Publications by authors named "Anne Vincent-Salomon"

254 Publications

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

Cancers (Basel) 2022 Jan 7;14(2). Epub 2022 Jan 7.

The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.

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 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 wild-type tumours. mutant tumours also exhibited a higher mutation burden as well as increased presence of APOBEC-dependent mutational signatures 2 and 13 compared to 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.
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http://dx.doi.org/10.3390/cancers14020295DOI Listing
January 2022

Value of the loss of heterozygosity to BRCA1 variant classification.

NPJ Breast Cancer 2022 Jan 17;8(1). Epub 2022 Jan 17.

Department of Medical Biology and Pathology, Gustave Roussy, Cancer Genetics Laboratory, Gustave Roussy, Villejuif, France.

At least 10% of the BRCA1/2 tests identify variants of uncertain significance (VUS) while the distinction between pathogenic variants (PV) and benign variants (BV) remains particularly challenging. As a typical tumor suppressor gene, the inactivation of the second wild-type (WT) BRCA1 allele is expected to trigger cancer initiation. Loss of heterozygosity (LOH) of the WT allele is the most frequent mechanism for the BRCA1 biallelic inactivation. To evaluate if LOH can be an effective predictor of BRCA1 variant pathogenicity, we carried out LOH analysis on DNA extracted from 90 breast and seven ovary tumors diagnosed in 27 benign and 55 pathogenic variant carriers. Further analyses were conducted in tumors with PVs yet without loss of the WT allele: BRCA1 promoter hypermethylation, next-generation sequencing (NGS) of BRCA1/2, and BRCAness score. Ninety-seven tumor samples were analyzed from 26 different BRCA1 variants. A relatively stable pattern of LOH (65.4%) of WT allele for PV tumors was observed, while the allelic balance (63%) or loss of variant allele (15%) was generally seen for carriers of BV. LOH data is a useful complementary argument for BRCA1 variant classification.
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http://dx.doi.org/10.1038/s41523-021-00361-2DOI Listing
January 2022

« HER2-faible », un nouveau concept dans la prise en charge des cancers du sein: HER2-low breast cancer: a new concept in breast cancer treatment strategy.

Bull Cancer 2021 Dec;108(11S):11S1-11S7

Institut Curie, département de médecine diagnostique et théranostique, service de pathologie, université Paris-Sciences et Lettres, Unité INSERM U934, 26 rue d'Ulm, 75005 Paris, France.

HER2, a human epidermal growth factor, being activated by amplification, is a negative prognostic factor in breast cancer. HER2 is the target of anti-HER2 antibodies (Trastuzumab, Pertuzumab…). For more than 10 years, breast cancers have been classified into HER2 positive and HER2 negative. However, the advent of new cytotoxic drugs combined with anti-HER2 antibodies, such as TDM1 or trastuzumab déruxtécan, have shown very promising therapeutic activity in patients with low HER2 expression breast cancer. These new therapeutic perspectives encourage a better identification of low HER2 tumours in order to identify patients who could benefit from them. Thus, the classification of breast tumours evolves to individualize HER2-negative tumours (score 0), HER2-positive tumours (score 3+ and 2+ amplified) and HER2-low tumours (scores 1+ and 2+ not-amplified). HER2-low tumours are common and represent more than half of all breast cancers. To identify these HER2-low tumours, pathology laboratories should not change their usual technique calibrated according to ASCO/CAP and GEFPICS recommendations. Until more clinical data about response to these new treatment strategies are available, GEFPICS does not require pathologists to identify this HER2-low category. Nevertheless, this designation will allow clinicians to identify patients whose tumours fall into this category in the very short term and offer them new treatment options.
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http://dx.doi.org/10.1016/S0007-4551(21)00631-7DOI Listing
December 2021

Highly Sensitive Detection Method of DICER1 Tumor Hotspot Mutations by Drop-off Droplet Digital PCR.

Clin Chem 2021 Dec 20. Epub 2021 Dec 20.

Service de Génétique, Institut Curie, Paris, France.

Background: DICER1 syndrome is an autosomal dominant inherited syndrome predisposing to various benign and malignant tumors, mainly occurring in children and young adults, requiring broad surveillance starting at birth with repeated irradiating imaging exams and sedations for young patients. It is caused by monoallelic germline pathogenic variants in the DICER1 gene. More than 90% of tumors bear an additional somatic DICER1 missense hotspot mutation, as a second hit, involving 1 of 6 codons clustered in exons 24 and 25. We designed and in vitro validated a drop-off droplet digital PCR (ddPCR) system to scan all DICER1 hotspot codons, allowing for a liquid biopsy test, an alternative to sedation and radiation exposure.

Methods: Three drop-off ddPCR assays were designed, with 2 TaqMan probes per assay, 1 complementary to the wild-type sequence of the region containing hotspots and another 1 used as a reference. Eight tumor-derived DNAs and 5 synthetic oligonucleotides bearing DICER1 hotspot mutations were tested.

Results: All tested mutations were detected, with a limit of detection ranging from 0.07% to 0.31% for codons p. E1705, p. D1709, and p. D1713 in exon 24 and from 0.06% to 0.15% for codons p. G1809, p. D1810, and p. E1813 in exon 25.

Conclusions: The high sensitivity of this method is compatible with its use for plasma circulating tumor DNA (ctDNA) analysis for early tumor detection in DICER1 syndrome patients. It may reduce the need for radiation exposure and sedation in surveillance protocols and may also improve patient prognosis. Clinical trials are needed to evaluate ctDNA analysis in these patients.
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http://dx.doi.org/10.1093/clinchem/hvab248DOI Listing
December 2021

Inter-observer agreement for the histological diagnosis of invasive lobular breast carcinoma.

J Pathol Clin Res 2021 Dec 10. Epub 2021 Dec 10.

Institute of Pathology, Hannover Medical School, Hannover, Germany.

Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E-cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)-positive/HER2-negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)-stained sections. In set B (62 cases), participants were provided with HE-stained sections and E-cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non-lobular BC versus mixed BC versus ILC. Pairwise inter-observer agreement and agreement with a pre-defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E-cadherin mutation status. Thirty-five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter-observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48-0.66) and substantial in set B (median κ = 0.75, IQR: 0.56-0.86, p < 0.001). Agreement with the reference diagnosis was substantial in set A (median κ = 0.67, IQR: 0.57-0.75) and almost perfect in set B (median κ = 0.86, IQR: 0.73-0.93, p < 0.001). The median frequency of CDH1/E-cadherin mutations in specimens classified as ILC was 65% in set A (IQR: 56-72%) and 73% in set B (IQR: 65-75%, p < 0.001). Cases with variable subtype calls included E-cadherin-positive ILCs harboring CDH1 missense mutations, and E-cadherin-negative ILCs with tubular elements and focal P-cadherin expression. ILCs with trabecular growth pattern were often misclassified as non-lobular BC in set A but not in set B. In conclusion, subtyping of BC as ILC achieves almost perfect agreement with a pre-defined reference standard, if assessment is supported by E-cadherin IHC. CDH1 missense mutations associated with preserved E-cadherin protein expression, E- to P-cadherin switching in ILC with tubular elements, and trabecular ILC were identified as potential sources of discordant classification.
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http://dx.doi.org/10.1002/cjp2.253DOI Listing
December 2021

CD73-Mediated Immunosuppression Is Linked to a Specific Fibroblast Population That Paves the Way for New Therapy in Breast Cancer.

Cancers (Basel) 2021 Nov 23;13(23). Epub 2021 Nov 23.

Equipe labellisée Ligue Nationale Contre le Cancer, Stress and Cancer Laboratory, Institut Curie, PSL Research University, 26, rue d'Ulm, 75005 Paris, France.

Background: Cancer-associated fibroblasts (CAF) are heterogeneous with multiple functions in breast cancer. Recently, we identified a specific CAF subpopulation (referred to as CAF-S1), which promotes immunosuppression and immunotherapy resistance.

Methods And Results: Here, by studying a large collection of human samples, we highlight the key function of CD73/NT5E in CAF-S1-mediated immunosuppression in breast cancer. We first reveal that CD73 protein level specifically accumulates in CAF-S1 in breast cancer patients. Interestingly, infiltration of regulatory T lymphocytes (Tregs) is significantly correlated with CD73 expression in stroma but not in epithelium, indicating that CD73 contributes to immunosuppression when expressed in CAF-S1 and not in tumor cells. By performing functional assays based on relevant systems using primary CAF-S1 isolated from patients, we demonstrate that CAF-S1 increase the content in both PD-1+ and CTLA-4+ Tregs. Importantly, the use of a blocking anti-CD73 antibody on CAF-S1 reduces CAF-S1-mediated immunosuppression by preventing expression of these immune checkpoints on Tregs.

Conclusions: Our data support the potential clinical benefit of using both anti-CD73 and immune-checkpoint inhibitors in breast cancer patients for inhibiting CAF-S1-mediated immunosuppression and enhancing anti-tumor immune response.
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http://dx.doi.org/10.3390/cancers13235878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657241PMC
November 2021

Endometrial cancer may be part of the MUTYH-associated polyposis cancer spectrum.

Eur J Med Genet 2022 Jan 11;65(1):104385. Epub 2021 Nov 11.

Département de Génétique (Department of Genetics), Institut Curie, Paris, France; Paris Sciences & Lettres Research University, Paris, France. Electronic address:

The MUTYH gene encodes a DNA glycosylase that prevents G:C→T:A transversions. Patients with biallelic pathogenic germline MUTYH variants develop an adenomatous polyposis called MUTYH-associated polyposis (MAP). Endometrial cancers have been reported in patients with MAP, but the role of MUTYH loss of function in the oncogenesis remains unclear. We report for the first time a case of endometrial carcinoma with excess of G:C→T:A transversions in a 61-year-old patient with MAP. Single nucleotide variants of interest, Tumor Mutational Burden (TMB) and somatic mutation profile were obtained from Next-Generation Sequencing (NGS). The Tumor-Infiltrating Lymphocyte (TIL) level and immune infiltrate phenotype were assessed. The endometrial cancer had a high TMB (31.5 variants/Mb) with enrichment in G:C→T:A transversions and the presence of a driver pathogenic variant c.34G>T, p.(Gly12Cys) in KRAS, suggesting a role of MUTYH loss of function in oncogenesis. MUTYH loss of function could be involved in endometrial cancer in patients with MAP.
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http://dx.doi.org/10.1016/j.ejmg.2021.104385DOI Listing
January 2022

Neoadjuvant Concurrent Radiotherapy and Chemotherapy in Early Breast Cancer Patients: Long-Term Results of a Prospective Phase II Trial.

Cancers (Basel) 2021 Oct 12;13(20). Epub 2021 Oct 12.

Department of Radiation Oncology, Institut Curie, 75005 Paris, France.

Neoadjuvant concurrent radiochemotherapy makes it possible to increase the breast conservation rate. This study reports the long term outcome of this treatment. From 2001 to 2003, 59 women with T N M invasive breast cancer (BC) not amenable to upfront breast conserving treatment (BCS) were included in this prospective, non-randomized phase II study. Chemotherapy (CT) consisted of four cycles of continuous 5-FU infusion and Vinorelbine. Starting concurrently with the second CT cycle, normofractionated RT was delivered to the breast and LN. Breast surgery was then performed. Median follow-up (FU) was 13 years [3-18]. BCS was performed in 41 (69%) patients and mastectomy in 18 patients, with pathological complete response rate of 27%. Overall and distant-disease free survivals rates at 13 years were 70.9% [95% CI 59.6-84.2] and 71.5% [95% CI 60.5-84.5] respectively. Loco regional and local controls rates were 83.4% [95% CI 73.2-95.0] and 92.1% [95% CI 83.7-100], respectively. Late toxicity (CTCAE-V3) was assessed in 51 patients (86%) with a median follow-up of 13 years. Fifteen presented grade 2 fibrosis (29.4%), 8 (15.7%) had telangiectasia, and 1 had radiodermatitis. This combined treatment provided high long-term local control rates with limited side-effects.
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http://dx.doi.org/10.3390/cancers13205107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534073PMC
October 2021

HRAS is a therapeutic target in malignant chemo-resistant adenomyoepithelioma of the breast.

J Hematol Oncol 2021 09 8;14(1):143. Epub 2021 Sep 8.

Translational Research Department, Institut Curie, PSL Research University, 26 Rue d'Ulm, 75005, Paris, France.

