The results of an international multicenter study in patients with early-stage triple-negative breast cancer (TNBC) suggest that individuals with high levels of tumor infiltrating lymphocytes (TILs) in their tumor tissue may be at a comparatively lower risk of cancer recurrence and exhibit better survival rates—even when not treated using chemotherapy— than individuals with lower levels of TILs. Findings from the retrospective analysis of data from nearly 2000 early TNBC patients treated using locoregional therapy but without adjuvant or neoadjuvant chemotherapy, indicate that TIL abundance may represent a prognostic marker, and potentially help to inform on the best course of therapy for individual patients. The study was carried out by the Mayo Clinic and Gustave Roussy researchers, in collaboration with the International Immuno-Oncology Biomarker Working Group.
“This is an important finding because it highlights that the abundance of TILs in breast tissue is a prognostic biomarker in people with early-stage triple-negative breast cancer, even when chemotherapy is not administered,” said Roberto Leon-Ferre, MD, a breast medical oncologist at Mayo Clinic Comprehensive Cancer Center. “The study’s findings may inspire future clinical trials to explore whether patients with a favorable prognosis (high TILs) can avoid intensive chemotherapy regimens.”
Leon-Ferre is first author of the team’s published report in JAMA, titled “Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer.”
TNBC is a breast cancer subtype that does not respond to drugs targeting the estrogen receptor or the HER2 protein. It grows rapidly, is more likely to spread beyond the breast before diagnosis and is more likely to recur than other breast cancers. TNBC represents about 15% of all breast cancers and is more common in younger people and in women of African American, Hispanic, and Indian descent.
Most people with early-stage TNBC undergo chemotherapy either before or after surgery, including people with stage 1 breast cancer. Patients may commonly receive multiple chemotherapy drugs in combination, which can cause significant side effects. Currently, the main factors taken into consideration to determine the course of chemotherapy treatment for each person are the tumor size and the presence of lymph node metastases.
“Patients with triple-negative breast cancer (TNBC) have higher recurrence and mortality rates following tumor resection compared with patients who have hormone receptor–positive or ERBB2 (formerly HER2)-positive breast cancer,” the team noted. “Because of this, adjuvant or neoadjuvant chemotherapy is recommended for most patients with early-stage TNBC.” And while a prognostic marker associated with a lower risk of TNBC recurrence could help to identify patients who might not need intensive therapy. “Biomarkers guiding optimal systemic treatment, while avoiding overtreatment, have not been Identified,” the researchers pointed out.
Tumor-infiltrating lymphocytes are naturally existing immune system cells that can move from the bloodstream into a tumor and can recognize and destroy cancer cells. “Tumor-infiltrating lymphocyte (TIL) levels are markers of an active antitumor immune response,” the team continued. Studies have shown that early-stage TNBC patients with higher TIL levels in breast cancer tissue have longer survival following adjuvant chemotherapy, and higher rates of pathologic complete response after neoadjuvant chemotherapy, than individuals with lower TIL levels.
However, the team pointed out, “While the association of TIL levels with clinical outcomes in early-stage TNBC has been previously reported, in most studies, patients were exposed to chemotherapy, making it challenging to assess whether TIL levels were independently associated with prognosis or simply associated with greater chemotherapy responsiveness … associations of TNBC TIL abundance with breast cancer recurrence and mortality rates among women who do not undergo chemotherapy remain unclear.”
For the newly reported study, the researchers collected data on 1,966 participants with early-stage TNBC who only underwent surgery with or without radiation therapy but did not receive chemotherapy. The participants had been followed for a median of 18 years. The study results showed that higher levels of TILs in breast cancer tissue were associated with lower recurrence rates among participants with early-stage TNBC. “… survival rates were 90% for patients with a TIL level of 50% or greater, compared with 72% for patients with a TIL level of less than 30% at five-year follow-up,” the team wrote.
“Five years after surgery, 95% of participants with small tumors, stage 1 TNBC, and whose tumors had high TILs were alive, compared to 82% of patients whose tumors had low TILs,” said co-senior author, Stefan Michiels, PhD, head of the Oncostat team, Gustave Roussy. “Importantly, the breast cancer recurrence rate was significantly lower among patients whose tumors had high TILs … With nearly 2,000 participants involved in the study, we have now assembled the largest international cohort across three continents of people with TNBC in which the primary treatment was surgery without chemotherapy.”
Co-first author Sarah Flora Jonas, PhD, a statistician at Gustave Roussy, added, “This meta-analysis confirms robustly the prognostic value of TILs that we have previously reported in TNBC patients treated with chemotherapy and expands it to patients treated without chemotherapy. Future studies may allow the use of this biomarker along with standard clinicopathological factors to inform treatment decisions in TNBC patients.”
Study co-lead Roberto Salgado, MD, co-chair of the International Immuno-Oncology Biomarker Working Group, pointed out, “Of interest, the first report suggesting that an increased number of immune cells being associated with better prognosis in breast cancer patients was described by doctors at Mayo Clinic more than 100 years ago … It took a global effort and a century later to reexamine this biomarker and bring it closer to application in patient care.”
Co-senior author Matthew Goetz, MD, a medical oncologist at Mayo Clinic Comprehensive Cancer Center and the Erivan K. Haub Family Professor of Cancer Research Honoring Richard F. Emslander, MD, further commented, “TILs are not currently measured or reported in the routine examination of tissue samples of breast cancer. While prior studies have focused on measuring TILs in people treated with chemotherapy, this is the largest study to comprehensively demonstrate that the presence of TILs influences the natural behavior of breast cancer in people who have surgery and/or radiation with no additional medical treatment.”
Salgado added, “The results of this study could lead to a recommendation to include TILs in the pathology reports of early-stage TNBC worldwide, as it has the potential to inform clinicians and patients when they discuss treatment options.”
Assessing TILs as a biomarker would only require a visual evaluation by a pathologist looking through a microscope, meaning there are no additional costs associated with identifying the presence of immune cells. “TIL measurement is inexpensive and requires only visual assessment by a trained pathologist using a routine hematoxylin and eosin–stained slide (the same slide used to diagnose breast cancer and describe pathologic features),” the team wrote in their report. “TIL levels could be measured in low-resource settings, as they require minimal time and are inexpensive to perform.” This could be particularly beneficial to regions with limited resources, added Leon-Ferre.
The researchers plan to evaluate TILs as biomarkers in prospective clinical trials evaluating chemotherapy selection based on TIL levels. Ongoing efforts to conduct additional research with other potential biomarkers are underway. Noting strengths and limitations of their reported study, the team concluded, “These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early stage TNBC … Future clinical trials should consider including TIL levels as a biomarker to help evaluate whether less toxic chemotherapy could replace current multi-agent chemotherapy regimens for early-stage TNBC and high TIL levels.”
