The lack of T-cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLS), which are the local site of humoral and cellular immune responses against cancers, are associated with good prognosis and have recently been detected in Immune Checkpoint Blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing scRNA sequencing, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke the transition of postcapillary venules into inflamed high endothelial venules (HEVs), which generate permissive TA-TLS-like lymphocyte niches with PD1neg and PD1+TCF1+CD8 T cell progenitors that differentiate into GrzB+TCF1neg TIM3+ PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived lymphotoxin signals revealing that tumor-HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.
Background. Trastuzumab deruxtecan (T-DXd) has shown promising activity in patients with HER2-low metastatic breast cancer. As the HER2-status can vary between the primary and its corresponding metastases, treatment decisions should ideally be based on HER2 assessment of a recent biopsy. However, limited data is available on intra-patient inter-metastatic heterogeneity in HER2-status, affecting representability of a single biopsy and potential therapeutic options and outcome. We therefore assessed HER2 status on multiple metastases from patients with primary ER-positive/HER2-non-amplified breast cancer in our prospective post-mortem tissue donation program UPTIDER (NCT04531696). Methods. Ninety-one metastatic samples retrieved during the autopsies of 6 patients (range: 13–16/patient) and their respective primary tumours were immunohistochemically (IHC) stained for HER2 (HercepTestTM, RTU, ISO-15189 accredited) in our institution. Consensus scoring was performed between two pathologists according to ASCO/CAP 2018 guidelines. The observers were blinded for patient ID. Reflex fluorescence in situ hybridization (FISH) testing was performed for samples with IHC score of 2+. HER2 status was categorized as HER2-zero (IHC 0), HER2-low (IHC 1+ or IHC 2+ with negative FISH), or HER2-positive (IHC 3+ or IHC 2+ with positive FISH). To assess stability of the performance of IHC scoring in the post-mortem setting, an additional 13 samples taken from 3 metastases at regular (every 1.5h) time intervals during the autopsy underwent HER2 IHC scoring. Results. Evaluation of HER2-status in the primary tumour showed 2 patients with HER2-zero disease and 4 with HER2-low disease. A discordance between HER2 status of the metastases and their respective primary was seen in all patients. Not a single lesion was found to be HER2-positive. For every patient, at least one HER2-low metastasis was observed, with the percentage being highly variable between patients and ranging between 7 and 100%. No association was observed between HER2 status and organ site: HER2-low as well as HER2-zero lesions were found in all organs evaluated in at least 4 patients (liver, bone, pleura, lymph nodes). For 5 patients, multiple lesions within the liver were evaluated: while HER2-zero versus HER2-low status was concordant in those lesions in 4 patients, a mix of HER2 IHC scores was seen in 3 of them. IHC scores were stable over time for tumour lesions assessed repeatedly. Discussion. Important inter-lesion heterogeneity in terms of HER2-low status was observed in patients with primary ER-positive/HER2-non-amplified breast cancer participating to our post-mortem tissue donation program. This observed heterogeneity is unlikely to be due to post-mortem changes in HER2 expression. HER2-low status was found in at least one distant lesion in all patients, complicating therapeutic decision-making based on a single biopsy. Of note, IHC 1+ and 2+ scores varied between metastases of each patient too, making assessment on a single biopsy less reliable for stratification in clinical trials. Further assessment on samples from UPTIDER-patients with ER-negative disease is currently ongoing and results will be available to be presented. Citation Format: Tatjana Geukens, Maxim De Schepper, François Richard, Marion Maetens, Karen Van Baelen, Amena Mahdami, Ha-Linh Nguyen, Edoardo Isnaldi, Sophia Leduc, Anirudh Pabba, Imane Bachir, Freya Mertens, Sara Vander Borght, Ann Smeets, Ines Nevelsteen, Kevin Punie, Patrick Neven, Hans Wildiers, Wouter Van Den Bogaert, Giuseppe Floris, Christine Desmedt. HER2-16 Inter-lesion heterogeneity of HER2-status in metastatic breast cancer: possible implications for treatment with anti-HER2 antibody-drug conjugates. [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 HER2-16.
Introduction: Methylmalonic acid (MMA), a metabolite and by-product of propionate metabolism, promotes breast cancer (BC) progression in mice via the transforming growth factor-beta (TGFβ) signaling pathway (Gomes et al, Nature 2020). It is currently unknown if this effect also exists in patients with BC. Objectives: To investigate the association between baseline serum MMA concentrations in patients at BC diagnosis and development of distant metastases via a matched case-control study. Methods: We included 32 patients with early Luminal B-like BC (Lumb, median age 62.4y) and 52 patients with early triple-negative BC (TNBC, median age 50.5y) who developed distant metastases within 5 years. They were matched to an equal number of early BC patients with at least 5 years of follow-up (median age 62.2y for Lumb and 50.5y for TNBC) who did not develop distant metastases with at least 5 years of follow-up. Matching was performed based on age at diagnosis date (± 5y), tumor stage, and treatment received ((neo)adjuvant chemotherapy and radiotherapy, yes/no). Serum MMA concentrations were determined by liquid chromatography with tandem mass spectrometry (LC-MS-MS). Summary statistics, paired analyses, and multiple conditional logistic regression analyses were performed with and without adjusting for potential covariates (age, kidney function, and tumor stage). Results: Baseline serum MMA at BC diagnosis significantly correlated with age (rs=0.35, p=.005 in Lumb; rs=0.35, p=.0003 in TNBC), and negatively correlated with kidney function assessed by estimated glomerular filtration rate (eGFR, rs= -0.42, p=.0005 in Lumb; rs= -0.32, p=.0009 in TNBC). MMA concentrations at diagnosis were not associated with distant metastases in either subtype, after adjusting for kidney function, age, and tumor stage (all p>.05). Next, we categorized BC cases in the public TCGA (n=174 for Lumb; n=140 for TNBC), METABRIC (n=461 for Lumb; n=199 for TNBC), and GSE25066 (n=78 for Lumb; n=182 for TNBC) database according to their 5-year metastatic status, and analyzed the TGFβ signaling pathway activity of primary BC. Like MMA concentrations, a gene expression signature of TGFβ signaling was not associated with distant metastases in patients with BC. Conclusion: Baseline serum MMA concentrations and a gene signature for TGFβ signaling at BC diagnosis are not associated with distant metastases among patients with Lumb and TNBC subtypes. Citation Format: Qi Wu, Sigrid Hatse, Juan F. García, Patricia Altea-Manzano, Jaak Billen, Mélanie Planque, Anke Vandekeere, Yentl Lambrechts, François Richard, Annouschka Laenen, Kevin Punie, Patrick Neven, Ines Nevelsteen, Giuseppe Floris, Christine Desmedt, Ana Gomes, Sarah-Maria Fendt, Hans Wildiers. Serum methylmalonic acid concentrations at breast cancer diagnosis are not associated with distant metastases [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 P2-11-18.
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