ABSTRACT

As biotechnology innovations move from the bench to the bedside and, recently, also to the Internet, a myriad of emanating challenges and potentials may rise under distinct sociocultural and political economic contexts. Using a grounded-theory-inspired case study focused on the Brazilian research consortium for Medullary Endocrine Neoplasia type 2 (BrasMEN) – an inherited syndrome where genetic tests define cost-effective interventions – we outline facilitators and barriers to both development and implementation of a ‘public health genomics’ strategy under a developing country scenario. The study is based on participant observation at three centres and interviews with all who might hold an interest in MEN2 around Brazil. We discuss how a ‘solidarity’-based motivation for individual and collective ‘biocitizenship’ is driving people’s pre-emptive actions for accessing and making personalised healthcare available at Brazil’s Unified Health System (SUS) via the ‘co-production’ of science, technology and the culture for precision medicine – termed Brazil’s ‘hidden’ biomedical innovation system. Given the establishment of BrasMEN as ‘solidarity networks’ – promoting and supporting the cancer precision medicine’s rationale – our data illustrates how a series of new bioethical challenges raise from such engagement with familial cancer genomics under Brazil’s developing country scenario and how this social/soft technology constitute a solution for Euro/North American societies.

KEYWORDS
Science, technology and society; Technological development and innovation projects; Multiple Endocrine Neoplasia Type 2; Solidarity; Brazil

RESUMO

Ao passo em que as inovações biotecnológicas migram da bancada para o leito e, mais recentemente, também para a Internet, uma miríade de desafios e potenciais pode surgir em contextos socioculturais e político-econômicos distintos. Usando um estudo de caso inspirado na teoria embasada em dados focado no consórcio de pesquisa brasileiro sobre a Neoplasia Endócrina Múltipla do Tipo 2 (BrasMEN) – uma síndrome rara em que testes genéticos definem intervenções custo-efetivas – ressaltamos facilitadores e barreiras para ambos desenvolvimento e implementação de uma estratégia de genômica em saúde pública no cenário de um país em desenvolvimento. O estudo foi baseado em observação participante em três centros e entrevistas com todos que podem ter um interesse sobre a MEN2 no Brasil. Discutimos como uma motivação baseada em ‘solidariedade’ para uma ‘biocidadania’ individual e coletiva está impulsionando ações preventivas nas pessoas para acessar e fazer com que cuidados em saúde personalizados sejam disponibilizados no Sistema Único de Saúde (SUS) do Brasil via a ‘coprodução’ de ciência, tecnologia e a cultura para medicina de precisão – denominado sistema de inovação biomédico brasileiro ‘escondido’. Dado o estabelecimento do BrasMEN como ‘redes de solidariedade’ – promovendo e apoiando a abordagem da medicina de precisão em câncer – nossos dados ilustram como uma série de novos desafios bioéticos surgem desse engajamento com a genômica do câncer familiar no cenário de país em desenvolvimento brasileiro e como esta tecnologia social/leve constitui uma solução para sociedades europeias e norte-americanas.

PALAVRAS-CHAVE
Ciência, tecnologia e sociedade; Projetos de desenvolvimento tecnológico e inovação; Neoplasia Endócrina Múltipla Tipo 2; Solidariedade; Brasil

Introduction

As society creates and defies new scientific and ethical dilemmas in the post-genomic era¹1 Prainsack B, Vayena E. Beyond the clinic: 'direct-to-consumer' genomic profiling services and pharmacogenomics. Pharmacogenomics. 2013; 14(4):403-12., clinical diagnosis alone – symptoms, physical examination, biochemical and imaging tests – is not sufficient without the concomitant use of genetic tests to identify potentially affected individuals. Continuous research on genes and their signalling pathways inducing inherited diseases expands the understanding of human genetics, and offer unique opportunities for new approaches to prevention, diagnosis and treatment for various forms of illnesses such as cancer²2 Prainsack B, Buyx A. Solidarity in contemporary bioethics - towards a new approach. Bioethics. 2012; 26:343-50. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/22827315.
https://www.ncbi.nlm.nih.gov/pubmed/2282... ^,33 Jameson JL, Longo DL. Precision Medicine - Personalized, Problematic and Promising. N Engl J Med. 2015; 372(23):2229-2234.. In this sense, advances in precision medicine promote the development of novel biotechnologies to track altered genes and transform medicine’s modus operandi around treatment, moving from symptomatic to a pre-symptomatic approach for patients’ maximum benefit³3 Jameson JL, Longo DL. Precision Medicine - Personalized, Problematic and Promising. N Engl J Med. 2015; 372(23):2229-2234..

These new ‘technologies of the self’⁴4 Heath D, Rapp R, Taussig KS. 'Genetic Citizenship'. In: Vincent DNAJ, editor. Companion to the Handbook of Political Anthropology. Nova Jersey: Blackwell Publishing; 2003. – i.e. genetic tests – carry novel challenges and dilemmas posed by a new culture of potentially enhanced health self-management. When physicians and researchers deal with patients and their families as they engage with genetic testing, for either preventive or curative purposes, in distinct sociocultural and political economic contexts in diverse countries⁵5 Gibbon S, Kampriani E, Zur Nieden A. BRCA patients in Cuba, Greece and Germany: Comparative perspectives on public health, the state and the partial reproduction of 'neoliberal' subjects. BioSocieties. 2010; 5(4):440-466.^,66 Gibbon S, Joseph G, Mozersky J, et al. Breast Cancer Gene Research and Medical Practices Transnational Perspectives in the Time of BRCA. New York: Genetics and Society. Hoboken; 2015., bioethical issues arise under what has been termed as ‘biological citizenship’ (‘biocitizenship’) – to encompass all citizenship projects that have linked people’s beliefs about the intersecting concepts of politics, identity and biology in the era of precision medicine³3 Jameson JL, Longo DL. Precision Medicine - Personalized, Problematic and Promising. N Engl J Med. 2015; 372(23):2229-2234.. This particular kind of ‘biosocial identities’ tend to gather health beliefs and perceptions about shared or collective health (genetic) risks and responsibilities within an ethics of (self) care and empowerment⁷7 Rose N, Novas C. Biological Citizenship. Londres: Blackwell; 2002.^,88 Rabinow P, Rose N. Biopower Today. BioSocieties. 2006; 1(2):195-217. [accessed in 2019 Nov 20]. Available in: http://imap.anthropos-lab.net/wp/publications/2007/01/rabinow-rose.pdf.
http://imap.anthropos-lab.net/wp/publica... . The limits to ‘biocitizenship’ have already been outlined at Euro/North American contexts, and according to this evidence, ‘biocitizenship’ and patient ‘empowerment’

In this sense, there is the need to consider socio-ethical, cultural and political economic facilitators and barriers for both the development and implementation of a precision medicine approach in countries outside Euro/North American contexts. Comprehension of national and local circumstances and demands are necessary to help understand different types of societal motivations for individual and collective citizenship driving pre-emptive actions for accessing and making precision medicine available. For this, we developed a grounded theory-inspired case study that included participant observation in São Paulo, Ceará and Espírito Santo regional centres of the Brazilian Multiple Endocrine Neoplasia Type 2 (MEN2) research consortium (BrasMEN) and conducted first-person interviews with all who hold an interest in a national precision medicine rationale for MEN2 across Brazil, i.e. patients, family members, health professionals, researchers, policy and decision-makers. We focused on MEN2 as it constitutes a rare example of research in precision medicine where genetic testing enables disease risk-classification defining cost-effective clinical interventions for timely personalised curative and/or preventive treatment¹⁰10 Wells SAJ, Asa SL, Dralle H, et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/25810047.
https://www.ncbi.nlm.nih.gov/pubmed/2581... ^,1111 Maciel RM, Camacho CP, Assumpção LV, et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study. Endocr Connect. 2019; 1;8(3):289-298.. We aimed to observe how, where and who engages with cancer precision medicine for public health purposes in a developing country like Brazil.

