Abstract PO3-15-05: B cell immunology predict response and survival in PD-1/PD-L1 targeting immune checkpoint inhibition of metastatic breast cancer
Authors: Fremd Carlo , Schulze Markus , Cetin Miray , Boehm Hannah , Lenoire Bénédicte , Akilli-Oeztuerk Oezlem , Zörnig Inka , Charoentong Pornpimol , Lyu Yanhong , Collaborators Catch , Hübschmann Daniel , Kommoss Felix , Thewes Verena , Schneeweiss Andreas , Zapatka Marc , Hartmann Felix , Lichter Peter 
Published: May 2024

Abstract
Critically understudied in the era of T cell immunotherapies, aggregation of B cells within tertiary lymphoid structures (TLS) has recently been linked to improved response and survival in immune checkpoint inhibition (ICI). While this has been reported for several cancers, including melanoma, lung cancer, bladder and renal cell cancer, there is an unmet need to understand molecular patterns in tumors with limited mutational burden (TMB) and low overall abundance of tumor infiltrating lymphocytes (TILs). Here, we report on the landscape of B cells in metastatic breast cancer, inferred by bulk sequencing (WGS/RNAseq) and multiplexed ion beam imaging (MIBI-TOF) in 203 patients across the breast cancer biology (ER/PR/HER2), collected from real world data (CATCH diagnostic and register study, NCT05652569). Median age was 53 years (range, 23-79), with a median of 3 systemic treatment lines for advanced or metastatic disease. The majority of biopsies were taken from the liver (49%), followed by breast (15%), lymph node (13%), skin (6%) and lung (6%). Immunohistochemistry based subtyping revealed 61% of the HR+/HER2- (or Luminal HER2-), followed by 26% of HR-/HER2- (TNBC), and 15% of HER2+ subtype. Immunological subtyping by stromal TILs and CD8+ infiltrates defined 3 subgroups with 57% being desert, 18% inflamed and 19% of no special type (6% NA). The majority (52%) was scored CD20+ with minimal colocalization in 45% of samples. MIBI-TOF demonstrated a continuum of coordinated B cell and T cell aggregation in the tumor microenvironment with lymphoid aggregates in 29% and mature TLS structures in 26% of patients. No correlation with conventional biomarkers for immunogenicity (PD-L1, TMB) has been observed. Chart review identified 21 patients treated by immune checkpoint blockade (ICI) targeting PD-1 (Pembrolizumab) or PD-L1 (Atezolizumab), either as monotherapy or in combination with chemotherapy/targeted therapy. Overall response rate (ORR) at week 12 was 57%, disease control rate (DCR) was 71%. RNA signature levels for germinal center signalling, B cell activation and antibody secretion correlated with quality of B cell aggregation and, importantly, significantly with response to ICI (Kruskal Wallis p=0,028). B cell derived prediction of response was independent of PD-L1 protein expression, breast cancer subtype, BRCA mutation status or TMB. Downstream single cell analysis, computational immunogenomics as well as spatial neighbourhoods will be reported at the meeting. These results extent B cell centered molecular insights to metastatic breast cancer and may pave the way for a composite biomarker, selecting patients for ICI who benefit meaningful and would not have been identified by the current standard of care.
Citation Format: Carlo Fremd, Markus Schulze, Miray Cetin, Hannah Boehm, Bénédicte Lenoire, Oezlem Akilli-Oeztuerk, Inka Zörnig, Pornpimol Charoentong, Yanhong Lyu, Catch Collaborators, Daniel Hübschmann, Felix Kommoss, Verena Thewes, Andreas Schneeweiss, Marc Zapatka, Felix Hartmann, Peter Lichter. B cell immunology predict response and survival in PD-1/PD-L1 targeting immune checkpoint inhibition of metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-15-05.