Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancer

Lips, Esther H.; Kumar, Tapsi; Megalios, Anargyros; Visser, Lindy L.; Sheinman, Michael; Fortunato, Angelo; Shah, Vandna; Hoogstraat, Marlous; Sei, Emi; Mallo, Diego; Roman-Escorza, Maria; Ahmed, Ahmed A.; Xu, Min; Belt-Dusebout, Alexandra W. van den; Brugman, Wim; Casasent, Anna; Clements, Karen; Davies, Helen; Fu, Liping; Grigoriadis, Anita; Hardman, Timothy; King, Lorraine; Krete, Marielle; Kristel, Petra; Maaker, Michiel de; Maley, Carlo C.; Marks, Jeffrey R.; Menegaz, Brian A.; Mulder, Lennart; Nieboer, Frank; Nowinski, Salpie; Pinder, Sarah; Quist, Jelmar; Salinas-Souza, Carolina; Schaapveld, Michael; Schmidt, Marjanka K.; Shaaban, Abeer M.; Shami, Rana; Sridharan, Mathini; Zhang, Junyi; Stobart, Hilary; Collyar, Deborah; Nik-Zainal, Serena; Wessels, Lodewyk F.A.; Navin, Nicholas E.; Futreal, Andrew; Futreal, P. Andrew; Hwang, E. Shelley; Jonkers, Jos; Jacco,; Behbod, Fariba; Rea, Daniel; Bhattacharjee, Proteeti; Pinto, Donna; Verschuur, Ellen; Oirsouw, Marja van; Thompson, Alastair; Wesseling, Jelle; Sawyer, Elinor J.

doi:10.1038/s41588-022-01082-3

Cited by 54 publications

(31 citation statements)

References 38 publications

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“…This clearly has potential clinical relevance but requires further validation. Molecular signatures that distinguish poor prognosis DCIS that is likely to progress to invasive carcinoma/metastasise are being investigated, and recent genomic data from the Sloane cohort highlighted clonal similarities between the primary DCIS and the subsequent invasive recurrences in 75% of cases [ 25 ]. Going forward, the molecular profile may provide an attractive companion to standard histopathological examination to dissect the good prognosis microinvasive lesions from those that have the potential to frankly invade/metastasise.…”

Section: Discussionmentioning

confidence: 99%

The presentation, management and outcome of patients with ductal carcinoma in situ (DCIS) with microinvasion (invasion ≤1 mm in size)—results from the UK Sloane Project

Shaaban

Hilton²,

Clements³

et al. 2022

Br J Cancer

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Background The diagnosis, management and prognosis of microinvasive breast carcinoma remain controversial. Methods We analysed the outcomes of patients with DCIS with and without microinvasion diagnosed between 2003 and 2012 within the Sloane project. Results Microinvasion was recorded in 521 of 11,285 patients (4.6%), with considerable variation in reported incidence among screening units (0–25%). Microinvasion was associated with high-grade DCIS, larger DCIS size, comedo necrosis and solid, cribriform architecture (all P < 0.001). Microinvasion was more frequent in patients who underwent mastectomy compared with breast-conserving surgery (BCS) (6.9% vs 3.6%, P < 0.001), and in those undergoing axillary nodal surgery (60.4% vs 30.3%, P < 0.001) including the subset undergoing BCS (43.4% vs 8.5%, P < 0.001). Nodal metastasis rate was low and not statistically significant difference from the DCIS only group (P = 0.68). Following median follow-up of 110 months, 3% of patients had recurrent ipsilateral high-grade DCIS, and 4.2% developed invasive carcinoma. The subsequent ipsilateral invasion was of Grade 3 in 71.4% of patients with microinvasion vs 30.4% in DCIS without microinvasion (P = 0.02). Distant metastasis and breast cancer mortality were higher with microinvasion compared with DCIS only (1.2% vs 0.3%, P = 0.01 and 2.1% vs 0.8%; P = 0.005). Conclusions The higher breast cancer mortality with microinvasion indicates a more aggressive disease.

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Section: Discussionmentioning

confidence: 99%

The presentation, management and outcome of patients with ductal carcinoma in situ (DCIS) with microinvasion (invasion ≤1 mm in size)—results from the UK Sloane Project

Shaaban

Hilton²,

Clements³

et al. 2022

Br J Cancer

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“…This limitation is systematic in the vast majority of studies of DCIS, as longitudinal sampling cannot be performed. But since not all DCIS patients progress to IDC, there is increasing evidence that host specific factors contribute to DCIS progression or containment 44,45 and cross sectional studies cannot capture their contributions.…”

Section: Discussionmentioning

confidence: 99%

Differential Analysis of Stromal-Epithelial Interactions between In Situ and Invasive Breast Cancer using Gene Expression Profiling