The BrasMEN case study

MEN2 is a syndrome including MTC, pheochromocytoma, primary hyperparathyroidism, and other abnormalities and follows an autosomal dominant inheritance¹⁰10 Wells SAJ, Asa SL, Dralle H, et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/25810047.
https://www.ncbi.nlm.nih.gov/pubmed/2581... – meaning that, if the carrier inherits the mutated gene from only one parent, he or she has a greater chance of developing the disease. The study of its biology has had unique implications for the establishment of comprehensive and integrated clinical services comprising genetic testing to manage patients and their families affected by this rare disease.

Over 95% of MEN2 patients carry different single-nucleotide mutations in the gene RET (REarranged during Transfection). These mutations promote constitutive activation of the tyrosine-kinase transmembrane receptor in thyroid C-cells, which promotes tumorigenesis¹⁰10 Wells SAJ, Asa SL, Dralle H, et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/25810047.
https://www.ncbi.nlm.nih.gov/pubmed/2581... . For this reason, depending on the mutation found, a positive genetic test for germline RET mutations – that can be transmitted onto one or all progeny – can determine people’s risk for manifesting the disease. According to the tiered-risk classification – from ‘A’, low, to ‘D’, high – health professionals’ shared decision-making with patients and families drives clinical interventions, ranging from asymptomatic thyroidectomy to metastatic follow-up and tyrosine-kinase receptor inhibitor trial therapeutics¹⁰10 Wells SAJ, Asa SL, Dralle H, et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/25810047.
https://www.ncbi.nlm.nih.gov/pubmed/2581... ^,1111 Maciel RM, Camacho CP, Assumpção LV, et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study. Endocr Connect. 2019; 1;8(3):289-298..

For asymptomatic high-risk RET-mutation carriers, prophylactic thyroid removal implies lifelong referral for daily hormonal reposition. For symptomatic patients carrying high-risk RET-mutations and MTC, thyroidectomy referral may also include cervical central and/or bilateral lymph nodes dissection, adrenalectomy for pheochromocytoma, as well as selective resection of parathyroid glands for primary hyperparathyroidism, and regular follow-up to verify post-surgical absence of MEN2 signs and symptoms over a five years period. Otherwise, low- to moderate-risk RET-mutations carriers may share decision-making with health professionals based on regular (six months) image and biochemical investigation for nodule and/or tumour growth, hormonal changes (elevated calcitonin and metanephrines) and other MEN2 symptoms that characterise disease outbreak and/or progression, all of which may engender surgical referrals¹⁰10 Wells SAJ, Asa SL, Dralle H, et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/25810047.
https://www.ncbi.nlm.nih.gov/pubmed/2581... ^,1111 Maciel RM, Camacho CP, Assumpção LV, et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study. Endocr Connect. 2019; 1;8(3):289-298..

A recent study investigating depression, anxiety, quality of life and coping in long-standing MEN2 patients in Brazil¹²12 Rodrigues KC, Toledo RA, Coutinho FL, et al. Assessment of depression, anxiety, quality of life and coping in long-standing multiple endocrine neoplasia type 2 patients. Thyroid. 2017; 27(5):693-706. deployed its semi-qualitative approach to pair patients psychological and clinical status. Here, our work aims to bridge this gap in robust qualitative – grounded theory-based – methodologies to not only identify but contextualise such consequences of both MEN2 individual and familial genetic testing in Brazil. Hence, given the recent national politicisation of rare genetic conditions – with both public health system (Unified Health System – in Portuguese, Sistema Único de Saúde, SUS) and private health insurance plans now obligated to pay for genetic testing for some rare diseases, including breast cancer and MEN2¹³13 Brasil. Ministério da Saúde. Gabinete do Ministro. Portaria no 199 de 30 janeiro 2014 [internet]. Institui a Política Nacional de Atenção Integral às Pessoas com Doenças Raras, aprova as Diretrizes para Atenção Integral às Pessoas com Doenças Raras no âmbito do Sistema Único de Saúde (SUS) e institui incentivos financeiros de custeio. [accessed in 2017 Nov 19]. Available in: http://bvsms.saude.gov.br/bvs/saudelegis/gm/2014/prt0199_30_01_2014.html.
http://bvsms.saude.gov.br/bvs/saudelegis... ^,1414 Melo DG, De Paula PK, De Araujo Rodrigues S, et al. Genetics in primary health care and the National Policy on Comprehensive Care for People with Rare Diseases in Brazil: opportunities and challenges for professional education. J Community Genet. 2015; 6(3):231-240., besides the wider context of judicialisation of health – especially in terms of accessing new high cost drugs and interventions¹⁵15 Biehl J, Amon JJ, Socal MP, et al. Between the court and the clinic: Lawsuits for medicines and the right to health in Brazil. Health Hum Rights. 2012; 14(1):36-52., our BrasMEN case study provides a unique and timely scenario to underline socio-ethical, cultural and political economic barriers and facilitators to the efficient and effective implementation of a cancer precision medicine approach outside Euro/North American contexts.

Methodology

Participants and recruitment

Following ethical approval (Federal University of São Paulo REC 0468/10), after a first interview with health professionals at BrasMEN founding centre in São Paulo (n=9), snowball sampling was deployed and an invitation to conduct interviews was two-fold: health professionals and decision-makers were sent e-mail messages with participant information and informed consent forms; patients and family members were approached individually during remote centre’s clinical assistance visits, when participant information, informed consent and interviews occurred. Health professionals and decision-makers were interviewed according to respondents’ availability. Interviewees comprised three sample groups: 16 patients-participants, 21 health professionals and 4 decision-makers (summarised in chart 1).

Inclusion criteria were: health professionals (n=14) and (clinical) researchers (n=6) involved with MEN2 in Brazil; patients (n=8) and relatives (n=7) at all levels of clinical assistance (pre- and post-genetic testing-counselling / thyroidectomy / follow-up) within the BrasMEN consortium; user (n=1) and provider (n=1; health professional) of direct-to-consumer genetic testing in Brazil; and representatives (n=4) of governmental agencies involved with regulation of genetic tests nationally. Exclusion criteria were failure to: agree with informed consent, response to invitation contact after two trials, and validate narrative after interview. Response to invitation was 78.85% (41/52) and 100% for narrative validation.

Data collection

Participant observation notes¹⁶16 Denzin NK, Lincoln YS. Handbook of Qualitative Research. London: Sage; 1994.^,1717 Geertz C. Works and Lives: The Anthropologist as Author. California: Stanford University Press; 1988. derived from fieldwork during clinical consultations at three BrasMEN centres where patients-participants were interviewed: São Paulo, Ceará and Espírito Santo. Information on other interviewees are summarised in chart 1. All forty-one interviews lasted between one and two hours and were audio-recorded, transcribed and ‘transcreated’ into oral life history narratives¹⁸18 Meihy JCSB, Ribeiro SLS. Guia prático de histórial oral: para empresas, universidades, comunidades e famílias. São Paulo: Contexto; 2011.. All interviews were conducted as a series of in-depth semi-structured open-ended questions meant to introduce interviewees to talk about individual/familial/professional experience with the subject, and from which further questions derived. Exploratory questions focused on: individual/familial/professional experience with MEN2 and/or RET genetic testing and/or precision medicine; perceptions about the future of precision medicine; perceptions and attitudes about sociocultural, ethical, political, economic, and regulatory facilitators and barriers for the implementation of ongoing genetic testing programs in Brazil; individual future plans.

