The study provides a more accurate tool to stratify patients with HER2-positive breast cancer

The study provides a more accurate tool to stratify patients with HER2-positive breast cancer

Patients with a type of breast cancer called HER2-positive are less likely to survive if their initial treatment does not completely eradicate the tumor and they have high levels of immune cells called tumor-infiltrating lymphocytes in the residual disease.

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

In patients with HER2-positive breast cancer undergoing neoadjuvant treatment, it is known that higher levels of tumor-infiltrating lymphocytes at initial diagnosis are associated with a greater likelihood of clearance of the cancer from the breast and axillary lymph nodes and with improved survival. However, there have been conflicting data regarding the role of TILs in patients who still have residual disease after neoadjuvant treatment.”

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

Cancer researchers are increasingly interested in the role of the immune system in cancer and ways to harness it to fight the disease. Therefore, Dr. Miglietta and her colleagues analyzed data from 295 HER2-positive breast cancer patients treated between 2001 and 2021 in 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 about the extent of residual cancer load and TILs in the residual tumors was available for 180 and 159 patients, respectively.

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

68% of patients with high TIL levels in their residual disease were still alive after five years, compared to 84% of patients with low TIL levels.

"We know that the tumor is surrounded by the so-called tumor microenvironment, a complex ecosystem in which tumor cells and the patient's normal cells, including immune cells, influence and shape each other. Our results suggest that the immune microenvironment of residual disease, after chemotherapy and HER2-targeted therapy, promotes the growth of cancer cells, rather than causing them “This phenomenon appears to have a profound impact on the natural history of the disease,” said Dr. Miglietta.

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

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"The fact that higher TIL levels in residual disease are associated with worse outcomes appears to be a unique feature of HER2-positive cancers. In fact, the opposite has been consistently reported in triple-negative breast cancer. The disease's immune system microenvironment is highly dynamic and is closely related to the type of breast cancer and exposure to treatment."

The researchers used the information on TILs, residual disease burden (residual cancer burden), and patient outcomes to develop a prognostic model that can reliably predict the probability of overall survival.

"This provides a more accurate tool to properly stratify patients from a prognostic perspective so that we can know how the disease is likely to progress, and this information, when validated, can potentially be used to plan treatments accordingly after neoadjuvant therapy and surgery. Our new prognostic model is linked to overall survival, which is one of the most reliable and clinically relevant information for cancer patients and their doctors represents,” she said.

If the prognostic model is validated through further studies, it could not only improve predictions of outcomes for patients with HER2-positive breast cancer in whom neoadjuvant treatment has not completely eradicated the cancer cells, but it could also be used to redefine targets for new clinical trials of neoadjuvant therapies and to identify patients suitable for other treatments. if the neoadjuvant treatments are ineffective.

Strengths of the study include that it is multicenter, that 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 treatments.

The researchers plan to conduct a more comprehensive assessment of the composition of TILs, analyze gene expression to identify genomic differences associated with TIL levels and composition after neoadjuvant treatment, and validate their findings in larger, prospective studies.

The President of the European Breast Cancer Council, Professor David Cameron of the Cancer Research Center at the University of Edinburgh, UK, represents the Council at EBCC13 and was not involved in the research. He commented: "We have been interested in the role of the immune system in cancer for some time. We have seen that some cancers respond well to drugs such as checkpoint inhibitors, which help the immune system recognize and kill cancer cells. In HER2-positive breast cancer, it appeared that higher levels of tumor-infiltrating lymphocytes resulted in better responses and outcomes in patients predicted. But until now, people hadn't really looked at cancer that wasn't eliminated with treatment. This study suggests that TILs in residual disease are not good news.

"We don't know if this result will be seen in other studies, but if so, it suggests that the immune system is dysfunctional in these cases because more lymphocytes don't seem to help. This shows that the history of the immune system and breast cancer may be more complex than we suspected."

Source:

European Organization for Research and Treatment of Cancer

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