Breast cancer can undergo genomic and tumor microenvironment modifications during the administration of preoperative therapies

A study by Leticia de Mattos Arruda, principal investigator at IrsiCaixa, published in npj Breast Cancer, part of the Nature Partner Journals series, determines the genomic and tumor microenvironment changes of breast cancer biopsies during preoperative chemotherapy. The project, which began at the Cancer Research UK Cambridge Institute and the Vall d'Hebron Institute of Oncology, has characterized the genomic profile and the microenvironment surrounding the tumor in order to understand how primary breast cancer tumors are remodeled during chemotherapy. Specifically, they have focused on two subtypes of breast cancer called HER2-negative and triple-negative.

Clinical decisions in patients with early-stage breast cancer are made on the basis of molecular markers, which classify breast tumors into different subtypes. These markers are based on specific characteristics of the tumors at the time of diagnosis, but it is necessary to take into account the changes that tumors undergo during the administration of systemic treatment, i.e., between the time of diagnostic biopsy and surgical intervention. "There is very little information about the characteristics of tumors during this interval and this is why we wanted to understand whether changes occur during preoperative therapy," explains Leticia De Mattos Arruda, principal investigator of the Neoantigens and Therapeutic Vaccines against Cancer (NeoVaCan) group at IrsiCaixa and first author of the study.

In order to study possible tumor variations, the research team studied sequential samples from 35 patients with early-stage breast cancer before, during and 12 weeks after treatment with eribulin. This drug, which is a chemotherapeutic approved as standard therapy for advanced disease, was administered preoperatively in a clinical trial conducted at the Vall d'Hebron Hospital. Mutations, gene expression profile and the microenvironment surrounding the tumor were analyzed from the samples in order to gather information on HER2-negative primary breast cancers.

The results show that the mutation profile varied between patients but that very few changes were detected intrapatient during the study. Possible neoantigens were also predicted from the genomic analysis. These small proteins have mutations that are characteristic of the tumor and may have therapeutic applications, as they can be used to differentiate cancer cells from normal cells and to design targeted anticancer strategies.

The study also characterized the tumoral microenvironment and the presence of lymphocytes, cells of the immune system, infiltrated in the tumor after receiving preoperative therapy. This second characteristic is usually related to a good prognosis of the disease, since it means that the defenses are acting against the cancer cells. The results show a higher lymphocyte infiltration in patients with the triple-negative subtype, increased presence of proteins related to immune infiltration and reduced levels of proteins related to programmed cell death in those who responded well to therapy. Moreover, the reversion to the epithelial-mesenchymal transition (EMT) and remodelling of hypoxia after recieving eribulina could drive to a better immunosupresive characteristics in primary breast cancer tumors responding to therapy.

All these results suggest that genetic and environmental variations in the tumor may influence the response against preoperative treatment in early stages of breast cancer. "The results have made it possible to characterize in great detail what is happening inside the tumor while preoperative chemotherapy is being administered," adds De Mattos. "These data will be useful to take clinical decisions based on tumor status and monitor treatment efficacy very precisely," he concludes.