Malignant adenomyoepithelioma (AME) of the breast is an exceptionally rare form of breast cancer, with a significant metastatic potential. Chemotherapy has been used in the management of advanced AME patients, however the majority of treatments are not effective. Recent studies report recurrent mutations in the HRAS Q61 hotspot in small series of AMEs, but there are no preclinical or clinical data showing H-Ras protein as a potential therapeutic target in malignant AMEs. We performed targeted sequencing of tumours' samples from new series of 13 AMEs, including 9 benign and 4 malignant forms. Samples from the breast tumour and the matched axillary metastasis of one malignant HRAS mutated AME were engrafted and two patient-derived xenografts (PDX) were established that reproduced the typical AME morphology. The metastasis-derived PDX was treated in vivo by different chemotherapies and a combination of MEK and BRAF inhibitors (trametinib and dabrafenib). All malignant AMEs presented a recurrent mutation in the HRAS G13R or G12S hotspot. Mutation of PIK3CA were found in both benign and malignant AMEs, while AKT1 mutations were restricted to benign AMEs. Treatment of the PDX by the MEK inhibitor trametinib, resulted in a marked anti-tumor activity, in contrast to the BRAF inhibitor and the different chemotherapies that were ineffective. Overall, these findings further expand on the genetic features of AMEs and suggest that patients carrying advanced HRAS-mutated AMEs could potentially be treated with MEK inhibitors.
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http://dx.doi.org/10.1186/s13045-021-01158-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424935PMC
September 2021

[2021 update of the GEFPICS' recommendations for HER2 status assessment in invasive breast cancer in France].

Ann Pathol 2021 Nov 12;41(6):507-520. Epub 2021 Aug 12.

Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France.

The last international guidelines on HER2 determination in breast cancer have been updated in 2018 by the American Society of Clinical Oncology and College of American Pathologists, on the basis of a twenty-year practice and results of numerous clinical trials. Moreover, the emerging HER2-low concept for 1+ and 2+ non amplified breast cancers lead to refine French practices for HER2 status assessment. The GEFPICS group, composed of expert pathologists, herein presents the latest French recommendations for HER2 status evaluation in breast cancer, taking into account the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, HER2 status assessment remains one of the most important biomarkers in breast cancer and its quality guaranties the optimal patients' care. French pathologists' commitment in theranostic biomarker quality is more than ever required to provide the most efficient cares in oncology.
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http://dx.doi.org/10.1016/j.annpat.2021.07.014DOI Listing
November 2021

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

Cancers (Basel) 2021 Jul 22;13(15). Epub 2021 Jul 22.

Department of Diagnostic and Theranostic Medicine, Department of Pathology, Institute Curie, PSL-Research University, 26 rue d'Ulm, 75005 Paris, France.

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 -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.
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http://dx.doi.org/10.3390/cancers13153695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345067PMC
July 2021

Identification of Tissue of Origin and Guided Therapeutic Applications in Cancers of Unknown Primary Using Deep Learning and RNA Sequencing (TransCUPtomics).

J Mol Diagn 2021 10 26;23(10):1380-1392. Epub 2021 Jul 26.

INSERM U830, Équipe Labellisée Ligue Nationale Contre le Cancer, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, Institut Curie Research Center, Paris, France; Department of Medical Oncology, Institut Curie Hospital, Paris, France. Electronic address:

Cancers of unknown primary (CUP) are metastatic cancers for which the primary tumor is not found despite thorough diagnostic investigations. Multiple molecular assays have been proposed to identify the tissue of origin (TOO) and inform clinical care; however, none has been able to combine accuracy, interpretability, and easy access for routine use. We developed a classifier tool based on the training of a variational autoencoder to predict tissue of origin based on RNA-sequencing data. We used as training data 20,918 samples corresponding to 94 different categories, including 39 cancer types and 55 normal tissues. The TransCUPtomics classifier was applied to a retrospective cohort of 37 CUP patients and 11 prospective patients. TransCUPtomics exhibited an overall accuracy of 96% on reference data for TOO prediction. The TOO could be identified in 38 (79%) of 48 CUP patients. Eight of 11 prospective CUP patients (73%) could receive first-line therapy guided by TransCUPtomics prediction, with responses observed in most patients. The variational autoencoder added further utility by enabling prediction interpretability, and diagnostic predictions could be matched to detection of gene fusions and expressed variants. TransCUPtomics confidently predicted TOO for CUP and enabled tailored treatments leading to significant clinical responses. The interpretability of our approach is a powerful addition to improve the management of CUP patients.
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http://dx.doi.org/10.1016/j.jmoldx.2021.07.009DOI Listing
October 2021

Primary vitreoretinal lymphoma: short review of the literature, results of a European survey and French guidelines of the LOC network for diagnosis, treatment and follow-up.

Curr Opin Oncol 2021 09;33(5):420-431

Member of European Reference Network on Rare Hematological Diseases (ERN-EuroBloodNet).

Purpose Of Review: The aim of this study was to highlight the diagnostic and management challenges of primary vitreoretinal lymphoma (PVRL) through a review of the literature and a European survey on real-life practices for PVRL.

Recent Findings: The care of PVRL patients is heterogeneous between specialists and countries. Upfront systemic treatment based on high-dose methotrexate chemotherapy, with or without local treatment, might reduce or delay the risk of brain relapse.Ibrutinib, lenalidomide with or without rituximab, and temozolomide are effective for patients with relapsed/refractory PVRL and should be tested as first-line treatments.

Summary: The prognosis of PVRL remains dismal. No firm conclusion regarding optimal treatment can yet be drawn. The risk of brain relapse remains high. Diagnostic procedures and assessment of therapeutic responses need to be homogenized. Collaboration between specialists involved in PVRL and multicentric prospective therapeutic studies are strongly needed. The recommendations of the French group for primary oculocerebral lymphoma (LOC network) are provided, as a basis for further European collaborative work.
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http://dx.doi.org/10.1097/CCO.0000000000000776DOI Listing
September 2021

The alternative RelB NF-κB subunit is a novel critical player in diffuse large B-cell lymphoma.

