They discover what factors make triple negative breast cancer progress

The exhaustive analysis of a case allows us to observe how the genetics of the tumor and the patient's immune system evolve in parallel. The research highlights the need to implement combined therapies to achieve results in advanced stages of the disease and the importance of diagnosing and treating it as soon as possible.

The IrsiCaixa AIDS Research Institute has led the study of a case of triple negative breast cancer which demonstrates how cancer cells present multiple genetic alterations, but also protein and cellular processes, which allow them to escape the body's own defenses and immunotherapies.

The results published in the journal Nature Communications. show that, although the immune response against cancer remains firm until the end of the disease, the genetic complexity of cancer cells and their ability to evade immunity prevent it from winning.

“The patient's follow-up has been unique both in terms of the follow-up time and the number of samples and parameters studied. “We have looked at every corner of the tumor and the person's immune system for more than 5 years,” he explains. Leticia De Mattos-Arruda, oncologist at IrsiCaixa during the study, senior lead author of the article and currently at BioNTech.

The patient's follow-up has been unique both in terms of the follow-up time and the number of samples and parameters studied. Leticia De Mattos-Arruda, IrsiCaixa

Triple negative breast cancer It is one of the most aggressive and difficult to treat since it does not respond to classic treatments. However, immunotherapy is usually an option for these patients since they have many more mutations than the rest, and these make them visible to the immune system.

“We wanted to understand how the immune system manages to fight cancer at each stage of the disease and what mechanisms make it so that, later on, the defenses are not able to defeat it,” highlights De Mattos-Arruda.

From left to right, researchers De la Iglesia and De Mattos-Arruda appear in the image. / IrsiCaixa

Mutation and evasion of the immune system

The study has had 112 samples from 12 patients of metastatic triple negative breast cancer, including primary tumors and metastases present during the course of the disease and at the time of autopsy. In the case of one of these patients, it has been possible to follow up from diagnosis, through the progression of metastases, and until death.

“We have studied sequential samples of blood, primary tumor and metastasis with multi-omics techniques, which allow access to all the information on the genes, proteins and even the cellular composition of the samples,” he indicates. Núria of the Church, co-author and researcher at IrsiCaixa. “Getting all that huge amount of data and making sense of it has been the most difficult.”

The study included 112 samples from 12 patients with metastatic triple-negative breast cancer, including primary tumors and metastases present during the course of the disease and at autopsy.

Filtering this data has made it possible to see that the genetic and immune variability both within each tumor and between the different metastases is very large, and that some of these genetic changes provide cancer cells with the ability to escape the body's defenses.

The mechanisms through which cells avoid them are very varied, from preventing the production of inflammatory molecules that attract immune cells to the tumor to hiding tumor proteins recognized by the defenses.

However, what is more important is that the study demonstrates that these mechanisms act all at the same time in synergy within the same tumor, which leads to the progression of the disease despite the continued efforts of the immune system to fight it.

Combined therapies to combat it

The team has identified which are the tumor proteins capable of stimulating the immune system – called neoantigens – at each stage of the disease process. In this way, they have drawn a molecular clock to understand tumor diversity and have possible targets for future treatments.

“By delving deeper into these tumor proteins, we have found a mutation in the p53 gene which is especially interesting since it activates the defenses against the tumor. This mutation could be the basis for the development of future therapeutic vaccines aimed at patients with triple negative breast cancer that present this genetic alteration,” says De la Iglesia.

Cancer is a dynamic process and there are multiple mechanisms that evolve and converge, even within the same patient. This shows that the enemy we face is very intelligent.. Leticia De Mattos-Arruda, IrsiCaixa

However, the study results show that a single therapy is not enough. “Cancer is a dynamic process and there are multiple mechanisms that evolve and converge, even within the same patient. This shows that the enemy we face is very intelligent,” says De Mattos-Arruda.

"In addition, the molecular clock advances at different rates when we are in advanced stages, making the precision therapies are more difficult to apply. That is why it is necessary to develop therapies that block various immune evasion mechanisms at the same time and attack cancer from different sides,” he concludes.

Reference:

Blanco-Heredia, J. et al. “Converging and evolving immuno-genomic routes toward immune escape in breast cancer.” Nature Communications. (2024)

The project has had the help of Merck Research 2020 in Immuno-oncology and has been carried out in collaboration with centers in Spain, the United Kingdom and the United States, such as the National Center for Genomic Analysis, the Rosell Cancer Institute, the Memorial Sloan Kettering Cancer Center and the Cancer Research UK Cambridge Institute.

Source: IrsiCaixa/ Sync Agency

Rights: Creative Commons.