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Progressing precision medicine in a world of randomized trials

There can be no debate about the fact that modern oncology has developed on the back of rigorously conducted and solidly evidence-based clinical investigation. This effort has been brilliantly led by the widely acknowledged gold standard of cancer research the phase 3 randomized trial. Today, it is not easy to envision a world where such trials had not existed. To do so requires us to imagine surgeons continuing to routinely perform radical mastectomies in themanagement of early stage breast cancer and medical oncologists still administering single alkylating agents in the initial chemotherapeutic management of epithelial ovarian cancer (EOC). In an era where the therapy of cancers was entirely based on its site of presumed anatomic origin and when a basic assumption was for the relative homogeneity of all malignant disease from these sites, it was not difficult to conceive of a randomized trial where all patients with a similar tumor stage would be potential candidates for participation in that single study encompassing all cancers of a specific organ (e.g. all lung cancers). This quite simplistic view of cancer biology began to change with the recognition of very different natural histories of tumors originating at a given site; for example, small cell versus non-small cell cancer of the lung; estrogen-receptor positive versus estrogen-receptor negative breast cancer. However, in both of these situations, the relatively large number of patients in the individual subgroups still permitted the conduct of randomized trials to assess the efficacy of new/ novel therapeutic strategies in disease management of the individual small populations. Before discussing the substantial impact of our rapidly evolving understanding of the molecular biology of malignant disease on the just highlighted existing clinical research paradigm, it is important to note another increasingly recognized concern associated with the reliance of oncologists, drug regulators, payers, and patients on phase 3 trial data. Unfortunately, in the United States, it has been documented that a distressingly limited percentage (variously estimated at 2–4%) of cancer patients actually participate in clinical trials [1]. Thus, considering the remarkably small fraction of individuals who comprise a given trial’s data set, it is appropriate to challenge the wisdom of attempting to generalize either the clinical utility or the toxicity of the strategy examined when subsequently employed in the real world of clinical care. Further, it is also recognized that even this limited group of research subjects often seriously fails to represent highly clinically relevant subgroups, with studies frequently either intentionally or unintentionally excluding the elderly (>65–70 years of age) or individuals with common co-morbidities (e.g. cardiac, hepatic, renal disease, obesity, and diabetes). Again, the question to be asked is how can the results of trials and specifically so-called ‘evidence-based’ randomized phase 3 studies be considered the definitive test of clinical utility when they are simply not representative of the large fraction of patients encountered in routine clinical practice? Now, returning to the question of the actual ability of investigators to consider conducting gold standard randomized trials, it is essential to fully appreciate that over the past decade, our increasing understanding of the basic biology of cancer, its development, progression, and mechanisms of resistance has resulted in a correspondingly rapid acceleration in the recognition of unique clinically relevant, molecularly defined patient subgroups within a given organ site. Further, our ability to study this biology in detail at the individual patient level has simply exploded, driven in large part by stunning technological advancements which have permitted obtaining critically detailed molecular data in an increasingly quick (measured in ‘days to a few weeks,’ rather than ‘months to a few years’) and cost-effective manner. As a result, it is currently possible to accurately define the presence of specific molecular abnormalities (mutations; rearrangements; overexpression) at a routine clinical level through the use of a variety of testing platforms (e.g. single gene analysis, small panel of <50 genes, larger panel of 100–400 genes, and whole gene sequencing). Thus, translation of molecular findings in individual patients into actual clinical decision-making has been transformed over the past two decades from nothing more than a theoretical construct into objective reality. And the process of attempting to define the clinical utility of a particular antineoplastic strategy against a unique molecular ‘target’ in an individual cancer patient goes under the name of precision cancer medicine. Of course, the fact we can now actually explore the relevance of the hypothesis that ‘drug A’ will be an effective inhibitor of ‘target B,’ believed to a relevant ‘driver mutation of pathway C,’ does not mean the concept is either