Blood 2022 Jan;139(3):384-398

Université de Paris, NF-κB, Différenciation et Cancer, Paris, France.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy affecting adults. The NF-κB transcription factor family is activated by 2 main pathways, the canonical and the alternative NF-κB activation pathway, with different functions. The alternative NF-κB pathway leads to activation of the transcriptionally active RelB NF-κB subunit. Alternative NF-κB activation status and its role in DLBCL pathogenesis remain undefined. Here, we reveal a frequent activation of RelB in a large cohort of DLBCL patients and cell lines, independently of their activated B-cell-like or germinal center B-cell-like subtype. RelB activity defines a new subset of patients with DLBCL and a peculiar gene expression profile and mutational pattern. Importantly, RelB activation does not correlate with the MCD genetic subtype, enriched for activated B-cell-like tumors carrying MYD88L265P and CD79B mutations that cooperatively activate canonical NF-κB, thus indicating that current genetic tools to evaluate NF-κB activity in DLBCL do not provide information on the alternative NF-κB activation. Furthermore, the newly defined RelB-positive subgroup of patients with DLBCL exhibits a dismal outcome after immunochemotherapy. Functional studies revealed that RelB confers DLBCL cell resistance to DNA damage-induced apoptosis in response to doxorubicin, a genotoxic agent used in the front-line treatment of DLBCL. We also show that RelB positivity is associated with high expression of cellular inhibitor of apoptosis protein 2 (cIAP2). Altogether, RelB activation can be used to refine the prognostic stratification of DLBCL and may contribute to subvert the therapeutic DNA damage response in a segment of patients with DLBCL.
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http://dx.doi.org/10.1182/blood.2020010039DOI Listing
January 2022

Interobserver variability in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative invasive breast carcinoma influences the association with pathological complete response: the IVITA study.

Mod Pathol 2021 12 3;34(12):2130-2140. Epub 2021 Jul 3.

Department of Pathology, Onze-Lieve-Vrouwziekenhuis Aalst, Aalst, Belgium.

High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland-Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from -0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for eight participants (20%). Post hoc sTILs cutoffs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the 'ideal' sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions.
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http://dx.doi.org/10.1038/s41379-021-00865-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595512PMC
December 2021

Multi-Omics Marker Analysis Enables Early Prediction of Breast Tumor Progression.

Front Genet 2021 3;12:670749. Epub 2021 Jun 3.

Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

Ductal carcinoma (DCIS) is a preinvasive form of breast cancer with a highly variable potential of becoming invasive and affecting mortality of the patients. Due to the lack of accurate markers of disease progression, many women with detected DCIS are currently overtreated. To distinguish those DCIS cases who are likely to require therapy from those who should be left untreated, there is a need for robust and predictive biomarkers extracted from molecular or genetic profiles. We developed a supervised machine learning approach that implements multi-omics feature selection and model regularization for the identification of biomarker combinations that could be used to distinguish low-risk DCIS lesions from those with a higher likelihood of progression. To investigate the genetic heterogeneity of disease progression, we applied this approach to 40 pure DCIS and 259 invasive breast cancer (IBC) samples profiled with genome-wide transcriptomics, DNA methylation, and DNA copy number variation. Feature selection using the multi-omics Lasso-regularized algorithm identified both known genes involved in breast cancer development, as well as novel markers for early detection. Even though the gene expression-based model features led to the highest classification accuracy alone, methylation data provided a complementary source of features and improved especially the sensitivity of correctly classifying DCIS cases. We also identified a number of repeatedly misclassified DCIS cases when using either the expression or methylation markers. A small panel of 10 gene markers was able to distinguish DCIS and IBC cases with high accuracy in nested cross-validation (AU-ROC = 0.99). The marker panel was not specific to any of the established breast cancer subtypes, suggesting that the 10-gene signature may provide a subtype-agnostic and cost-effective approach for breast cancer detection and patient stratification. We further confirmed high accuracy of the 10-gene signature in an external validation cohort (AU-ROC = 0.95), profiled using distinct transcriptomic assay, hence demonstrating robustness of the risk signature.
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http://dx.doi.org/10.3389/fgene.2021.670749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209521PMC
June 2021

The LINC01119-SOCS5 axis as a critical theranostic in triple-negative breast cancer.

NPJ Breast Cancer 2021 May 31;7(1):69. Epub 2021 May 31.

Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

The development of triple-negative breast cancer (TNBC) is critically regulated by certain tumor-microenvironment-associated cells called mesenchymal stem/stromal cells (MSCs), which we and others have shown promote TNBC progression by activating pro-malignant signaling in neighboring cancer cells. Characterization of these cascades would better our understanding of TNBC biology and bring about therapeutics that eliminate the morbidity and mortality associated with advanced disease. Here, we focused on the emerging class of RNAs called long non-coding RNAs or lncRNAs and utilized a MSC-supported TNBC progression model to identify specific family members of functional relevance to TNBC pathogenesis. Indeed, although some have been described to play functional roles in TNBC, activities of lncRNAs as mediators of tumor-microenvironment-driven TNBC development remain to be fully explored. We report that MSCs stimulate robust expression of LINC01119 in TNBC cells, which in turn induces suppressor of cytokine signaling 5 (SOCS5), leading to accelerated cancer cell growth and tumorigenesis. We show that LINC01119 and SOCS5 exhibit tight correlation across multiple breast cancer gene sets and that they are highly enriched in TNBC patient cohorts. Importantly, we present evidence that the LINC01119-SOCS5 axis represents a powerful prognostic indicator of adverse outcomes in TNBC patients, and demonstrate that its repression severely impairs cancer cell growth. Altogether, our findings identify LINC01119 as a major driver of TNBC development and delineate critical non-coding RNA theranostics of potential translational utility in the management of advanced TNBC, a class of tumors in most need of effective and targeted therapy.
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http://dx.doi.org/10.1038/s41523-021-00259-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166834PMC
May 2021

Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance.

Oncogene 2021 06 19;40(23):4019-4032. Epub 2021 May 19.

INSERM UMR_S 938, Saint-Antoine Research Center, CRSA, University Sorbonne, Paris, France.

