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Clinical, Pathological and Molecular Peculiarities of Lobular Breast Cancer

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 63618

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Prof. Dr. Christine Desmedt

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Guest Editor

Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, 3000 Leuven, Belgium
Interests: breast cancer; lobular breast cancer; genomics; transcriptomics; tumor microenvironment; obesity; adiposity; inflammatory breast cancer; cancer progression; dormancy

Prof. Dr. Patrick W. B. Derksen

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Guest Editor

Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands
Interests: lobular breast cancer; cell adhesion; extra cellular matrix; metastasis; mouse models

Prof. Dr. Anne Vincent-Salomon

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Guest Editor

Department of Diagnostic and Theranostic Medicine, Department of Pathology, INSERM U934, INSTITUT CURIE 26 rue d’ULM 75005 PARIS, FRANCE
Interests: molecular and phenotypical characteristics of breast cancer histological subtypes; pathology; lobular carcinoma; stroma

Special Issue Information

Invasive lobular breast cancer (ILC) represents the second most common histological subtype of invasive breast cancer. Large efforts in biomedical sciences and clinical research have yielded a wealth of data and insight into ILC development, diagnosis, progression, and responses to treatment. This knowledge has culminated in the awareness that ILC is a specific cancer type that should be recognized and treated as such.

There are nevertheless still important knowledge gaps with regard to this cancer type at the clinical, pathological, immune, and molecular level that need to be addressed. Implications of specific genomic alterations should be studied. The composition and role of the tumor microenvironment needs to be fully uncovered. Mechanisms explaining the long-term clinical dormancy observed in many of these ILC patients should be investigated. Additionally, adequate experimental models should be generated, properly described, and shared.

This Special Issue of Cancers therefore encompasses new research articles and timely reviews on all aspects of clinical, pathological, and molecular peculiarities of ILC.

Prof. Dr. Christine Desmedt
Prof. Dr. Patrick W. B. Derksen
Prof. Dr. Anne Vincent-Salomon
Guest Editors

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Keywords

invasive lobular breast cancer
treatment
pathology
tumor microenvironment
dormancy
experimental models
genomics
transcriptomics
single-cell characterization
cancer progression

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Published Papers (10 papers)

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Research

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13 pages, 1466 KiB

Open AccessArticle

The Prognostic Role of Intratumoral Stromal Content in Lobular Breast Cancer

by Carina Forsare, Sara Vistrand, Anna Ehinger, Kristina Lövgren, Lisa Rydén, Mårten Fernö and Ulrik Narbe

Cancers 2022, 14(4), 941; https://doi.org/10.3390/cancers14040941 - 14 Feb 2022

Cited by 5 | Viewed by 2559

Abstract

Previous studies have shown that high intratumoral stromal content is associated with a worse prognosis in breast cancer, especially in the triple-negative subtype. However, contradictory results have been reported for estrogen-receptor-positive (ER+) breast cancer, indicating that the prognostic role of intratumoral stromal content may be subtype-dependent. In this study, we investigated the importance of intratumoral stromal content for breast cancer-specific mortality (BCM) in a well-defined subgroup (n = 182) of ER+/human-epidermal growth-factor-receptor-2 negative (HER2−) invasive lobular breast cancer (ILC). The intratumoral stromal content was assessed on hematoxylin–eosin-stained whole sections and graded into high stroma (>50%) or low stroma (≤50%). A total of 82 (45%) patients had high-stroma tumors, and 100 (55%) had low-stroma tumors. High-stroma tumors were associated with a lower Nottingham histological grade, low Ki67, and a luminal A-like subtype. After a 10-year follow-up, the patients with high-stroma tumors had a lower BCM (HR: 0.43, 95% CI: 0.21–0.89, p = 0.023) in univariable analysis. Essentially the same effect was found in both the multivariable analysis (10-year follow-up) and univariable analysis (25-year follow-up), but these findings were not strictly significant. In ER+/HER2− ILC, high intratumoral stromal content is an easily assessable histological indicator of a good prognosis. Full article

(This article belongs to the Special Issue Clinical, Pathological and Molecular Peculiarities of Lobular Breast Cancer)

