Gene signature could predict response to key breast cancer treatment

CDK4/6 inhibitors, combined with hormone therapy, are now the standard treatment for an advanced type of breast cancer; specifically, the one that is characterized by the expression of hormone receptors (HR+) and HER2 negative (HER2-). This treatment works by blocking the proteins CDK4 and CDK6, which are responsible for controlling cell division and growth.

By inhibiting them, cancer cells do not grow as quickly. However, not all patients respond in the same way: the tumors of some of them progress rapidly despite treatment. Therefore, it is essential to find biomarkers that allow predicting the efficacy of these drugs and personalizing the approach.

A study coordinated from Badalona by IrsiCaixa, the Catalan Institute of Oncology and the Germans Trias i Pujol Research Institute (within the CARE program) has identified KIMA, a genomic signature that makes it possible to anticipate which patients with HR+/HER2- breast cancer will respond less well to CDK4/6 inhibitors. The finding, published in the journal Clinical and Translational Medicine, may help personalize therapies and design new combinations.

“From the IrsiCaixa-IGTP-ICO consortium we analyze almost a hundred patients treated at ICO Badalona. 57% of them had a good response to treatment, with more than two years without progression of the tumor, while the remaining 43% showed an unfavorable evolution, with relapse after a few months,” explain the first authors of the study, Dr. Eudald Felip, ICO oncologist and postdoctoral researcher at IrsiCaixa, and Dr. Edurne Garcia-Vidal, postdoctoral researcher at IrsiCaixa.

An immune activation that works against

When comparing the two groups, researchers found that poorly responding patients had tumors with abnormal immune system activation. This, far from favoring the fight against the tumor, is associated with an immune environment that helps the cancer to resist treatment.

From this analysis, KIMA (Key Immune Activation) was born, a signature composed of the combined expression of nine genes—including STAT1, FOXP3 and TIGIT—whose high presence predicts a worse evolution of the disease: faster progression and shorter overall survival. In fact, the mean time to disease progression varies from 11 months in patients with high KIMA presence to 36 months in those with low KIMA presence.

The result was further validated in a second clinical study, which also found that patients who did not respond to CDK4/6 inhibitors had higher levels of KIMA.

“What we have seen is that, in this type of cancer, a highly activated immune system does not mean more defense, but more resistance of the tumor. This genetic signature allows us to identify these patients early on and opens the door to combining CDK4/6 inhibitors with novel immunomodulatory strategies,” explain the co-senior authors of the study, Dr. Ester Ballana, leader of the Virus-Host Interactions (ViHIT) research group at IrsiCaixa, and Dr. Mireia Margelí, oncologist and researcher at ICO and IGTP in the Applied Research Group in Oncology of Badalona (B· ARGO).

The results of the study suggest that KIMA could be used as a clinical tool to better select treatments.