A working model
After the researchers integrated their new cancer biopsies as well as other datasets, including transcriptomic data and images from thousands of healthy cells, the AI program – which they named SEQUOIA (slide-based expression quantification using linearized attention) – was able to predict the expression patterns of more than 15,000 different genes from the stained images. For some cancer types, the AI-predicted gene activity had a more than 80% correlation with the real gene activity data. In general, the more samples of any given cancer type that were included in the initial data, the better the model performed on that cancer type.
“It took a number of iterations of the model for it to get to the point where we were happy with the performance,” Gevaert said. “But ultimately for some tumor types, it got to a level that it can be useful in the clinic.”
Gevaert pointed out that doctors are often not looking at genes one at a time to make clinical decisions, but at gene signatures that include hundreds of different genes. For instance, many cancer cells activate the same groups of hundreds of genes related to inflammation, or hundreds of genes related to cell growth. Compared with its performance at predicting individual gene expression, SEQUOIA was even more accurate at predicting whether such large genomic programs were activated.
To make the data accessible and easy to interpret, the researchers programmed SEQUOIA to display the genetic findings as a visual map of the tumor biopsy, letting scientists and clinicians see how genetic variations might be distinct in different areas of a tumor.
Predicting patient outcomes
To test the utility of SEQUOIA for clinical decision-making, Gevaert and his colleagues identified breast cancer genes that the model could accurately predict the expression of and that are already used in commercial breast cancer genomic tests. (The Food and Drug Administration-approved MammaPrint test, for instance, analyzes the levels of 70 breast-cancer-related genes to provide patients with a score of the risk their cancer is likely to recur.)
“Breast cancer has a number of very well-studied gene signatures that have been shown over the past decade to be highly correlated with treatment responses and patient outcomes,” Gevaert said. “This made it an ideal test case for our model.”
SEQUOIA, the team showed, could provide the same type of genomic risk score as MammaPrint using only stained images of tumor biopsies. The results were repeated on multiple different groups of breast cancer patients. In each case, patients identified as high risk by SEQUOIA had worse outcomes, with higher rates of cancer recurrence and a shorter time before their cancer recurred.
The AI model can’t yet be used in a clinical setting – it needs to be tested in clinical trials and be approved by the FDA before it’s used in guiding treatment decisions – but Gevaert said his team is improving the algorithm and studying its potential applications. In the future, he said, SEQUOIA could reduce the need for expensive gene expression tests.
“We’ve shown how useful this could be for breast cancer, and we can now use it for all cancers and look at any gene signature that is out there,” he said. “It’s a whole new source of data that we didn’t have before.”
Scientists from Roche Diagnostics were also authors of the paper.
Funding for this research was provided by the National Cancer Institute (grant R01 CA260271), a fellowship of the Belgian American Educational Foundation, a grant from Fonds Wetenschappelijk Onderzoek-Vlaanderen, the Fulbright Spanish Commission, and Ghent University.
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