Data analysis

We based our methods on grounded theory, as both development and implementation of diagnostic molecular genetic testing for cancer and its regulation are complex and require conceptually dense theory emanating from empirical data. This methodological approach can account for a great deal of variation in the studied phenomena¹⁹19 Strauss AL. Qualitative Analysis for Social Scientists. Cambridge: Cambridge University Press; 2003.. All data was coded, according to arising and/or previously outlined themes drawing from fieldwork notes and systematic analysis of interview narratives. Codes were summarised with respective quotations in spreadsheets for manual analysis. Quotes are representative, illustrating selected themes that met saturation criteria. Anonymity was guaranteed for all interviewees. Narratives underwent respondent validation for internal validity of collected data²⁰20 Mays N, Pope C. Qualitative research in health care. Assessing quality in qualitative research. BMJ; 2000; 320(1):50-2..

Results

Brazil’s ‘hidden’ biomedical innovation system: ‘co-production’ of science, technology and the cancer precision medicine culture via solidarity networks

A – THE SOUTHEAST-SOUTH AXIS OF EXPERTISE AND TECHNOLOGY CONCENTRATION

During fieldwork, we observed that BrasMEN comprises seventeen national research and clinical assistance groups from six federative states (Ceará, Espírito Santo, Minas Gerais, Rio de Janeiro, Rio Grande do Sul and São Paulo) with large expertise in cost-effective MEN2 clinical management with RET-mutations testing and associated symptoms description for a large number of patients (n=2,201) and families (n=176)¹¹11 Maciel RM, Camacho CP, Assumpção LV, et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study. Endocr Connect. 2019; 1;8(3):289-298.. São Paulo is the founding reference centre of BrasMEN, thus focusing on more complex and aggressive MEN2 cases referred from all over Brazil, and on prophylaxis for children carrying mutations. The Espírito Santo cohort was first identified in São Paulo – proband patient referral to access the BrasMEN precision medicine’s modus operandi revealed a new RET mutation¹¹11 Maciel RM, Camacho CP, Assumpção LV, et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study. Endocr Connect. 2019; 1;8(3):289-298.. Ten years after first local assistance to screen and follow-up one large (seven generations) MEN2 family (n=728), we encountered people at all ages and stages of health care regarding existing: RET-mutation identification, MEN2 symptoms manifestation, curative or preventive surgery and follow-up. The majority presented high mean level of education and higher than average socioeconomic status, mainly relying on private insurance plans for long-term healthcare access. First local assistance in Ceará identified and assisted (potential) MEN2 carrier individuals (n=113). Families lived in a rural area, presented high levels of consanguinity (several first-cousin marriages) and lower than average socioeconomic status, generally relying on the public health system (SUS) to access health care.

On the BrasMEN cancer precision medicine’s modus operandi, an experienced surgeon explained that by replicating international MEN2 guidelines¹⁰10 Wells SAJ, Asa SL, Dralle H, et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/25810047.
https://www.ncbi.nlm.nih.gov/pubmed/2581... in Brazil, they “managed to live, today, part of what the future holds for medicine in this area […] [as] many serum biomarkers will be replaced by genetic tests”.

Corroborating previous literature findings on the European MEN2 research consortium – EuroMEN²¹21 Romei C, Mariotti S, Fugazzola L, et al. Multiple Endocrine Neoplasia Type 2 Syndromes (MEN2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol. 2010; 163:301-308. – all health professionals (n=21) outlined the relevance of BrasMEN for the establishment of a national MEN2 precision medicine’s modus operandi. Despite its cost-effectiveness, the perception of all interviewees is that, today, access to genetic testing remains scarce, mainly restricted to the southeast-south axis of expertise and technology concentration in Brazil. Most patients-participants (n=11/16) and all health professionals (n=21) and decision-makers (n=4) illuminated on how such regional disparities reflect the way health care and technology have been unequally developed and distributed around Brazil, historically²²22 Thorsteinsdottir H. The Role of the Health System in Health Biotechnology in Developing Countries. Techn. Analysis Strat. Manag. 2007; 19(5):659-675^,2323 Paim J, Travassos C, Almeida C, et al. The Brazilian health system: history, advances, and challenges. The Lancet. 2011; 377(9779):1778-97., especially in the case of clinical genetics services²⁴24 Osada NM. O processo de biomedicalização no Brasil: estudo da prática científica em pesquisas sobre doenças genéticas [thesis]. Campinas: Universidade Estadual de Campinas; 2012. 213 p.^,2525 Ashton-Prolla P, Goldim JR, Vairo FP, et al. Genomic analysis in the clinic: benefits and challenges for ehalth care professionals and patients in Brazil. J. Community Genetics; 2015; 6:275-83.. This finding corroborates previous conclusions from a World Health Organization (WHO)²⁶26 World Health Organization. Community genetics services - Report of a WHO Consultation on community genetics in low- and middle-income countries. Switzerland: World Health organization; 2011. consultation on community genetics services for genetic disorders in developing countries.

During fieldwork, narratives from patients-participants and health professionals alike confirmed our participant observations on this barrier, as both expertise and tools to implement MEN2 precision medicine approach remained restricted to three reference centres: two in São Paulo and one in Rio Grande do Sul. Widening the availability and access to genetic testing and follow-up care in the north, northeast and centre-west regions was observed as key to all respondents.

All BrasMEN health professionals (n=21) and most patients-participants (n=9/16) viewed both SUS and Brazil’s biomedical innovation system – the ‘health industry complex’²²22 Thorsteinsdottir H. The Role of the Health System in Health Biotechnology in Developing Countries. Techn. Analysis Strat. Manag. 2007; 19(5):659-675^,2424 Osada NM. O processo de biomedicalização no Brasil: estudo da prática científica em pesquisas sobre doenças genéticas [thesis]. Campinas: Universidade Estadual de Campinas; 2012. 213 p.^,2727 Albuquerque EM, Cassioalto JE. As especificidades do sistema de inovação do Setor Saúde: uma resenha da literatura como introdução a uma discussão sobre o caso brasileiro. In: Albuquerque EM, Cassioalto JE, editors. Estudos FeSBE. Águas de Lindóia: Instituto de Ciências Biomédicas da Universidade de São Paulo; 2000. – as non-developed and with scarce resources. According to national in vitro medical devices entrepreneurs, innovation must meet local demand to grant people access²⁸28 Rezaie R, Frew SE, Sammut SM, et al. Brazilian health biotech--fostering crosstalk between public and private sectors. Nature biotechnology. 2008; (26):627-44. and produce an impact on national public health priorities²⁹29 Teixeira MO, Machado CS. The dynamics of biomedical research organization in Brazil: the anatomy of a recent experience at the Oswaldo Cruz Foundation. Reciis [internet]; 2009 [accessed in 2018 Nov 9]; 3(2):47-72. Available in: http://www.reciis.cict.fiocruz.br.
http://www.reciis.cict.fiocruz.br... .

B – BRAZIL’S ‘HIDDEN’ BIOMEDICAL INNOVATION SYSTEM

Recognising such regional disparities as a barrier for the implementation of precision medicine as a public health initiative in a developing country scenario, BrasMEN researchers developed an arrangement that we termed Brazil’s ‘hidden’ biomedical innovation system. This terminology refers to how cancer genetic testing has been developed in UK’s hospitals and research institutions – under what has been named ‘hidden research system’³⁰30 Hopkins MM. The hidden research system: The evolution of cytogenetic testing in the national health service. Science as Culture; 2006; 15(3):253-276..

