Interobserver variability in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative invasive breast carcinoma influences the association with pathological complete response: the IVITA study

Abstract

High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland-Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from −0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for 8 participants (20%). Post hoc sTILs cut-offs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the ‘ideal’ sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions.

HER2-low breast cancer shows a lower immune response compared to HER2-negative cases

“…Overall, our results suggest that HER2low breast cancer is associated with a limited immune response compared to HER2-breast cancer, as shown by the gene-expression data of the ER+ cohort and the TIL-score of the ER-cohort. Several previous studies reported that high levels of TILs are associated with a higher probability of treatment response and an improved outcome 18,27,28 . In our study, no difference in survival was observed between these two HER2 groups, neither in the ER+ nor in the ER-cohort.…”

Interobserver Agreement of PD-L1/SP142 Immunohistochemistry and Tumor-Infiltrating Lymphocytes (TILs) in Distant Metastases of Triple-Negative Breast Cancer: A Proof-of-Concept Study. A Report on Behalf of the International Immuno-Oncology Biomarker Working Group

“…The degree of interobserver variability seems similar to the one observed in TILs evaluation in primary TNBCs [40]. Although earlier reports questioned the influence of this interobserver variability on the predictive value of TILs for achieving a pathological complete response (pCR) in the neoadjuvant setting [37,39], it was recently shown that TILs assessment according to the Working Group's method is a robust predictive marker for pCR at the group level [41]. The predictive value of TILs for pCR is not negatively affected by inter-pathologist disagreement [38], but other patient-related characteristics such as high body mass index may have an adverse impact on the prediction of pCR and remain to be further elucidated [42].…”

Predictive Biomarkers of Response to Neoadjuvant Chemotherapy in Breast Cancer: Current and Future Perspectives for Precision Medicine

“…In TNBC, lymphocyte infiltrates have been found to be increased compared to other subtypes, with stromal TILs ranging from 15 to 90% and intra-tumoral TILs ranging from 5 to 10% [ 63 , 72 ]. The GeparSixto trial evaluated 314 patient samples and showed that highly infiltrated tumors were associated with pCR [ 73 ].…”

“…The variability between centers and pathologists remains an important issue to be solved for future trials. Nevertheless, Van Bockstal et al showed that, despite the inter-observer variability, stromal TILs were significantly correlated with pCR [ 72 , 75 ].…”