Identification of lesion subtypes in biopsies of ductal carcinoma in situ of the breast using biomarker ratio imaging microscopy.
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ABSTRACT:
SUBMITTER: Clark AJ
PROVIDER: S-EPMC4887986 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A 26-year-old woman presented with a slow-growing right breast lump. Excision biopsy of the lump showed invasive ductal carcinoma with adjacent ductal carcinoma in situ (DCIS). Preoperative imaging was performed to assess the extent of disease. Magnetic resonance (MR) imaging of the breasts showed an area of clustered ring enhancement deep to the biopsy site, which was representative of residual DCIS. DCIS is a common noninvasive malignancy that manifests as a primary breast tumour or in association with other lesions. The radiological features of DCIS are discussed herein, with special attention to the clustered ring enhancement pattern on MR imaging.
| S-EPMC5651503 | biostudies-literature
Project description:Human models of noninvasive breast tumors are limited, and the existing in vivo models do not mimic inter- and intratumoral heterogeneity. Ductal carcinoma in situ (DCIS) is the most common type (80%) of noninvasive breast lesions. The aim of this study was to develop an in vivo model whereby the natural progression of human DCIS might be reproduced and studied. To accomplish this goal, the intraductal human-in-mouse (HIM) transplantation model was developed. The resulting models, which mimicked some of the diversity of human noninvasive breast cancers in vivo, were used to show whether subtypes of human DCIS might contain distinct subpopulations of tumor-initiating cells.The intraductal models were established by injection of human DCIS cell lines (MCF10DCIS.COM and SUM-225), as well as cells derived from a primary human DCIS (FSK-H7), directly into the primary mouse mammary ducts via cleaved nipple. Six to eight weeks after injections, whole-mount, hematoxylin and eosin, and immunofluorescence staining were performed to evaluate the type and extent of growth of the DCIS-like lesions. To identify tumor-initiating cells, putative human breast stem/progenitor subpopulations were sorted from MCF10DCIS.COM and SUM-225 with flow cytometry, and their in vivo growth fractions were compared with the Fisher's Exact test.Human DCIS cells initially grew within the mammary ducts, followed by progression to invasion in some cases into the stroma. The lesions were histologically almost identical to those of clinical human DCIS. This method was successful for growing DCIS cell lines (MCF10DCIS.COM and SUM-225) as well as a primary human DCIS (FSK-H7). MCF10DCIS.COM represented a basal-like DCIS model, whereas SUM-225 and FSK-H7 cells were models for HER-2+ DCIS. With this approach, we showed that various subtypes of human DCIS appeared to contain distinct subpopulations of tumor-initiating cells.The intraductal HIM transplantation model provides an invaluable tool that mimics human breast heterogeneity at the noninvasive stages and allows the study of the distinct molecular and cellular mechanisms of breast cancer progression.
| S-EPMC2790841 | biostudies-other
Project description:BackgroundStudies have failed to identify characteristics of women who have been diagnosed with ductal carcinoma in situ (DCIS) and have a high or low risk of subsequent invasive cancer.MethodsWe conducted a nested case-control study in a population-based cohort of 1162 women who were diagnosed with DCIS and treated by lumpectomy alone from 1983 to 1994. We collected clinical characteristics and information on subsequent tumors, defined as invasive breast cancer or DCIS diagnosed in the ipsilateral breast containing the initial DCIS lesion or at a regional or distant site greater than 6 months after initial treatment of DCIS (N = 324). We also conducted standardized pathology reviews and immunohistochemical staining for the estrogen receptor (ER), progesterone receptor, Ki67 antigen, p53, p16, epidermal growth factor receptor-2 (ERBB2, HER2/neu oncoprotein), and cyclooxygenase-2 (COX-2) on the initial paraffin-embedded DCIS tissue. Competing risk models were used to determine factors associated with risk of subsequent invasive cancer vs DCIS, and cumulative incidence survival functions were used to estimate 8-year risk.ResultsFactors associated with subsequent invasive cancer differed from those associated with subsequent DCIS. Eight-year risk of subsequent invasive cancer was statistically significantly (P = .018) higher for women with initial DCIS lesions that were detected by palpation or that were p16, COX-2, and Ki67 triple positive (p16(+)COX-2(+)Ki67(+)) (19.6%, 95% confidence interval [CI] = 18.0% to 21.3%) than for women with initial lesions that were detected by mammography and were p16, COX-2, and Ki67 triple negative (p16(-)COX-2(-)Ki67(-)) (4.1%, 95% CI = 3.4% to 5.0%). In a multivariable model, DCIS lesions that were p16(+)COX-2(+)Ki67(+) or those detected by palpation were statistically significantly associated with subsequent invasive cancer, but nuclear grade was not. Eight-year risk of subsequent DCIS was highest for women with DCIS lesions that had disease-free margins of 1 mm or greater combined with either ER(-)ERBB2(+)Ki67(+) or p16(+)COX-2(-)Ki67(+) status (23.6%, 95% CI = 18.1% to 34.0%).ConclusionBiomarkers can identify which women who were initially diagnosed with DCIS are at high or low risk of subsequent invasive cancer, whereas histopathology information cannot.