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19 pages, 6219 KiB

Open AccessArticle

Characterisation of the Stromal Microenvironment in Lobular Breast Cancer

by Laura Gómez-Cuadrado, Esme Bullock, Zeanap Mabruk, Hong Zhao, Margarita Souleimanova, Pernille Rimmer Noer, Arran K. Turnbull, Claus Oxvig, Nicholas Bertos, Adam Byron, J. Michael Dixon, Morag Park, Syed Haider, Rachael Natrajan, Andrew H. Sims and Valerie G. Brunton

Cancers 2022, 14(4), 904; https://doi.org/10.3390/cancers14040904 - 11 Feb 2022

Cited by 15 | Viewed by 5376

Abstract

Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer, and it exhibits a number of clinico-pathological characteristics distinct from the more common invasive ductal carcinoma (IDC). We set out to identify alterations in the tumor microenvironment (TME) of ILC. We used laser-capture microdissection to separate tumor epithelium from stroma in 23 ER+ ILC primary tumors. Gene expression analysis identified 45 genes involved in regulation of the extracellular matrix (ECM) that were enriched in the non-immune stroma of ILC, but not in non-immune stroma from ER+ IDC or normal breast. Of these, 10 were expressed in cancer-associated fibroblasts (CAFs) and were increased in ILC compared to IDC in bulk gene expression datasets, with PAPPA and TIMP2 being associated with better survival in ILC but not IDC. PAPPA, a gene involved in IGF-1 signaling, was the most enriched in the stroma compared to the tumor epithelial compartment in ILC. Analysis of PAPPA- and IGF1-associated genes identified a paracrine signaling pathway, and active PAPP-A was shown to be secreted from primary CAFs. This is the first study to demonstrate molecular differences in the TME between ILC and IDC identifying differences in matrix organization and growth factor signaling pathways. Full article

(This article belongs to the Special Issue Clinical, Pathological and Molecular Peculiarities of Lobular Breast Cancer)

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15 pages, 1900 KiB

Open AccessArticle

Assessment of the Molecular Heterogeneity of E-Cadherin Expression in Invasive Lobular Breast Cancer

by John Alexander, Odette Mariani, Celine Meaudre, Laetitia Fuhrmann, Hui Xiao, Kalnisha Naidoo, Andrea Gillespie, Ioannis Roxanis, Anne Vincent-Salomon, Syed Haider and Rachael Natrajan

Cancers 2022, 14(2), 295; https://doi.org/10.3390/cancers14020295 - 7 Jan 2022

Cited by 9 | Viewed by 3747

Abstract

Mutations and loss of E-cadherin protein expression define the vast majority of invasive lobular carcinomas. In a subset of these cases, the heterogeneous expression of E-cadherin is observed either as wild-type (strong membranous) expression or aberrant expression (cytoplasmic expression). However, it is unclear as to whether the two components would be driven by distinct genetic or epigenetic alterations. Here, we used whole genome DNA sequencing and methylation array profiling of two separately dissected components of nine invasive lobular carcinomas with heterogeneous E-cadherin expression. E-cadherin negative and aberrant/positive components of E-cadherin heterogeneous tumours showed a similar mutational, copy number and promoter methylation repertoire, suggesting they arise from a common ancestor, as opposed to the collision of two independent tumours. We found that the majority of E-cadherin heterogeneous tumours harboured CDH1 mutations in both the E-cadherin negative and aberrant/positive components together with somatic mutations in additional driver genes known to be enriched in both pure invasive carcinomas of no special type and invasive lobular breast cancers, whereas these were less commonly observed in CDH1 wild-type tumours. CDH1 mutant tumours also exhibited a higher mutation burden as well as increased presence of APOBEC-dependent mutational signatures 2 and 13 compared to CDH1 wild-type tumours. Together, our results suggest that regardless of E-cadherin protein expression, tumours showing heterogeneous expression of E-cadherin should be considered as part of the spectrum of invasive lobular breast cancers. Full article

(This article belongs to the Special Issue Clinical, Pathological and Molecular Peculiarities of Lobular Breast Cancer)

