Cancer clinical trials in the era of genomic signatures: Biomedical innovation, clinical utility, and regulatory-scientific hybrids

Abstract

The paper examines two large-scale, North-American and European clinical trials designed to validate two commercially available genomic tumor signatures that predict a patient's risk of breast cancer recurrence and response to chemotherapy. The paper builds on empirical evidence from the two trials to explore the emergence of diverse regulatoryscientific hybrids, i.e. configurations of genomic practice and bioclinical work that depend on linkages between technical, commercial, patient, clinical, and legal interests and institutions. The development of the genomic signatures for each trial -Oncotype DX and MammaPrint -has followed quite different routes. Oncotype began as a commercial platform: the company that produced it did not discover a signature but rather constructed it by asking users at every step what clinical question they wanted the signature to answer and what data would be credible in that regard. The test has been designed to minimally disrupt existing clinical workflows. MammaPrint, on the other hand, began as a breast cancer signature: the researchers who discovered it, at the Netherlands Cancer Institute (NKI), established a company to commercialize it as a test after the fact. MammaPrint requires a change in pathologists' routines. Thus, while these two trials signify a new departure for clinical cancer trials on a number of levels -they both incorporate new models of interaction between biotech companies and public research, and they both aim to establish the clinical relevance of genomic markersthey also embody different socio-technical scripts: one attempts to accommodate established routines, while the other openly challenges prevailing evidential hierarchies and existing biomedical configurations.

“Unsettling circularity”: Clinical trial enrichment and the evidentiary politics of chronic pain

“…Medical oncology has emerged as an area of considerable experimentation with clinical trial design and execution, often under the banner of 'enrichment' Kohli-Laven et al, 2011;American Society of Clinical Oncology, 2015;Catenacci, 2015). Indeed, an approach similar to EERWrandomized discontinuation design -has been employed in cancer research for many years, but only as part of the biomarker validation process (mostly in phase II trials for cytostatic agents) (Kopec et al, 1993;Freidlin and Simon, 2005;Galsky et al, 2010).…”

The challenge of implementing genetic tests with clinical utility while avoiding unsound applications

“…Mammaprint® and OncotypeDX® are new tests that differentiate breast tumors according to prognosis (Kohli-Laven et al 2011). In a platform, several genes with prognostic value are tested.…”

Regulating diagnosis in post-genomic medicine: Re-aligning clinical judgment?

“…Their deployment has resulted in the definition of new subtypes of this family of diseases (Perou et al, 2000;Alizadeh et al, 2000), and led to the clinical implementation of molecular tests for cancer prognosis and prediction. Although many of these technologies remain experimental, a number of commercial tests have made significant inroads, such as the breast tumor signatures MammaPrint and Oncotype Dx marketed, respectively, by Agendia, a spin-off of the Netherlands Cancer Institute, and the California company Genomic Health (Kohli-Laven et al, 2011).…”

“…"chemotherapy", or, more decisively, in relation to a specific drug as part of the promissory program of "personalized medicine". The prognostic/predictive distinction is widely reflected in debates and controversies over the different clinical and statistical procedures used to validate prognostic vs. predictive claims, over the extent to which the prognostic and/or predictive properties of a test contribute to its clinical utility, and to disputes about the comparative value of competing commercial assays such as the Oncotype DX and MammaPrint tests (Kohli-Laven et al, 2011). Conference sessions and even entire meetings (e.g., the Conference on "Prognosis and Prediction in Breast Cancer" held in Monaco in October 2008) have been devoted to this thorny issue.…”