Ductal carcinoma in situ (DCIS) is a non-invasive breast neoplasia that accounts for 25% of all screen-detected breast cancers diagnosed annually. Neoplastic cells in DCIS are confined to the ductal ...system of the breast, although they can escape and progress to invasive breast cancer in a subset of patients. A key concern of DCIS is overtreatment, as most patients screened for DCIS and in whom DCIS is diagnosed will not go on to exhibit symptoms or die of breast cancer, even if left untreated. However, differentiating low-risk, indolent DCIS from potentially progressive DCIS remains challenging. In this Review, we summarize our current knowledge of DCIS and explore open questions about the basic biology of DCIS, including those regarding how genomic events in neoplastic cells and the surrounding microenvironment contribute to the progression of DCIS to invasive breast cancer. Further, we discuss what information will be needed to prevent overtreatment of indolent DCIS lesions without compromising adequate treatment for high-risk patients.
Ductal carcinoma
(DCIS) is treated to prevent progression to invasive breast cancer. Yet, most lesions will never progress, implying that overtreatment exists. Therefore, we aimed to identify factors ...distinguishing harmless from potentially hazardous DCIS using a nested case-control study.
We conducted a case-control study nested in a population-based cohort of patients with DCIS treated with breast-conserving surgery (BCS) alone (
= 2,658) between 1989 and 2005. We compared clinical, pathologic, and IHC DCIS characteristics of 200 women who subsequently developed ipsilateral invasive breast cancer (iIBC; cases) and 474 women who did not (controls), in a matched setting. Median follow-up time was 12.0 years (interquartile range, 9.0-15.3). Conditional logistic regression models were used to assess associations of various factors with subsequent iIBC risk after primary DCIS.
High COX-2 protein expression showed the strongest association with subsequent iIBC OR = 2.97; 95% confidence interval (95% CI), 1.72-5.10. In addition, HER2 overexpression (OR = 1.56; 95% CI, 1.05-2.31) and presence of periductal fibrosis (OR = 1.44; 95% CI, 1.01-2.06) were associated with subsequent iIBC risk. Patients with HER2
/COX-2
DCIS had a 4-fold higher risk of subsequent iIBC (vs. HER2
/COX-2
DCIS), and an estimated 22.8% cumulative risk of developing subsequent iIBC at 15 years.
With this unbiased study design and representative group of patients with DCIS treated by BCS alone, COX-2, HER2, and periductal fibrosis were revealed as promising markers predicting progression of DCIS into iIBC. Validation will be done in independent datasets. Ultimately, this will aid individual risk stratification of women with primary DCIS.
.
Although ductal carcinoma in situ (DCIS) is a non-obligate precursor to ipsilateral invasive breast cancer (iIBC), most DCIS lesions remain indolent. Hence, overdiagnosis and overtreatment of DCIS is ...a major concern. There is an urgent need for prognostic markers that can distinguish harmless from potentially hazardous DCIS. We hypothesised that features of the breast adipose tissue may be associated with risk of subsequent iIBC. We performed a case-control study nested in a population-based DCIS cohort, consisting of 2658 women diagnosed with primary DCIS between 1989 and 2005, uniformly treated with breast conserving surgery (BCS) alone. We assessed breast adipose features with digital pathology (HALO
, Indica Labs) and related these to iIBC risk in 108 women that developed subsequent iIBC (cases) and 168 women who did not (controls) by conditional logistic regression, accounting for clinicopathological and immunohistochemistry variables. Large breast adipocyte size was significantly associated with iIBC risk (odds ratio (OR) 2.75, 95% confidence interval (95% CI) = 1.25-6.05). High cyclooxygenase (COX)-2 protein expression in the DCIS cells was also associated with subsequent iIBC (OR 3.70 (95% CI = 1.59-8.64). DCIS with both high COX-2 expression and large breast adipocytes was associated with a 12-fold higher risk (OR 12.0, 95% CI = 3.10-46.3, P < 0.001) for subsequent iIBC compared with women with smaller adipocyte size and low COX-2 expression. Large breast adipocytes combined with high COX-2 expression in DCIS is associated with a high risk of subsequent iIBC. Besides COX-2, adipocyte size has the potential to improve clinical management in patients diagnosed with primary DCIS.
Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer (IBC). Due to a lack of biomarkers able to distinguish high- from low-risk cases, DCIS is treated similar to ...early IBC even though the minority of untreated cases eventually become invasive. Here, we characterized 115 patient-derived mouse-intraductal (MIND) DCIS models reflecting the full spectrum of DCIS observed in patients. Utilizing the possibility to follow the natural progression of DCIS combined with omics and imaging data, we reveal multiple prognostic factors for high-risk DCIS including high grade, HER2 amplification, expansive 3D growth, and high burden of copy number aberrations. In addition, sequential transplantation of xenografts showed minimal phenotypic and genotypic changes over time, indicating that invasive behavior is an intrinsic phenotype of DCIS and supporting a multiclonal evolution model. Moreover, this study provides a collection of 19 distributable DCIS-MIND models spanning all molecular subtypes.
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•Development of a biobank of DCIS-MIND models retaining primary features•Identification of multiple factors associated with invasive progression of DCIS•Identification of two distinct 3D growth patterns associated with outcome•Development of a collection of 19 distributable DCIS models
Hutten et al. generate 115 DCIS-MIND models and characterize them with genomic, transcriptomic, and imaging data. With this biobank they identify risk factors associated with progression of ductal carcinoma in situ to invasive breast cancer and create a collection of 19 distributable DCIS models, providing a resource for further research.
Abstract
Background
Ductal carcinoma in situ (DCIS) is treated to prevent subsequent ipsilateral invasive breast cancer (iIBC). However, many DCIS lesions will never become invasive. To prevent ...overtreatment, we need to distinguish harmless from potentially hazardous DCIS. We investigated whether the immune microenvironment (IME) in DCIS correlates with transition to iIBC.
Methods
Patients were derived from a Dutch population-based cohort of 10,090 women with pure DCIS with a median follow-up time of 12 years. Density, composition and proximity to the closest DCIS cell of CD20
+
B-cells, CD3
+
CD8
+
T-cells, CD3
+
CD8
−
T-cells, CD3
+
FOXP3
+
regulatory T-cells, CD68
+
cells, and CD8
+
Ki67
+
T-cells was assessed with multiplex immunofluorescence (mIF) with digital whole-slide analysis and compared between primary DCIS lesions of 77 women with subsequent iIBC (cases) and 64 without (controls).
Results
Higher stromal density of analysed immune cell subsets was significantly associated with higher grade, ER negativity, HER-2 positivity, Ki67 ≥ 14%, periductal fibrosis and comedonecrosis (
P
< 0.05). Density, composition and proximity to the closest DCIS cell of all analysed immune cell subsets did not differ between cases and controls.
Conclusion
IME features analysed by mIF in 141 patients from a well-annotated cohort of pure DCIS with long-term follow-up are no predictors of subsequent iIBC, but do correlate with other factors (grade, ER, HER2 status, Ki-67) known to be associated with invasive recurrences.
Ductal carcinoma in situ (DCIS) is considered a potential precursor of invasive breast carcinoma (IBC). Studies aiming to find markers involved in DCIS progression generally have compared ...characteristics of IBC lesions with those of adjacent synchronous DCIS lesions. The question remains whether synchronous DCIS and IBC comparisons are a good surrogate for primary DCIS and subsequent IBC. In this study, we compared both primary DCIS and synchronous DCIS with the associated IBC lesion, on the basis of immunohistochemical marker expression. Immunohistochemical analysis of ER, PR, HER2, p53, and cyclo-oxygenase 2 (COX-2) was performed for 143 primary DCIS and subsequent IBC lesions, including 81 IBC lesions with synchronous DCIS. Agreement between DCIS and IBC was assessed using kappa, and symmetry tests were performed to assess the pattern in marker conversion. The primary DCIS and subsequent IBC more often showed discordant marker expression than synchronous DCIS and IBC. Strikingly, 18 of 49 (36%) women with HER2-positive primary DCIS developed an HER2-negative IBC. Such a difference in HER2 expression was not observed when comparing synchronous DCIS and IBC. The frequency of discordant marker expression did not increase with longer time between primary DCIS and IBC. In conclusion, comparison of primary DCIS and subsequent IBC yields different results than a comparison of synchronous DCIS and IBC, in particular with regard to HER2 status. To gain more insight into the progression of DCIS to IBC, it is essential to focus on the relationship between primary DCIS and subsequent IBC, rather than comparing IBC with synchronous DCIS.