Differently from the UK’s ‘hidden research system’, the BrasMEN arrangement additionally aims to rectify the aforementioned unequal access to such comprehensive and integrated clinical service encompassing clinical genetics for patients who would otherwise remain unidentified and/or unassisted²⁴24 Osada NM. O processo de biomedicalização no Brasil: estudo da prática científica em pesquisas sobre doenças genéticas [thesis]. Campinas: Universidade Estadual de Campinas; 2012. 213 p.. During fieldwork, we observed how health professionals deployed funding from state-sponsored research grants for the establishment of this ‘hidden’ biomedical innovation system for RET-mutations testing and follow-up centralised in São Paulo – this constitutes the basis for the Brazilian ‘health industry complex’.

According to all health professionals (n=21) and several patients-participants (n=8/15) this ‘friendly arrangement’ constitutes BrasMEN’s underlying ‘tiers-1 and 2 solidarity’ ethos, and a facilitator for the implementation of precision medicine into SUS, under a developing country scenario. These respondents described BrasMEN as the ‘co-production’³¹31 Jasanoff S. States of knowledge: co-production of science and social order. London: Routledge; 2004. of science (new RET mutations and associated MEN2 symptoms epidemiological data description), technology (cost-effective RET mutations identification) and a new culture for prevention in health³3 Jameson JL, Longo DL. Precision Medicine - Personalized, Problematic and Promising. N Engl J Med. 2015; 372(23):2229-2234..

On the other hand, several health professionals (n=10/21) were concerned that over-relying on BrasMEN may undermine policy and decision-makers’ recognition of the real demand for a cancer precision medicine approach to adequately manage MEN2 patients and families across Brazil. During fieldwork, we observed that the majority of BrasMEN patients/participants (four patients, three relatives) and all health professionals deployed individual out-of-pocket investments to ensure delivery of the BrasMEN’s modus operandi.

Therefore, BrasMEN case study illustrates these ‘hidden’ initiatives for the construction of ‘need’ (i.e. demand) for clinical usership³²32 Ferreira CS, Franco TB, Merhy EE. Processo de trabalho do agente comunitário de saúde e a reestruturação produtiva. Cad. Saúde Pública. 2009; 25(4):898-906. of genetic screening for both diagnosis and follow-up of a large group of MEN2 patients in the Brazilian public national health system as a public health strategy for accessing value chains through this new market-building of the in vitro diagnostic medical devices sub-sector of the Brazilian ‘health industry complex’. In this sense, ‘tier-3 level of solidarity enactment’ as contractual and legal manifestations would constitute a key political economic and regulatory facilitator to the efficient and effective implementation of a cancer precision medicine approach outside Euro/North American contexts. Now, we outline how BrasMEN ‘solidarity networks’ enacted both tiers-1 and 2 of a ‘solidarity’-based (‘global south’ type of) ‘biocitizenship’.

C – ‘TIERS-1 AND 2 SOLIDARITY NETWORKS’

Deepening ourselves into participants’ self-reported motivation for engaging with the BrasMEN’s modus operandi, the majority of patients-participants (n=12/15) based it on two areas of reasoning. First, participation enabled molecular diagnosis for the family; hence, granting access to adequate therapeutics in a timely manner for all mutation-carriers. Corroborating previous MEN2 literature data¹²12 Rodrigues KC, Toledo RA, Coutinho FL, et al. Assessment of depression, anxiety, quality of life and coping in long-standing multiple endocrine neoplasia type 2 patients. Thyroid. 2017; 27(5):693-706., patients-participants viewed themselves as gatekeepers to access alongside health professionals.

Second, there was a willingness to contribute to scientific scholarship so that other potentially affected families around Brazil might also benefit from the research consortium’s outcomes – the solidarity-based ethos. Their reasons were narrativised in relation to feeling ‘safe’, ‘confident’, ‘grateful’ and in terms of the ‘need to reciprocate’.

Health professionals’ additional motivation for participating was that they also recognised being affected in at least one relevant aspect with fellow health professionals and/or patients-participants. They further commented feeling ‘happiness’, ‘satisfaction for contributing’, ‘professional achievement’ and ‘mission’ as they narrated individual and professional motivations for participating at BrasMEN.

Moreover, all stakeholders’ (n=35) self-reported motivations for participating at the BrasMEN arrangement referred to both ‘tier-1 personal level of solidarity enactment’ and ‘tier-2 group practices’²2 Prainsack B, Buyx A. Solidarity in contemporary bioethics - towards a new approach. Bioethics. 2012; 26:343-50. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/22827315.
https://www.ncbi.nlm.nih.gov/pubmed/2282... , commenting that their common goal was assisting each other secure MEN2 patients’ and families’ sustained wellbeing. All health professionals (n=21) and most patients-participants from Ceará (n=5/5), Espírito Santo (n=3/4) and São Paulo (n=3/6) argued that their willingness to assist others was not only based on family ties (shared biological/ DNA making or ‘blood’). They recognised others as ‘fellows in the same journey’ as they experienced ignorance, despair, resignation and hopelessness in the face of future suffering upon themselves and the life of others whom they assisted – regardless whether ‘others’ were health professionals, patients or family members. This two-fold identification – individuals under: similar biological features (genetic mutations and/or disease manifestation); and/or similar affections (suffering, privation and inequity) – drove not only the ‘personal level of solidarity’ enactment (tier-1 solidarity), but also the ‘group practices’ (tier-2) we observed. Moved by ‘common goals’, such stakeholders manifested ‘willingness to carry costs to assist others [who [we]re all linked by means of a shared situation or cause] with whom [they] recognise[d] sameness or similarity in at least one relevant respect’²2 Prainsack B, Buyx A. Solidarity in contemporary bioethics - towards a new approach. Bioethics. 2012; 26:343-50. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/22827315.
https://www.ncbi.nlm.nih.gov/pubmed/2282... , via the ‘trust, safety and reciprocity’ networks they created within BrasMEN. These ‘solidarity networks’ constitute the basis for the ‘me’ to ‘us’ shift in respondents’ attitudes around BrasMEN’s modus operandi.

Our data shows how this ‘solidarity’-based ‘biocitizenship’ constituted a facilitator for the implementation of a Brazilian type of ‘global south’ solution for a ‘public health genomics’ initiative that enabled a more sustainable and equitable opportunity for cancer precision medicine outside Euro/North American contexts. Still, do our findings illustrate other facilitators and barriers for the implementation of the stakeholders’ claims for (tier-3 solidarity via) contractual and other legal manifestations for the incorporation of an ongoing RET-screening program within SUS for MEN2?

New bioethical challenges in cancer precision medicine under ‘solidarity networks’ in Brazil

We now outline how a series of new bioethical challenges we observed during fieldwork are being differently managed within BrasMEN, as compared to findings from Euro/North American contexts. Our data also illuminates which bioethical challenge constituted a facilitator or a barrier to the implementation of a ‘public health genomics’ initiative as a ‘global south’ social³³33 Dagnino R. A tecnologia social e seus desafios. In: Dagnino R. Tecnologia Social: contribuições conceituais e metodológicas. Eduepb; 2014. p.19-34. /soft technology³⁴34 Ferreira CS, Franco TB, Merhy EE. Processo de trabalho do agente comunitário de saúde e a reestruturação produtiva. Cad. Saúde Pública. 2009; 25(4):898-906.^,3535 Campos GWS. A mediação entre conhecimento e práticas sociais: a racionalidade da tecnologia leve, da práxis e da arte. Ciênc. Saúde Colet. 2011; 16(7):3033-40. (i.e. processes of human interaction, in the sense of thinking scientific methods/modus operandi to deal with social structures, human relationships and motivation techniques) that is both more sustainable and equitable under Brazil’s developing country scenario.

