La crisi consiste appunto nel fatto che il vecchio muore e il nuovo non può nascere: in questo interregno si verificano i fenomeni morbosi più svariati.

Thecrisisconsists precisely in the fact that the old is dying and the new cannot be born: in thisinterregnuma great variety ofmorbid symptomsoccur. (Gramsci, 1930, Prison Notebooks)

The Biomarkers That Cannot Be Born: The Unsustainable Political Economy of Cancer Research

Having read more than a dozen chapters about cancerbiomarkers and precision oncology, the readers of this book are likely to have made up their own minds about the issues at stake and the matters of concern. We expect and hope that the readers’ thoughts differ from ours, to be presented in this final little chapter, and we furthermore hope that such differences can be a point of departure for new engagements with the fascinating topic of the future of cancer research and cancer medicine. We have called this part “Conclusions” but only to signify the finalisation of this book project and not at all as the final word in the debates into which it enters.

Biomedical literature within cancer biomarker research serves the function of organising the field, delineating and structuring what is known and highlighting promising avenues for further scientific work. This book is about cancer biomarker research as culture and practice, and precision oncology as a sociotechnical imaginary that inhabits and surrounds that culture and practice. As such it serves a quite different purpose than that of normal science: our task has been to open up the black boxes of the field and display complexities, tensions and paradoxes. This task does not help to streamline biomedical research or make it more efficient. As we argued in the Preface and Introduction, however, such an exercise may expose unsustainable realities and imaginaries and subject them to a broader debate that, with luck and with time, might make them better aligned with ethical, social and political values and in this sense become more sustainable and responsible, leading to responsibleresearch and innovation.

Indeed, our first conclusion is that several of our chapters have shown various aspects of the unsustainablepolitical economy of cancerresearch. There are very strong arguments in favour of the vision of personalised cancer medicine, in the sense of a medicine that successfully provides the right drug for the right person at the right time and the right dose to maximise clinical benefit and minimise harmful side-effects. Biomarkers play a key role in that vision. Yet, as discussed in the chapter by Bremer et al., very few biomarkers identified in the laboratory actually make it to the clinic and to the market. In this sense, some biomarkers cannot be born for biological reasons. Biomarkers are a means to account for and manage biological complexity but within limits. The story about the anti-HER2 treatment of trastuzumab indeed shows how neat and benign the complexity had to be in order for the drug and its accompanying biomarker to become such a success. The FLT3 story presented by Engen gives a quite different example in which possible biomarkers dissolve themselves in an almost fractal-like type of biological complexity.

Still, biology alone cannot fully explain why cancerbiomarkers struggle to come into clinical use. Indeed, almost all chapters in this book contribute to casting light upon the political economy of cancerresearch and how the business models of cancerdrugs get in the way of biomarker deployment. If we think of blockbuster drugs and “one-size-fits-all” as the old type of medicine that we would like to retire, and personalised medicine as the new to be born, the allusion to Antonio Gramsci’s famous statement (quoted above) can serve to suggest that innovation in the cancer field to some extent is in a state of crisis. The old “un-personalised medicine” is no longer fit for purpose, but still the political economy remains situated in the old by which revenues are created by economies of scale, implying that the pharmaceutical industry either has to keep selling big volumes of the same drug or increase the prices pr volume. This has led to an escalation of prices as well as total costs that indeed has created “a great variety of morbid symptoms”. These symptoms are seen in the clinic, when clinicians are not allowed to use the “right drug” because it cannot be afforded; in the innovative ways to get patients enrolled in trials and in this way receive novel treatments (see the chapter by Hillersdal & Svendsen); in the priority-setting institutions in countries with public health services (see chapters by Cairns, Fleck, Kang and Tranvåg & Strand); in the media (see Stenmarck & Nilsen), and in scientific practices where striving for hyper-precision is conducive to publication bias (see the chapter by Lie Lotsberg & D’mello Peters).

