The future of breast cancer research is animal free 

Almost two decades ago, I took my lab coat off for the last time. I had chosen to ‘leave the lab’ and my biomedical research career behind. Driven by a passion for focusing on what I saw as a huge injustice and for trying to play a part in righting it.  – Dr Jarrod Bailey – Science Director, Animal Free Research UK 

That injustice was and remains animal experimentation. The more I learned about it, the more I felt it was ethically wrong. Certainly, we should not inflict pain, suffering and death on sensitive beings for any reason. But on top of that, there was a burgeoning epiphany that it was poor science.  

I increasingly shared a view with many other scientists that science could and should be doing better. I held a conviction that research into human diseases should move away from futile attempts to translate data from animals to humans and focus instead on the species at hand. Only by conducting research with a uniquely human perspective could we hope to understand human biology and disease and find new and effective therapies for them.  

And so, this shift in how research should be conducted is a human ethical issue as well as an animal one. If we use research methods that confound instead of inform, particularly when better approaches exist, we are letting down billions of people and patients. 

I set about building on the evidence base that is needed to change this. Evidence was already out there, but it was being ignored; there wasn’t enough. Some 200 million animals every year are used globally in science. Around 3 million in the UK alone.  

In the UK, we are where we were for much of the past four decades and even as far back as the 1960s. This is not just in terms of how many animals we use in science but also in what we know about many diseases and what we can do to treat them. Those billions of animals’ lives have delivered nowhere near enough useful data, and it can be soundly argued that much progress has been made despite their use rather than because of it. 

My own published research has added to the canon of work, showing the need to ‘do something different’ in many areas of biomedical research. Areas that have been highlighted which offer poor results using animal models include: 

• testing drugs and chemicals for their capacity to harm unborn children 
• using nonhuman primates in neuroscience research and many other fields 
• testing new human drugs for safety in monkeys, dogs and other animals 
• using chimpanzees for hepatitis C, HIV/AIDS, cancer and other research 
• why genetic differences between different species mean animal research can never be reliable for humans 
• why genetically modifying animals doesn’t help 
• how much dogs suffer in research labs; how much lab-associated stress affects experimental results as well as animal welfare 
• how little animal research ever translates directly to human benefit 
• and much more (see Research Gate).  

The future of animal-free research

In short, I (and many other scientists) believe that the human relevance of animal research is so poor we simply have to do something else. Crucially, that ‘something else’ has never been more exciting, promising and capable than it is currently.  

With specific regard to cancer, all the above appears to be especially true. We know that predicting the risk of cancer from exposure to certain chemicals, which can account for up to 20% of all cancers, cannot be predicted reliably from animal tests. The ‘general’ nature of tests using animals cannot translate to specific types of cancer, including the four most prevalent types, one of which is breast cancer (1-8). 

We also know that relying on animals to understand what is going on in cancers and to identify and test new drugs isn’t working well at all. The failure rate of new drugs generally, over time, in human clinical trials is more than 92%. For anti-cancer drugs specifically, the rate is even higher at around 96%.  

In other words, fewer than 4 in every 100 anti-cancer drugs that appear safe and effective in animal tests go on to be licensed for use in people – mostly due to unforeseen issues with safety and efficacy (9-10).  

Focus on human biology

In short, to tackle cancer from all sides – preventive and therapeutic – we need to move away from using animals and focus on human biology from start to finish. Meetings of scientists to discuss what should be done have highlighted overly defensive attitudes to animal use, overly critical attitudes to using human-specific methods, issues with requirements to ‘prove’ findings in humans and human tissues in animals, and more. Yet, amazing, positive and hugely encouraging progress is being made. 

In cancer research generally, as well as for breast cancer specifically, human-focused methods are paying dividends. The analysis of biomarkers, biological molecules found in the body’s tissues and fluids, helps to predict if new chemicals could cause cancers, including those of the breast (8).  As do various methods using cultured human cells and analysis of the activity of their genes (11-12).  

The future is in 3D

In research into cancer itself, there is growing and substantial evidence that using new 3-dimensional cultures of human cells is vastly superior to the 2-dimensional cultures used historically. 3D breast cancer cells have been shown to be more relevant in the screening of potentially effective drugs for the disease (13).  For example, by more effectively modelling the responses of breast tumours to chemotherapy drugs targeting HER2, a gene that has increased activity in one-third of breast cancers,  – researchers were able to offer a more effective drug treatment for HER positive breast cancer (14). 

3D cultures more accurately model the environments around tumours and the interactions between tumour cells and immune cells. They more accurately model how cells function in human bodies, how changes occur around tumours and more accurately predict a new drug’s safety and efficacy in humans. This is very important because the ‘tumour microenvironment’ differs between species—notably between animals used in research and humans. 

Animal Free Research UK and Breast Cancer UK

Animal Free Research UK, in collaboration with BCUK, funded human-relevant research into this specific area of breast cancer research. Our work examined the effects of certain chemicals we encounter in the environment, known as endocrine disruptors, on the risk of developing breast cancer. All use advanced, human-relevant 3D models. For more details about this work, see here. 

We also supported researchers at Aberdeen University to grow cells from breast cancer patients on plastic chips, each equipped with their own blood supply, enabling the study of cells and molecules in the human tumour microenvironment in real time, closely mimicking what happens in people. The researchers have genetically manipulated these cultures to investigate which genes might control angiogenesis (the development of new blood vessels) in breast tumours. This offers new and important insights into potential new drugs to block tumour angiogenesis.  

