Genomic and Transcriptomic Analyses of Breast Cancer Primaries and Matched Metastases in AURORA, the Breast International Group (BIG) Molecular Screening Initiative

Aftimos, Philippe; Oliveira, Mafalda; Irrthum, Alexandre; Fumagalli, Debora; Sotiriou, Christos; Gal‐Yam, Einav Nili; Robson, Mark E.; Ndozeng, Justin; Leo, Angelo Di; Ciruelos, Eva; Azambuja, Evandro de; Viale, Giuseppe; Scheepers, Elsemieke D.; Curigliano, Giuseppe; Bliss, Judith; Reis‐Filho, Jorge S.; Colleoni, Marco; Balić, Marija; Cardoso, Fátima; Albanell, Joan; Duhem, Caroline; Marréaud, Sandrine; Romagnoli, Dario; Rojas, Beatriz; Gombos, Andrea; Wildiers, Hans; Guerrero-Zotano, Ángel; Hall, Peter; Bonetti, Andrea; Larsson, Karin; Degiorgis, Martina; Khodaverdi, Silvia; Greil, Richard; Sverrisdóttir, Ásgerður; Paoli, Marta; Seyll, Ethel; Loibl, Sibylle; Linderholm, Barbro; Zoppoli, Gabriele; Davidson, Nancy E.; Jóhannsson, Óskar T.; Bédard, Philippe L.; Loi, Sherene; Knox, Susan; Cameron, David; Harbeck, Nadia; Montoya, Maite Lasa; Brandão, Mariana; Vingiani, Andrea; Caballero, C.; Hilbers, Florentine; Yates, Lucy R.; Benelli, Matteo; Venet, David; Piccart, Martine

doi:10.1158/2159-8290.cd-20-1647

Cited by 89 publications

(71 citation statements)

References 54 publications

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“…Acquisition of the HER2E subtype in the absence of gain of HER2-amplification in metastatic samples has been reported 3,16,34 , but this is the first instance to demonstrate its' association with a DNA clonality change.…”

Section: Clonal Evolution and Subtype Switchingmentioning

confidence: 74%

“…Changes in the somatic genetics of metastatic breast tumors are well documented 2,3 , and here we extend the changes seen in metastatic tumors into the epigenetic landscape (i.e., DNA methylation and gene expression features). In 1/3 of the patients, we identified a gene expression-defined tumor subtype switch, especially frequent in luminal/ER+ patients, wherein these gene expression changes were mirrored by DNA clonality and methylation changes.…”

mentioning

confidence: 70%

“…An early focus on metastatic disease has been to identify somatic alterations that might be unique to this setting, and/or that may be clinically actionable, especially when metastasis surgical resection may not be a viable option. Numerous seminal publications on MBC genomics have shown that almost no recurrent mutations are unique to the metastatic landscape, with perhaps the exception of ESR1 mutations, most of which are a thought to be tied to endocrine therapy resistance 2,3 .…”

Section: Introductionmentioning

confidence: 99%

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Multiplatform Analysis of Primary and Metastatic Breast Tumors from the AURORA US Network identifies microenvironment and epigenetics drivers of metastasis

Perou

García-Recio²,

Wheeler

et al. 2022

Preprint

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Patients with metastatic breast cancer (MBC) typically have short survival times and their successful treatment represents one of most challenging aspects of patient care. This poor prognostic behavior is in part due to molecular features including increased tumor cell clonal heterogeneity, multiple drug resistance mechanisms, and alterations of the tumor microenvironment. The AURORA US Metastasis Project was established with the goal to identify molecular features specifically associated with metastasis. We therefore collected and molecularly characterized specimens from 55 metastatic breast cancer (BC) patients representing 51 primary cancers and 102 metastases. The 153 unique tumors were assayed using RNAseq, tumor/germline DNA exomes and low pass whole genome sequencing, and global DNA methylation microarrays. We found intrinsic molecular subtype differences between primary tumors and their matched metastases to be rare in triple negative breast cancer (TNBC)/Basal-like subtype tumors. Conversely, tumor subtype changes were relatively frequent in estrogen receptor positive (ER+) cancers where ~30% of Luminal A cases switched to Luminal B or HER2-enriched (HER2E) subtypes. Clonal evolution studies identified changes in expression subtype coincident with DNA clonality shifts, especially involving HER2 amplification and/or the HER2E expression subtype. We further found evidence for ER-mediated downregulation of genes involved in cell-cell adhesion in metastases. Microenvironment differences varied according to tumor subtype where ER+/Luminal metastases had lower fibroblast and endothelial cell content, while TNBC/Basal-like metastases showed a dramatic decrease in B cells and T cells. In 17% of metastatic tumors, we identified DNA hypermethylation and/or focal DNA deletions near HLA-A that were associated with its’ significantly reduced expression, and with lower immune cell infiltrates. We also identified low immune cell features in brain and liver metastases when compared to other metastatic sites, even within the same patient. These findings have direct implications for the treatment of metastatic breast cancer patients with immune- and HER2-targeting therapies and suggest potential novel therapeutic avenues for the improvement of outcomes for some patients with MBC.