The response within cancer research as in any field of biomedicine has largely been to try to alleviate and overcome these morbid symptoms by incremental progress. This book was written in 2020–2021, after half a century that at least to us contemporaries appeared as marked by neoliberal ideologies and policies, and even more so after the end of the Cold War and the apparent victory of free-market capitalism at the entry of the 1990s. In this sense, it was not a period in which academic researchers were encouraged to challenge capitalism and the profit maximisation of big pharma. Rather, they were encouraged to play by the rules and engage in so-called triple helix interactions with private enterprises and governmental support that ultimately played into and contributed to support the political economy that was the old that arguably was dying. An additional driver for the status quo was the governmentality (sensu Michel Foucault) that disciplined citizens into accepting the political and economic structures as given and instead criticising and improving themselves and their own work effort to alleviate the morbid symptoms. And in the orchestration of the sciences, medicine – perhaps partly due to its orientation towards problem-solving at the individual level and partly due to its history - was definitely not the science with the strongest presence of structural critique and political protest. To give an example, the chapter by Tranvåg and Strand argues that the morbid symptoms in priority-setting institutions cannot be solved by incremental improvements but call for more radical change. This type of structural critique, however, is almost absent in the relevant academic fields of medical ethics and sociology of medicine.

So the first issue at stake is whether a biomarker-based personalised cancer medicine can be born at all, and the first matter of concern is the political economy of medical research and innovation that impedes it.

If we continue to liken this situation with Gramsci’s notion of the crisis, it is both similar and different. What Gramsci had in mind was the type of social and political crisis in which the ruling class continues to stay in power by sheer dominance, but where the ruling ideology is no longer credible or legitimate among the subjects of that ruling class. As a thinker in the Marxist tradition, Gramsci conceptualised the crisis in material terms, as power differentials in physical force and in capital, but notably also in terms of power over cultural institutions. Developing Marxist thought and preparing the ground for Michel Foucault’s concepts of power as enacted through discourse, Gramsci maintained that the bourgeoisie could oppress the working class by means of cultural hegemony.

Almost a century after Gramsci’s reflections during imprisonment, and 30 years after the end of the Cold War, Marxist critique has become so rare, even in academe, that it almost feels idiosyncratic to point out the power differential between big, rich, globalised pharma on one hand and increasingly disempowered nation states on the other, to the extent that big pharma in some cases dictate states to keep their drug prices secret from the public. We shall refrain from suggesting how these power differentials can be overcome or even believing that there could be a quick fix of the pharmaceutical sector of capitalist societies.

Still, as scholars we are entitled to imagine what personalised cancer medicine might look like if its old political economy finally dies and gives rise to the new. Knowing that the link between market cost and product development cost of medical innovations is spurious at best, it makes perfect sense to ask: What if the price problem was solved, and the drugs and biomarkers actually became affordable? What if our friends in cancer research were provided with the resources they needed, and the outputs and outcomes of their research remained in the public domain, available to all? What if the toolbox of drugs and biomarkers became so big and well developed that by the time its tools went off license, there was no further need for new and therefore astronomically expensive drugs?

In this post-capitalist dream scenario, one could definitely imagine new clinical benefits produced and old harmful side effects being prevented. One could imagine more QALYs – quality-adjusted life years – for the patients, QALYs that at present are unavailable. And one could imagine not only more utility (for which QALY is a much used currency) but also other values, such as increased autonomy. Patients would perhaps be able to choose therapies better tailored to their own person, not only to maximise the standardised and abstract measures of overall survival, QALYs or “progression-free survival”, but also taking into account their own capabilities, dispositions, needs and desires. One could certainly expect some good prospects there, but still few miracles and silver bullets, because cancer is a system disease that often is complex, heterogenous and adaptive even within one and the same patient, as explained in the chapters by Bremer et al., Engen, Gissum and Strand & Engen. If our relationship to cancer is war, the scenario would not necessarily be that of a quick surrender on the part of the disease.

Precision Oncology: Cartesian Dream or Nightmare?

And then again, to politicians from Richard Nixon to Barack Obama, to Nobel laureates such as Peyton Rous, and to citizens and patient organisations and even the communications department of the editors’ own university, cancer must be fought by warfare and surrender must be demanded, with the greatest ferocity and persistence and at any financial cost and also, metaphorically and literally, accepting loss of civilians in the form of collateral harm in patients and beyond (see chapters by Dillekås and Strand & Engen). It is in this context that the imaginary of precision oncology emerged as the promise of making cancer research into exact science. If exact science could create rockets, dynamite, mustard gas and even the nuclear bomb, why shouldn’t it be able to kill something as lowly as abnormal proliferating cells?

As explained by Engen (chapter “Introduction to the Imaginary of Precision Oncology”), the sociotechnical imaginary of precision oncology has come to influence and to some extent replace the earlier and less extreme imaginary of personalised medicine. The second issue at stake that we wish to highlight in this final chapter, is the role of the imaginary of precision oncology in cancer research. The main matter of concern is of the normative type: What does that imaginary entail, and would its realisation be a desirable development?

