Selecting Systemic Cancer Therapy One Patient at a Time: Is There a Role for Molecular Profiling of Individual Patients With Advanced Solid Tumors?

Recommending the most effective treatment that scientific evidence can support is a fundamental goal of oncologic practice. However, as every oncologist knows, providing such a recommendation becomes increasingly difficult as patients move through progressively less effective lines of therapy. Thus, almost from medical oncology’s beginning as a recognized specialty, cancer physicians have sought to tailor systemic treatment to the biologic characteristics of their patients’ tumors. These efforts began with studies of hematopoietic malignancies, but soon progressed to the evaluation of clinical specimens from patients with advanced solid tumors. With the development of each generation of molecular technology, interest in measurement of the biologic characteristics of malignant tissue that could be significantly associated with response (or resistance) to specific therapeutic modalities has been renewed. Therefore, each time a new molecular technology is applied to the question of predicting therapeutic response, it is prudent to consider why and how the new approach differs from those examined in the past. Why has the search for biologic markers that predict response to treatment been so difficult? For patients with solid tumors, a major obstaclehasbeentheavailabilityandquantityoftissuethatcanbestudiedinthe period immediately before the initiation of treatment, especially for individuals with recurrent disease. Although the safety and usefulness of performing needle biopsies for research purposes in the context of earlyphase,proof-of-mechanismclinical trialshasbeendemonstrated, there remainethicalconcernssurroundingtherequirement for the inclusionof such biopsies in clinical trials. These concerns can be overcome through careful evaluation of the scientific rationale for the research biopsy and stringent attention to the character of the informed consent for the procedure. Even if the biopsy material can be obtained in the appropriate time frame, standard operating procedures for tissue handling, specimen preparation, and laboratory assays that possess sufficient analytic performancecharacteristics tomeetClinicalLaboratory ImprovementAmendments standards are all required if the outcome of the biologic marker evaluation is to be used to guide patient treatment. Furthermore, scientifically well-qualified assays must also overcome substantive regulatory hurdles to achieve US Food and Drug Administration approval. Finally, if these obstacles are surmounted, widespread adoption of a predictive therapeutic biomarker assumes, as a matter of course, that the assay(s) for the biomarker in question is fit for its scientific purpose, and that our understanding of the molecular pathways to be investigated justifies the specific use of a particular portfolio of gene expression or mutational analyses, for example, and these are anything but trivial assumptions. Clinical trial design considerations also shape the evaluation of a biologic marker as a predictor of therapeutic efficacy. The choices of trial designs for biomarker-based studies vary considerably on the basis of the phase and the goals of the clinical investigation. Although there is still considerable discussion about the general use of randomized designs in the phase II setting, use of a randomized design toscreenmolecularlytargetedagentsandtoavoidbias intheevaluationof a biomarker used for treatment decisions has strong rationale. Randomization is also important when combinations of approved and investigationalagentsareunderexaminationorwhenprogression-freesurvival is chosen as the preferred end point. The importance of specifying the scientific justification for the particular biomarkers under study as well as the statistical characteristics of those biomarkers (such as cutoff values) to be used in a trial well in advance of study initiation has also been emphasized. In light of these complex issues, it has recently been suggested that broad sets of mechanism-specific biomarkers will be required for every drug in each disease-specific context. Currently, the development of biologic markers that predict therapeutic outcome often follows one of two general paradigms. In one model, the focus is on the development of a novel therapeutic agent for which clinical benefit could be predicted by the presence of certain molecular characteristics in the tumor that are highly correlated with a favorable pharmacologic effect. The examination of chronic myelogenous leukemia cells for BCR-ABL mutations before the choice of an ABL inhibitor is an example of the application of this model. In the second paradigm, the focus is on the description of subpopulations of patients with a specific cancer whose tumors are characterized by the expression of a gene product or series of gene products; these patients are then identified as benefiting (or not) from standard or investigational treatment programs. However, in this issue of Journal of Clinical Oncology, Von Hoff et al take the novel approach of developing individualized molecular tumor profiles to define therapy for every patient enrolled onto their prospective trial—in essence, performing a series of gene expression–guided pilot studies, each with a sample size of one (so-called N 1 design). JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 28 NUMBER 33 NOVEMBER 2