Presence of Tumor-Infiltrating Lymphocytes Following Neoadjuvant Treatment May Contribute to Worse Survival in Patients With HER2-Positive Breast Cancer

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Patients with HER2-positive breast cancer may be less likely to survive if their initial treatment fails to eradicate the tumor completely and they have high levels of tumor-infiltrating lymphocytes in their residual tumors, according to a new study published by Miglietta et al in the European Journal of Cancer. The findings were also presented at the 13th European Breast Cancer Conference (Abstract 4).

Study Background

While tumor-infiltrating lymphocytes normally help the body’s immune system fight cancer cells, in HER2-positive breast cancer, the presence of posttreatment tumor-infiltrating lymphocytes seemed to be counterproductive if any tumors remained after patients had received neoadjuvant treatment.

“In patients with HER2-positive breast cancer undergoing neoadjuvant treatment, higher levels of tumor-infiltrating lymphocytes when patients are first diagnosed are known to be associated with a greater likelihood of the cancer disappearing from the breast and the axillary lymph nodes and with improved survival,” said lead study author Federica Miglietta, a research fellow in the Department of Surgery, Oncology, and Gastroenterology at the University of Padova and a medical oncologist at the Institute Oncology Veneto. “However, there have been conflicting data on the role of [tumor-infiltrating lymphocytes] in patients who still have residual disease after neoadjuvant treatment.”

Research Methods and Results

Dr. Miglietta and her colleagues looked at data from 295 patients with HER2-positive breast cancer, 66% of whom (n = 195) had residual tumors after neoadjuvant treatment. Information on residual cancer burden and tumor-infiltrating lymphocytes in the residual tumors was available for 180 and 159 patients, respectively.

“We evaluated the levels of [tumor-infiltrating lymphocytes] in surgical samples of residual disease after neoadjuvant treatment and also assessed their prognostic role,” explained Dr. Miglietta. “We found that overall survival for patients with HER2-positive breast cancer who had [tumor-infiltrating lymphocytes] on more than 15% of the surface area of their tumor[s] was significantly shorter than patients with lower levels of [tumor-infiltrating lymphocytes].”


  • Overall survival for patients with HER2-positive breast cancer who had tumor-infiltrating lymphocytes on more than 15% of the surface area of their tumor(s) was significantly shorter than patients with lower levels of tumor-infiltrating lymphocytes.
  • 68% of patients with high levels of tumor-infiltrating lymphocytes in their residual tumors were alive after 5 years, compared with 84% of patients with low levels of tumor-infiltrating lymphocytes.

Approximately 68% of patients with high levels of tumor-infiltrating lymphocytes in their residual tumors were alive after 5 years, compared with 84% of patients with low levels of tumor-infiltrating lymphocytes.

“We know that the tumor is surrounded by the so-called tumor microenvironment, like a complex ecosystem where tumor cells and the patient’s normal cells—including immune cells—affect and shape one another. 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 fighting against them, and this phenomenon seems to profoundly affect the natural history of the disease,” emphasized Dr. Miglietta, noting that these findings applied only to patients with HER2-positive breast cancer and not to patients with other types of breast cancer.

“The fact that higher levels of [tumor-infiltrating lymphocytes] in residual disease is associated with worse outcomes seems to be a distinct feature of HER2-positive [breast] cancer. Indeed, the opposite has been consistently reported for triple-negative breast cancer. This suggests that the behavior of the residual disease immune microenvironment is highly dynamic and is strictly related to breast cancer type and exposure to treatment,” continued Dr. Miglietta.

Patient Stratification With New Prognostic Model

The researchers used the information on tumor-infiltrating lymphocytes, residual cancer burden, and patient outcomes to develop a new prognostic model for reliably predicting the probability of overall survival.

“This provides a more accurate tool to stratify patients properly from a prognostic point of view so that we can know how the disease is likely to evolve, and this information can be potentially used—if validated—to plan treatments accordingly following neoadjuvant therapy and surgery. Our new prognostic model is associated with overall survival, which represents one of the most reliable and clinically relevant pieces of information for patients with cancer and their doctors,” Dr. Miglietta highlighted.

If validated by further studies, the new prognostic model may not only improve predictions of outcomes for patients with HER2-positive breast cancer where neoadjuvant treatment has failed to completely eradicate cancer cells, but it could also be used to redefine objectives for new clinical trials of neoadjuvant therapies and to identify patients who are suitable for other treatments when the neoadjuvant treatments are ineffective.


The researchers plan to undertake a more comprehensive evaluation of the composition of tumor-infiltrating lymphocytes; an analysis of gene expression to identify genomic differences that are associated with the levels of tumor-infiltrating lymphocytes and their composition after neoadjuvant treatment; and a validation of their results in larger, prospective studies.

“The role of the immune system in cancer has been interesting [to] us for some time. We have seen that some cancers respond well to drugs, such as checkpoint inhibitors, that help the immune system to recognize and kill cancer cells. In HER2-positive breast cancer, it appeared that higher levels of tumor-infiltrating lymphocytes predicted better responses and outcomes in patients. But, until now, [researchers] had not really looked at cancer that has not been cleared by treatment. This study suggests that [tumor-infiltrating lymphocytes] in residual disease are not good news,” underscored David Cameron, MD, Professor of Medical Oncology at the University of Edinburgh Cancer Research Centre, Deputy Director of the Innovative Health Care Delivery Programme, and President of the European Breast Cancer Council, who was not involved in the study.

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

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