| S-EPMC2864293 | biostudies-literature
Project description:We examined a set of human breast cancers that were laser-microdissected from archived formalin fixed paraffin embedded (FFPE) tissue. These samples represent an important resource; however, they also represent a challenging aCGH application, as they tend to have significant amounts of noise. Our goal was to use known aberrations within these samples as a benchmark for determining the ability to differentiate between sample noise and real signal. Keywords: aCGH
2007-07-27 | GSE8591 | GEO
Project description:Ductal carcinoma in situ (DCIS) is a heterogeneous disease in both its biology and clinical course. In the past, recurrence rates after breast-conserving surgery have been as high as 30% after 10 years. The introduction of mammography screening and advances in imaging have led to an increase in the detection of DCIS. The focus of this review is on the role of radiotherapy in the multidisciplinary treatment, including current developments in hypofractionation and boost delivery, and attempts to define low-risk subsets of DCIS for which the need for adjuvant radiation is repeatedly questioned.
| S-EPMC4608608 | biostudies-literature
Project description:PurposeThe future of non-operative management of DCIS relies on distinguishing lesions requiring treatment from those needing only active surveillance. More accurate preoperative staging and grading of DCIS would be helpful. We identified determinants of upstaging preoperative breast biopsies showing ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC), or of upgrading them to higher-grade DCIS, following examination of the surgically excised specimen.MethodsWe studied all women with DCIS at preoperative biopsy in a large specialist cancer centre during 2000-2014. Information from clinical records, mammography, and pathology specimens from both preoperative biopsy and excised specimen were abstracted. Women suspected of having IBC during biopsy were excluded.ResultsAmong 606 preoperative biopsies showing DCIS, 15.0% (95% confidence interval 12.3-18.1) were upstaged to IBC and a further 14.6% (11.3-18.4) upgraded to higher-grade DCIS. The risk of upstaging increased with presence of a palpable lump (21.1% vs 13.0%, pdifference?=?0.04), while the risk of upgrading increased with presence of necrosis on biopsy (33.0% vs 9.5%, pdifference?<?0.001) and with use of 14G core-needle rather than 9G vacuum-assisted biopsy (22.8% vs 7.0%, pdifference?<?0.001). Larger mammographic size increased the risk of both upgrading (pheterogeneity?=?0.01) and upstaging (pheterogeneity?=?0.004).ConclusionsThe risk of upstaging of DCIS in preoperative biopsies is lower than previously estimated and justifies conducting randomized clinical trials testing the safety of active surveillance for lower grade DCIS. Selection of women with low grade DCIS for such trials, or for active surveillance, may be improved by consideration of the additional factors identified in this study.
| S-EPMC6797705 | biostudies-literature
Project description:Although ductal carcinoma in situ (DCIS) precedes invasive ductal carcinoma (IDC), the related genomic alterations remain unknown. To identify the genomic landscape of DCIS and better understand the mechanisms behind progression to IDC, we performed whole-exome sequencing and copy number profiling for six cases of pure DCIS and five pairs of synchronous DCIS and IDC. Pure DCIS harbored well-known mutations (e.g., TP53, PIK3CA and AKT1), copy number alterations (CNAs) and chromothripses, but had significantly fewer driver genes and co-occurrence of mutation/CNAs than synchronous DCIS-IDC. We found neither recurrent nor significantly mutated genes with synchronous DCIS-IDC compared to pure DCIS, indicating that there may not be a single determinant for pure DCIS progression to IDC. Of note, synchronous DCIS genomes were closer to IDC than pure DCIS. Among the clinicopathologic parameters, progesterone receptor (PR)-negative status was associated with increased mutations, CNAs, co-occurrence of mutations/CNAs and driver mutations. Our results indicate that although pure DCIS has already acquired some drivers, more changes are needed to progress to IDC. In addition, IDC-associated DCIS is more aggressive than pure DCIS at genomic level and should really be considered IDC. Finally, the data suggest that PR-negativity could be used to predict aggressive breast cancer genotypes.