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19 pages, 2269 KiB

Open AccessArticle

Survival Outcomes in Invasive Lobular Carcinoma Compared to Oestrogen Receptor-Positive Invasive Ductal Carcinoma

by Jasmine Timbres, Charlotte Moss, Anca Mera, Anna Haire, Cheryl Gillett, Mieke Van Hemelrijck and Elinor Sawyer

Cancers 2021, 13(12), 3036; https://doi.org/10.3390/cancers13123036 - 18 Jun 2021

Cited by 11 | Viewed by 6166

Abstract

Invasive lobular breast cancer (ILC) accounts for 10–15% of breast cancers and has distinct characteristics compared with the more common invasive ductal carcinoma (IDC). Studies have shown that ILC may be less sensitive to chemotherapy than IDC, with lower rates of complete pathological response after neo-adjuvant chemotherapy, but it is not clear how this affects long-term survival. Patients at Guy’s and St Thomas’ NHS Foundation Trust between 1975 and 2016 diagnosed with ER+ IDC or ER+ ILC were eligible for inclusion. Kaplan–Meier plots and Cox proportional-hazards regression models were used for analysis. There was no difference in overall survival comparing ER+ ILC to ER+ IDC (OR: 0.94, 95% CI: 0.83, 1.04) with a median follow-up time of 8.3 years compared to 8.4 years in IDC. However, ER+HER2− ILC had worse survival compared to ER+HER2− IDC in those that received chemotherapy (OR: 1.46, 95% CI: 1.06, 2.01). Here, median follow-up time was 7.0 years in ILC compared to 8.1 years in IDC. These results indicate worse overall survival after chemotherapy (neo-adjuvant and adjuvant) in ILC compared to ER+HER2− IDC even when correcting for tumour grade, age, size, and nodal involvement, but validation is needed in a larger study population. Full article

(This article belongs to the Special Issue Clinical, Pathological and Molecular Peculiarities of Lobular Breast Cancer)

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14 pages, 4864 KiB

Open AccessArticle

The Genomic Landscape of Lobular Breast Cancer

by Amy E. McCart Reed, Samuel Foong, Jamie R. Kutasovic, Katia Nones, Nicola Waddell, Sunil R. Lakhani and Peter T. Simpson

Cancers 2021, 13(8), 1950; https://doi.org/10.3390/cancers13081950 - 18 Apr 2021

Cited by 18 | Viewed by 4804 | Correction

Abstract

Invasive lobular carcinoma (ILC) is the second most common breast cancer histologic subtype, accounting for approximately 15% of all breast cancers. It is only recently that its unique biology has been assessed in high resolution. Here, we present a meta-analysis of ILC sequencing datasets, to provide a long-awaited ILC-specific resource, and to confirm the prognostic value and strength of association between a number of clinico-pathology features and genomics in this special tumour type. We consider panel (n = 684), whole exome (n = 215) and whole genome sequencing data (n = 48), and review histology of The Cancer Genome Atlas cases to assign grades and determine whether the ILC is of classic type or a variant, such as pleomorphic, prior to performing statistical analyses. We demonstrate evidence of considerable genomic heterogeneity underlying a broadly homogeneous tumour type (typically grade 2, estrogen receptor (ER)-positive); with genomes exhibiting few somatic mutations or structural alterations, genomes with a hypermutator phenotype, and tumours with highly rearranged genomes. We show that while CDH1 (E-cadherin) and PIK3CA mutations do not significantly impact survival, overall survival is significantly poorer for patients with a higher tumour mutation burden; this is also true for grade 3 tumours, and those carrying a somatic TP53 mutation (and these cases were more likely to be ER-negative). Taken together, we have compiled a meta-dataset of ILC with molecular profiling, and our analyses show that the genomic landscape significantly impacts the tumour’s variable natural history and overall survival of ILC patients. Full article

(This article belongs to the Special Issue Clinical, Pathological and Molecular Peculiarities of Lobular Breast Cancer)

