Decision-making as discovery: Vetting clinical research in a leading precision oncology service.

Based on fieldwork carried out at the Early Drug Development Service of a world-leading cancer institution, our study sheds lights on decision-making processes at the stage where decisions are made about which clinical trial to pursue and thus which experimental drugs will feed the growing pipeline of molecularly guided therapies and therapeutic strategies available to treating physicians. The paper shows how such collective decision-making practices by a translational research unit employ formal tools and ad hoc valuation strategies that interweave technical-scientific matters of concern with patient-oriented clinical ones, as part of the institutional assetization of biomedical knowledge production. In the process, decision-making practices in part define the conditions of possibility for the provision of care in what is increasingly becoming a 'clinic of variants.' They do so by reconfiguring on an evolving basis the socio-material ecosystem through which precision oncology is enacted as a rapidly evolving assemblage of patients, physicians, research and support staff, protocols, molecular markers, drugs and administrative components.

Histology agnosticism: Infra-molecularizing disease?

The term "molecularization" has been used by historians and sociologists of science to describe the transition from an anatomic view of the body to a submicroscopic one, where health and illness, indeed life itself, are increasingly defined in terms of an individual's "genetic landscape." Here we introduce the notion of the infra-molecular as a way of extending and nuancing the molecularization trope as it applies to the domain of (post)genomic oncology. In particular we look at how infra-molecularity is enacted in practice as part of the so-called "histology-agnostic" turn in clinical cancer research and care. Drawing on fieldwork in North American oncology settings, we analyze how histology agnosticism partially reconfigures knowledge and practice across the linked domains of drug development and clinical trials, therapeutic decision making, and regulation, and the implications of this for an ongoing revision of how we understand the biopathology and temporality of cancer. We show how, in practice, the inframolecular gaze entails a "return" of histology as a modulator of histology-agnostic drugs and background for interpretation of mutational complexity.

Genomic expertise in action: molecular tumour boards and decision-making in precision oncology.

The recent development of cancer precision medicine is associated with the emergence of 'molecular tumour boards' (MTBs). Attended by a heterogenous set of practitioners, MTBs link genomic platforms to clinical practices by establishing 'actionable' connections between drugs and molecular alterations. Their activities rely on a number of evidential resources - for example databases, clinical trial results, basic knowledge about mutations and pathways - that need to be associated with the clinical trajectory of individual patients. Experts from various domains are required to master and align diverse kinds of information. However, rather than examining MTBs as an institution interfacing different kinds of expertise embedded in individual experts, we argue that expertise is the emergent outcome of MTBs, which can be conceptualised as networks or 'agencements' of humans and devices. Based on the ethnographic analysis of the activities of four clinical trial MTBs (three in France and an international one) and of two French routine-care MTBs, the paper analyses how MTBs produce therapeutic decisions, centring on the new kind of expertise they engender. The development and activities of MTBs signal a profound transformation of the evidentiary basis and processes upon which biomedical expertise and decision-making in oncology are predicated and, in particular, the emergence of a clinic of variants.

Medical Genetics at McGill: The History of a Pioneering Research Group.

The McGill Group in Medical Genetics was formed in 1972, supported by the Medical Research Council and successor Canadian Institutes for Health Research until September 2009, making it the longest active biomedical research group in the history of Canada. We document the history of the McGill Group and situate its research within a broader history of medical genetics. Drawing on original oral histories with the Group's members, surviving documents, and archival materials, we explore how the Group's development was structured around epistemological trends in medical genetics, policy choices made by research agencies, and the development of genetics at McGill University and its hospitals.

Organizing precision medicine: A case study of Memorial Sloan Kettering Cancer Center's engagement in/with genomics.

Recent decades have seen a dramatic rise of in the number of initiatives designed to promote precision oncology, a domain that has played a pioneering role in the implementation of post-genomic approaches and technologies such as innovative clinical trial designs and molecular profiling. In this paper, based on fieldwork carried out at the Memorial Sloan-Kettering Cancer Center from 2019 onwards, we analyze how a world-leading cancer center has adapted, responded, and contributed to the challenge of "doing" precision oncology by developing new programs and services, and building an infrastructure that has created the conditions for genomic practices. We do so by attending to the "organizing" side of precision oncology and to the nexus between these activities and epistemic issues. We situate the work that goes into making results actionable and accessing targeted drugs within the larger process of creating a precision medicine ecosystem that includes purpose-built institutional settings, thus simultaneously experimenting with bioclinical matters and, reflexively, with organizing practices. The constitution and articulation of innovative sociotechnical arrangements at MSK provides a unique case study of the production of a large and complex clinical research ecosystem designed to implement rapidly evolving therapeutic strategies embedded in a renewed and dynamic understanding of cancer biology.