The chapter by Strand and Chu performed a formal and foundational examination of that claim and arrived at the general, abstract conclusion that in order for cancer medicine to become exact, the object of study has to change. Specifically, in order for exact science to work, its subject matter has to be tamed so as to not exert certain forms of complexity and indeterminacy; it has to “cross the Styx” and lose some of its features of being fully alive, as materially and semiotically open and evolving systems. The type of self-discipline and self-monitoring that we above connected to governmentality in neoliberal societies would be but a mere beginning of that journey towards Hades. For humans to transform themselves into proper subjects of exact science, they would have to engage in biological self-monitoring and discipline of unheard dimensions. This would not be a venture of a tinkering, personalised, patient-centred medicine where therapeutic strategies would be negotiated against individual needs and desires. All variables, inputs as well as outputs, would have to be precisely measurable and strictly defined. Worse, the type of knowledge produced would likely escape human sense-making faculties, leaving therapeutic trade-offs and other value-laden decisions to algorithms or artificial intelligences. We would all become cyborgs.

Fortunately, one might say, the rigorous vision of precision oncology as an exact science seems unlikely to be realised on philosophical grounds. Still, the imaginary in its less precise manifestations gives direction to actual cancer research and practice, as illustrated in several of the chapters (Gissum, Bremer et al., Engen, Strand & Engen, Hillersdal and Svendsen). In an ever more integrated and hybrid practice of cancer research-cancer treatment, scientific goals are pursued with patients also being the means and where measurable outcomes such as progression-free survival take on more meaning than just a scientific variable. By stating this observation, we do not intend to claim that the development goes against the will of the patients or that they are not being listened to. Rather, from the co-production perspective one can witness how scientific knowledge and medical technology advances together with the fears, hopes and desires of patients, scientists and health workers, giving ever more prominence to the delay of death and creating a culture in which the good cancer patients are those who subject themselves to clinical trials and do everything to fight, resist and refuse to surrender to their horrific enemy. This cultural framing effectively implies that cancer patients with incurable disease are bound to end up as losers, and their end a failure. It also implies a cultural and scientific encouragement to try every treatment and innovation to enact the proper fighting spirit and induce hope without necessarily asking if the treatment results in less suffering rather than more. In this way the Cartesian dream of perfect knowledge and total control, including over death, risks becoming a nightmare even as the science progresses.

From Precision to Personalized Oncology: Biomarkers for Dignity?

Returning to the Gramscian trope, it is accordingly possible to view the imaginary of precision oncology as a morbid symptom of another complicated generational shift that Descartes himself managed to undertake within his own lifetime, at least if we are to believe his own words: The shift from trying to conquer death to accepting it and living one’s life in that acceptance (Strand 2021).

While reflecting on this alternative rendering of the crisis in the light of the present anthology on cancerbiomarkers and the imaginary of precision oncology, we cannot avoid taking into account the chapter that was not part of the text but in which we have lived during this book project, namely the 2020–2021 COVID-19 epidemic.

Comments and interpretations around COVID-19 should not be made lightly, and at least not until the most acute phase of the epidemic is over. Nevertheless, it has been impossible for us not to use it as an additional lens to understanding the cultural and political relationship to illness, disease and death in our society. By “our society” we should be careful to point out that both editors, Bremer and Strand, live and work in Norway. We are aware that the trajectories of COVID-19 at the time of writing, March 2021, both in terms of disease and societal measures against it, vastly differ on different continents and even neighbouring countries.

In the case of Norway, however, what has been striking is the strict and disciplined compliance with which its population has followed the governmental measures to control the spread of the Sars-CoV-2 virus, and the strong degree of public support in the governmental policies. Without presenting empirical material as evidence to that claim, we have also lived the latter 13 months within a public sphere characterised by journalists’, politicians’ and citizens’ expressions of fear of the disease and an intense if not obsessive focus on the statistics of infection rates, COVID-19 case numbers and numbers of COVID-19 related deaths. At the same time, due to the fortunate state of the Norwegian healthcare system and our affluent welfare state, even by the worst-case scenarios of Norwegian public health authorities the epidemic would not have given rise to any large increase in mortality in, say, a two- or three-year span even without vaccines and without strict measures. Unlike certain other parts of the world, the mortality of COVID-19 in Norway and Northern Europe is almost exclusively a phenomenon among the 70+ age group. Even with an uncontrolled spread of the disease, the health loss would have been much less than the health gain and the increase in life expectancy the latter 20–30 years.

