Evaluation of the Predictive and Prognostic Values of Stromal Tumor-Infiltrating Lymphocytes in HER2-Positive Breast Cancers treated with neoadjuvant chemotherapy

Abstract

BackgroundStromal tumor-infiltrating lymphocytes (sTILs) have been identified as a predictive biomarker for response to neoadjuvant chemotherapy (NAC) and prognosis in human epidermal growth factor receptor 2 (HER2)-positive breast cancers. However, standardized scoring methods for use in clinical practice need to be established, and the optimal threshold of sTILs to predict pathological complete response (pCR) and prognosis in HER2+ breast cancers has not yet been defined.ObjectiveThe predictive and prognostic values of sTILs in patients with HER2-positive breast cancer treated with NAC were evaluated, with the aim to explore the optimal thresholds of sTILs and to investigate the feasibility of scoring methods in clinical practice.Patients and MethodsA total of 143 core needle biopsy specimens of HER2-positive invasive breast cancers obtained from Chinese patients who had been treated with trastuzumab-based NAC followed by surgery between 2009 and 2015 were extracted from the pathology database of Fudan University Shanghai Cancer Center. sTIL levels in the pre-NAC core needle biopsy specimens were scored using methods recommended by the International TILs Working Group 2014. The associations between sTILs and pCR, disease-free survival (DFS), and overall survival (OS) were evaluated, and the optimal thresholds for predictive and prognostic values of sTILs were analyzed.ResultsFirst, sTILs were associated with a higher pCR rate in HER2-positive breast cancers. Univariate (per 10% sTILs: odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02–1.08, p = 0.001) and multivariate regression analyses (per 10% sTILs: OR 1.04, 95% CI 1.00–1.07, p = 0.034) indicated that sTILs as a continuous variable were a significant predictor of pCR in HER2-positive breast cancers. Receiver operating characteristics (ROC) curve analysis showed that a 20% threshold best distinguished the pCR subgroup from the non-pCR subgroup. The dichotomized sTILs with a threshold set at 20% was a strong predictor of pCR in the univariate (OR 0.25, 95% CI 0.12–0.52, p < 0.001) and multivariate analyses (OR 0.35, 95% CI 0.14–0.87, p = 0.024). Second, sTILs were associated with better prognosis in HER2-positive breast cancers. Univariate (DFS: hazard ratio [HR] 0.91, 95% CI 0.88–0.95, p < 0.001; OS: HR 0.88, 95% CI 0.83–0.94, p < 0.001), and multivariate analyses (DFS: HR 0.93, 95% CI 0.90–0.97, p < 0.001; OS: HR 0.92, 95% CI 0.86–0.98, p = 0.009) suggested that sTILs as a continuous variable had a strong predictive value for improved DFS and OS. As a binary variable with a threshold of 20%, univariate (DFS: HR 6.60, 95% CI 2.91–14.95, p < 0.001; OS: HR 10.29, 95% CI 2.37–44.66, p = 0.002) and multivariate analyses (DFS: HR 3.87, 95% CI 1.65–9.12, p = 0.002; OS: HR 4.74, 95% CI 1.02–22.01, p = 0.047) indicated that patients with ≥ 20% sTILs had a significantly better prognosis than the patients with < 20% sTILs.ConclusionsOur study indicates that baseline sTILs scored by methods recommended by the International TILs Working Group in pre-NAC core needle ...

Predictive Value of Tumor Infiltrating Lymphocytes in Neoadjuvant Chemotherapy Treated Breast Cancer: A Meta-Analysis of 8052 Patients

“…We analyzed the relationship between TILs and clinicopathological characteristics. As reported in most literature, total TILs are not associated with age or tumor size in breast cancer patients [33,35,39,43,50]. Earlier published showed that there was major correlation between the expression of TILs and lymph node status [49,52], which was similar with our research.…”

“…1). Finally, 11 potentially eligible RCTs [33][34][35][36][37][38][39][40][41][42]54] and 11 case-control studies [43][44][45][46][47][48][49][50][51][52][53] were considered, consisting of approximately 8 052 participants. The population of patients in each study varied from 50 to 1 060 cases, and the follow-up time ranged from 3.4 to 120 months.…”

<p>Predictors of Neoadjuvant Chemotherapy Response in Breast Cancer: A Review</p>

“…98 Both of them were associated with pCR in HER2+ and TNBC breast cancers. 95,99,100 The Breast International Group 02-08 trial indicated that each 10% elevation in intra-tumoral and stromal TILs was respectively related to 17% and 15% reduced relapse risk (adjusted P=0.1 and P=0.025), 27% and 17% reduced death risk (adjusted P=0.035 and P=0.023) in node-positive, ER-/HER2-breast cancer patients. 101 Interestingly, sTILs alone may be an essential evaluation in the assessment of pCR rates to NAC and prognosis in HER2+ breast cancers.…”

“…101 Interestingly, sTILs alone may be an essential evaluation in the assessment of pCR rates to NAC and prognosis in HER2+ breast cancers. 100,102 The majority of TILs are T lymphocytes, and B lymphocyte infiltrations are less common. 103 Abundant counts of CD8+ TILs were verified to be associated with improved prognosis and prolonged survivals of less aggressive breast cancer subtypes with over 1300 cases.…”

Predictive and Prognostic Role of Tumor Infiltrating Lymphocytes in Breast Cancer Patients With Different Molecular Subtypes: a Meta-Analysis

“…Fifteen of these researches provided HRs data of DFS or OS and we performed the pooled analysis. Twelve researches furnished HRs data of DFS [5, 13, 15-17, 24, 26, 29-31, 37, 40], and ten researches furnished HRs data of OS [5,13,15,17,18,20,21,24,26,29]. Table 1, summarized the main baseline characteristics.…”