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22 pages, 4085 KiB

Open AccessArticle

Estrogen Regulation of mTOR Signaling and Mitochondrial Function in Invasive Lobular Carcinoma Cell Lines Requires WNT4

by Madeleine T. Shackleford, Deviyani M. Rao, Evelyn K. Bordeaux, Hannah M. Hicks, Christina G. Towers, Joseph L. Sottnik, Steffi Oesterreich and Matthew J. Sikora

Cancers 2020, 12(10), 2931; https://doi.org/10.3390/cancers12102931 - 12 Oct 2020

Cited by 21 | Viewed by 4762

Abstract

Invasive lobular carcinoma of the breast (ILC) is strongly estrogen-driven and represents a unique context for estrogen receptor (ER) signaling. In ILC, ER controls the expression of the Wnt ligand WNT4, which is critical for endocrine response and anti-estrogen resistance. However, signaling mediated by WNT4 is cell type- and tissue-specific, and has not been explored in ILC. We utilized reverse phase protein array (RPPA) to characterize ER and WNT4-driven signaling in ILC cells and identified that WNT4 mediates downstream mTOR signaling via phosphorylation of S6 Kinase. Additionally, ER and WNT4 control levels of MCL-1, which is associated with regulation of mitochondrial function. In this context, WNT4 knockdown led to decreased ATP production and increased mitochondrial fragmentation. WNT4 regulation of both mTOR signaling and MCL-1 were also observed in anti-estrogen resistant models of ILC. We identified that high WNT4 expression is associated with similar mTOR pathway activation in ILC and serous ovarian cancer tumors, suggesting that WNT4 signaling is active in multiple tumor types. The identified downstream pathways offer insight into WNT4 signaling and represent potential targets to overcome anti-estrogen resistance for patients with ILC. Full article

(This article belongs to the Special Issue Clinical, Pathological and Molecular Peculiarities of Lobular Breast Cancer)

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Review

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35 pages, 2166 KiB

Open AccessReview

Atlas of Lobular Breast Cancer Models: Challenges and Strategic Directions

by George Sflomos, Koen Schipper, Thijs Koorman, Amanda Fitzpatrick, Steffi Oesterreich, Adrian V. Lee, Jos Jonkers, Valerie G. Brunton, Matthias Christgen, Clare Isacke, Patrick W. B. Derksen and Cathrin Brisken

Cancers 2021, 13(21), 5396; https://doi.org/10.3390/cancers13215396 - 27 Oct 2021

Cited by 25 | Viewed by 9717

Abstract

Invasive lobular carcinoma (ILC) accounts for up to 15% of all breast cancer (BC) cases and responds well to endocrine treatment when estrogen receptor α-positive (ER⁺) yet differs in many biological aspects from other ER⁺ BC subtypes. Up to 30% of patients with ILC will develop late-onset metastatic disease up to ten years after initial tumor diagnosis and may experience failure of systemic therapy. Unfortunately, preclinical models to study ILC progression and predict the efficacy of novel therapeutics are scarce. Here, we review the current advances in ILC modeling, including cell lines and organotypic models, genetically engineered mouse models, and patient-derived xenografts. We also underscore four critical challenges that can be addressed using ILC models: drug resistance, lobular tumor microenvironment, tumor dormancy, and metastasis. Finally, we highlight the advantages of shared experimental ILC resources and provide essential considerations from the perspective of the European Lobular Breast Cancer Consortium (ELBCC), which is devoted to better understanding and translating the molecular cues that underpin ILC to clinical diagnosis and intervention. This review will guide investigators who are considering the implementation of ILC models in their research programs. Full article

(This article belongs to the Special Issue Clinical, Pathological and Molecular Peculiarities of Lobular Breast Cancer)

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34 pages, 4539 KiB

Open AccessReview

Lobular Breast Cancer: Histomorphology and Different Concepts of a Special Spectrum of Tumors

by Matthias Christgen, Gábor Cserni, Giuseppe Floris, Caterina Marchio, Lounes Djerroudi, Hans Kreipe, Patrick W. B. Derksen and Anne Vincent-Salomon

Cancers 2021, 13(15), 3695; https://doi.org/10.3390/cancers13153695 - 22 Jul 2021