Membrane Type 1 Matrix Metalloprotease (MT1-MMP) contributes to the invasive progression of breast cancers by degrading extracellular matrix tissues. Nucleoside diphosphate kinase, NME1/NM23-H1, has been identified as a metastasis suppressor; however, its contribution to local invasion in breast cancer is not known. Here, we report that NME1 is up-regulated in ductal carcinoma in situ (DCIS) as compared to normal breast epithelial tissues. NME1 levels drop in microinvasive and invasive components of breast tumor cells relative to synchronous DCIS foci. We find a strong anti-correlation between NME1 and plasma membrane MT1-MMP levels in the invasive components of breast tumors, particularly in aggressive histological grade III and triple-negative breast cancers. Knockout of NME1 accelerates the invasive transition of breast tumors in the intraductal xenograft model. At the mechanistic level, we find that MT1-MMP, NME1 and dynamin-2, a GTPase known to require GTP production by NME1 for its membrane fission activity in the endocytic pathway, interact in clathrin-coated vesicles at the plasma membrane. Loss of NME1 function increases MT1-MMP surface levels by inhibiting endocytic clearance. As a consequence, the ECM degradation and invasive potentials of breast cancer cells are enhanced. This study identifies the down-modulation of NME1 as a potent driver of the in situ-to invasive transition during breast cancer progression.
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http://dx.doi.org/10.1038/s41388-021-01826-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195739PMC
June 2021

Infantile Rhabdomyosarcomas With VGLL2 Rearrangement Are Not Always an Indolent Disease: A Study of 4 Aggressive Cases With Clinical, Pathologic, Molecular, and Radiologic Findings.

Am J Surg Pathol 2021 06;45(6):854-867

Genetics Unit, Department of Tumor Biology.

VGLL2-rearranged rhabdomyosarcomas (RMS) are rare low-grade tumors with only favorable outcomes reported to date. We describe 4 patients with VGLL2-rearranged RMS confirmed by molecular studies, who experienced local progression and distant metastases, including 2 with fatal outcomes. Tumors were diagnosed at birth (n=3) or at 12 months of age (n=1), and were all localized at initial diagnosis, but unresectable and therefore managed with chemotherapy and surveillance. Metastatic progression occurred from 1 to 8 years from diagnosis (median, 3.5 y). Three patients experienced multimetastatic spread and one showed an isolated adrenal metastasis. At initial diagnosis, 3 tumors displaying bland morphology were misdiagnosed as fibromatosis or infantile fibrosarcoma and initially managed as such, while 1 was a high-grade sarcoma. At relapse, 3 tumors showed high-grade morphology, while 1 retained a low-grade phenotype. Low-grade primary tumors showed only very focal positivity for desmin, myogenin, and/or MyoD1, while high-grade tumors were heterogenously or diffusely positive. Whole-exome sequencing, performed on primary and relapse samples for 3 patients, showed increased genomic instability and additional genomic alterations (eg, TP53, CDKN2A/B, FGFR4) at relapse, but no recurrent events. RNA sequencing confirmed that high-grade tumors retained VGLL2 fusion transcripts and transcriptomic profiles consistent with VGLL2-rearranged RMS. High-grade samples showed a high expression of genes encoding cell cycle proteins, desmin, and some developmental factors. These 4 cases with distinct medical history imply the importance of complete surgical resection, and suggest that RMS-type chemotherapy should be considered in unresectable cases, given the risk of high-grade transformation. They also emphasize the importance of correct initial diagnosis.
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http://dx.doi.org/10.1097/PAS.0000000000001702DOI Listing
June 2021

Phenotypic discordance between primary and metastatic breast cancer in the large-scale real-life multicenter French ESME cohort.

NPJ Breast Cancer 2021 Apr 16;7(1):41. Epub 2021 Apr 16.

Gustave Roussy Cancer Campus, Villejuif, France.

Expression of hormone receptor (HR) for estrogens (ER) and progesterone (PR) and HER2 remains the cornerstone to define the therapeutic strategy for breast cancer patients. We aimed to compare phenotypic profiles between matched primary and metastatic breast cancer (MBC) in the ESME database, a National real-life multicenter cohort of MBC patients. Patients with results available on both primary tumour and metastatic disease within 6 months of MBC diagnosis and before any tumour progression were eligible for the main analysis. Among the 16,703 patients included in the database, 1677 (10.0%) had available biopsy results at MBC diagnosis and on matched primary tumour. The change rate of either HR or HER2 was 27.0%. Global HR status changed (from positive = either ER or PR positive, to negative = both negative; and reverse) in 14.2% of the cases (expression loss in 72.5% and gain in 27.5%). HER2 status changed in 7.8% (amplification loss in 45.2%). The discordance rate appeared similar across different biopsy sites. Metastasis to bone, HER2+ and RH+/HER2- subtypes and previous adjuvant endocrine therapy, but not relapse interval were associated with an HR discordance in multivariable analysis. Loss of HR status was significantly associated with a risk of death (HR adjusted = 1.51, p = 0.002) while gain of HR and HER2 discordance was not. In conclusion, discordance of HR and HER2 expression between primary and metastatic breast cancer cannot be neglected. In addition, HR loss is associated with worse survival. Sampling metastatic sites is essential for treatment adjustment.
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http://dx.doi.org/10.1038/s41523-021-00252-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052407PMC
April 2021

Molecular features of untreated breast cancer and initial metastatic event inform clinical decision-making and predict outcome: long-term results of ESOPE, a single-arm prospective multicenter study.

Genome Med 2021 03 15;13(1):44. Epub 2021 Mar 15.

Department of Medical Oncology, Institut Curie, PSL Research University, 26 rue d'Ulm, 75005, Paris, France.

Background: Prognosis evaluation of advanced breast cancer and therapeutic strategy are mostly based on clinical features of advanced disease and molecular profiling of the primary tumor. Very few studies have evaluated the impact of metastatic subtyping during the initial metastatic event in a prospective study. The genomic landscape of metastatic breast cancer has mostly been described in very advanced, pretreated disease, limiting the findings transferability to clinical use.

Methods: We developed a multicenter, single-arm, prospective clinical trial in order to address these issues. Between November 2010 and September 2013, 123 eligible patients were included. Patients at the first, untreated metastatic event were eligible. All matched primary tumors and metastatic samples were centrally reviewed for pathological typing. Targeted and whole-exome sequencing was applied to matched pairs of frozen tissue. A multivariate overall survival analysis was performed (median follow-up 64 months).

