Intra-patient and inter-metastasis heterogeneity of HER2-low status in metastatic breast cancer

Geukens, Tatjana; Schepper, Maxim De; Richard, François; Maetens, Marion; Baelen, Karen Van; Mahdami, Amena; Nguyen, Ha-Linh; Isnaldi, Edoardo; Leduc, Sophia; Pabba, Anirudh; Zels, Gitte; Mertens, Freya; Borght, Sara Vander; Smeets, Ann; Nevelsteen, Ines; Punie, Kevin; Neven, Patrick; Wildiers, Hans; Bogaert, Wouter Van Den; Floris, Giuseppe; Desmedt, Christine

doi:10.1016/j.ejca.2023.04.026

Cited by 18 publications

(12 citation statements)

References 26 publications

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“…Next, micro-environment-specific features of the tumor, such as metabolic pathway reliance and immune infiltration, can be investigated and compared between organs. Heterogeneity of emerging biomarkers used as therapeutic target, a predictive or a prognostic tool can be evaluated in the metastatic setting 14 . While all these would not be possible on the limited number of samples that can be obtained from living patients, we acknowledge the limitations specific to the post-mortem setting, allowing only for single timepoint observations in a heavily pre-treated context.…”

Section: Discussionmentioning

confidence: 99%

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Rapid autopsies to enhance metastatic research: the UPTIDER post-mortem tissue donation program

Geukens,

De Schepper,

Van Den Bogaert

et al. 2024

npj Breast Cancer

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Research on metastatic cancer has been hampered by limited sample availability. Here we present the breast cancer post-mortem tissue donation program UPTIDER and show how it enabled sampling of a median of 31 (range: 5-90) metastases and 5-8 liquids per patient from its first 20 patients. In a dedicated experiment, we show the mild impact of increasing time after death on RNA quality, transcriptional profiles and immunohistochemical staining in tumor tissue samples. We show that this impact can be counteracted by organ cooling. We successfully generated ex vivo models from tissue and liquid biopsies from distinct histological subtypes of breast cancer. We anticipate these and future findings of UPTIDER to elucidate mechanisms of disease progression and treatment resistance and to provide tools for the exploration of precision medicine strategies in the metastatic setting.

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Section: Discussionmentioning

confidence: 99%

“…This lack of common features impairs systemic treatment successes, and invariably therapeutic resistance will develop. It also complicates predictive biomarker profiling at one point in time, as a single biopsy might not reflect the susceptibility to treatment of the different tumor subclones co-existing at any given moment 14 .…”

Section: Introductionmentioning

confidence: 99%

Rapid autopsies to enhance metastatic research: the UPTIDER post-mortem tissue donation program

Geukens,

De Schepper,

Van Den Bogaert

et al. 2024

npj Breast Cancer

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“…Methylation of assessed promotor regions was more similar [68] Limited heterogeneity in driver events, copy number profile, cell cycle activity, and androgen receptor activity between metastases within one patient with prostate cancer [44] Important heterogeneity in subclonal structure between primary and metastatic disease in breast cancer. Treatment drives genomic subclonal heterogeneity [15] Analysis of multiple metastases per patient allowed the evaluation of intra-patient heterogeneity in the presence of specific gene fusion events in breast cancer [45] Multiple subclones with a variety of mechanisms of therapeutic resistance can co-exist in one patient with ovarian cancer [46] Intra-patient inter-metastasis heterogeneity of HER2-low status complicates its assessment on one biopsy in metastatic breast cancer [69] Characterisation and evaluation of distribution of polypoid giant cancer cells in metastatic castration-resistant prostate cancer [72] Intra-patient inter-lesion heterogeneity in phenotype was observed in metastatic prostate cancer, including differences in androgen receptor expression and PSA expression [70] DNA methylation changes are very similar between metastases within patients with prostate cancer. Regions with consistent methylation show enrichment for cancer-related genes [47] Metastatic lesions within patients and between patients with urothelial carcinoma shared actionable mutations [48] Many of the genetic changes conferring treatment resistance were shared between metastases in the same patient with melanoma [49] No correlation between ERG and expression of PSA or androgen receptor in individual metastases in prostate cancer [71] Prognostic and predictive biomarker expression differs between primary breast cancer and matched metastases and might depend on the organ of metastasis.…”