| S-EPMC4480702 | biostudies-literature
Project description:Endocrine therapy initiation after ductal carcinoma in situ (DCIS) is highly variable and largely unexplained. National guidelines recommend considering tamoxifen for women with estrogen receptor-positive (ER+) DCIS or who undergo excision alone. We evaluated endocrine therapy use after DCIS over a 15-year period in an integrated health care setting to identify factors related to initiation.Female Group Health Cooperative enrollees ages 18-89 years with a DCIS diagnosis during 1996-2011 were eligible for inclusion. Endocrine therapy was identified through pharmacy records. Tumor and treatment information were from tumor registry reports; demographics and other risk factors were from questionnaires and electronic medical records. Relative risks (RRs) and 95% confidence intervals (CIs) for endocrine therapy initiation were calculated using multivariable generalized linear models.We identified 727 women with a DCIS diagnosis, including 163 (22%) who initiated endocrine therapy (149 tamoxifen, 14 aromatase inhibitor). Younger women were more likely to initiate endocrine therapy (RR 1.69; 95% CI 1.16-2.46 for ages 45-54 vs. 65-74 years). Compared with breast-conserving surgery (BCS) with radiation, women who had BCS alone (RR 0.46; 95% CI 0.25-0.84) or mastectomy (RR 0.54; 95% CI 0.39-0.75) were less likely to use endocrine therapy. ER testing increased from 4% of DCIS cases in 2001 to 71% in 2011; however, endocrine therapy initiation decreased from 58% of ER+ DCIS in 2001-2005 to 37% in 2009-2011.Increasing ER testing since 2001 has not corresponded to parallel increases in endocrine therapy initiation. Age, surgery, and radiation were the primary factors associated with initiation.National guidelines recommend considering tamoxifen for women with ductal carcinoma in situ (DCIS) who are estrogen receptor-positive (ER+) or who undergo excision alone. In this study, the rapid increase in ER testing caused by tamoxifen's approval in 2000 did not lead to increases in endocrine therapy initiation, despite recognition of an increasing number of DCIS tumors as ER+ each year. Contrary to the suggested guidelines, women who had breast-conserving surgery without radiation were less likely to use tamoxifen than those who had radiation. Future Food and Drug Administration approval of new endocrine agents for DCIS (such as aromatase inhibitors) may provide an opportunity to reemphasize benefits by ER and surgery status.
| S-EPMC4746086 | biostudies-other
Project description:Multiple invasive foci has been shown to increase the risk of lymph node metastasis (LNM) in early breast cancer, but its prognostic implication remains unknown. We aimed to identify the prognostic value of the number of invasive foci in ductal carcinoma in situ with minimal invasion of the breast (DCIS-MI), and further establish a prognostic invasive lesion index (ILI). A total of 193 patients with DCIS-MI (the invasive component was up to 10 mm in diameter) were included. Univariate and multivariate analysis (logistic regression) were used to evaluate the predictive value of the number of invasive foci in LNM. The Kaplan-Meier curve was used for survival analysis. More than five invasive foci was an independent predictor for LNM (OR, 2.67, 95% CI, 1.12-6.33, P = 0.026), and associated with significantly shorter disease-free survival (DFS) and overall survival (OS) compared with no more than five invasive foci (mean DFS 123.8 vs. 148.0 months, P = 0.002; and mean OS 133.5 vs. 151.4 months, P = 0.025). The ILI was established by the sum scores of the number of invasive foci and the invasive component size, having an optimal cut-off point of 5.5 scores. The high-ILI group (ILI >5 scores) had a higher incidence of LNM (23.6% vs. 6.9%) and worse prognosis than the low-ILI group (ILI ≤5 scores). In conclusion, more than five invasive foci was an independent predictor for LNM and an unfavorable prognostic parameter. The ILI could potentially be used to predict survival prognosis in patients with DCIS-MI.
| S-EPMC5673919 | biostudies-literature
Project description:To combine dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging with x-ray fluorescence microscopy (XFM) of mammary gland tissue samples from mice to identify the spatial distribution of gadolinium after intravenous injection.C3(1) Sv-40 large T antigen transgenic mice (n = 23) were studied with institutional animal care and use committee approval. Twelve mice underwent DCE MR imaging after injection of gadodiamide, and gadolinium concentration-time curves were fit to a two-compartment pharmacokinetic model with the following parameters: transfer constant (K(trans)) and volume of extravascular extracellular space per unit volume of tissue (v(e)). Eleven mice received gadodiamide before XFM. These mice were sacrificed 2 minutes after injection, and frozen slices containing ducts distended with murine ductal carcinoma in situ (DCIS) were prepared for XFM. One mouse received saline and served as the control animal. Elemental gadolinium concentrations were measured in and around the ducts with DCIS. Hematoxylin-eosin-stained slices of mammary tissues were obtained after DCE MR imaging and XFM.Ducts containing DCIS were unambiguously identified on MR images. DCE MR imaging revealed gadolinium uptake along the length of ducts with DCIS, with an average K(trans) of 0.21 min(-1) +/- 0.14 (standard deviation) and an average v(e) of 0.40 +/- 0.16. XFM revealed gadolinium uptake inside ducts with DCIS, with an average concentration of 0.475 mmol/L +/- 0.380; the corresponding value for DCE MR imaging was 0.30 mmol/L +/- 0.13.These results provide insight into the physiologic basis of contrast enhancement of DCIS lesions on DCE MR images: Gadolinium penetrates and collects inside neoplastic ducts.
| S-EPMC2770112 | biostudies-literature