferation of new disease markers, particularly genomic markers, in combination with conventional immunohistochemistry or in situ methods. Also, we’re going from a phase where we used to have one test and one marker to a phase where we are now able to use multiplexing, made possible by new testing methods such as next-generation sequencing. Indeed, we need to use multiple markers in order to decide which is the best treatment to offer a specific patient, following the overall goals of precision medicine.
In colorectal cancer, as in other cancers, it has become apparent that we need to unify all this information in the most straightforward way possible, so that labs and clinicians can put it into practice. Guidelines—especially guidelines that, once in existence, have a structure that supports ongoing updates—seem to be the way to go.
CLP: The goal of incorporating all molecular markers relevant to colorectal cancer was ambitious at the outset. Why was it important to compile the guidelines in this way?
Sepulveda: In colorectal cancer, treatment generally involves a complex decision process that utilizes results from combinations of molecular markers—particularly their mutational status, and in some cases also their expression status. For patients who are being considered for targeted anti-EGFR therapy, for example, the guideline recommends mutational analysis of exons 2, 3, and 4 of both KRAS and NRAS (“expanded” or “extended” RAS). As another example, BRAF mutation status can be helpful to guide patient management, but information about the tumor’s mismatch repair and microsatellite instability status are also necessary in order to interpret the potential clinical implications of a BRAF mutation.
So the reason for addressing all markers for colorectal cancer in these guidelines was to provide information from multiple markers to guide treatment decisions for either targeted or conventional cancer therapies.
Another goal—not yet apparent in the current version of the guidelines—was to introduce emerging markers that will appear in the final document. A number of potential prognostic or predictive markers such as gene expression or microRNA profiles, for example, may not yet have sufficient evidence for a recommendation about their use to be issued. But in the guidelines we anticipate discussing needs for future research that might make those biomarkers available in the clinical setting.
CLP: Does it help laboratories and clinicians to locate reimbursement for particular tests—and even emerging tests—when they are included in a unified and comprehensive set of guidelines?
Sepulveda: In terms of reimbursement, the positive impact of our guidelines would be primarily for tests that are given strong recommendations. The guidelines can inform laboratories about which molecular markers have strong recommendations, meaning that they have been evaluated and are already being reimbursed, versus other tests where the evidence might be more controversial and for which we do not provide a recommendation.
On the other hand, emerging biomarkers typically remain within the research setting, and are not considered in the clinical testing environment. For example, clinicians who are involved in conducting clinical trials might need to use certain tests that they know to be under development. But in that case reimbursement would typically come from the sponsor of the clinical trial, not from Medicare or other third-party payors.
CLP: The project brought together four major organizations and many specialists. What challenges did you face in helping everyone get along and keeping the process moving?
Sepulveda: This project required a significant time commitment from its participants, but it has gone very smoothly. Each of the four cochairs represents a society, and together we have continuously outlined strategies for the next operational steps needed to compile the guidelines. The societies also provided a very well organized and efficient support staff group—about nine people overall—who interact regularly with the cochairs, coordinate conference calls and meetings, distribute minutes, distribute assignments, and generally help to bring the project’s groups and subgroups together.
In addition to the cochairs and staff members, there is an expert panel of about nine members that covers all areas of specialty expertise, including oncology, pathology, surgery, gastroenterology, genetics, and so on. We have frequently invited members of this panel to participate in our conference calls and face-to-face meetings, and every step of the way we shared with them the drafts that had been generated.
Following standard procedures outlined by the Institute of Medicine, we’ve been able to take into account a very robust selection of evidence-based studies, and we’ve also incorporated the insights of a very complex network of experts who provided their own experience.
We have held three face-to-face meetings. The most recent one lasted a day and a half, and was entirely focused on drafting and voting on the guidelines prior to making them available for public comment.
CLP: What is the nature of the research and evidence that underlies the guidelines? Are any of the recommendations considered controversial in light of current understandings?
Sepulveda: The systematic review was conducted according to Institute of Medicine standards, and followed well-defined criteria established during one of our early meetings. A librarian expert performed the literature searches, and an expert in systematic review and guideline development methodologies provided expertise in data analysis. A program called DistillerSR was used to identify the studies that met our high-level criteria, which included systematic reviews and meta-analyses as well as original papers developed from studies that generally involved at least 100 patients.
We generally excluded small studies (unless they were captured because they were included in meta-analyses), studies considered merely descriptive, and studies that examined germline polymorphisms but did not look at the tumor tissue, per se.
