The thorough monitoring of a patient with triple-negative breast cancer reveals the triggers for the progression of the disease

The IrsiCaixa AIDS Research Institute, jointly supported by the "la Caixa" Foundation and the Department of Health of the Generalitat de Catalunya, has spearheaded an in-depth study of a case of triple-negative breast cancer. The study demonstrates that cancer cells exhibit multiple genetic, protein, and cellular alterations, enabling them to evade the body's defenses and immunotherapies. Published in the journal Nature Communications, the results reveal that, despite a persistent immune response against cancer throughout the disease, the genetic complexity of cancer cells and their ability to evade immunity prevent overcoming the cancer. Oncologist and lead researcher Leticia de Mattos-Arruda, senior author of the article and currently Senior Director of Global Clinical Development at BioNTech, highlights the uniqueness of the patient's follow-up in terms of duration and the extensive analysis of samples and parameters over more than 5 years.

Triple-negative breast cancer is among the most aggressive and challenging to treat, as it does not respond to traditional breast cancer treatments. However, immunotherapy is often an option for these patients, given the higher mutation rate in this breast cancer type, making it more visible to the immune system. "We wanted to understand how the immune system fights against cancer at each stage of the disease and the mechanisms that later hinder the defenses from overcoming it," emphasizes De Mattos-Arruda.

Mutation capacity and immune system evasion, a deadly combination

The study involved 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 the time of autopsy. In the case of one of these patients, monitoring was possible from diagnosis through metastatic progression to death. "We studied sequential samples of blood, primary tumor, and metastasis using multiomic techniques. These techniques allow us to access all the information about genes, proteins, and even the cellular composition of the samples," explains Núria de la Iglesia, co-author and principal investigator of the Neoantigens and Vaccines against Cancer group at IrsiCaixa. "Obtaining such an immense amount of data and making sense of it has been the most challenging aspect," she details. Data filtering revealed that genetic and immune variability within each tumor and among different metastases is substantial, and some of these genetic changes provide cancer cells with the ability to escape the immune system. The mechanisms through which cells evade defenses are diverse, ranging from preventing the production of inflammatory molecules that attract immune cells to hiding tumor proteins recognized by defenses. However, more importantly, the study demonstrates that these mechanisms all act synergistically within the same tumor, leading to disease progression despite the immune system's continued efforts to combat it.

Combined therapies to combat diversity

The team has identified which tumor proteins are capable of stimulating the immune system – called neoantigens – at each stage of the disease process. In this way, they have drawn a "molecular clock" that allows them to understand tumor diversity throughout the course of the disease and identify potential targets for future treatments. "Upon delving into these tumor proteins, we have discovered a mutation in the p53 gene that is particularly intriguing as it is recognized by the immune system and, therefore, activates defenses against the tumor. This mutation could serve as the foundation for the development of future therapeutic vaccines targeted at patients with triple-negative breast cancer exhibiting this genetic alteration," comments De la Iglesia.

However, the study's results demonstrate that a single therapy is not sufficient. “Cancer is a dynamic process, and there are multiple mechanisms, both genetic and immune, that evolve and converge, even within the same patient. This shows us that the enemy we are facing is very intelligent, and furthermore, the molecular clock advances at different rates in advanced stages, making precision therapies more challenging to implement. That's why it is necessary to develop therapies that can block various immune evasion mechanisms simultaneously and attack cancer from different angles," concludes De Mattos-Arruda.

About the Study

The project has received support from “Ayuda Merck de Investigación 2020” in Immuno-oncology and has been conducted in collaboration with centers in Spain, the United Kingdom, and the United States, including the National Center for Genomic Analysis, Omniscope, the Institut Oncològic Rosell, the Memorial Sloan Kettering Cancer Center and the Cancer Research UK Cambridge Institute.