Abstract S1-09: Evaluation of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarker in different subtypes of breast cancer treated with neoadjuvant therapy - A metaanalysis of 3771 patients
Authors: Denkert C , von Minckwitz G , Darb-Esfahani S , Ingold Heppner B , Klauschen F , Furlanetto J , Pfitzner B , Huober J , Schmitt W , Blohmer J-U , Kümmel S , Engels K , Lederer B , Schneeweiss A , Hartmann A , Jakisch C , Untch M , Hanusch C , Weber K , Loibl S 
Published: March 2017

Abstract
Background: Tumor-infiltrating lymphocytes (TILs) have been shown to be predictive for response to neoadjuvant therapy, in particular in triple-negative and HER2 positive breast cancer, suggesting that subtypes of breast cancer are immunogenic. The role of TILs in luminal breast cancer as well as the impact on prognosis in the different subtypes is less clear. In this study we evaluated TILs in a total of 3771 breast carcinomas from 6 prospective neoadjuvant clinical trials and evaluated their relevance for pCR, DFS and OS in different molecular subtypes.
Methods: A total of 3771 tumors from the clinical studies GeparDuo, GeparTrio, GeparQuattro, GeparQuinto, GeparSixto, GeparSepto were evaluated for stromal TILs by standardized methodology. Data on pCR were available for all tumors, DFS and OS was available for 2560 tumors. Logistic regressions, Cox regressions and Kaplan-Meier analyses were performed. In addition, a combined analysis of pCR, survival and TILs in different subtypes was performed.
Results: In the complete cohort of 3771 tumors, increased TILs (&gt;=60%) were observed in 19% of tumors, these tumors with &gt;=60% TILs had a pCR rate of 44% (p&lt;0.0005). Increased stromal TILs (&gt;=60%) were observed in 30% of TNBC (n=906), in 19% of HER2+ tumors (n=1379) and in 13% of HR+/HER2- tumors (n=1366). In all three subtypes, increased TILs were significantly associated with increased pCR rates (p&lt;0.0005). In univariate logistic regression analysis of stromal TILs as a continuous variable, a 10% increase in TILs increased the probability to achieve a pCR by 16% in TNBC (OR 1.16), 13% in HER2+ (OR 1.13) and 33% in HR+/HER2- (OR 1.31,p&lt;0.0005 for all three groups). Similar results were observed in multivariate logistic regression (p&lt;0.0005 for all three groups). In univariate Cox regression, increased TILs were associated with improved DFS survival in TNBC (HR 0.93 per 10% TILs, p=0.01) and HER2+ BC (HR 0.93 per 10% TILs, p=0.02). In luminal (HR+/HER-) tumors there was no effect of TILs observed on DFS (p=0.46). In the luminal group increased TILs were associated with reduced OS (HR 1.10 per 10% increase in TILs, p=0.01), and increased TILs (&gt;=60%) were associated with worse survival in Kaplan-Meier analysis in luminal tumors (DFS: p=0.04, OS: p&lt;0.0005). A detailed analysis of subgroups of luminal BC as well as the link to pCR will be presented.
Conclusion: Our results suggest that tumor-infiltrating lymphocytes are a strong predictive marker for response to neoadjuvant chemotherapy in all molecular subtypes, and this predictive effect is translated into a survival benefit in HER2+ BC and TNBC. In contrast, a survival benefit is not observed in luminal BC, suggesting a different biology of the immunological infiltrate in this subtype.
Citation Format: Denkert C, von Minckwitz G, Darb-Esfahani S, Ingold Heppner B, Klauschen F, Furlanetto J, Pfitzner B, Huober J, Schmitt W, Blohmer J-U, Kümmel S, Engels K, Lederer B, Schneeweiss A, Hartmann A, Jakisch C, Untch M, Hanusch C, Weber K, Loibl S. Evaluation of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarker in different subtypes of breast cancer treated with neoadjuvant therapy - A metaanalysis of 3771 patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-09.