[The emergence and development of gene expression profiling: a key component of the 3B (bench, bedside, bytes) in translational research]. / Les réseaux de l'expression génique - Émergence et développement d'un domaine clé de la génomique.

This paper examines the emergence and development of one of the key components of genomics, namely gene expression profiling. It does so by resorting to computer-based methods to analyze and visualize networks of scientific publications. Our results show the central role played by oncology in this domain, insofar as the initial proof-of-principle articles based on a plant model organism have quickly led to the demonstration of the value of these techniques in blood cancers and to applications in the field of solid tumors, and in particular breast cancer. The article also outlines the essential role played by novel bioinformatics and biostatistical tools in the development of the domain. These computational disciplines thus qualify as one of the three corners (in addition to the laboratory and the clinic) of the translational research triangle.

Multi-polar scripts: Techno-regulatory environments and the rise of precision oncology diagnostic tests.

The paper examines the development and marketing of five multi-gene tests, a.k.a. as tumor signatures, designed to aid clinicians and cancer patients in therapeutic decision-making, and, in particular, to avoid overtreatment. We build on a 2011 paper that investigated the emergence of this new domain by opening the 'black box' of two pioneering tests and analyzing the hybrid, scientific-regulatory 'scripts' that were built into them. In subsequent years, second-generation tests, produced by a diverse blend of academic and commercial initiatives, have become available, and they all built into their scripts the lessons learned from their predecessors. The present paper confirms the heuristic value of the initial script-analysis but expands it to consider the multi-polar nature of the space within which multigene tests mutually position themselves. We examine how the tests were first problematized - i.e. how they described and prescribed the kind of world in which they would operate - and how their initial problematization was re-specified following the emergence of a comparative arena and their resulting informational enrichment. In parallel, we explore valuation processes, i.e. the evolving definition of the set of referents against which the assays are mutually compared, and the debates about the appropriate criteria for doing so. We note that the cancer diagnostic industry is involved in the reconfiguration of the multi-polar environment defined by socio-technical, techno-scientific, and regulatory matters of concern that seamlessly blend commercial and scientific considerations.

Domain-topic models with chained dimensions: Charting an emergent domain of a major oncology conference.

This paper presents a contribution to the study of bibliographic corpora through science mapping. From a graph representation of documents and their textual dimension, stochastic block models can provide a simultaneous clustering of documents and words that we call a domain-topic model. Previous work investigated the resulting topics, or word clusters, while ours focuses on the study of the document clusters we call domains. To enable the description and interactive navigation of domains, we introduce measures and interfaces that consider the structure of the model to relate both types of clusters. We then present a procedure that extends the block model to cluster metadata attributes of documents, which we call a domain-chained model, noting that our measures and interfaces transpose to metadata clusters. We provide an example application to a corpus relevant to current science, technology and society (STS) research and an interesting case for our approach: the abstracts presented between 1995 and 2017 at the American Society of Clinical Oncology Annual Meeting, the major oncology research conference. Through a sequence of domain-topic and domain-chained models, we identify and describe a group of domains that have notably grown through the last decades and which we relate to the establishment of "oncopolicy" as a major concern in oncology.

Healthcare policy by other means: Cancer clinical research as "oncopolicy".

Social studies of biomedicine often focus on how exogenous policies shape the medical domain. While policy agendas no doubt affect complex biomedical projects, in the present paper we analyze a different dynamic, namely how oncologists enact policy as part of several flagship precision oncology endeavors. Empirically, the article focuses on the U.S. TAPUR trial, the Dutch DRUP trial, and the Canadian CAPTUR trial, which have recently been joined by similar Scandinavian studies. Taken together, these trials represent innovative forms of clinical research that, beyond their varying experimental nature, have been designed to transform the evidential processes to provide access to biomarker-driven treatments. Along with gathering evidence on effectiveness of off-label targeted therapies, their explicit goals include the recentering of a major professional organization around research, and the reframing of healthcare as a learning system seamlessly connecting epistemic, organizational, and economic issues. Accordingly, we analyze the design and implementation of these trials as a form of (onco)policy by other means.