Results: Per central review in 84 patients (out of 130), we show that luminal A breast tumors are more prone to subtype switching. By combining targeted sequencing of a 91 gene panel (n = 67) and whole-exome sequencing (n = 30), a slight excess of mutations is observed in the metastases. Luminal A breast cancer has the most heterogeneous mutational profile and the highest number of mutational signatures, when comparing primary tumor and the matched metastatic tissue. Tumors with a subtype change have more mutations that are private. The metastasis-specific mutation load is significantly higher in late than in de novo metastases. The most frequently mutated genes were TP53 and PIK3CA. The most frequent metastasis-specific druggable genes were PIK3CA, PTEN, KDR, ALK, CDKN2A, NOTCH4, POLE, SETD2, SF3B1, and TSC2. Long-term outcome is driven by a combination of tumor load and metastasis biology.

Conclusions: Profiling of the first, untreated, metastatic event of breast cancer reveals a profound heterogeneity mostly in luminal A tumors and in late metastases. Based on this profiling, we can derive information relevant to prognosis and therapeutic intervention, which support current guidelines recommending a biopsy at the first metastatic relapse.

Trial Registration: The trial was registered at ClinicalTrials.gov ( NCT01956552 ).
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http://dx.doi.org/10.1186/s13073-021-00862-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962302PMC
March 2021

Total orbital exenteration with temporalis muscle transfer and secondary healing.

Can J Ophthalmol 2021 Mar 11. Epub 2021 Mar 11.

Institut Curie, Service d'oncologie oculaire, Paris, France.

Objective: To evaluate the outcomes of orbital exenteration with temporalis muscle flap repair of the socket and secondary healing of the anterior surface of the flap in ocular, conjunctival, and eyelid malignancies.

Design: Retrospective single-centre study.

Participants: Consecutive patients who underwent total exenteration for malignancy with temporal muscle flap repair of the socket between December 2009 and January 2016.

Methods: We report the outcomes of this surgical technique in terms of healing without fistula formation and time to epithelialization.

Results: Twenty-nine patients underwent surgery using this technique. Diagnoses consisted of 18 conjunctival melanomas, 2 choroidal melanomas, 6 squamous cell carcinomas, 2 sebaceous cell carcinomas, and 1 basal cell carcinoma. Mean age at surgery was 70.7 years and mean follow-up was 27.4 months. On histological analysis, tumour excision was complete in 25 patients, of whom 3 had an orbital recurrence after exenteration (3 conjunctival melanomas). Four patients had incomplete tumour excision, of whom 3 underwent postoperative orbital radiotherapy with no subsequent orbital recurrences. Complete epithelialization of the socket occurred in mean 7.9 weeks (range 2-16 weeks). Flap necrosis occurred in 1 patient after postoperative radiotherapy (with sino-nasal fistula formation); 2 other patients developed sino-orbital fistulas.

Conclusion: After orbital exenteration, spontaneous epithelialization of the socket may take up to several months. Use of a temporalis muscle flap can reduce the duration of socket healing postoperatively, even if left to heal by secondary intention. This may facilitate early postoperative radiotherapy when indicated. Aesthetic results are acceptable and local surgical complications are rare.
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http://dx.doi.org/10.1016/j.jcjo.2021.02.005DOI Listing
March 2021

Circulating tumor DNA as a dynamic biomarker of response to palbociclib and fulvestrant in metastatic breast cancer patients.

Breast Cancer Res 2021 03 6;23(1):31. Epub 2021 Mar 6.

Circulating Tumor Biomarkers Laboratory, Inserm CIC-BT 1428, Institut Curie, PSL Research University, 26 rue d'Ulm, 75005, Paris, France.

Background: Following the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib has been shown to increase the progression-free survival (PFS) overall but no predictive biomarker of palbociclib efficacy has been validated so far. We thus evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency.

Methods: ER+ HER2- MBC patients were included in a prospective observational cohort before treatment initiation. Tumor response was assessed by radiological evaluation (RECIST v1.1) every 3 months. Plasma samples were collected before treatment (baseline), at day 15 (D15), at day 30 (D30), and at disease progression. We searched for somatic mutations from archived tumor tissues by targeted deep sequencing. For patients with somatic mutations identified, circulating tumor DNA (ctDNA) was tracked using digital droplet PCR. Ratios of ctDNA levels ([D15/baseline] and [D30/baseline]) were then correlated with prospectively registered patient characteristics and outcomes.

Results: Twenty-five of the 61 patients enrolled had a somatic mutation testable in plasma (N = 21, N = 2, N = 2). At baseline, 84% of patients had detectable ctDNA levels but ctDNA levels had no prognostic impact on PFS (p = 0.10). Among those patients, ctDNA was still detected in 82% at D15 and 68% at D30. ctDNA clearance observed at day 30 was associated with longer PFS (HR = 7.2, 95% CI = 1.5-32.6, p = 0.004). On the contrary, a [D30/baseline] ctDNA ratio > 1 was associated with a shorter PFS (HR = 5.1, 95% CI = 1.4-18.3, p = 0.02) and all 5 patients with increased ctDNA levels at D30 showed disease progression after 3 months under palbociclib-fulvestrant. Finally, at the time of radiological tumor progression, ctDNA was detected in all patients tested.

Conclusion: Our study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS.
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http://dx.doi.org/10.1186/s13058-021-01411-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937332PMC
March 2021

PD-L1 Expression after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancers Is Associated with Aggressive Residual Disease, Suggesting a Potential for Immunotherapy.

Cancers (Basel) 2021 Feb 11;13(4). Epub 2021 Feb 11.

Residual Tumor & Response to Treatment Laboratory, RT2Lab, Translational Research Department, INSERM, U932 Immunity and Cancer, University Paris, 75005 Paris, France.