We included original research that encompassed clinical trials with a prospective randomized control arm, as well as some original studies that were analyzed in meta-analyses or systematic reviews. In the latter part of 2014, for example, a very significant meta-analysis summarized data on extended RAS testing, and we performed a “literature refresh” in order to ensure that relevant studies such as that one were captured. Had we not done that, such data would not have been integrated into our guideline, because while we were going through the review of several thousand papers already identified, a lot of new work was being published, as is usual.
For some biomarkers—because of the limited strength of evidence, or the retrospective nature or small size of the studies—it was judged that there was not enough information to support a recommendation. In such cases, the guidelines provide an expert consensus opinion rather than a recommendation. In general, the guidelines do not offer a recommendation if testing for a specific marker has been controversial in the literature.
CLP: The guidelines specify formalin-fixed, paraffin-embedded tissue as the sample of choice. In the future, will the refinement of techniques for liquid biopsies change this recommendation?
Sepulveda: Following our methodological approach, there is not currently enough data to permit a recommendation for tests involving specimens such as those from liquid biopsies. However, our guidelines are expected to be updated regularly. When such evidence becomes available, we’ll revisit the guidelines in light of the new evidence and update it accordingly. Liquid biopsies are currently a very trendy type of specimen, and research in that area is moving fast. We’ll be ready to address an update for that area when it becomes pertinent.
CLP: What will be the process for making revisions on the basis of new evidence? Is there a regular schedule for review and revision?
Sepulveda: The guideline group of societies expect that the guideline will be reviewed at least every 4 years—or earlier if there are new publications with substantial, high-quality evidence that could alter the original recommendations. The cochairs and staff representing the societies will remain engaged and linked to the guidelines, and through that process literature searches will be done regularly—probably annually. Those searches will then lead to a review and determination of whether we need to update the guidelines.
I think it’s critical that these guidelines are constantly being updated, because the trend is for the field to evolve rapidly.
CLP: These guidelines are meant to guide molecular testing, but how do you hope they might also improve patient treatment?
Sepulveda: Today’s multidisciplinary cancer care teams include both pathologists who provide test results and oncologists who directly treat patients. Integrating complex molecular test results helps to implement the appropriate use of both conventional and novel targeted therapies, to treat patients across the country. It would be difficult to achieve that goal in the absence of uniform, comprehensive guidelines, and with multiple societies issuing their own occasional guidelines. And that’s essentially where we are today.
In the future we will be watching for the impact of these guidelines—probably through feedback from ASCO, and potentially through the proficiency testing mechanisms of CAP and others—to determine whether the guidelines have extended the use of appropriate testing, and how they have affected the utilization and selection of therapies.
CLP: Studies about the effects of the guidelines could make for some interesting papers at ASCO and elsewhere every year.
Sepulveda: Studies could certainly compare practices before and after publication of the guidelines. I think this is truly a process improvement that will have an impact on patient care.
CLP: Have you been surprised by any of the comments submitted during the public comment period?
Sepulveda: The comments I’ve seen appear to be within the realm of what I would expect, but they will certainly help us refine the final guidelines. We have already scheduled follow-up subgroup meetings to address those comments, and by the end of May we should be conducting a final voting round among the cochairs and the panel of experts to reach the final guidelines.
CLP: Is the IOM-based process used to compile these guidelines one that can be replicated for other areas of molecular testing?
Sepulveda: This has been a very large project, but I do feel that a comprehensive, integrated evaluation of biomarkers is the most productive way to go. In the future, in fact, it might be that the same group of societies could join with other societies that have a subspecialty focus, to develop guidelines for other areas along the lines of what has been done for colorectal cancer.
CLP: Which areas would you consider early candidates for such treatment, and why?
Sepulveda: Many solid tumors and hematologic malignancies, inclusive of pediatric tumors, seem like good near-term candidates. There has been such extensive development of molecular testing in all of these areas that each subspecialty group may soon find it valuable to have such guidelines. They may well propose such projects to the societies, but it would be up to the societies, of course, to decide which projects to take on.
Both breast cancer and lung cancer already have guidelines in place. There are many studies supporting molecular testing for brain tumors—namely gliomas and glioblastomas—thyroid tumors, renal tumors, prostate cancer, leukemia and lymphomas, and other tumors, and some of those tests are currently being used in clinical practice.
It is quite possible that all these developments will start happening in parallel. I think this is the direction of the future and it’s a commitment that is of great value to laboratories and clinical practitioners—and certainly to patients.
Steve Halasey is chief editor of CLP.