A – FEARS, UNCERTAINTY, DENIAL, STIGMATISATION AND DISCRIMINATION

Similar to Euro/North American MEN2 studies¹⁰10 Wells SAJ, Asa SL, Dralle H, et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/25810047.
https://www.ncbi.nlm.nih.gov/pubmed/2581... , BrasMEN patients-participants presented no difficulty in communicating: ‘fears’ and ‘uncertainty’, especially regarding lack of continuity of care, ‘relief’ for negative test results, and ‘reliance’ on family and health providers for information and support. Different from Euro/North American findings, BrasMEN health professionals enumerated ‘religious reasons’, ‘fatalism’, and ‘denial’ as the most common reasons for refusal to undergo genetic testing and/or surgery. Such attitude mainly occurred for patients from lower sociocultural and/or socioeconomic strata outside the southeast-south axis in Brazil.

Counterbalancing those barriers, according to health professionals (n=6/21) who pursued part of their careers in Euro/North American countries, sociocultural differences constituted a facilitator for the implementation of BrasMEN’s modus operandi as health professionals engaged ‘more openly’ with patients.

According to a clinical researcher, the ‘trust, safety and reciprocity’ networks created under BrasMEN ‘tiers-1 and 2 solidarity’-based ‘biocitizenship’ constituted another facilitator for the implementation of its precision medicine’s modus operandi. Letting families with different RET-mutations and distinct levels of MEN2 manifestation spontaneously exchange their individual/familial diagnostic and disease experiences during clinical visits constituted one of the key aspects of BrasMEN social/soft technology – a ‘global south’ solution to fears, uncertainty, denial, stigmatisation and discrimination.

Regionally, we identified two barriers for the implementation of such modus operandi. First, we observed fears about stigmatisation and/or discrimination for patients-participants from higher sociocultural and/or socioeconomic strata, especially those carrying low-risk RET-mutations under longer (ten years) follow-up (São Paulo n=4/6; Espírito Santo n=3/4) along the southeast-south axis. Health professionals (n=9/21) further illustrated how unidentified and/or undiagnosed family members from such cohorts seemed more reticent about undergoing testing and/or (curative/prophylactic) treatment, depending on different individual and/or familial: disease understanding, risk perception (for disease outbreak and progression) and stigmatisation/discrimination.

Second, during fieldwork, we observed concerns about environmental interferences on disease outbreak and progression at the Ceará cohort (n=5), as people learned about the increasing cancer prevalence after plane-pulverised harvests were established locally by multinational enterprises³⁶36 Rigotto RM, Carneiro FF, Marinho AMCP, et al. The green rural economy: challenges to research and to public health policies posed by agricultural modernization. Ciênc. Saúde Colet. 2012; 17(6):1533-1542.. Therefore, patients-participants from higher sociocultural and/or socioeconomic strata carrying better prognosis (lower-risk gene mutations) might have constituted a barrier due to fears of stigmatisation/discrimination, despite BrasMEN ‘solidarity’-based ‘biocitizenship’ enactment that has otherwise prevented it for patients-participants from lower sociocultural and/or socioeconomic strata. Looking deeper into this profile during fieldwork, as we searched for reasons for such barrier, we observed various levels of ‘lay expertise’.

B – ‘LAY EXPERTISE’ AND ‘GENETICISATION’

Although the majority of patients-participants interviewed (n=13/15) fully understood the genetic compound about the disease, health professionals reported difficulty when approaching families from lower sociocultural and/or socioeconomic strata about BrasMEN’s prophylactic and early detection goals, especially at remote regions (n=4/20). All BrasMEN endocrinologists (n=12) revealed that ‘lay expertise’ about such new culture for prevention enhanced patient adherence, thus constituting a facilitator to the implementation of BrasMEN’s modus operandi.

We further observed how the engagement with genetic testing and/or the BrasMEN’s modus operandi changed individual and/or familial perception about various aspects of the disease’s symptoms and diagnosis. Most BrasMEN patients-participants (n=12/16) from all regions pre-emptively searched for health information on the Internet and/or with relatives or friends with previous professional experience in the health sector. In this sense, ‘lay expertise’ constituted a facilitator within BrasMEN.

Outside BrasMEN, the direct-to-consumer genetic test user explained how ‘lay expertise’, in fact, constituted a barrier to the implementation of precision medicine worldwide by arguing that knowledge translation on both molecular biology and clinical genetics, including probability concepts, must improve to aid ‘early adopters’ of such new health technologies fully understand their genetic reports – this includes not only patients and/or consumers but also health professionals and society in general. All decision-makers (n=4) and health professionals (n=21) agreed with this argument, mentioning the need to formalise what types of health professionals can deliver genetic counselling, and the adequate types of training they must undergo before talking with patients and/or consumers.

‘Geneticisation’ also constituted a barrier outside BrasMEN. Despite two surgeons’ positive attitude towards wider availability of genetic testing, three BrasMEN (clinical) researchers, the private health sector (direct-to-consumer) genetic test developer and all decision-makers commented similar concerns, further suggesting the potentiality for over-prescription and over-diagnosis. Their negative perceptions followed counselling Brazilians who bought direct-to-consumer genetic tests on the Internet, as they worried about ‘geneticisation’³⁷37 Hedgecoe A. Geneticization, medicalisation and polemics. Medicine, Healthcare and Philosophy. 1998; 1:235-243. and the lack of a comprehensive regulatory context guiding genetic testing and all clinical activities that could engender stigmatisation, discrimination and over-prescription of non-directed clinical interventions.

The Anvisa (National Health Surveillance Agency) decision-maker also commented that the current regulatory context does not forbid the direct-to-consumer availability of genetic testing but, at the same time, requires a medical referral/prescription to enable the access to any type of health technology. He also discussed how both national regulatory and political-economic environment do not seem inclined to change in the near future (2022). Therefore, differently from previous MEN2 findings in Euro/North American societies, the BrasMEN ‘tiers-1 and 2 solidarity’-based ‘biocitizenship’ prevented ‘lay expertise’ and ‘geneticisation’ from becoming barriers to a ‘global south solution’ for the implementation of a ‘public health genomics’ initiative under the Brazilian developing country scenario due to how individual and familial genetic counselling was delivered by the consortium’s modus operandi.

C – ‘BOUNDARY WORK’ AND JUDICIALISATION OF MEDICINE

Deepening ourselves into the underlying reasons of how BrasMEN ‘tiers-1 and 2 solidarity’-based ‘biocitizenship’ enabled this successful genetic counselling delivery, we observed the relationship between patients-participants and BrasMEN health professionals. Although the majority of patients-participants interviewed (n=13/15) fully understood their participation in a research initiative, the private sector (ANS – National Regulatory Agency for Private Health Insurance and Plans) decision-maker remained sceptical about patients’ full comprehension of the thin ‘boundary’ over what was deemed research and clinical assistance in the BrasMEN’s modus operandi.

