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Prognostic and predictive impacts of tumor-infiltrating lymphocytes differ between Triple-negative and HER2-positive breast cancers treated with standard systemic therapies.

ABSTRACT: Tumor-infiltrating lymphocytes (TILs) have potential value for stratifying the treatment of breast cancer (BC), though their precise use remains unclear. We aimed to investigate the utility of TILs using an alternative approach in different settings. We reviewed patients with triple-negative (TN) or human epithelial growth factor receptor 2 (HER2)-positive invasive ductal carcinomas from a single institutional cohort and classified archived hematoxylin-eosin-stained samples in terms of TIL score as low (<10 %), intermediate, and high (>50 %). The prognostic and predictive values of TILs were analyzed retrospectively in both adjuvant and neo-adjuvant settings. In the adjuvant setting, the presence of TILs at primary surgery was a significant favorable prognostic factor among 154 TNBCs [relapse-free survival (RFS): p = 0.015], but not among 183 HER2+ BCs (RFS: p = 0.097). The TNBC low-TIL group tended to relapse earlier. In the neo-adjuvant setting, detection of TILs on biopsy before primary systemic therapy was associated with the ratio of patients achieving pathological complete response among 48 TNBCs (p = 0.024), but not among 58 HER2+ BCs (p = 0.30). The presence of TILs in surgical specimens after systemic therapy had prognostic value in HER2+ BC (RFS: p = 0.007). The impact of TILs differs between patients with TN and HER2+ BC treated with standard therapies. Our three-grade scale for TILs may contribute to our understanding of the importance of the tumor microenvironment in routine practice. TILs after primary systemic therapy may be useful for the further stratification of treatment of HER2+ BC.

SUBMITTER: Hida AI

PROVIDER: S-EPMC4937092 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeThe aim of the current study was to conduct a pooled analysis of studies that have investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in early-stage triple negative breast cancer (TNBC).MethodsParticipating studies had evaluated the percentage infiltration of stromally located TILs (sTILs) that were quantified in the same manner in patient diagnostic samples of early-stage TNBC treated with anthracycline-based chemotherapy with or without taxanes. Cox proportional hazards regression models stratified by trial were used for invasive disease-free survival (iDFS; primary end point), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors.ResultsWe collected individual data from 2,148 patients from nine studies. Average age was 50 years (range, 22 to 85 years), and 33% of patients were node negative. The average value of sTILs was 23% (standard deviation, 20%), and 77% of patients had 1% or more sTILs. sTILs were significantly lower with older age ( P = .001), larger tumor size ( P = .01), more nodal involvement ( P = .02), and lower histologic grade ( P = .001). A total of 736 iDFS and 548 D-DFS events and 533 deaths were observed. In the multivariable model, sTILs added significant independent prognostic information for all end points (likelihood ratio χ2, 48.9 iDFS; P < .001; χ2, 55.8 D-DFS; P < .001; χ2, 48.5 OS; P < .001). Each 10% increment in sTILs corresponded to an iDFS hazard ratio of 0.87 (95% CI, 0.83 to 0.91) for iDFS, 0.83 (95% CI, 0.79 to 0.88) for D-DFS, and 0.84 (95% CI, 0.79 to 0.89) for OS. In node-negative patients with sTILs ≥ 30%, 3-year iDFS was 92% (95% CI, 89% to 98%), D-DFS was 97% (95% CI, 95% to 99%), and OS was 99% (95% CI, 97% to 100%).ConclusionThis pooled data analysis confirms the strong prognostic role of sTILs in early-stage TNBC and excellent survival of patients with high sTILs after adjuvant chemotherapy and supports the integration of sTILs in a clinicopathologic prognostic model for patients with TNBC. This model can be found at www.tilsinbreastcancer.org .

Project description:BackgroundThe influence of the tumor microenvironment and tumor-stromal interactions on the heterogeneity of response within breast cancer subtypes have just begun to be explored. This study focuses on patients with estrogen receptor-positive/human epidermal growth factor receptor 2-positive (ER+/HER2+) breast cancer receiving neoadjuvant chemotherapy and HER2-targeted therapy (NAC+H), and was designed to identify novel predictive biomarkers by combining gene expression analysis and immunohistochemistry with pathologic response.MethodsWe performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients. Gene set enrichment analysis identified potentially relevant pathways, and immunohistochemical staining of pre-treatment biopsies was used to measure protein levels of those pathways, which were correlated with pathologic response in both univariate and multivariate analysis.ResultsIncreased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response. Lower TILs in tumor biopsies correlated with reduced likelihood of achieving an optimal pathologic response, but increased expression of the Col10A1 gene product, colXα1, had greater predictive value than stromal abundance for poor response (OR = 18.9, p = 0.003), and the combination of increased colXα1 expression and low TILs was significantly associated with poor response in multivariate analysis. ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response.ConclusionsIncreased expression of stromal colXα1 and low TILs correlate with poor pathologic response in ER+/HER2+ breast tumors. Further studies are needed to confirm their predictive value and impact on long-term outcomes, and to determine whether this collagen exerts a protective effect on the cancer cells or simply reflects other factors within the tumor microenvironment.

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Prognostic and predictive impacts of tumor-infiltrating lymphocytes differ between Triple-negative and HER2-positive breast cancers treated with standard systemic therapies.

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