The consequences of neoadjuvant chemotherapy (NAC) for PD-L1 activity in triple-negative breast cancers (TNBC) are not well-understood. This is an important issue as PD-LI might act as a biomarker for immune checkpoint inhibitors' (ICI) efficacy, at a time where ICI are undergoing rapid development and could be beneficial in patients who do not achieve a pathological complete response. We used immunohistochemistry to assess PD-L1 expression in surgical specimens (E1L3N clone, cutoff for positivity: ≥1%) on both tumor (PD-L1-TC) and immune cells (PD-L1-IC) from a cohort of T1-T3NxM0 TNBCs treated with NAC. PD-L1-TC was detected in 17 cases (19.1%) and PD-L1-IC in 14 cases (15.7%). None of the baseline characteristics of the tumor or the patient were associated with PD-L1 positivity, except for pre-NAC stromal TIL levels, which were higher in post-NAC PD-L1-TC-positive than in negative tumors. PD-L1-TC were significantly associated with a higher residual cancer burden ( = 0.035) and aggressive post-NAC tumor characteristics, whereas PD-L1-IC were not. PD-L1 expression was not associated with relapse-free survival (RFS) (PD-L1-TC, = 0.25, and PD-L1-IC, = 0.95) or overall survival (OS) (PD-L1-TC, = 0.48, and PD-L1-IC, = 0.58), but high Ki67 levels after NAC were strongly associated with a poor prognosis (RFS, = 0.0014, and OS, = 0.001). A small subset of TNBC patients displaying PD-L1 expression in the context of an extensive post-NAC tumor burden could benefit from ICI treatment after standard NAC.
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http://dx.doi.org/10.3390/cancers13040746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916886PMC
February 2021

Stiffness increases with myofibroblast content and collagen density in mesenchymal high grade serous ovarian cancer.

Sci Rep 2021 02 18;11(1):4219. Epub 2021 Feb 18.

Stress and Cancer Laboratory, Institut Curie, PSL Research University, Equipe labelisée Ligue Nationale Contre le Cancer, 26, rue d'Ulm, 75248, Paris Cedex 05, France.

Women diagnosed with high-grade serous ovarian cancers (HGSOC) are still likely to exhibit a bad prognosis, particularly when suffering from HGSOC of the Mesenchymal molecular subtype (50% cases). These tumors show a desmoplastic reaction with accumulation of extracellular matrix proteins and high content of cancer-associated fibroblasts. Using patient-derived xenograft mouse models of Mesenchymal and Non-Mesenchymal HGSOC, we show here that HGSOC exhibit distinct stiffness depending on their molecular subtype. Indeed, tumor stiffness strongly correlates with tumor growth in Mesenchymal HGSOC, while Non-Mesenchymal tumors remain soft. Moreover, we observe that tumor stiffening is associated with high stromal content, collagen network remodeling, and MAPK/MEK pathway activation. Furthermore, tumor stiffness accompanies a glycolytic metabolic switch in the epithelial compartment, as expected based on Warburg's effect, but also in stromal cells. This effect is restricted to the central part of stiff Mesenchymal tumors. Indeed, stiff Mesenchymal tumors remain softer at the periphery than at the core, with stromal cells secreting high levels of collagens and showing an OXPHOS metabolism. Thus, our study suggests that tumor stiffness could be at the crossroad of three major processes, i.e. matrix remodeling, MEK activation and stromal metabolic switch that might explain at least in part Mesenchymal HGSOC aggressiveness.
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http://dx.doi.org/10.1038/s41598-021-83685-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892556PMC
February 2021

In vitro bone metastasis dwelling in a 3D bioengineered niche.

Biomaterials 2021 02 24;269:120624. Epub 2020 Dec 24.

Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005, Paris, France; ART Group, Inserm U830, 75005, Paris, France. Electronic address:

Bone is the most frequent metastasis site for breast cancer. As well as dramatically increasing disease burden, bone metastases are also an indicator of poor prognosis. One of the main challenges in investigating bone metastasis in breast cancer is engineering in vitro models that replicate the features of in vivo bone environments. Such in vitro models ideally enable the biology of the metastatic cells to mimic their in vivo behavior as closely as possible. Here, taking benefit of cutting-edge technologies both in microfabrication and cancer cell biology, we have developed an in vitro breast cancer bone-metastasis model. To do so we first 3D printed a bone scaffold that reproduces the trabecular architecture and that can be conditioned with osteoblast-like cells, a collagen matrix, and mineralized calcium. We thus demonstrated that this device offers an adequate soil to seed primary breast cancer bone metastatic cells. In particular, patient-derived xenografts being considered as a better approach than cell lines to achieve clinically relevant results, we demonstrate the ability of this biomimetic bone niche model to host patient-derived xenografted metastatic breast cancer cells. These patient-derived xenograft cells show a long-term survival in the bone model and maintain their cycling propensity, and exhibit the same modulated drug response as in vivo. This experimental system enables access to the idiosyncratic features of the bone microenvironment and cancer bone metastasis, which has implications for drug testing.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120624DOI Listing
February 2021

Neuroendocrine tumours of the breast: a genomic comparison with mucinous breast cancers and neuroendocrine tumours of other anatomic sites.

J Clin Pathol 2022 Jan 4;75(1):10-17. Epub 2020 Nov 4.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York City, New York, USA

Aims: Breast neuroendocrine tumours (NETs) constitute a rare histologic subtype of oestrogen receptor (ER)-positive breast cancer, and their definition according to the WHO classification was revised in 2019. Breast NETs display histologic and transcriptomic similarities with mucinous breast carcinomas (MuBCs). Here, we sought to compare the repertoire of genetic alterations in breast NETs with MuBCs and NETs from other anatomic origins.

Methods: On histologic review applying the new WHO criteria, 18 breast tumours with neuroendocrine differentiation were reclassified as breast NETs (n=10) or other breast cancers with neuroendocrine differentiation (n=8). We reanalysed targeted sequencing or whole-exome sequencing data of breast NETs (n=10), MuBCs type A (n=12) and type B (n=11).

Results: Breast NETs and MuBCs were found to be genetically similar, harbouring a lower frequency of mutations, 1q gains and 16q losses than ER-positive/HER2-negative breast cancers. 3/10 breast NETs harboured the hallmark features of ER-positive disease (ie, mutations and concurrent 1q gains/16q losses). Breast NETs showed an enrichment of oncogenic/likely oncogenic mutations affecting transcription factors compared with common forms of ER-positive breast cancer and with pancreatic and pulmonary NETs.

Conclusions: Breast NETs are heterogeneous and are characterised by an enrichment of mutations in transcription factors and likely constitute a spectrum of entities histologically and genomically related to MuBCs. While most breast NETs are distinct from ER-positive/HER2-negative IDC-NSTs, a subset of breast NETs appears to be genetically similar to common forms of ER-positive breast cancer, suggesting that some breast cancers may acquire neuroendocrine differentiation later in tumour evolution.
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http://dx.doi.org/10.1136/jclinpath-2020-207052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260149PMC
January 2022

The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas.