Health professionals (n=3/21), decision-makers (n=4) and the three patients-participants who underwent private health insurance discrimination commented on the 1988 Constitution ‘solidarity’ and ‘humanitarian right to health’ ethos²³23 Paim J, Travassos C, Almeida C, et al. The Brazilian health system: history, advances, and challenges. The Lancet. 2011; 377(9779):1778-97.. Two key aspects based their concerns: first, the recent politicisation of rare genetic conditions in Brazil, with SUS now paying for genetic testing for some rare diseases¹³13 Brasil. Ministério da Saúde. Gabinete do Ministro. Portaria no 199 de 30 janeiro 2014 [internet]. Institui a Política Nacional de Atenção Integral às Pessoas com Doenças Raras, aprova as Diretrizes para Atenção Integral às Pessoas com Doenças Raras no âmbito do Sistema Único de Saúde (SUS) e institui incentivos financeiros de custeio. [accessed in 2017 Nov 19]. Available in: http://bvsms.saude.gov.br/bvs/saudelegis/gm/2014/prt0199_30_01_2014.html.
http://bvsms.saude.gov.br/bvs/saudelegis... ^,2525 Ashton-Prolla P, Goldim JR, Vairo FP, et al. Genomic analysis in the clinic: benefits and challenges for ehalth care professionals and patients in Brazil. J. Community Genetics; 2015; 6:275-83.^,3838 Agência Nacional de Saúde Suplementar. Caderno de Informação da Saúde Suplementar: beneficiários, operadoras e planos [internet]. Rio de Janeiro: ANS; 2014. [accessed in 2019 Nov 19]. Disponível em: http://www.ans.gov.br/portal/site/informacoesss/informacoesss.asp.
http://www.ans.gov.br/portal/site/inform... . Second, the post-1988 Constitution wider context of judicialisation of health, with the growing demand by those who remain unattended by SUS and cannot afford private health insurance plans, fuelling a consumerist approach to health care and technologies. During fieldwork, participant observation data confirmed such health consumerism findings – especially for the increasing out-of-pocket consumption of genetic testing, as outlined by both direct-to-consumer genetic testing user and the private sector genetic test developer. These fieldwork findings also refuted the ‘therapeutic misconception’ hypothesis³⁹39 Hallowell N, Cooke S, Crawford G, et al. Distinguishing research from clinical care in cancer genetics: Theoretical justifications and practical strategies. Soc Sci Med. 2009; 68(11):2010-2017., as most health professionals and patients-participants, in fact, presented a positive attitude towards such ‘lack of boundary’ over what was deemed research and clinical assistance. Therefore, both ‘lack of boundaries’ and the judicialisation of medicine have so far constituted facilitators for a public health genomics initiative as part of BrasMEN’s modus operandi.

D – ‘BIOPOWER’ AND ‘BIOCITIZENSHIP’

Given all findings thus far support the tier-3 solidarity claims made by stakeholders, first we outline that most BrasMEN patients-participants (n=13/15) illuminated how ‘lay expertise’ played only a partial role in individual, familial and shared decision-making among patients/families and health professionals. Therefore, indicating that the BrasMEN’s modus operandi helped surpass ‘lay expertise’, ‘geneticisation’, ‘boundary work’ and ‘judicialisation’ barriers.

Second, more experienced health professionals (n=6) and two decision-makers (ANS and SBPC/ML – Brazilian Society of Clinical Pathology/Laboratory Medicine) commented on the controversial issue of autonomy versus paternalism²⁵25 Ashton-Prolla P, Goldim JR, Vairo FP, et al. Genomic analysis in the clinic: benefits and challenges for ehalth care professionals and patients in Brazil. J. Community Genetics; 2015; 6:275-83.. However, few BrasMEN patients-participants (n=6/15) – from those (n=13/15) who recognised such ‘boundary work’ – actively negotiated their ‘[bio]power to define, describe and classify normality as well as abnormality’. These respondents presented higher than mean level of education, previous experience in the health sector (i.e. professional or familial/individual disease experience) and lived along the southeast-south axis in Brazil.

Unlike other more prevalent cancer types such as breast and ovary cancer syndrome, or other rare genetic disorders, we did not identify any patients’ associations or advocacy groups for MEN2 in Brazil, thus far, as opposed to the UK, confirming our findings. This constitutes both tiers-1 and 2 of solidarity enactment²2 Prainsack B, Buyx A. Solidarity in contemporary bioethics - towards a new approach. Bioethics. 2012; 26:343-50. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/22827315.
https://www.ncbi.nlm.nih.gov/pubmed/2282... that we observed, as all patients-participants (n=15) and health professionals (n=21) regarded both health professionals’ and patients-participants’ commitment, availability, openness and knowledgeable attitude as ‘ideal’, while absent outside BrasMEN. This is why the ‘tiers-1 and 2 solidarity’-based ‘biocitizenship’ BrasMEN enabled, in fact, surpassing most potential barriers we identified for the implementation of this cancer precision medicine tool in Brazil – at both public and private sectors. In this sense, our findings illuminate how the stakeholders’ claims for the incorporation of the RET-mutation test (with adequate individual and familial genetic counselling, as established by the BrasMEN’s modus operandi) into SUS constitutes the ‘tier-3 solidarity’-based ‘biocitizenship’ via contractual and other legal manifestations for a Brazilian ‘public health genomics’ initiative, more sustainable and equitable than other precision medicine implementation alternatives at Euro/North American contexts⁴⁰40 Shuman AG, Shaha AR, Tuttle RM, et al. Medullary thyroid carcinoma: ethical issues for the surgeon. Annals of surgical oncology. 2012; 19:2102-7..

Discussion

Precision medicine is the means through which governments are distancing themselves from their citizens⁴¹41 Webster A. Health, Technology & Society: a Sociological Critique. Hampshire: Palgrave Macmillan; 2007., by sharing the biomedical collective’s chief task with lay people – enhancing their responsibility to self-regulate their health status. These empowered ‘biocitizens’ shape new ways of understanding, judging and acting on themselves, as well as on those to whom they owe responsibilities. These groups may encompass offspring, family members, health professionals, co-citizens, and ultimately, their community and society. Consequently, via such forms of ‘biological collectivisation’, these moral pioneers, ‘as prudent yet enterprising individuals’, engage in new practices of biological choices within a ‘regime of the self’. Their demands include recognition of lay expertise, access to biotechnologies, and financial support from governmental authorities to act upon themselves, via social activism³3 Jameson JL, Longo DL. Precision Medicine - Personalized, Problematic and Promising. N Engl J Med. 2015; 372(23):2229-2234.^,44 Heath D, Rapp R, Taussig KS. 'Genetic Citizenship'. In: Vincent DNAJ, editor. Companion to the Handbook of Political Anthropology. Nova Jersey: Blackwell Publishing; 2003.^,77 Rose N, Novas C. Biological Citizenship. Londres: Blackwell; 2002..

Different from this type of ‘biocitizenship’ – defined as such due to the context where it has arisen (i.e. USA⁷7 Rose N, Novas C. Biological Citizenship. Londres: Blackwell; 2002.^,88 Rabinow P, Rose N. Biopower Today. BioSocieties. 2006; 1(2):195-217. [accessed in 2019 Nov 20]. Available in: http://imap.anthropos-lab.net/wp/publications/2007/01/rabinow-rose.pdf.
http://imap.anthropos-lab.net/wp/publica... ) – and the more generally described paternalism exerted by health professionals in Brazil – as outlined by a group of clinical geneticist/researchers from southern Brazil²⁵25 Ashton-Prolla P, Goldim JR, Vairo FP, et al. Genomic analysis in the clinic: benefits and challenges for ehalth care professionals and patients in Brazil. J. Community Genetics; 2015; 6:275-83. – our findings outline a ‘solidarity’-based ‘biocitizenship’: our first novelty. We argue that Brazil’s underlying socio-ethical, cultural and political economic contexts, as observed both on fieldwork notes and oral life history narratives, influenced the way through which people have been engaging with cancer precision medicine tools and enabling their co-production for a ‘public health genomics’ culture around Brazil’s developing country scenario.