So in terms of “rational” priority-setting, maximising the quality-adjusted lifetime of the population, the COVID-19 measures in our country are likely to be the most expensive QALYs in history, given not only the economic costs but also the collateral health loss from long-term unemployment, isolation, disrupted education et cetera.

We do not tell this story in order to criticise Norwegian authorities or citizens. If that were our aim, first of all we would have had to present rigorous evidence, and secondly it would not have been the right book for it. Rather, our aim is to use these observations to increase the scope of interpretation of what is at stake in the crisis of which precision oncology can be seen as morbid symptom.

One interpretation is that precision oncology and the Norwegian fear of COVID-19 are both symptoms of a culture characterised by the denial of the inevitability of death. In Norway, this cultural interpretation is above all due to the work of the philosopher Arne Johan Vetlesen (2009). If we were to paint with a broad brush, we could engage in the narrative of how the modern and secularised European subject has taken the shape of an atomised individual ego who finds incommensurately little value in everything but his (or even her) own persistent existence: Me, me, me. For this subject, death is not only unbearable: it is unacceptable. It should be prevented and delayed at any cost. The technological fantasies of immortality by deep-freezing the body or uploading the mind into the digital cloud belong to this realm; the insistence that all social activity must be controlled in order to control the virus, and the desire to transform medicine into exact science could be interpreted along the same lines. And from the co-production perspective, it would be easy to make the argument that modern Western biomedicine is closely co-produced with this subject. In terms of sustainability, such a trajectory seems to have its final destination in ecological collapse. Life on this planet cannot simply be humans.

Still, this is obviously not the only interpretation. As the book moves towards its end, we would like to propose another line of thought that nurtures more hope about a sustainable and responsible trajectory for modern society, modern medicine, cancer research and even down to cancerbiomarkers.

If a single tumour can be heterogenous, then certainly a society and a culture is, and a single human being is capable of holding a rich variety of thoughts, attitudes and emotions. Perhaps Vetlesen’s diagnosis about the denial of death is true – to some extent. This does not preclude that individuals and collectives still know perfectly well of their own mortality and frailty. In some of the chapters of this book patients appeared, with their fears, hopes and their suffering. Is it so certain that they have bought into the rationality of the QALYs, or does the prospect of a new drug represent something else – perhaps a distraction, a sense of meaning, a comforting thought that one is being taken care of, or the delay of the fear of the cruelty of the final phase of the disease?

At the same time, with a side glance to the Norwegian COVID-19 debates, the imagery that was most often invoked, was that of the Italian hospitals Spring 2020. It was an imagery not of the sheer number of deaths – they were still vastly outnumbered by the annual number of children who die from malaria – but of chaos, of desperately tired doctors who had lost control in the hospital, of patients lying unattended in the corridor as they perished. It was disordered, undignified death.

Studies that take a critical view on biomedicine (e.g. philosophy, sociology or nursing science) sometimes describe a tension between, on one hand, the biomedical focus on disease and hard endpoints and the utilitarian focus on the QALYs, and on the other, “softer” human values such as integrity, dignity and of sense of meaning and coherence.

We see no reason why personalised cancer medicine could not incorporate these human values. We wrote above that biomarkers could be developed to support a personalised medicine designed to tailor therapies according to the patient’s own capabilities, dispositions, needs and desires. More generally, they could be developed to tailor therapies aiming not only to extend life and alleviate disease symptoms but to reducesuffering, which involves much more than pain and a reduced health state. To give just one example, one of our clinician friends in the CCBIO, the Centre for CancerBiomarkers that is the source environment for this book, was asked what he thought is the most important for his (very ill) patients. His immediate reply was “a swift exit”, that is, to know that if I do not get better, at least the course of death will not be unnecessary cruel. The division of labour as of today is to leave that concern to palliative care; one could very well imagine tailored therapy that is designed for the benefit of the entire course of disease from the beginning.

Such ideas may well not be easy to operationalise and implement. Indeed, we promised that this book will not make cancer biomarker research more streamlined or efficient in the short run. But we have not written this book for its thoughts to be implemented into practice in 2022, or even 2030. We have written it for 2100 and 2200. And while the old is dying, the new, in order to be born, has to be conceived and gestated in order to nourish and develop into existence.