Mol Oncol 2021 04 19;15(4):1024-1039. Epub 2021 Feb 19.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Metaplastic breast carcinoma (MBC) and uterine carcinosarcoma (UCS) are rare aggressive cancers, characterized by an admixture of adenocarcinoma and areas displaying mesenchymal/sarcomatoid differentiation. We sought to define whether MBCs and UCSs harbor similar patterns of genetic alterations, and whether the different histologic components of MBCs and UCSs are clonally related. Whole-exome sequencing (WES) data from MBCs (n = 35) and UCSs (n = 57, The Cancer Genome Atlas) were reanalyzed to define somatic genetic alterations, altered signaling pathways, mutational signatures, and genomic features of homologous recombination DNA repair deficiency (HRD). In addition, the carcinomatous and sarcomatous components of an additional cohort of MBCs (n = 11) and UCSs (n = 6) were microdissected separately and subjected to WES, and their clonal relatedness was assessed. MBCs and UCSs harbored recurrent genetic alterations affecting TP53, PIK3CA, and PTEN, similar patterns of gene copy number alterations, and an enrichment in alterations affecting the epithelial-to-mesenchymal transition (EMT)-related Wnt and Notch signaling pathways. Differences were observed, however, including a significantly higher prevalence of FAT3 and FAT1 somatic mutations in MBCs compared to UCSs, and conversely, UCSs significantly more frequently harbored somatic mutations affecting FBXW7 and PPP2R1A as well as HER2 amplification than MBCs. Genomic features of HRD and biallelic alterations affecting bona fide HRD-related genes were found to be more prevalent in MBCs than in UCSs. The distinct histologic components of MBCs and UCSs were clonally related in all cases, with the sarcoma component likely stemming from a minor subclone of the carcinoma component in the samples with interpretable chronology of clonal evolution. Despite the similar histologic features and pathways affected by genetic alterations, UCSs differ from MBCs on the basis of FBXW7 and PPP2R1A mutations, HER2 amplification, and lack of HRD, supporting the notion that these entities are more than mere phenocopies of the same tumor type in different anatomical sites.
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http://dx.doi.org/10.1002/1878-0261.12813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024717PMC
April 2021

Combination of Olaparib and Radiation Therapy for Triple Negative Breast Cancer: Preliminary Results of the RADIOPARP Phase 1 Trial.

Int J Radiat Oncol Biol Phys 2021 02 21;109(2):436-440. Epub 2020 Sep 21.

Department of Radiation Oncology, Institut Curie, Paris, France.

Purpose: Preclinical studies have evidenced that triple-negative breast cancer (TNBC) cell lines are more sensitive to poly (ADP-ribose) polymerase inhibitors. This provides a strong rationale for developing a new therapeutic approach for TNBC management based on poly (ADP-ribose) polymerase inhibition. The primary goal of the RADIOPARP phase 1 trial was to evaluate the dose-limiting toxicities (DLT) and the maximum tolerated dose of olaparib combined with locoregional radiation therapy.

Methods And Materials: RADIOPARP was a single institutional phase 1 trial which evaluated olaparib-radiation therapy combination in patients with inflammatory, locoregionally advanced or metastatic TNBC who received neoadjuvant chemotherapy. Radiation therapy delivered 50 Gy to the breast or to the chest wall. Lymph nodes could be included in target volumes according to local guidelines. The dose-finding toxicity-based study was conducted in sequential and adaptive Bayesian scheme using the time-to-event continual reassessment method, with 4 olaparib dose levels (50 mg, 100 mg, 150 mg, and 200 mg twice per day).

Results: Twenty-four patients with Eastern Cooperative Oncology Group Performance Status of 0 or 1 were enrolled from September 2017 to November 2019. Twenty-one patients (87.5%) received the olaparib-radiation therapy combination after breast surgery owing to residual disease after neoadjuvant chemotherapy, and the 3 other patients (12.5%) had unresectable tumors which were refractory to neoadjuvant chemotherapy. All patients received full course combination treatment as follows: 4 patients (pts) at 50 mg twice a day, 8 pts at 100 mg twice a day, 7 pts at 150 mg twice a day, and 5 pts at 200 mg twice a day. No DLT was observed.

Conclusions: Olaparib was escalated to the maximum target dose of 200 mg twice a day without DLT. Further follow-up is needed to evaluate the late toxicities. Pending the long-term results of the RADIOPARP trial, we suggest using 200 mg of olaparib twice per day for future trials.
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http://dx.doi.org/10.1016/j.ijrobp.2020.09.032DOI Listing
February 2021

Characterization of Stromal Tumor-infiltrating Lymphocytes and Genomic Alterations in Metastatic Lobular Breast Cancer.

Clin Cancer Res 2020 12 17;26(23):6254-6265. Epub 2020 Sep 17.

Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium.

Purpose: Invasive lobular carcinoma (ILC) represents the second most common histologic breast cancer subtype after invasive ductal carcinoma (IDC). While primary ILC has been extensively studied, metastatic ILC has been poorly characterized at the genomic and immune level.

Experimental Design: We retrospectively assembled the multicentric EuroILC series of matched primary and metastatic samples from 94 patients with estrogen receptor (ER)-positive ILC. Stromal tumor-infiltrating lymphocytes (sTILs) were assessed by experienced pathologists. Targeted sequencing and low pass whole-genome sequencing were conducted to detect mutations and copy-number aberrations (CNAs). We compared the frequencies of the alterations in EuroILC with those from patients with ER-positive metastatic ILC ( = 135) and IDC ( = 563) from MSK-IMPACT.

Results: Low sTIL levels were observed in ILC metastases, with higher levels in the mixed nonclassic histology. Considering ILC metastases from EuroILC and MSK-IMPACT, we observed that >50% of tumors harbor genomic alterations that have previously been associated with endocrine resistance. A matched primary/metastasis comparison in EuroILC revealed mutations (, or ) and CNAs ( or deletion, amplification) associated with endocrine resistance that were private to the metastasis in 22% (7/32) and 19% (4/21) of patients, respectively. An increase in , and mutations, in deletions and a decrease in mutations was observed in ILC as compared with IDC metastases.

Conclusions: ILC metastases harbor genomic alterations that may potentially explain endocrine resistance in a large proportion of patients, and present genomic differences as compared with IDC metastases.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2268DOI Listing
December 2020
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