Ashton-Prolla et al.²⁵25 Ashton-Prolla P, Goldim JR, Vairo FP, et al. Genomic analysis in the clinic: benefits and challenges for ehalth care professionals and patients in Brazil. J. Community Genetics; 2015; 6:275-83. outlined how “molecular genetic testing was accessible only through a few commercial laboratories, for patients able to pay out-of-pocket, or through research projects in reference centres”. Our case study findings further illuminate how both the research consortium and the 1988 Constitution ‘solidarity’ ethos comprised the socio-cultural and political-economic basis for promoting this different type of individual and collective citizenship, based on what we termed the ‘trust, safety and reciprocity’ networks – BrasMEN ‘solidarity networks’. In this sense, our findings outline how all stakeholders developed a ‘global south’ solution to not only help each other but also compensate for the historical, sociocultural and political economic processes around how health care and innovations have been differently developed and distributed sub-nationally – chiefly associated with state-funded academic reference research centres along the southeast-south axis²²22 Thorsteinsdottir H. The Role of the Health System in Health Biotechnology in Developing Countries. Techn. Analysis Strat. Manag. 2007; 19(5):659-675

23 Paim J, Travassos C, Almeida C, et al. The Brazilian health system: history, advances, and challenges. The Lancet. 2011; 377(9779):1778-97.

24 Osada NM. O processo de biomedicalização no Brasil: estudo da prática científica em pesquisas sobre doenças genéticas [thesis]. Campinas: Universidade Estadual de Campinas; 2012. 213 p.^-2525 Ashton-Prolla P, Goldim JR, Vairo FP, et al. Genomic analysis in the clinic: benefits and challenges for ehalth care professionals and patients in Brazil. J. Community Genetics; 2015; 6:275-83.^,4242 Gadelha CA. Development, health-industrial complex and industrial policy. Rev. Saúde Públ. 2006; 40(spe):11-23.

43 Landim A, Gomes R, Pimentel V, et al. Equipamentos e tecnologias para saúde - oportunidades para uma inserção competitiva da indústria brasileira. In: Social BBNDDEE (ed.). BNDES Setorial; 2013.

44 Rezaie R, Mcgahan AM, Frew SE, et al. Emergence of biopharmaceutical innovators in China, India, Brazil, and South Africa as global competitors and collaborators. Health research policy and systems/BioMed Central; 2012; 10:18.^-4545 Victora CG, Barreto ML, Do Carmo Leal, et al. Health conditions and health-policy innovations in Brazil: the way forward. The Lancet. 2011; 377(9782)2042-53.. This is our second innovative finding: BrasMEN ‘solidarity networks’ as basis for the national ‘health industry complex’ for cancer/rare diseases.

All BrasMEN stakeholders deployed the concept of ‘solidarity’ to describe how each part, “as singular and essentially autonomous actors, form[ed] social and political coalitions out of their free will […] by bonds of mutual assistance and common goals”²2 Prainsack B, Buyx A. Solidarity in contemporary bioethics - towards a new approach. Bioethics. 2012; 26:343-50. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/22827315.
https://www.ncbi.nlm.nih.gov/pubmed/2282... to enable the BrasMEN’s ‘hidden’ biomedical innovation system for the co-production of such high-risk health technologies – i.e. molecular genetic diagnosis/prognosis. This is what differentiates BrasMEN’s modus operandi from the UK’s ‘hidden research system’: ‘tiers-1 and 2 solidarity’-based ‘biocitizenship’. This type of ‘biocitizenship’ is

For this reason, we argue that our findings evidence the enactment of ‘tier-1 (personal level) solidarity’ from the 3-tiered bioethical conceptualisation of ‘solidarity’²2 Prainsack B, Buyx A. Solidarity in contemporary bioethics - towards a new approach. Bioethics. 2012; 26:343-50. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/22827315.
https://www.ncbi.nlm.nih.gov/pubmed/2282... , whereby tier-1

We further argue that, if ‘tier-1 solidarity’ had not occurred, there would be no guarantee that contractual and legal manifestations (tier 3) would have enforced real group practices (tier 2) as institutionalised conduct to both develop and implement genetic testing around Brazil, as previously discussed by Osada²⁴24 Osada NM. O processo de biomedicalização no Brasil: estudo da prática científica em pesquisas sobre doenças genéticas [thesis]. Campinas: Universidade Estadual de Campinas; 2012. 213 p. and observed in this case study. In fact, it was the tier-1 solidarity enactment that enabled the spontaneous appearance of group practices (tier-2), fostering the stakeholders’ claims for the incorporation of RET-screening into SUS, under contractual and legal manifestations (tier-3) by the health technology assessment agency of the Ministry of Health of Brazil – Conitec (National Commission for the Incorporation of Technologies into SUS).

We also observed similarities of restricted availability and access to a cancer precision medicine rationale with other non-developed scarce-resources national health systems regarding local primary healthcare programs, as previously discussed for a catholic nuns-led breast and ovary cancer syndrome BRCA1/BRCA2 genetic testing and follow-up monitoring health service for women at risk/or manifesting breast and ovary cancer in Cuba⁴⁷47 Gibbon S. Genomics as public health? Community genetics and the challenge of personalised medicine in Cuba. Anthropol Med. 2009; 16(2):131-146.. Our BrasMEN findings presented further similarities with the more religious-based sociocultural practices grounding people’s philanthropic behaviour around pastoral care (and paternalism) as reported for Greek Orthodox Christians, when compared to other Euro/North American societies for this same cancer type⁴⁸48 Whyte SR & Gibbon S. Special Edition for Anthropology and Medicine Biomedical Technology and Health Inequities in the Global North and South. Anthropol Med. 2009; 16:97-103.. Therefore, we questioned the existence of a potential ‘global south’ (tiers-1 and 2) ‘solidarity’-based ‘biocitizenship’ – our third innovative finding. As foreseen by Rabinow and Rose⁸8 Rabinow P, Rose N. Biopower Today. BioSocieties. 2006; 1(2):195-217. [accessed in 2019 Nov 20]. Available in: http://imap.anthropos-lab.net/wp/publications/2007/01/rabinow-rose.pdf.
http://imap.anthropos-lab.net/wp/publica... , if this pre-symptomatic interventions model is to be deployed as a national public health program,

Our findings favour such predictions for the Brazilian developing country scenario.

It could be argued that our findings confirm and illustrate Ashton-Prolla and colleagues’²⁵25 Ashton-Prolla P, Goldim JR, Vairo FP, et al. Genomic analysis in the clinic: benefits and challenges for ehalth care professionals and patients in Brazil. J. Community Genetics; 2015; 6:275-83. point that the Brazilian population holds potentiality to fully portray the ‘biological citizenship’ as described for Euro/North American societies due to the rising consumerism of precision medicine tools. Our findings support that most health professionals and decision-makers – besides the direct-to-consumer genetic testing user – have already reproduced and/or encountered the more consumerist attitude towards healthcare for health technologies users, at both private and public health sectors, due to fashion, persuasive marketing, or ‘hypochondria’, especially along Brazil’s southeast-south axis¹¹11 Maciel RM, Camacho CP, Assumpção LV, et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study. Endocr Connect. 2019; 1;8(3):289-298. – our fourth innovative finding. Before the 1988 health system reform, private healthcare insurance plans proliferated around Brazil, fuelling a consumerist approach to health care and technologies uptake, which only deepened inequity causing a consequent crisis in the social security system and reform aspiration²³23 Paim J, Travassos C, Almeida C, et al. The Brazilian health system: history, advances, and challenges. The Lancet. 2011; 377(9779):1778-97.. Given SUS’s and Brazil’s ‘health industry complex’ non-advanced and scarce resources context, millions are still denied access to basic health technologies and care being used for over half a century. Hence, the consequent construction of the ‘need’/demand (consumerism) for the clinical usership of cancer precision medicine that the BrasMEN ‘solidarity’ case study tries to avoid by proposing a more sustainable and equitable ‘global south’ solution via a public health genomics initiative. The aim is to avoid judicialisation of medicine.

