How to better predict human cancer risk and reduce unnecessary animal testing

When the pharmaceutical industry develops a new drug product, they need to be sure that it will be safe for humans, and most of the times this includes assessing the risk of cancer.
But how should this be done?
The risk of a drug causing cancer has historically been evaluated using animals, based on the ICH S1 international guidelines.
This means that the drug will be given to animals, usually rats and mice, for their lifetime, to then see if tumours develop.
This is what we call a carcinogenicity study. Such a study is not only time-consuming and expensive, but also requires around 600 animals per drug - which raises many ethical concerns.
Also, data suggest that studies in rodents may not be the best way to predict what will happen in humans. After all, a person is not a big rat, these are different species, so findings in rodents may not necessarily represent what we would expect for humans.
So can we do anything to better predict human risk and reduce the use of animals in these studies?
The good news is the answer is yes!
Taking into account the principles of the 3Rs - reduce, refine and replace the use of animals - there has been a proposal to find alternative ways to conclude if the animal study is indeed required: an addendum to ICH S1B was published, saying that an integrative approach that provides specific weight of evidence criteria can be used to inform whether or not an animal study adds value when assessing carcinogenicity.
This sounds like a brilliant idea, but how would this work in practice?
An effective way to achieve this is by the use of AOPs.
AOP stands for adverse outcome pathway. It basically represents the cascade of molecular events that happen in our body to lead to a disease or an adverse outcome - for example, cancer.
We know that there are different ways in which a chemical can lead to cancer. It could, for example, react with the DNA, cause mutations and then lead to cancer through a genotoxic pathway. We also know that multiple non-genotoxic pathways can lead to cancer as well.
Each of these simple events that can happen across the cascade can be measured by different test systems, including in vitro assays, so if we have these results, we can actually understand what would happen in the body and whether cancer is expected or not.
This approach has been published, and while a manual assessment may be quite complex, there is now an in silico system that can help make this process a lot faster and easier: Kaptis was developed through collaborations with industry and regulators across the world by providing best practise. It allows users to visualise all the AOPs and the different factors leading to carcinogenicity, along with the data that is available. This facilitates the expert review process, supporting decisions on how to conclude the assessment.
Now imagine the number of animal lives that will be spared as more companies start to use this approach!

The industry has already been using predictions for simple endpoints like mutagenicity, to replace the Ames test as described in ICH M7, but this is the first time that we can assess the risk of a very complex disease like cancer without the need for long term rodent carcinogenicity studies.

This is a promise of a very positive future ahead, showing how the advancement of our knowledge can now not only save time and money, spare the lives of hundreds of animals, but also give human-relevant and much better predictions of cancer risk, using science to better protect human health.

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References:
Stalford S.A., Cayley A.N., Oliveira A.A.F. Employing an adverse outcome pathway framework for weight-of-evidence assessment with application to the ICH S1B guidance addendum. Regulatory Toxicology and Pharmacology, 127, 2021,
105071, ISSN 0273-2300, https://doi.org/10.1016/j.yrtph.2021.....