Detection and characterization of translational research in cancer and cardiovascular medicine.

BACKGROUND: Scientists and experts in science policy have become increasingly interested in strengthening translational research. Efforts to understand the nature of translational research and monitor policy interventions face an obstacle: how can translational research be defined in order to facilitate analysis of it? We describe methods of scientometric analysis that can do this. METHODS: We downloaded bibliographic and citation data from all articles published in 2009 in the 75 leading journals in cancer and in cardiovascular medicine (roughly 15,000 articles for each field). We calculated citation relationships between journals and between articles and we extracted the most prevalent natural language concepts. RESULTS: Network analysis and mapping revealed polarization between basic and clinical research, but with translational links between these poles. The structure of the translational research in cancer and cardiac medicine is, however, quite different. In the cancer literature the translational interface is composed of different techniques (e.g., gene expression analysis) that are used across the various subspecialties (e.g., specific tumor types) within cancer research and medicine. In the cardiac literature, the clinical problems are more disparate (i.e., from congenital anomalies to coronary artery disease); although no distinctive translational interface links these fields, translational research does occur in certain subdomains, especially in research on atherosclerosis and hypertension. CONCLUSIONS: These techniques can be used to monitor the continuing evolution of translational research in medicine and the impact of interventions designed to enhance it.

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

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 regulatory-scientific hybrids; that is, the paper discusses 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 markers--they also embody different socio-technical scripts: one attempts to accommodate established routines, while the other openly challenges prevailing evidential hierarchies and existing biomedical configurations.

Who's minding the data? Data Monitoring Committees in clinical cancer trials.

Modern biomedicine is based on a number of novel institutions and practices that, in order to function, require some degree of formal and informal regulation. This paper contributes to the ongoing investigation of these processes, and the forms of objectivity they generate, by examining the emergence, development and deployment of Data Monitoring Committees in the field of clinical trials. The idea of a DMC had originally been raised in the clinical trial methodology literature in the 1970s so as to solve the problem of the management of interim trial data. Many leading clinical trial statisticians proposed that interim data and analyses be restricted to members of a DMC. Since the late 1980s, DMCs have evolved considerably in a constant search for ethical neutrality and objectivity through the use of sophisticated statistical techniques and novel organisational strategies. They have also been beset by a fundamental tension as to who or what should count as objective in such an undertaking. The paper examines the evolution of this institution in terms of the techniques brought to bear on the issues that they are expected to solve, the organisational forms through which DMCs have evolved and the ideals of objectivity that these forms embody.

Making a new technology work: the standardization and regulation of microarrays.

The translation of laboratory innovations into clinical tools is dependent upon the development of regulatory arrangements designed to ensure that the new technology will be used reliably and consistently. A case study of a key post-genomic technology, gene chips or microarrays, exemplifies this claim. The number of microarray publications and patents has increased exponentially during the last decade and diagnostic microarray tests already are making their way into the clinic. Yet starting in the mid-1990s, scientific journals were overrun with criticism concerning the ambiguities involved in interpreting most of the assumptions of a microarray experiment. Questions concerning platform comparability and statistical calculations were and continue to be raised, in spite of the emergence by 2001 of an initial set of standards concerning several components of a microarray experiment. This article probes the history and ongoing efforts aimed at turning microarray experimentation into a viable, meaningful, and consensual technology by focusing on two related elements:1) The history of the development of the Microarray Gene Expression Data Society (MGED), a remarkable bottom-up initiative that brings together different kinds of specialists from academic, commercial, and hybrid settings to produce, maintain, and update microarray standards; and 2) The unusual mix of skills and expertise involved in the development and use of microarrays. The production, accumulation, storage, and mining of microarray data remain multi-skilled endeavors bridging together different types of scientists who embody a diversity of scientific traditions. Beyond standardization, the interfacing of these different skills has become a key issue for further development of the field.

Informing materials: drugs as tools for exploring cancer mechanisms and pathways.

