Higher levels of stromal tumor infiltrating lymphocytes (sTILs) at diagnosis of early triple-negative breast cancer (TNBC) had a significant association with improved disease-free survival (DFS) and overall survival, data for more than 2,000 patients showed.
Each 10% increment in baseline sTILs correlated with a 13% reduction in the hazard ratio for invasive disease-free survival (iDFS), a 17% reduction in hazard for distant (d)DFS, and a 16% reduction in the hazard for overall survival (OS). Patients with negative nodes and sTILs ≥30% had a 3-year iDFS of 92%, dDFS of 97%, and OS of 99%.
The pooled analysis confirmed previous evidence of sTILs as a potential prognostic marker in early TNBC, Sherene Loi, MD, of Peter MacCallum Cancer Center in Melbourne, Australia, and colleagues reported online in the Journal of Clinical Oncology.
“Our study supports the use of TILs as a prognostic biomarker for early TNBC,” co-author Sylvia Adams, MD, of NYU Langone Medical Center in New York City, told MedPage Today via email. “TILs can be used to define a patient’s prognosis beyond the standard pathology parameters. At present, TILs should not be used in decision making to deviate from current standard practices such as adjuvant chemotherapy. However, TILs are immensely useful as a stratifier as well as biologic rationale for clinical trials.”
Previous studies showed that a higher quantity of immune filtrate was associated improved outcomes in both early TNBC and early HER2-positive breast cancer. Quantification of TILs by standard H&E pathology techniques — as a percentage infiltration in the tumor and surrounding stroma — proved to be a reproducible biomarker that could be implemented in a relatively straightforward manner in clinical pathology labs, the authors noted.
Currently, factors associated with anatomic tumor burden form the basis for assessment of prognosis in early TNBC. Loi, Adams, and colleagues performed a large pooled analysis of patient data to establish the prognostic value of TILs in the cancer subtype.
“Such evidence would strongly support the implementation of a novel biological marker in future breast cancer prognostic staging systems for early-stage TNBC, as a clinical trials stratification factor, and potentially guide immunotherapeutic development in breast cancer,” the authors wrote.
The data comprised 2,148 patients from nine studies of early TNBC treated with surgery and standard adjuvant chemotherapy. The studies employed the same approach to quantification of TILs by means of H&E staining. The primary data analysis focused on sTILs, and intratumoral (i)TILs were the focus of secondary analyses. The primary outcome was iDFS, and dDFS and OS were secondary outcomes.
The mean sTILs level was 23% and the median was 15%. A third of the patients had node-negative disease, associated with a mean sTILs level of 20.2%, all treated with adjuvant anthracycline therapy alone (55.8%) or with a taxane (44.2%). Quantification of iTILs was performed for 1,592 patients, including 1,144 with complete clinicopathologic information.
The data showed significant inverse associations of sTILs with older age (P<0.001) and increasing tumor burden (P=0.01 for tumor size, P=0.02 for extent of nodal involvement) and a positive association with higher tumor grade (P=0.001).
In a multivariable model, sTILs proved to be an independent prognostic factor for all endpoints (P<0.001 for iDFS, dDFS, and OS). The analysis demonstrated that every 10% increase in sTILs was associated with a statistically significant reduction in the hazard ratio for:
- iDFS: HR 0.87 (95% CI 0.83-0.91)
- dDFS: HR 0.83 (95% CI 0.79-0.88)
- OS: HR 0.84 (95% CI 0.79-0.89)
“Our study showed that quantity mattered,” said Adams. “While we know from other studies that immune infiltrates are mainly composed of T cells, with the method used (evaluation of tumors on H&E stained slides), subsets of T cells cannot be assessed, and therefore no data is available on the quality of the infiltrate.”
Though emphasizing the need for additional studies, the authors offered a bit of speculation about the findings.
“One could speculate that generating an effective antitumor immune response may result in significant survival improvements for patients with low TIL levels, though our data do not directly support this,” they said. “Given that the vast majority of early-stage TNBCs contained at least 1% TILs, it would seem that immunotherapeutic agents that require a preexisting response are likely to be efficacious in this setting.”
The study was supported by the Ligue Nationale Contre le Cancer, the International Breast Cancer Study Group, the Swedish Cancer League, the Cancer Council Australia, the Australia and New Zealand Breast Cancer Trials Group, the Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, the Swiss Cancer League/Oncosuisse, and the NIH.
Loi disclosed relevant relationships with AstraZeneca, MedImmune, Seattle Genetics, Bristol-Myers Squibb (BMS), Pfizer, Novartis, Genentech, Merck Sharp & Dohm, and Puma Biotechnology, as well as support from Cancer Council Victoria John Colebatch Fellowship, the Breast Cancer Research Foundation, NY, and the National Breast Cancer Foundation of Australia.
Adams disclosed relevant relationships with GlaxoSmithKline, Merck, Genentech, BMS, Celgene, Amgen, and Novartis.