Officer

Dempsey

Murrow

et al. 2022

Preprint

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Background: Changes in microenvironment cell-cell interactions (CCI) during the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are poorly understood. Gene expression studies are confounded by cellular heterogeneity and few separate stromal and epithelial contributions, resulting in a lack of reliable prognostic biomarker to guide treatment decisions. Methods: The gene expression of 293 microdissected regions from DCIS (92 epithelial, 31 stromal) and IDC (78 epithelial, 30 stromal) cases was aggregated from 6 datasets. Expression signatures of 6 cell lineages extracted from normal breast single-cell profiling were used to correct for differences in cell abundance. Subtype-specific functional differences between DCIS and IDC were measured for each region type using Gene Set Enrichment Analysis (GSEA). DCIS-IDC stromal-epithelial interactions were compared using the expression product of 139 ligand-receptor (LR) pairs permuting the DCIS-IDC labels to assess significance. Results: Variation in cell-lineage abundance separated epithelial regions into 4 clusters, including one enriched for DCIS (Myoepi-Enriched) and two for IDC (Infiltrated, Vascularized). GSEA on cell lineage normalized expression data identified subtype-independent changes in epithelial regions (induction of Extracellular Matrix maintenance genes, reduction of Tp53 signaling in IDC), as well as subtype-specific changes (proliferation in ER- and Her2- IDC, reduction in Nucleotide Excision Repair in ER+ IDC). In the stroma, Notch and Rho-GTPase signaling were induced in IDC irrespective of subtype. The stromal-epithelial interaction level of 6 and 4 LR pairs were significantly enriched in DCIS and IDC, respectively. Five of the 6 DCIS-enriched LR pairs involved ephrin interactions, with interaction level progressively decreasing from normal to DCIS to IDC. In contrast, 2 IDC-enriched LR pairs involved T-cell activity likely regulating Treg proliferation (CD28-CD86) or T and NK cells stimulation (CD226-PVR). Notably, the bulk expression product of one identified LR pair (EPHB4-EFNB1) was associated with poor survival in IDC (HR=1.47, p=0.04) suggesting that early remodeling of this stromal-epithelial interaction may have long-lasting impact on disease severity. Conclusions: The observed changes in cell states and stromal-epithelial interactions, beyond those driven by difference in cell abundance, may lead to new biomarkers for prognosis and targets for secondary prevention.

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“…Another issue, currently underappreciated, is whether recurrent DCIS has arisen from the primary tumour or is independent. A recent study has shown that ~18% of ‘recurrent’ DCIS may, in fact, be new primary tumours 22 . This proportion of cases will dramatically reduce the power of biomarker studies examining tumour‐intrinsic markers when it is not known which recurrences are truly arising from the primary tumour.…”

Section: Predictive Markers In Dcismentioning

confidence: 99%

“…DCIS can recur both as DCIS in the same breast (ipsilateral) and as invasive cancer, with approximately equal incidence overall. The recurrences are largely molecularly related to the original DCIS, but there is a subset that are clonally unrelated and are considered de‐novo tumours 22 . Because of the histological heterogeneity of DCIS that is also reflected in the immunophenotype, 23 it is a clinical challenge to determine an individual patient's risk of recurrence or progression to invasive disease, thereby making decisions regarding the efficacy of adjuvant therapies difficult.…”

Section: Risk Of Recurrencementioning

confidence: 99%

“…However, this simplistic model is challenged when we consider the DCIS to invasive transition, as DCIS can be as genetically advanced as invasive disease 52,53 . Nonetheless, it is clear that DCIS is a genetically related precursor to invasive disease in most cases when found in the same person, either at the same time or on recurrence 22,54 . Thus, the independent lineage model of progression, whereby DCIS and IDC arise separately and coexist, is not a complete model, as it would only explain the synchronous presence of DCIS and IDC with different clonal origins that have both arisen within a predisposing field.…”

Section: Proposed Mechanisms For the Development Of Invasive Breast C...mentioning

confidence: 99%

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Identifying recurrences and metastasis after ductal carcinoma in situ (DCIS) of the breast

et al. 2022

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Identifying recurrences and metastasis after ductal carcinoma in situ (DCIS) of the breast Ductal carcinoma in situ (DCIS) of the breast is a non-invasive tumour that has the potential to progress to invasive ductal carcinoma (IDC). Thus, it represents a treatment dilemma: alone it does not present a risk to life, however, left untreated it may progress to a life-threatening condition. Current clinico-pathological features cannot accurately predict which patients with DCIS have invasive potential, and therefore clinicians are unable to quantify the risk of progression for an individual patient. This leads to many women being over-treated, while others may not receive sufficient treatment to prevent invasive recurrence. A better understanding of the molecular features of DCIS, both tumour-intrinsic and the microenvironment, could offer the ability to better predict which women need aggressive treatment, and which can avoid therapies carrying significant sideeffects and such as radiotherapy. In this review, we summarise the current knowledge of DCIS, and consider future research directions.

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Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancer

Cited by 54 publications

References 38 publications

The presentation, management and outcome of patients with ductal carcinoma in situ (DCIS) with microinvasion (invasion ≤1 mm in size)—results from the UK Sloane Project

The presentation, management and outcome of patients with ductal carcinoma in situ (DCIS) with microinvasion (invasion ≤1 mm in size)—results from the UK Sloane Project

Differential Analysis of Stromal-Epithelial Interactions between In Situ and Invasive Breast Cancer using Gene Expression Profiling

Identifying recurrences and metastasis after ductal carcinoma in situ (DCIS) of the breast

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