Breast cancer metastasis (‘spreading’ to other parts of the body) and dormancy (where small tumours remain dormant for years before starting to grow again) are being studied in cultures of human liver cells seeded with cancer cells. The blood supply to breast tumours, and the action of potential new drugs for breast cancer, are being investigated in ‘organ on a chip’ approaches.  This is where human tumours with physical and functional characteristics of actual human tumours in individual patients are modelled on small ‘chips’ with circulatory systems which help mimic human physiological environments (15-17). 

The benefit of new approaches

Crucially, human-specific 3D models and organ-on-a-chip approaches are facilitating research that is significantly more relevant to the human disease than animal methods, as well as being humane. But they are also enabling and accelerating ‘personalised medicine’—the study of patient-specific diseases, treatments, and human variation. Scientists take small samples of blood or skin from patients and reprogram cells in those samples to be stem cells, which are then turned into specific types of cells for research that are specific to the donor’s biology. 

All of this could have a huge impact on saving lives from cancer and ending animal suffering. In the UK alone, around 55,000 women every year are affected by breast cancer, and it is estimated that more than 4,000 animals are used and die directly in laboratory experiments associated with breast cancer (not including breeding). The future is already here: forward-looking research funders and scientists are embracing it, and we all stand to benefit. 

For more information about me, Animal Free Research UK and everything discussed in this blog, you can listen to our podcasts.

Dr Jarrod Bailey – Science Director, Animal Free Research UK 

References 

1. Jacobs MN, Colacci A, Corvi R et al. Chemical carcinogen safety testing: OECD expert group international consensus on the development of an integrated approach for the testing and assessment of chemical non-genotoxic carcinogens. Arch Toxicol. 2020;94:2899-2923.
2. Corvi R, Spielmann H, Hartung T. Alternative approaches for carcinogenicity and reproductive toxicity. In: Balls M, Combes R, Worth A, editors. The History of Alternative Test Methods in Toxicology (History of Toxicology and Environmental Health). Cambridge (MA): Academic Press; 2018.
3. Corvi R, Madia F, Guyton KZ et al. Moving forward in carcinogenicity assessment: Report of an EURL ECVAM/ESTIV workshop. Toxicol In Vitro. 2017;45:278-286.
4. Knight A, Bailey J, Balcombe J. Cancerous contradictions: The mis-regulation of human carcinogens based on animal data. ALTEX (Special Issue; Proceedings 5th World Congress). 2006;23:445-449.
5. Ennever FK, Lave LB. Implications of the lack of accuracy of the lifetime rodent bioassay for predicting human carcinogenicity. Regul Toxicol Pharmacol. 2003;38:52-57.
6. Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment (COC). Statement COC/G07 – Version 1.1 Alternatives to the 2-year Bioassay. 2017
7. Wolf DC, Cohen SM, Boobis AR et al. Chemical carcinogenicity revisited 1: A unified theory of carcinogenicity based on contemporary knowledge. Regul Toxicol Pharmacol. 2019;103:86-92.
8. Madia F, Worth A, Whelan M, Corvi R. Carcinogenicity assessment: Addressing the challenges of cancer and chemicals in the environment. Environ Int. 2019;128:417-429.
9. Thomas DW, Chancellor D, Micklus A et al. Clinical development success rates and contributing factors 2011-2020. Available: https://pharmaintelligence.informa.com/~/media/informa-shop-window/pharma/2021/files/reports/2021-clinical-development-success-rates-2011-2020-v17.pdf. 2021pp34.
10. Thomas DW, Burns J, Audette J, Carroll A, Dow-Hygelund C, Hay M. Clinical development success rates 2006-2015. Available: http://www.amplion.com/clinical-development-success-rates. 2016pp28.
11. Li A, Lu X, Natoli T et al. The Carcinogenome Project: In Vitro Gene Expression Profiling of Chemical Perturbations to Predict Long-Term Carcinogenicity. Environ Health Perspect. 2019;127:47002.
12. Chapman KE, Wilde EC, Chapman FM et al. Multiple-endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non-carcinogens and highlights mechanisms of action. Arch Toxicol. 2021;95:321-336.
13. Hofmann S, Cohen-Harazi R, Maizels Y, Koman I. Patient-derived tumor spheroid cultures as a promising tool to assist personalized therapeutic decisions in breast cancer. Transl Cancer Res. 2022;11:134-147.
14. Falkenberg N, Höfig I, Rosemann M et al. Three-dimensional microtissues essentially contribute to preclinical validations of therapeutic targets in breast cancer. Cancer Med. 2016;5:703-710.
15. Bano S, Ujjwal RD, Sarita M et al. Breast tumor-on-chip models: From disease modeling to personalized drug screening. Journal of Controlled Release. 2021;331:103-120.
16. Imparato G, Urciuolo F, Netti PA. Organ on Chip Technology to Model Cancer Growth and Metastasis. Bioengineering (Basel). 2022;9(1):28
17. Moccia C, Haase K. Engineering Breast Cancer On-chip—Moving Toward Subtype Specific Models. Frontiers in Bioengineering and Biotechnology. 2021;9

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