Section: Intra-patient Inter-lesion Heterogeneity In Genomic and Phen...mentioning

confidence: 99%

“…Phenotyping has highlighted heterogeneity in clinically used biomarkers and the inadequacy of a single biopsy to assess treatment eligibility [11,[68][69][70][71][72]. Autopsy programmes have comprehensively assessed metastatic organ involvement [70,73] and have facilitated the establishment of patient-derived xenografts (PDXs) and other experimental models with subsequent investigation of treatment sensitivity [74,75].…”

Section: Intra-patient Inter-lesion Heterogeneity In Genomic and Phen...mentioning

confidence: 99%

Research autopsy programmes in oncology: shared experience from 14 centres across the world

Geukens,

Maetens,

Hooper

et al. 2024

The Journal of Pathology

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While there is a great clinical need to understand the biology of metastatic cancer in order to treat it more effectively, research is hampered by limited sample availability. Research autopsy programmes can crucially advance the field through synchronous, extensive, and high‐volume sample collection. However, it remains an underused strategy in translational research. Via an extensive questionnaire, we collected information on the study design, enrolment strategy, study conduct, sample and data management, and challenges and opportunities of research autopsy programmes in oncology worldwide. Fourteen programmes participated in this study. Eight programmes operated 24 h/7 days, resulting in a lower median postmortem interval (time between death and start of the autopsy, 4 h) compared with those operating during working hours (9 h). Most programmes (n = 10) succeeded in collecting all samples within a median of 12 h after death. A large number of tumour sites were sampled during each autopsy (median 15.5 per patient). The median number of samples collected per patient was 58, including different processing methods for tumour samples but also non‐tumour tissues and liquid biopsies. Unique biological insights derived from these samples included metastatic progression, treatment resistance, disease heterogeneity, tumour dormancy, interactions with the tumour micro‐environment, and tumour representation in liquid biopsies. Tumour patient‐derived xenograft (PDX) or organoid (PDO) models were additionally established, allowing for drug discovery and treatment sensitivity assays. Apart from the opportunities and achievements, we also present the challenges related with postmortem sample collections and strategies to overcome them, based on the shared experience of these 14 programmes. Through this work, we hope to increase the transparency of postmortem tissue donation, to encourage and aid the creation of new programmes, and to foster collaborations on these unique sample collections. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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“…Finally, when we analyzed the connective tissue of the mediastinum, we found an isolated tumor cell fragment close to the esophagus (approximately 250 µm) (Figure 7D). Motivated by recent clinical advances in treating HER2-low tumors [27,28] and the reported change of the hormone receptors and HER2 status between primary lobular cancer and metastasis [29], we assessed the HER2 score in metastasis and primary lobular tumors. Interestingly, the primary tumors scored HER2 2+, which categorized the intraductal xenografts of IPH-926 as having a HER2-low status (Figure 4L).…”

Section: Comprehensive Histopathological Characterization Of Metastat...mentioning

confidence: 99%

Optimized Modeling of Metastatic Triple-Negative Invasive Lobular Breast Carcinoma

Sflomos

Schaumann

Christgen

et al. 2023

Cancers

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Invasive lobular carcinoma (ILC) is a common breast cancer subtype that is often diagnosed at advanced stages and causes significant morbidity. Late-onset secondary tumor recurrence affects up to 30% of ILC patients, posing a therapeutic challenge if resistance to systemic therapy develops. Nonetheless, there is a lack of preclinical models for ILC, and the current models do not accurately reproduce the complete range of the disease. We created clinically relevant metastatic xenografts to address this gap by grafting the triple-negative IPH-926 cell line into mouse milk ducts. The resulting intraductal xenografts accurately recapitulate lobular carcinoma in situ (LCIS), invasive lobular carcinoma, and metastatic ILC in relevant organs. Using a panel of 15 clinical markers, we characterized the intratumoral heterogeneity of primary and metastatic lesions. Interestingly, intraductal IPH-926 xenografts express low but actionable HER2 and are not dependent on supplementation with the ovarian hormone estradiol for their growth. This model provides a valuable tool to test the efficiency of potential new ILC therapeutics, and it may help detect vulnerabilities within ILC that can be exploited for therapeutic targeting.

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Intra-patient and inter-metastasis heterogeneity of HER2-low status in metastatic breast cancer

Cited by 18 publications

References 26 publications

Rapid autopsies to enhance metastatic research: the UPTIDER post-mortem tissue donation program

Rapid autopsies to enhance metastatic research: the UPTIDER post-mortem tissue donation program

Research autopsy programmes in oncology: shared experience from 14 centres across the world

Optimized Modeling of Metastatic Triple-Negative Invasive Lobular Breast Carcinoma

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