Cited by 59 | Viewed by 14817

Abstract

Invasive lobular breast cancer (ILC) is the most common special histological type of breast cancer (BC). This review recapitulates developments in the histomorphologic assessment of ILC from its beginnings with the seminal work of Foote and Stewart, which was published in 1941, until today. We discuss different concepts of ILC and their implications. These concepts include (i) BC arising from mammary lobules, (ii) BC growing in dissociated cells and single files, and (iii) BC defined as a morpho-molecular spectrum of tumors with distinct histological and molecular characteristics related to impaired cell adhesion. This review also provides a comprehensive overview of ILC variants, their histomorphology, and differential diagnosis. Furthermore, this review highlights recent advances which have contributed to a better understanding of the histomorphology of ILC, such as the role of the basal lamina component laminin, the molecular specificities of triple-negative ILC, and E-cadherin to P-cadherin expression switching as the molecular determinant of tubular elements in CDH1-deficient ILC. Last but not least, we provide a detailed account of the tumor microenvironment in ILC, including tumor infiltrating lymphocyte (TIL) levels, which are comparatively low in ILC compared to other BCs, but correlate with clinical outcome. The distinct histomorphology of ILC clearly reflects a special tumor biology. In the clinic, special treatment strategies have been established for triple-negative, HER2-positive, and ER-positive BC. Treatment specialization for patients diagnosed with ILC is just in its beginnings. Accordingly, ILC deserves greater attention as a special tumor entity in BC diagnostics, patient care, and cancer research. Full article

(This article belongs to the Special Issue Clinical, Pathological and Molecular Peculiarities of Lobular Breast Cancer)

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4 pages, 1496 KiB

Open AccessCorrection

Correction: McCart Reed et al. The Genomic Landscape of Lobular Breast Cancer. Cancers 2021, 13, 1950

by Amy E. McCart Reed, Samuel Foong, Jamie R. Kutasovic, Katia Nones, Nicola Waddell, Sunil R. Lakhani and Peter T. Simpson

Cancers 2021, 13(16), 4010; https://doi.org/10.3390/cancers13164010 - 9 Aug 2021

Cited by 1 | Viewed by 1940

Abstract

The authors wish to make the following corrections to this paper [...] Full article

(This article belongs to the Special Issue Clinical, Pathological and Molecular Peculiarities of Lobular Breast Cancer)

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12 pages, 1557 KiB

Open AccessCommentary

How Researchers, Clinicians and Patient Advocates Can Accelerate Lobular Breast Cancer Research

by Leigh Pate, Christine Desmedt, Otto Metzger, Laurie Burgess Hutcheson, Claire Turner, Siobhán Freeney and Steffi Oesterreich

Cancers 2021, 13(13), 3094; https://doi.org/10.3390/cancers13133094 - 22 Jun 2021

Cited by 10 | Viewed by 6338

Abstract

Breast cancer research and therapies have significantly advanced in recent years. However, Invasive Lobular Carcinoma (ILC), the second most common histological type of breast cancer and the sixth most frequently diagnosed cancer of women, has not always benefited from critical analysis, missing opportunities to better understand this important subtype. Recent progress understanding the biological and behavioral differences of ILC demonstrates that it is a unique subtype of breast cancer which can respond differently to common therapies. These new insights have increased interest in researching lobular breast disease. Concurrently, the formation of motivated patient-led advocacy organizations working in partnership with basic, translational and clinical researchers creates new opportunities, including connecting a dispersed patient population to research, encouraging new research funding and connecting patient advocates to researchers to advance common goals. This commentary will explore the unprecedented opportunity to drive multidisciplinary, multicenter and international collaborative research into lobular breast cancer that builds on recent research progress. Collaborative research partnerships that include advocates can result in a better understanding of ILC, identify targeted therapies and refine standard of care therapies that are currently equally applied to all breast cancers, resulting in improvements in the diagnosis, treatment and follow-up care for patients with ILC. Full article

(This article belongs to the Special Issue Clinical, Pathological and Molecular Peculiarities of Lobular Breast Cancer)

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