The study provides a more accurate tool for stratifying patients with HER2-positive breast cancer

The study provides a more accurate tool for stratifying patients with HER2-positive breast cancer

Patients with a type of breast cancer called HER2-positive have a lower chance of survival if their initial treatment fails to completely eradicate the tumor and they have high levels of tumor-infiltrating immune cells called lymphocytes in the residual disease.

Dr Federica Miglietta said on the 13thThursday European Breast Cancer Conference that normally tumor-infiltrating lymphocytes (TILs) help the body’s immune system fight cancer cells. However, in this particular breast cancer, which is driven by human epidermal growth factor receptor 2 (HER2) receptors on the surface of cancer cells, TILs appeared to be counterproductive after treatment if any disease persisted after patients received chemotherapy and antiretroviral therapy. – HER2 therapy before surgery (known as “neoadjuvant therapy”).

In patients with HER2-positive breast cancer undergoing neoadjuvant therapy, higher levels of tumor-infiltrating lymphocytes when patients are first diagnosed are known to be associated with a greater likelihood of cancer clearance from the breast and axillary lymph nodes and improved survival. However, there are conflicting data on the role of TILs in patients who still have residual disease after neoadjuvant therapy.”

Dr Federica Miglietta, researcher at the University of Padua and medical oncologist at the Istituto Oncologico Veneto, Italy

Cancer scientists are increasingly interested in the role of the immune system in cancer and ways to use it to fight the disease. Dr. Miglietta and her colleagues therefore looked at data from 295 HER2-positive breast cancer patients treated between 2001 and 2021 at three Italian centers: Istituto Oncologico Veneto, Azienda Unità Sanitaria Locale di Reggio Emilia and IRCCS Humanitas Research Hospital – Humanitas Cancer Center. Sixty-six percent of patients (195) had residual disease after neoadjuvant treatment. Information on the amount of residual disease (“residual cancer burden”) and TILs in residual tumors was available for 180 and 159 patients, respectively.

“We evaluated the levels of TILs in surgical specimens of residual disease after neoadjuvant therapy and also assessed their prognostic role,” said Dr Miglietta. “We found that overall survival in patients with HER2-positive breast cancer who had TILs on more than 15% of their tumor surface was significantly shorter than in patients with lower levels of TILs.”

Sixty-eight percent of patients with high levels of TILs in their residual disease were alive at five years, compared with 84% of patients with low levels of TILs.

We know that a tumor is surrounded by the so-called tumor microenvironment, as a complex ecosystem where tumor cells and the patient’s normal cells, including immune cells, interact and shape each other. Our results suggest that the immune microenvironment of residual disease after exposure to chemotherapy and anti-HER2-targeted therapy promotes the growth of cancer cells rather than combats them, and this phenomenon appears to profoundly influence the natural history of the disease.” said Dr. Miglietta.

She said the findings apply only to HER2-positive breast cancer and not to other types of breast cancer.

“The fact that higher TIL levels in residual disease are associated with poorer outcomes appears to be a distinct feature of HER2-positive cancer. In fact, the opposite has been consistently reported in triple-negative breast cancer. This suggests that the behavior of residual cancer. The immune microenvironment of the disease is highly dynamic and closely related to breast cancer type and treatment exposure.”

The researchers used information on TIL, residual disease burden (“residual cancer burden”) and patient outcomes to create a prognostic model to reliably predict the probability of overall survival.

“This provides a more accurate tool to correctly stratify patients from a prognostic point of view so that we can know how the disease is likely to develop, and this information can potentially be used, if validated, to plan treatment after neoadjuvant therapy and surgery. Our new prognostic model is associated with overall survival, representing some of the most reliable and clinically relevant information for cancer patients and their physicians,” she said.

If confirmed by further studies, the prognostic model could not only improve outcome predictions for patients with HER2-positive breast cancer where neoadjuvant therapy has failed to completely eradicate the cancer cells, but could also be used to redefine targets for new clinical trials of neoadjuvant therapies and identify patients suitable for other treatment when neoadjuvant treatment is ineffective.

Strengths of the study include the fact that it is multicenter, that the patients had the same type of breast cancer and neoadjuvant treatment, and that the presence of TILs was assessed in a standardized manner. Limitations include that this is a retrospective study and not all patients received current standard adjuvant treatment.

The researchers plan to more comprehensively assess TIL composition, gene expression analysis to identify genomic differences that are associated with TIL levels and composition after neoadjuvant therapy, and validate their results in larger prospective studies.

The Chair of the European Breast Cancer Council, Professor David Cameron of the University of Edinburgh Cancer Research Centre, UK, is representing the Council at EBCC13 and was not involved in the research. He commented: “The role of the immune system in cancer has been of interest for some time. We have seen that some cancers respond well to drugs such as checkpoint inhibitors that help the immune system recognize and kill cancer cells. In HER2-positive breast cancer, higher levels of tumor-infiltrating lymphocytes appeared to predict better patient responses and outcomes. But until now, people haven’t really looked at cancer that hasn’t been eliminated by treatment. This study suggests that TILs in residual disease are not good news.

“We don’t know if this result will show up in other studies, but if it does, it suggests that there is something dysfunctional about the immune system in these cases, because more lymphocytes don’t seem to help. This shows that the story of the immune system and breast cancer may be more complex, than we expected.”


European Organization for Research and Treatment of Cancer

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