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Section: Clonal Evolution and Subtype Switchingmentioning

confidence: 74%

mentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

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Multiplatform Analysis of Primary and Metastatic Breast Tumors from the AURORA US Network identifies microenvironment and epigenetics drivers of metastasis

Perou

García-Recio²,

Wheeler

et al. 2022

Preprint

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“…Recent NGS analyses evaluating paired primary tumors and matched metastatic lesions confirm the molecular heterogeneity underpinning metastatic progression [17,[62][63][64][65]. Interestingly, a quota of mutations arisen during the metastatic process could be targeted by biological drugs (e.g., affecting ERBB2, BRCA2, PIK3CA) [66].…”

Section: Temporal Heterogeneitymentioning

confidence: 99%

“…They identified genomic alterations enriched in metastases namely ESR1, PTEN, CDH1, PIK3CA and RB1 mutations, MDM4 and MYC gene copy number gains, and ARID1A deletions. Moreover, ESMO Scale of Clinical Actionability for molecular Targets (ESCAT) tier I/II alterations were detected in over half of the patients, with crucial impact for target therapy selection; on the other hand, metastases had lower immune score and an increased number of immune permissive cells [62].…”

Section: Temporal Heterogeneitymentioning

confidence: 99%

Breast Cancer Heterogeneity

Fumagalli

Barberis

2021

Diagnostics

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Breast tumor heterogeneity is a major challenge in the clinical management of breast cancer patients. Both inter-tumor and intra-tumor heterogeneity imply that each breast cancer (BC) could have different prognosis and would benefit from specific therapy. Breast cancer is a dynamic entity, changing during tumor progression and metastatization and this poses fundamental issues to the feasibility of a personalized medicine approach. The most effective therapeutic strategy for patients with recurrent disease should be assessed evaluating biopsies obtained from metastatic sites. Furthermore, the tumor progression and the treatment response should be strictly followed and radiogenomics and liquid biopsy might be valuable tools to assess BC heterogeneity in a non-invasive way.

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Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple‐negative breast cancer to immune checkpoint inhibitors

Chen

Wang

et al. 2023

Cancer Communications

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BackgroundImmune checkpoint inhibitors (ICIs) shed new light on triple‐negative breast cancer (TNBC), but only a minority of patients demonstrate response. Therefore, adaptive immune resistance (AIR) needs to be further defined to guide the development of ICI regimens.MethodsDatabases, including The Cancer Genome Atlas, Gene Ontology Resource, University of California Santa Cruz Genome Browser, and Pubmed, were used to screen epigenetic modulators, regulators for CD8+ T cells, and transcriptional regulators of programmed cell death‐ligand 1 (PD‐L1). Human peripheral blood mononuclear cell (Hu‐PBMC) reconstruction mice were adopted for xenograft transplantation. Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed. RNA‐sequencing, Western blotting, qPCR and immunohistochemistry were used to assess gene expression. Coculture assays were performed to evaluate the regulation of TNBC cells on T cells. Chromatin immunoprecipitation and transposase‐accessible chromatin sequencing were used to determine chromatin‐binding and accessibility.ResultsThe epigenetic modulator AT‐rich interaction domain 1A (ARID1A) gene demonstrated the highest expression association with AIR relative to other epigenetic modulators in TNBC patients. Low ARID1A expression in TNBC, causing an immunosuppressive microenvironment, promoted AIR and inhibited CD8+ T cell infiltration and activity through upregulating PD‐L1. However, ARID1A did not directly regulate PD‐L1 expression. We found that ARID1A directly bound the promoter of nucleophosmin 1 (NPM1) and that low ARID1A expression increased NPM1 chromatin accessibility as well as gene expression, further activating PD‐L1 transcription. In Hu‐PBMC mice, atezolizumab demonstrated the potential to reverse ARID1A deficiency‐induced AIR in TNBC by reducing tumor malignancy and activating anti‐tumor immunity. In CTR20191353, ARID1A‐low patients derived more benefit from pucotenlimab compared to ARID1A‐high patients.ConclusionsIn AIR epigenetics, low ARID1A expression in TNBC contributed to AIR via the ARID1A/NPM1/PD‐L1 axis, leading to poor outcome but sensitivity to ICI treatment.

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Genomic and Transcriptomic Analyses of Breast Cancer Primaries and Matched Metastases in AURORA, the Breast International Group (BIG) Molecular Screening Initiative

Cited by 89 publications

References 54 publications

Multiplatform Analysis of Primary and Metastatic Breast Tumors from the AURORA US Network identifies microenvironment and epigenetics drivers of metastasis

Multiplatform Analysis of Primary and Metastatic Breast Tumors from the AURORA US Network identifies microenvironment and epigenetics drivers of metastasis

Breast Cancer Heterogeneity

Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple‐negative breast cancer to immune checkpoint inhibitors

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