Immunological markers in patients with breast cancer occurring during pregnancy - Results from GBG BCP study

Abstract Background: Breast cancer is one of the most common malignancies during pregnancy. Although breast cancer in pregnancy (BCP) is still a rare event (1 in 3000 to 10000 pregnancies), the incidence is likely to increase as more women tend to delay childbearing into later life and the overall lifetime cancer risk increases with age. Pregnancy presents a complex and unique immunological condition. Pregnant women are widely considered to be in an immunosuppressed state, making them more susceptible to infectious diseases. Recent studies have shown similarities between malignancies and the semi-allogenic fetus in terms of immune evasion strategies, for example upregulation of non-classical human leukocyte antigen G (HLA-G). The loss or downregulation of HLA class I is also a way to escape anti-tumor immunity. The aim of this study was to investigate the tumor biology and immunology of pregnant breast cancer patients and the impact of pregnancy on the immunological characteristics of the breast cancer. Methods: 196 of 2831 patient enrolled in the BCP registry (GBG 29) had available tumor material. After identifying representative tumor regions, tissue microarrays (TMAs) of formalin-fixed paraffin embedded core biopsies or surgical specimens from 126 pregnant breast cancer patients treated with neo-(adjuvant) chemotherapy were constructed. TMAs were stained via immunohistochemistry to assess estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki-67 (<20% vs ≥20%), and immune markers HLA class I (≤5% vs >5%), HLA-G (≤5% vs >5%), TIGIT and Nectin4 as well as hematoxylin-eosin for the prevalence of tumor-infiltrating lymphocytes (TILs, ≤30% vs 31-60% vs >60%). Results: Median age of the patients was 34 (range 26 - 47) years. At the time of diagnosis 50.8% of patients had cT2 tumor and 36.8% nodal involvement. The pre-dominant histological tumor type was ductal or ductal-lobular-invasive carcinoma (89.5%) with poor differentiation (G3: 68.3%). 78.5% of patients were centrally HER2 negative, 42.1% ER-positive and 53.2% PgR-positive; 53.3% had a high expression of Ki-67 (≥20%). With regards to breast cancer subtypes, most patients had either TNBC (34.7%) or HER2-/HR+ breast cancer (43.8%). HLA class I expression (≤5%) was downregulated in 21.3% of patients while 46.3% showed upregulation of HLA-G expression (>5%). Analyzing HLA-G as continuous variable demonstrated an increased but not significant median expression of HLA-G in T3-4 (N=27) compared to T1-2 (N=99) tumor stage (12.4% vs 3.4%, p=0.226). TILs were detected in 62 out of 126 analyzed patients, of whom 93.5% (N=58) had a low expression of TILs (≤30%). Analysis of TIGIT and Nectin4 is ongoing. Conclusions: The high prevalence of low TILs expression in breast cancer during pregnancy might be a sign of reduced maternal immunity associated with pregnancy. HLA class I downregulation detected in our cohort suggests that it is an independent factor of anti-tumor immunity. Additional immune markers and data from a non-pregnant cohort are currently evaluated to make valid conclusions regarding gestational effects on classical and immunological tumor features. Those data will be presented at the meeting. Citation Format: Kristin Galas, Moritz Gleitsmann, Julia Rey, Christine Solbach, Isabell Witzel, Thomas Karn, Andreas Schneeweiss, Bruno Sinn, Tanja Fehm, Carsten Denkert, Volkmar Müller, Anne-Sophie Litmeyer, Christian Schem, Paul Jank, Frederik Marmé, Jenny Furlanetto, Peter A. Fasching, Elmar Stickeler, Olaf Ortmann, Marion van Mackelenbergh, Valentina Nekljudova, Sibylle Loibl. Immunological markers in patients with breast cancer occurring during pregnancy - Results from GBG BCP study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-14.