"N-of-1" Research Findings Belong in the Peer-Reviewed Publishing Realm

Maurie Markman, MD

In this era of accelerated innovation in cancer research, it is vitally important that the oncology community be kept abreast of noteworthy developments through peer-reviewed reports that validate and disseminate the information. However, there are troubling signals that this established process is being circumvented either by design or circumstance when it comes to potentially transformative findings.

A trend in the biomedical industry to bypass the rigors of scientific publishing was highlighted recently in a provocative commentary regarding the virtual absence of data in the peer-reviewed literature demonstrating the utility of a novel proprietary laboratory testing platform.¹ Business and other lay publications widely reported that this platform could accurately report a large number of common laboratory test results at a very low cost and require only a “drop of blood.”

The commentary discussed possible reasons for why there essentially has been a complete absence of publicly available data in the form of peer-reviewed publications that are critical to validate the clinically relevant and more basic scientifically oriented claims of this company. The author notes: “The path to publication also involves peer review; for disruptive innovators, this may be perceived as an ordeal because they would have to respond to and satisfy the concerns and potential biases of mainstream reviewers who represent the very core traditions that the innovation specifically aims to disrupt.”

Importance of “N-of-1” Data

While highly speculative, this is a most interesting hypothesis for a justification for a company not seeking peer approval in the form of medical publications. Yet it would almost certainly be appropriate to make a nearly identical statement regarding the reception that many higher-impact medical/oncology journal editors, editorial boards, and peer reviewers seem to accord the rapidly evolving world of “N-of-1” clinical cancer research.

The National Cancer Institute is embarking on a much-publicized Exceptional Responders Initiative designed to examine the molecular background of 300 cancer patients whose response and/or survival far exceeded the anticipated outcome based on their tumor type and the therapy employed in their management.² This effort will surely produce an important paper regarding the population of patients studied. Already, there have been a number of patients reported in the literature whose favorable outcomes following the delivery of a targeted antineoplastic have been retrospectively related to the presence of an unusual mutation or molecular abnormality.

Yet on a broader basis, the question is how the academic community and high-impact medical/oncology journals view single-patient case reports dealing with the delivery of a specific targeted agent that has been based on a prospective evaluation of the presence of a molecular abnormality that appears to have successfully predicted for clinical benefit associated with that strategy.

This N-of-1 cancer clinical research paradigm has the legitimate potential to rather dramatically accelerate our knowledge of therapeutically relevant relationships between quite specific molecular drivers and particular antineoplastic agents by capturing the detailed experience of the rapidly increasing number of patients who are receiving a treatment regimen based on molecular profiling of their cancers.

It is hoped that a comprehensive publicly available database will soon be created to ensure that these N-of-1 experiences are captured, turning a single episode of targeted treatment of a rare mutation found within a cancer into five, 10, and 20-plus patient experiences. This will certainly provide critically relevant information to multiple interested parties (current and future patients, their families, community and academic oncologists, insurers, employers, regulators, industry) of the objective clinical utility, or lack thereof, associated with a particular molecular abnormality/drug combination.

However, the acceptance into high-impact peer-reviewed journal of well-written single-case reports of such N-of-1 experiences, including material coming from the community practice setting, would go a long way toward enhancing the relevance and importance within the oncology community of reporting such experiences. It is likely that this outcome would not only stimulate an increasing number of published reports, but also submission of manuscripts of superior quality.

Crizotinib Case

For example, one can speculate on the impact associated with the first reported response of a patient with lung cancer with a ROS1 mutation to crizotinib if this information had been first seen as a single-case report in a major medical/oncology medical journal.3 Instead, the outcome was unfortunately buried (pp 867) within an elegantly written paper whose primary focus was more on the translational aspects of the observations rather than on the dramatic objective response of the cancer:³

“… Restaging scans at 8 weeks demonstrated near complete resolution of his multifocal lung cancer, which was subsequently confirmed at 12 weeks. At the time of this report (6 months) the patient continues on crizotinib with no evidence of recurrence.”

Also buried was the reporting of the simply stunning clinical impact on the patient:

“… As a result of progressively worsening symptoms and hypoxia, he was referred … In less than 1 week he noted a significant improvement in symptoms, and by 2 weeks, his hypoxia had resolved.”

So, the question is as follows: If it is accepted by the oncology community that the ultimate goal of the discovery of molecular abnormalities in an individual patient’s cancer is to favorably impact relevant clinical outcomes such as described with crizotinib, why should the publication of unique observations demonstrating the unquestionable utility of a specific strategy not be as worthy of publication in a highimpact medical journal as the results of clinical trials or translational laboratory research?

References

1. Ioannidis JPA. Stealth research: Is biomedical innovation happening outside the peer-reviewed literature? JAMA. 2015;313(7):663-664.
2. Poh A. In search of exceptional responders published online January 5, 2015]. Cancer Discov. January 2015;5(1):8.
3. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define as unique molecular class of lung cancers [published online January 3, 2012]. J Clin Oncol. 2012;30(8):863-870.

Maurie Markman, MD, editor-in-chief, is president of Medicine & Science at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine. maurie.markman@ctca-hope.com.