Personalized Cancer Care: N-of-1

The New York Yankees catcher Yogi Berra famous quote, “Déjà vu all over again,” reminds me of the growing focus on the concept of “N- of-1.” For those of you unfamiliar with the catchphrase, it refers to a clinical trial of one subject.

In clinical research, studies are deemed reportable when they achieve statistical significance. The so-called power analysis is the purview of the biostatistician who examines the desired outcome and explores the number of patients (subjects) required to achieve significance. The term “N” is this number. The most famous clinical trials are those large, cooperative group studies that, when successful, are considered practice-changing. That is, a new paradigm for a disease is described. To achieve this level of significance it is generally necessary to accrue hundreds, even thousands of patients. This is the “N” that satisfies the power analysis and fulfills the investigators expectations.

So what about an N-of-1? This disrupts every tenet of cancer research, upends every power analysis, and completely rewrites the book of developmental therapeutics. Every patient is his or her own control. Their good outcome reflects the success or failure of “the trial.” There is no power analysis. It is an “N” of 1.

This “breakthrough” concept however, has been the underpinning of the work of investigators like Drs. Larry Weisenthal, Andrew Bosanquet, Ian Cree, myself and all the other dedicated researchers who pioneered the concept of advancing cancer outcomes one patient at a time. These intrepid scientists described the use of each patient’s tissue to guide therapy selection. They wrote papers, conducted trials and reported their successful results in the peer-reviewed literature. These results I might add have provided statistically significant improvements in clinical responses, times to progression, even survival. By incorporating the contribution of the cellular milieu into clinical response prediction, these functional platforms have consistently outperformed their genomic counterparts in therapy selection So why, one might ask, have the efforts of these dedicated investigators fallen on deaf ears?

I think that the explanation lies in the fact that we live in a technocracy. In this environment, science has replaced religion and medical doctors have abdicated control of clinical development to the basic scientists and basic scientists love genomics. It is no longer enough to have good results; you have to get the results the right way. And so, meaningful advances in therapeutics based on functional platforms have been passed over in favor of marginal advances based on genomic platforms.

There is nothing new about N-of-1. It has been the subject of these investigators compelling observations for more than two decades. Though functional platforms (such as our EVA-PCD®) are not perfect, they provide a 2.04 (1.62 to 2.57, P < 0.001) fold improvement in clinical response for virtually all forms of cancer – as we will be reporting (Apfel C, et al Proc ASCO, 2013).

It seems that in the field of cancer therapeutics “perfect is the enemy of good.” By this reasoning, good tests should not be used until perfect tests are available. Unfortunately, for the thousands of Americans who confront cancer each day there are no perfect tests. Perhaps we should be more willing to use good ones while we await the arrival of perfect ones. After all, it was Yogi Berra who said, “If the world was perfect, it wouldn’t be.”

Ovarian Cancer National Alliance 2011

The July meeting of the OCNA included a lecture by John Hays, MD, from the National Cancer Institute (NCI), entitled “Decision time: what is the right choice of chemotherapeutic agent(s)? Dr. Hays, part of the molecular signaling section at the NCI, reviewed literature on the topic. He described the need for prospective clinical trials to validate retrospective and in vitro results.

He then examined data from three technologies, the Oncotech extreme drug resistance test, Precision Therapeutics ChemoFX test and the ATP-based chemosensitivity test.

I found it odd that Dr. Dr. Hays spent time examining the EDR technology of Oncotech in as much as it is no longer offered and reflects proliferation-based studies, which have since largely been discredited.

The ATP assay was reviewed using the results of a study published by Dr. Ian Cree in which 180 patients received either assay-directed (ATP) or physician choice. This study actually provided an improvement for patients who received the ATP-based treatment but failed to achieve significance. Thus, it failed largely because it was underpowered.

But this reflected a more concerning aspect of the study.  It seems that the “physician choice” arm increasingly applied the best drug regimens developed in Dr. Cree’s own laboratory. As the trial continued to accrue, an increasing proportion of patients received Gemcitabine-based doublets (which were very new at the time) based upon Dr. Cree’s observation of activity for these novel combinations. This had the uncomfortable effect of forcing Dr. Cree to compete with himself. Had Dr. Hays been truly interested in examining this study as I have, he might have noticed the good control group response rate partly reflected the application of Dr. Cree’s’ own observations.

Indeed, when during my many attempts to conduct a prospective study with the GOG, I was at the very last moment confronted with a study design similar to Dr. Cree’s, (e.g. they could incorporate any treatment they chose, including those that I developed), my statistician demanded that I forego the pleasure, as he could see only too well that the trial had become impossible to power. You see, there was no true control arm for statistical comparison.

The final portion of Dr. Hays’ presentation was the ChemoFX assay. This technology propagates tissue biopsies to confluence and then conducts measurement of drug-induced cell death. With substantial funding largely provided by venture capital, Precision Therapeutics has leapt into the GOG with a series of trials. Should this hybrid technology fail to provide prospective results that meet significance, it will be a damaging blow to this unfairly maligned area of investigation. While I wish the ChemoFX investigators luck, a failure on their part could be harmful to the field. Their reliance on propagated, sub-cultured tissues grown to monoculture has been a concern to me since they first arose in the last few years as participants in the field. We await the results of their trials with great anticipation.

What is interesting in Dr. Hays’ review is not so much what he said, but what he didn’t say.

First, he did not mention the seminal work of Dr. Larry Weisenthal, a pioneer in the field.

Second, he did not describe the nearly 2,000 retrospective, yet statistically significant correlations in the literature in a wide variety of diseases. He neglected to mention that one of the most widely used regimens for breast and ovarian cancer was developed using the same human tumor culture analyses that he decries. If he actually treats patients, he no doubt uses the cisplatin gemcitabine doublets developed using one of these platforms.

Finally, Dr. Hays has failed evidence-based medicine 101. He has forgotten that in life-threatening illnesses where prospective clinical trial data is not available, in accordance with the dictates of evidence-based medicine, one should use the best available data to guide treatments.

There is a wealth of data supporting laboratory based drug selection.  Presentations like that described do not add to the discourse.