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.

[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.

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.

BRCA patients and clinical collectives: new configurations of action in cancer genetics practices.

Since the late 1980s, in France and in a number of other countries, cancer genetics testing has become a clinical reality, particularly for hereditary breast and ovarian cancer. BRCA tests allowing for the assessment of an increased cancer risk among patients and their healthy relatives are now being routinely performed as part of clinical practice. Based on fieldwork on French clinical cancer genetics and on the French Cancer Genetics Collaborative Network, this paper examines the configuration of entities, actors and activities mobilized by the performance of BRAC testing, and argues that the development of clinical molecular genetic practices is predicated upon the development of new forms of collaborative work that lead to a transformation of the content and organization of medical activities and judgements. The paper analyses three major collective configurations - local multidisciplinary collectives, data collectives and new clinical collectives - and argues that they not only provide the material conditions needed to carry out the relevant activities, but also articulate a series of distinctive bio-clinical interventions. These interventions provide an interface with research activities, produce the epidemiological measurements and tools that are a sine qua non for clinical work in this field, and, most importantly, establish the conventions that underlie practices, which define the criteria that turn tools and novel entities into operational components of clinical settings. It thus appears that in the field of clinical cancer genetics, bioclinical collectives, as a locus of expertise, have replaced the individual judgement of the practicing clinician.

[The supply of breast/ovarian cancer genetic susceptibility tests in France]. / L'offre de tests de prédisposition génétique au cancer du sein ou de l'ovaire en France.

One example of the recent advances of scientific research on the human genome is the identification of two susceptibility genes to breast/ovarian cancer, BRCA1 and BRCA2, making possible the introduction in medical practices of genetic testing to detect patients with an increased risk of developing such cancers. In this context of diffusion, two surveys were carried out to appraise the activity profiles in 1998 and in 2001 of all the different participants in those new medical practices in France, physicians in charge of genetic counselling, medical centres where consultations take place and laboratories. Results show that over the period 1998-2001, few changes occurred, mainly the reduction of the average waiting time to get the result of a genetic test, the increase in the annual number of BRCA2 families identified to a level similar to the one of BRCA1 and the automation of the biological analyses without noting a considerable increase in the annual output of laboratories till 2001 however. This surprising moderate evolution must be connected to the existence of some particular external factors making the framework of the development of these new medical and biological practices and their future really uncertain. The diffusion of BRCA1/2 genetic testing has been carried out facing the traditional difficulties of any innovating activities, but also the uncertainties related to intellectual property rights on genes and the reimbursement of genetic counselling and biological testing. These uncertainties have certainly restrained the pace of change as many actors in this field have opted for a wait and see strategy bearing in mind the possible future constraints imposed to their future activity, especially if European patents on the BRCA1/2 genes are finally granted by the European patent office (EPO).

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

In recent years, genomic technologies have entered oncology. In particular, so-called tumor signatures are now commercially available for diagnosing breast cancer. These new diagnostic tools have expanded the content and meaning of diagnosis, by adding a distinctive prognostic (will the disease recur?) and predictive (how will the disease react to treatment?) dimension to this activity, and modifying the relations between diagnosis and therapy. In particular, they raise the issue of the locus of clinical judgment and clinical decision-making insofar as they involve a re-alignment of the biological and clinical components of medical activities. Using as a case study a debate over the regulation of tests for genomic signatures by the US FDA, this paper examines how the actors problematize the issues related to the introduction of molecular diagnostics into clinical settings.