This paper builds on previous work that investigated anticancer drugs as 'informed materials', i.e., substances that undergo an informational enrichment that situates them in a dense relational web of qualifications and measurements generated by clinical experiments and clinical trials. The paper analyzes the recent transformation of anticancer drugs from 'informed' to 'informing material'. Briefly put: in the post-genomic era, anti-cancer drugs have become instruments for the production of new biological, pathological, and therapeutic insights into the underlying etiology and evolution of cancer. Genomic platforms characterize individual patients' tumors based on their mutational landscapes. As part of this new approach, drugs targeting specific mutations transcend informational enrichment to become tools for informing (and destabilizing) their targets, while also problematizing the very notion of a 'target'. In other words, they have become tools for the exploration of cancer pathways and mechanisms. While several studies in the philosophy and history of biomedicine have called attention to the heuristic relevance and experimental use of drugs, few have investigated concrete instances of this role of drugs in clinical research.

Correction to: Informing materials: drugs as tools for exploring cancer mechanisms and pathways.

The original version of this article unfortunately contained a mistake. Three entries are incorrect in the reference list. The corrected references are given below.

Mapping the emergence and development of translational cancer research.

Cancer research is one of the principal targets of translational research, yet the nature of the relationships between different forms of cancer research remains controversial. The paper examines publications in the cancer field during the 1980-2000 period. A network analysis software program was used to map evolving patterns of inter-citations between cancer publications, their different research levels and the transformation of their relational content. Both inter-citation and content maps provide striking evidence of the consolidation in the 1990s of a translational interface that was practically non existent a few decades before. In 1980, research was polarized according to the allegiance to either a clinical or a laboratory style. This same duality obtains in the year 2000, albeit with the additional presence of a third, biomedical player whose activities are similarly structured by a common orientation, rather than by an exclusive commitment to a specific sub-domain.

Regulatory objectivity and the generation and management of evidence in medicine.

The evolution of Western medicine since World War II has resulted in the emergence of new practices based on the direct interaction of biology and medicine. The post-war realignment of biology and medicine has been accompanied by the emergence of a new type of objectivity, regulatory objectivity, that is based on the systematic recourse to the collective production of evidence. Unlike forms of objectivity that emerged in earlier eras, regulatory objectivity consistently results in the production of conventions, sometimes tacit and unintentional but most often arrived at through concerted programs of action. These actions incorporate unprecedented levels of reflexivity, in the sense that biomedical practitioners in their debates and discussions take into account the conventional dimension of their endeavors. The conventions produced by regulatory objectivity create the conditions for a clinical objectivity that relies on the existence of entities and protocols produced and maintained far outside the intimate encounter between doctor and patient. By establishing endogenous forms of regulation, regulatory objectivity operates on a different plane and in a different mode from those suggested by analysts who treat all regulation as a form of rationalization imposed upon medicine from without.

"Triple negative breast cancer": Translational research and the (re)assembling of diseases in post-genomic medicine.

The paper examines the debate about the nature and status of "Triple-negative breast cancer", a controversial biomedical entity whose existence illustrates a number of features of post-genomic translational research. The emergence of TNBC is intimately linked to the rise of molecular oncology, and, more generally, to the changing configuration of the life sciences at the turn of the new century. An unprecedented degree of integration of biological and clinical practices has led to the proliferation of bio-clinical entities emerging from translational research. These translations take place between platforms rather than between clinical and laboratory settings. The complexity and heterogeneity of TNBC, its epistemic and technical, biological and clinical dualities, result from its multiple instantiations via different platforms, and from the uneven distribution of biological materials, techniques, and objects across clinical research settings. The fact that TNBC comes in multiple forms, some of which seem to be incompatible or, at least, only partially overlapping, appears to be less a threat to the whole endeavor, than an aspect of an ongoing translational research project. Discussions of translational research that rest on a distinction between basic research and its applications fail to capture the dynamics of this new domain of activity, insofar as application is built-in from the very beginning in the bio-clinical entities that emerge from the translational research domain.

[What is biomedicine? A socio-historical outline]. / Qu'est-ce que la biomédecine ? Repères socio-historiques.

The article examines the debates surrounding the emergence of the term biomedicine, with a particular focus on the relation between the pathological and the normal. The authors reject simplistic definitions of biomedicine as a one-way street leading to the application of medical knowledge to medicine, or even as a two-way street characterized by iterative exchanges between the clinic and the laboratory. Rather, the authors introduce the notion of a biomedical platform as the site where the clinic and the laboratory intermingle and are realigned in connection with the ongoing process of medical innovation and the increasing automation of molecular procedures. The examples used in the article are drawn mainly from the field of onco-hematology.