Breast cancer (BCa) is a highly heterogeneous disease, with hormone receptor status being a key factor in patient prognostication and treatment decision‐making. The majority of primary tumours are ...positive for oestrogen receptor alpha (ERα), which plays a key role in tumorigenesis and disease progression, and represents the major target for treatment of BCa. However, around one‐third of patients with ERα‐positive BCa relapse and progress into the metastatic stage, with 20% of metastatic cases characterised by loss of ERα expression after endocrine treatment, known as ERα‐conversion. It remains unclear whether ERα‐converted cancers are biologically similar to bona fide ERα‐negative disease and which signalling cascades compensate for ERα loss and drive tumour progression. To better understand the biological changes that occur in metastatic BCa upon ERα loss, we performed (phospho)proteomics analysis of 47 malignant pleural effusions derived from 37 BCa patients, comparing ERα‐positive, ERα‐converted and ERα‐negative cases. Our data revealed that the loss of ERα‐dependency in this metastatic site leads to only a partial switch to an ERα‐negative molecular phenotype, with preservation of a luminal‐like proteomic landscape. Furthermore, we found evidence for decreased activity of several key kinases, including serum/glucocorticoid regulated kinase 1 (SGK1), in ERα‐converted metastases. Loss of SGK1 substrate phosphorylation may compensate for the loss of ERα‐dependency in advanced disease and exposes a potential therapeutic vulnerability that may be exploited in treating these patients.
Breast cancer's hormone receptor status is pivotal in prognosis and treatment. Many tumours express oestrogen receptor alpha (ERα), which can be lost after treatment (ERα‐conversion). We studied 47 metastatic breast cancer samples—ERα‐positive, ERα‐converted and ERα‐negative. ERα‐converted tumours do not recapitulate ERα‐negative cancer; luminal‐like features persist. SGK1 kinase activity is reduced in ERα‐converted metastases, representing an interesting new therapeutic candidate.
The prognostic significance of histopathologic (sub)classes in the current classification of lupus nephritis (LN) is controversial. We analyzed clinical and histopathologic predictors of renal ...outcome in LN outside the framework of the classification.
Variables (50 histopathologic and ten clinical) were tested in mixed, linear, and Cox regression models for their association with renal flare, ESRD, and eGFR during follow-up (1, 5, and 10 years) in 105 patients with LN who underwent biopsy from 1987 to 2011. The Cockcroft-Gault (normalized to a body surface area of 1.73 m
) and Schwartz formulas were used to calculate eGFR for adults and children, respectively.
During median follow-up of 9.9 years (25th-75th percentile, 5.9-13.8), 47 patients experienced a renal flare and 21 progressed to ESRD. Renal flare was predicted by fibrinoid necrosis (hazard ratio HR, 1.04 per %; 95% confidence interval 95% CI, 1.00 to 1.07) and nonwhite race (HR, 2.23; 95% CI, 1.23 to 4.04). ESRD was predicted by fibrinoid necrosis (HR, 1.08 per %; 95% CI, 1.02 to 1.13), fibrous crescents (HR, 1.09 per %; 95% CI, 1.02 to 1.17), interstitial fibrosis/tubular atrophy (IF/TA) ≥25% (HR, 3.89; 95% CI, 1.25 to 12.14), eGFR at baseline (HR, 0.98 per ml/min per 1.73 m
; 95% CI, 0.97 to 1.00), and nonwhite race (HR, 7.16; 95% CI, 2.34 to 21.91). A higher mean eGFR during follow-up was associated with normal glomeruli (+0.2 ml/min per 1.73 m
per %; 95% CI, 0.1 to 0.4). Like ESRD, a lower eGFR during follow-up was associated with fibrous crescents, IF/TA≥25%, and nonwhite race, as well as with cellular/fibrocellular crescents (-0.4 ml/min per 1.73 m
per %; 95% CI, -0.6 to -0.2) and age (-0.8 ml/min per 1.73 m
per year; 95% CI, -1.2 to -0.4).
The LN classification should include an index of evidence-based prognosticators. Awaiting validation of a formal index, we suggest that at least fibrinoid necrosis, fibrous crescents, and IF/TA warrant explicit independent scoring to assess the risk of progressive renal dysfunction in conjunction with clinical findings.
The di-allelic HLA-A2 restricted minor histocompatibility Ag HA-1 locus codes for the highly immunogenic HA-1(His) and the nonimmunogenic HA-1(Arg) nonapeptides, differing in one amino acid. The ...HA-1(His) peptide is currently used for boosting the graft-vs-tumor responses after HLA matched HA-1 mismatched stem cell transplantation; usage of the HA-1(Arg) peptide would significantly enlarge the applicability for this therapy. Our studies on mechanisms causing the HA-1 unidirectional immunogenicity revealed marginal differences in proteasomal digestion, TAP translocation, and binding affinity, whereas both dissociation rates and structural analyses clearly showed marked differences in the stability of these two HLA-A2 bound alleles. These data provide a rationale for the lack of HA-1(Arg) peptide immunogenicity essential for the choice of tumor peptides for stem cell-based immunotherapeutic application.
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