Within the wider context of the ‘humanitarian right to health’ in Brazil, the issue of accessing new (and/or old) high cost health technologies – drugs and interventions⁴⁹49 Biehl J, Petryna A, Gertner A, et al. Judicialisation of the right to health in Brazil. The Lancet. 2009; 373 (9682):2182-2183. – called both private (ANS) and public health (Conitec, Anvisa, SBPC/ML) sectors decision-makers’ attention about new opportunities for public health policy-making to change national and subnational rationale for accessing and establishing clinical genetics services. Our findings, however, do not overly favour Rabinow and Rose’s prediction for the development of the more neoliberal precision medicine’s trend for enhanced health self-management outside a ‘medicalised’ environment in Brazil. Given BrasMEN ‘tiers-1 and 2 solidarity’-based ‘biocitizenship’, our data revealed that the sociocultural context about how health, disease and death are perceived – as patients and families are more ‘emotionally demanding’ at the personal level towards health professionals – differs from those from Euro/North American MEN2 findings¹⁰10 Wells SAJ, Asa SL, Dralle H, et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610. [accessed in 2019 Nov 20]. Available in: https://www.ncbi.nlm.nih.gov/pubmed/25810047.
https://www.ncbi.nlm.nih.gov/pubmed/2581...

11 Maciel RM, Camacho CP, Assumpção LV, et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study. Endocr Connect. 2019; 1;8(3):289-298.^-1212 Rodrigues KC, Toledo RA, Coutinho FL, et al. Assessment of depression, anxiety, quality of life and coping in long-standing multiple endocrine neoplasia type 2 patients. Thyroid. 2017; 27(5):693-706. – our fifth innovative finding. Our data further illuminates the way BrasMEN ‘solidarity networks’ constituted the driving-force for this shift from ‘me’ to ‘us’ in stakeholders’ attitude around how, where and who accesses and adheres to precision medicine, at both public and private sectors. These findings corroborate previous literature findings on cancer genomics implementation in Brazil²⁴24 Osada NM. O processo de biomedicalização no Brasil: estudo da prática científica em pesquisas sobre doenças genéticas [thesis]. Campinas: Universidade Estadual de Campinas; 2012. 213 p.. More importantly, our findings support that BrasMEN ‘solidarity networks’ have helped solve some of the new bioethical challenges that Euro/North American societies have been facing. By discussing the barriers and facilitators we observed under the BrasMEN case study, we can offer Euro/North American countries a ‘global south’ solution for those developing and implementing cancer precision medicine as a more sustainable and equitable public health strategy.

Differently from Euro/North American societies, when facing fears, uncertainty, denial, stigma and discrimination, BrasMEN patients-participants did not rely exclusively on ‘genetic test results’ – i.e. ‘lay expertise’ and ‘geneticisation’ – in a ‘political economy of hope’⁵⁰50 Novas C. The Political Economy of Hope: Patients' Organizations. Science and Biovalue. BioSocieties. 2006; 1(3):289-305., through which the biotechnologies of today will disclose cures and/or treatments for the future. Instead, patients-participants also relied on family, health professionals and, ultimately, on the BrasMEN ‘solidarity networks’ for information and support – the ‘global south’ solution. In this sense, we reiterate the limits of ‘biosociality’ to genetic testing because

We did not observe this more neoliberal type of ‘biosociality’ within the BrasMEN case study – our sixth innovative finding.

BrasMEN ‘friendly agreement’ was paramount to help MEN2 patients, RET-mutations carriers, and health professionals support each other emotionally, financially and with the adequate level of health information and technologies as people started feeling safer, and trusted family members and health professionals. ‘Tiers-1 and 2 of solidarity’-based ‘biosociality’ helped BrasMEN stakeholders manage risk, choice, agency and responsibility collectively, once the cancer precision medicine as a public health strategy was established locally. In this sense, we observed no boundary over stakeholders’ agency as people helped each other communicate and translate what they ‘know’ about cancer, genes, screening and familial diseases from an experiential perspective.

The BrasMEN health professionals’ willingness to share their biomedical collective responsibility for managing an individual’s health status with patients and families – the successful genetic counselling modus operandi – was a facilitator for individual/familial engagement and adherence to the cancer precision medicine as a ‘global south’ solution for a public health genomics initiative – our seventh innovative finding. Therefore, bridging this governmental gap in investments and sustainable public policies for the establishment of a precision medicine approach to tackle cancer as a public health issue, genetic testing and counselling engendered patients-participants’ and health professionals’ ‘biopower’ negotiation to construct family pedigrees. Our BrasMEN case study offers providential evidence for the fallibility of genetic tests (or better of ‘geneticisation’). Their potentiality for false-negatives and/or false-positive results can promote not only further uncertainty in patients and families, but also distrust, which attempts against professional and institutional integrity, besides requiring better ‘articulation’ skills from all parties involved in prophylactic approaches of healthcare delivery⁵¹51 Gibbon S. Re-Examining Geneticization: Family Trees in Breast Cancer Genetics, Sci Cult (Lond). 2002; 11(4):429-457.. Under such scenario, our findings illustrate how all collectively articulated their respective expertise to translate the individual lexicon employed by each party involved, when going from one social world to the other, without losing their inherited meaning through verbal communication. It is at tiers-1 (personal) and 2 (group practices) of the intersecting social worlds – where technologies go from the bench to the bedside, and vice versa – that we observed how BrasMEN ‘global south’ solution is innovating the 21st century of precision medicine and big data analysis as a successful ‘public health genomics’ initiative.

Finally, on the judicialisation issue, the three cases of private health insurance discrimination and stigmatisation identified along Brazil’s southeast-south axis reverberated the health professionals’ and decision-makers’ worries about wide implementation of genetic testing without prior discussion about an adequate regulatory context to guarantee systematic confidentiality of genomic individual (and big) data, as well as adequate training for health professionals performing genetic counselling. Given the high-rate consumerism along Brazil’s southeast-south axis and the rising marketing perspectives for non-directed genetic testing, our data suggests the pursuit of the stakeholders’ regulatory claims.

Concluding remarks

Despite having a public health system that is scarce in resources under Brazil’s developing country scenario, the BrasMEN initiative developed a ‘global south’ solution to invest in risky developments such as a cancer precision medicine to tackle a public health issue in a more sustainable and equitable manner than has been established in Euro/North American contexts for MEN2.

Our case study illuminates how the BrasMEN ‘solidarity networks’ can be proposed as a developing country (‘global south’) solution to mend such a risky investment and a series of bioethical challenges that have been identified as barriers to both development and implementation of precision medicine in Euro/North American countries – where they also rely on a ‘hidden research system’ for cancer genetic diagnosis. In this sense, we propose that the BrasMEN experience can become a pilot for testing a ‘public health genomics’ initiative as a way of reaching spaces outside the scope of the southeast-south axis in Brazil.

Most importantly, we reiterate that our work is the first to bridge this gap in robust qualitative – grounded theory-based – methodology and offer in depth findings on both psychological and social consequences of committing to undergo MEN2 prophylactic and/or curative treatment based on genetic testing, globally. We also outline that our findings are generalisable within the scope of familial cancer precision medicine and/or rare diseases, for which access to high-cost and high-density technologies such as genetic testing constitutes a matter of both social (amongst patients, family members and governments) and professional (amongst clinicians, clinical and/or genetics/molecular biology researchers) dispute. In this sense, our case study illuminates how Brazilian health professionals are actively sharing their biomedical collective’s chief task with lay people – enhancing a collective responsibility onto self-regulating individual and familial health status – as means to overcome paternalism and its health system’s shortcomings via a new form (a ‘global south’ type) of ‘biocitizenship’: the ‘solidarity’-based ‘biocitizenship’ – a Brazilian new (social/soft) technology in health.

Acknowledgements

The authors are grateful for the insightful comments and support from Barbara Prainsack, Professor in Sociology, Department of Global Health & Social Medicine, King’s College London, and Sarah Gibbon, Reader in Anthropology, Department of Anthropology, University College London, UK.

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