How certain immune cells contribute to reduced survival in patients with HER2-positive breast cancer

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

Dr.
Federica Miglietta told the ^13th European Breast Cancer Conference that tumor-infiltrating lymphocytes (TILs) normally help the body's immune system fight cancer cells
.
However, for this type of breast cancer, which is driven by human epidermal growth factor 2 (HER2) receptors on the surface of cancer cells, TILs after treatment appear to be counterproductive if the patient still has any disease after receiving chemotherapy and anti-HER2 therapy (called "neoadjuvant therapy") before surgery
.

"In HER2-positive breast cancer patients receiving neoadjuvant therapy, when patients were first diagnosed with higher levels of tumor-infiltrating lymphocytes, the cancer was more likely to disappear from the breast and axillary lymph nodes, improving survival," said Dr.
Miglietta, a researcher at the University of Padua and a medical oncologist
at the Veneto Cancer Institute in Italy.
"However, there are conflicting data
regarding the role of TILs in patients who still have residual disease after neoadjuvant therapy.
"

Cancer researchers are increasingly interested in
the role of the immune system in cancer and how it can be harnessed to fight cancer.
So Dr.
Miglietta and her colleagues studied data from 295 patients with HER2-positive breast cancer who were treated between 2001 and 2021 at three Italian centers: Istituto oncology ogico Veneto, Azienda Unità Reggio Health Center (Sanitaria Locale di Reggio).
Emilia) and IRCCS Humanitas Research Hospital - Humanitas Cancer Centre
.
66% of patients (195 cases) had residual disease
after neoadjuvant therapy.
Information on residual disease ("residual cancer burden") and TILs in residual tumors was obtained in 180 and 159 patients
, respectively.

"We assessed the levels of TILs in surgical samples of residual disease after neoadjuvant therapy and also assessed their prognostic role," Dr.
Miglietta said
.
"We found that overall survival (TILs in more than 15% of tumor surface area) was significantly shorter in patients with HER2-positive breast cancer than in patients
with lower TILs.
"

Among patients with high TILs levels in residual disease, 68% survived after 5 years, compared with 84%
of patients with lower TILs levels.

"We know that tumors are surrounded by what is called the tumor microenvironment, like a complex ecosystem where tumor cells and the patient's normal cells, including immune cells, interact and shape
each other.
Our findings suggest that after receiving chemotherapy and anti-HER2-targeted therapy, the immune microenvironment of residual disease promotes the growth of cancer cells rather than fighting them, a phenomenon that appears to profoundly influence the natural history of the disease," said
Dr.
Miglietta.

The findings only apply to HER2-positive breast cancer, not other types of breast cancer
, she said.

"The fact that higher levels of TILs in residual disease are associated with worse outcomes appears to be a clear feature of
HER2-positive cancers.
" In fact, triple-negative breast cancer has been reported to the contrary
.
This suggests that the behavior of the immune microenvironment of residual disease is highly dynamic and closely related
to breast cancer type and treatment exposure.
”

Using information on TILs, residual disease burden ("residual cancer burden"), and patient outcomes, the researchers developed a prognostic model
that reliably predicts the overall probability of 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 develop and, if this information is validated, can potentially be used in neoadjuvant therapy and corresponding treatment plans
after surgery.
" Our new prognostic model correlates with overall survival, which is one of
the most reliable and clinically relevant information for cancer patients and their doctors.
”

If validated by further studies, the prognostic model could not only improve prognosis in patients with HER2-positive breast cancer in cases where neoadjuvant therapy fails to completely eradicate cancer cells, but could also be used to retarget new clinical trials of neoadjuvant therapy and identify patients
suitable for other therapies if neoadjuvant therapy is ineffective.

The advantages of the study include the fact that it is multicenter, patients have the same type of breast cancer and neoadjuvant therapy, and the presence of
TILs is assessed in a standardized way.
Limitations include that this is a retrospective study and that not all patients received current standard adjuvant therapy
.

The researchers are planning a more comprehensive assessment of the composition of TIL, analyzing gene expression to identify genomic differences associated with TIL levels and its composition after neoadjuvant therapy, and validating its results
in larger prospective studies.

Professor David Cameron, from the Cancer Research Centre at the University of Edinburgh, UK, who chaired the European Breast Cancer Commission and was a representative of the EBCC13 committee, was not involved in the study
.
He commented: "The role of the immune system in cancer has been intriguing us for some time
.
We've seen that some cancers respond well to drugs like checkpoint inhibitors, which help the immune system recognize and kill cancer cells
.
In HER2-positive breast cancer, the higher the level of tumor-infiltrating lymphocytes, the better the patient's response and prognosis
.
But, until now, there hasn't been a real focus on cancers that haven't been cleared by treatment
.
This study shows 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 is, it suggests that in these cases, the immune system is dysfunctional because having more lymphocytes doesn't seem to help
.
" This suggests that the relationship between the immune system and breast cancer may be much
more complex than we think.
”

Exact Sciences, Gilead, Merck, Novartis, Pfizer, Haigen
.