Abstract P6-14-06: Histopathological and immune characterization of liver metastases from patients with breast cancer
Authors: Leduc Sophia , De Schepper Maxim , Vermeulen Peter , Floris Giuseppe , Biganzoli Elia , Donckier Vincent , Bohlok Ali , Gerling Marco , Richard François , Maetens Marion , Jaekers Joris , Topal Baki , Latacz Emily , Van Baelen Karen , Geukens Tatjana , Nguyen Ha Linh , Dirix Luc , Larsimont Denis , Van Kerckhove Sophie , Oliveira Rui Caetano , Kulka Janina , Lucidi Valerio , Meyer Yannick , Verhoef Cornelis , Santos Eva , Salamon Ferenc , Madaras Lilla , Szasz A. Marcell , Borbála Székely , Dede Kristòf , Engstrand Jennie , Moro Carlos Fernandez , Desmedt Christine 
Published: March 2023

Abstract
Background: Liver metastases (LM) are ultimately present in ~50% of all patients with metastatic breast cancer (BC). Metastatic seeding to the liver relies on the interaction between cancer cells and the host microenvironment, resulting into two main histopathological growth patterns (HGPs): the replacement HGP (metastasis mimics the liver architecture and exploits liver vasculature) and the desmoplastic HGP (presence of a fibrotic rim separating the hepatocytes from the tumor cells). While the prognostic value of these HGPs is established for colorectal cancer, with the desmoplastic HGP being associated with better prognosis, investigation is needed for BC. It has also been reported that patients with LM have a poorer response to immune checkpoints inhibitors. A systematic evaluation of the HGP and LM-associated immune infiltrates (stromal tumor infiltrating lymphocytes, sTIL) is currently lacking. In this study, we aimed at: (i) investigating HGPs and sTIL in LM from patients with BC, and, (ii) evaluating the association of these HGPs and sTIL with standard variables and outcome.
Patients and methods: The study currently includes clinical data and samples from: 1) a retrospective cohort of 122 patients from 7 hospitals with surgically resected LMs (represented by 548 hematoxylin and eosin (H&E)-sections), further referred to as ‘surgical cohort’ and, 2) LMs from 2 institutional post-mortem tissue donation studies for a total of 23 patients (97 H&E-sections). All available H&E-sections were used to assess HGP and sTIL. HGPs were scored according to a standardized method (PMIDs: 35650276) and categorized per patient as pure-replacement (rHGP, i.e. 100% of the tumor-liver interface is replacement) or any-desmoplastic (dHGP, i.e. at least 1% of the tumor-liver interface is desmoplastic). sTIL are expressed as the percentage of stromal area covered by mononuclear immune cells at the metastasis-liver interface. Associations were assessed using Fisher exact and Wilcoxon tests. Univariable and multivariable Cox regression analyses stratified by center were used to evaluate the role of HGP on progression-free (PFS) and overall survival (OS).
Results: In the surgical cohort, 54 (44%) of patients displayed a rHGP and 68 (56%) a dHGP. Intra-patient, meaning inter-slide, heterogeneity of the HGP was observed in 24/122 (20%) of the patients suggesting that scoring multiple slides is needed for accurate assessment of the HGPs. We did not find any statistically significant association between HGP and clinico-pathological data. Higher sTIL were associated with dHGP (p=.003), as well as with a higher histological grade (p= .087), estrogen receptor-positivity (p=0.062) and ductal histology (p= .08) of the primary tumor. rHGP was associated with worse PFS and OS, both at the univariable and multivariable level (Table). In the post-mortem cohort, we observed a higher frequency of rHGP patients (19/23 patients, 83 %) and significantly lower levels of sTIL in the rHGP patients as compared to the rHGP patients from the surgical cohort (p= .009).
Conclusion: This study represents the largest study evaluating HGPs and immune infiltrates of LMs from patients with BC. Approximately half of the surgically resected LMs have a dHGP, which is associated with higher sTIL and a better prognosis. The results from the LMs from the post-mortem cohort suggest that a more advanced stage of the disease is associated with an increase in rHGP and with a more immunosuppressed environment.
Table 1: Univariable and multivariable analyses
Citation Format: Sophia Leduc, Maxim De Schepper, Peter Vermeulen, Giuseppe Floris, Elia Biganzoli, Vincent Donckier, Ali Bohlok, Marco Gerling, François Richard, Marion Maetens, Joris Jaekers, Baki Topal, Emily Latacz, Karen Van Baelen, Tatjana Geukens, Ha Linh Nguyen, Luc Dirix, Denis Larsimont, Sophie Van Kerckhove, Rui Caetano Oliveira, Janina Kulka, Valerio Lucidi, Yannick Meyer, Cornelis Verhoef, Eva Santos, Ferenc Salamon, Lilla Madaras, A. Marcell Szasz, Székely Borbála, Kristòf Dede, Jennie Engstrand, Carlos Fernandez Moro, Christine Desmedt. Histopathological and immune characterization of liver metastases from patients with breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-06.