Dataset Information

A Quantitative Centrosomal Amplification Score Predicts Local Recurrence of Ductal Carcinoma In Situ.

ABSTRACT: PURPOSE:The purpose of this study is to predict risk of local recurrence (LR) in ductal carcinoma in situ (DCIS) with a new visualization and quantification approach using centrosome amplification (CA), a cancer cell-specific trait widely associated with aggressiveness. EXPERIMENTAL DESIGN:This first-of-its-kind methodology evaluates the severity and frequency of numerical and structural CA present within DCIS and assigns a quantitative centrosomal amplification score (CAS) to each sample. Analyses were performed in a discovery cohort (DC, n = 133) and a validation cohort (VC, n = 119). RESULTS:DCIS cases with LR exhibited significantly higher CAS than recurrence-free cases. Higher CAS was associated with a greater risk of developing LR (HR, 6.3 and 4.8 for DC and VC, respectively; P < 0.001). CAS remained an independent predictor of relapse-free survival (HR, 7.4 and 4.5 for DC and VC, respectively; P < 0.001) even after accounting for potentially confounding factors [grade, age, comedo necrosis, and radiotherapy (RT)]. Patient stratification using CAS (P < 0.0001) was superior to that by Van Nuys Prognostic Index (VNPI; HR for CAS = 6.2 vs. HR for VNPI = 1.1). Among patients treated with breast-conserving surgery alone, CAS identified patients likely to benefit from adjuvant RT. CONCLUSIONS:CAS predicted 10-year LR risk for patients who underwent surgical management alone and identified patients who may be at low risk of recurrence, and for whom adjuvant RT may not be required. CAS demonstrated the highest concordance among the known prognostic models such as VNPI and clinicopathologic variables such as grade, age, and comedo necrosis.

SUBMITTER: Mittal K

PROVIDER: S-EPMC7299818 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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A Quantitative Centrosomal Amplification Score Predicts Local Recurrence of Ductal Carcinoma <i>In Situ</i>.

Mittal Karuna K Toss Michael S MS Wei Guanhao G Kaur Jaspreet J Choi Da Hoon DH Melton Brian D BD Osan Remus M RM Miligy Islam M IM Green Andrew R AR Janssen Emiel A M EAM Søiland Håvard H Gogineni Keerthi K Manne Upender U Rida Padmashree P Rakha Emad A EA Aneja Ritu R

Clinical cancer research : an official journal of the American Association for Cancer Research 20200114 12

<h4>Purpose</h4>The purpose of this study is to predict risk of local recurrence (LR) in ductal carcinoma <i>in situ</i> (DCIS) with a new visualization and quantification approach using centrosome amplification (CA), a cancer cell-specific trait widely associated with aggressiveness.<h4>Experimental design</h4>This first-of-its-kind methodology evaluates the severity and frequency of numerical and structural CA present within DCIS and assigns a quantitative centrosomal amplification score (CAS) ...[more]

PMID: 31937618

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Project description:BackgroundThe following analysis explores clinicopathologic factors and the 12-gene Breast DCIS Score test result in order to better define an appropriate DCIS (ductal carcinoma in situ) population eligible for APBI (accelerated partial breast radiotherapy).MethodsThis exploratory analysis aimed to retrospectively measure the association between the 12-gene Oncotype DX Breast DCIS Score® assay (Redwood City, CA) and relevant clinicopathologic factors with locoregional recurrence in a pooled cohort of women treated with local excision and APBI on prospective phase II (NCT01185145) and phase III (NCT01185132) clinical trials. Univariable Cox proportional hazards regression was used to determine whether there was an association between local recurrence and DCIS Score result risk group (≥ 39 vs < 39) and clinicopathologic factors.ResultsThis analysis included 104 evaluable patients (n = 18 from NCT01185145 and n = 86 from NCT01185132). The median age was 60 years (range: 40-79). Seventy-nine percent of patients were postmenopausal. The median span of DCIS was 10 mm (range 2-45 mm). Two-thirds of the cohort presented with necrosis (71%). The distribution of DCIS Score® results ranged from 0 to 82, with 69% of patients having a DCIS Score result < 39. The median follow-up time was 8.2 years in NCT01185145 versus 3.0 years in NCT01185132. There were 6 local ipsilateral breast recurrences. DCIS Score result was significantly associated with local recurrence in univariable modeling, hazard ratio = 10.3 (95% CI 1.7, 198.4); p = 0.010. None of the clinicopathologic characteristics resulted in any significant association with locoregional recurrence.ConclusionThe Breast DCIS Score assay demonstrated risk stratification in this cohort of patients treated with local excision and APBI pooled from two clinical trials. These results are consistent with those recently published utilizing whole breast radiotherapy. Due to the small number of local recurrence events and limited follow-up time, further investigations are needed to confirm findings.

Project description:BackgroundDuctal carcinoma in situ (DCIS) accounts for approximately 20% of mammographically detected breast cancers. Although DCIS is generally highly curable, some women with DCIS will develop life-threatening invasive breast cancer, but the determinants of progression to infiltrating ductal cancer (IDC) are largely unknown.MethodsIn the current study, we used multiplex ligation-dependent probe amplification (MLPA), a multiplex PCR-based test, to compare copy numbers of 21 breast cancer related genes between laser-microdissected DCIS and adjacent IDC lesions in 39 patients. Genes included in this study were ESR1, EGFR, FGFR1, ADAM9, IKBKB, PRDM14, MTDH, MYC, CCND1, EMSY, CDH1, TRAF4, CPD, MED1, HER2, CDC6, TOP2A, MAPT, BIRC5, CCNE1 and AURKA.ResultsThere were no significant differences in copy number for the 21 genes between DCIS and adjacent IDC. Low/intermediate-grade DCIS showed on average 6 gains/amplifications versus 8 in high-grade DCIS (p?=?0.158). Furthermore, alterations of AURKA and CCNE1 were exclusively found in high-grade DCIS, and HER2, PRDM14 and EMSY amplification was more frequent in high-grade DCIS than in low/intermediate-grade DCIS. In contrast, the average number of alterations in low/intermediate and high grade IDC was similar, and although EGFR alterations were exclusively found in high grade IDC compared to low/intermediate-grade IDC, there were generally fewer differences between low/intermediate-grade and high-grade IDC than between low/intermediate-grade and high-grade DCIS.ConclusionIn conclusion, there were no significant differences in copy number for 21 breast cancer related genes between DCIS and adjacent IDC, indicating that DCIS is genetically as advanced as its invasive counterpart. However, high grade DCIS showed more copy number changes than low/intermediate grade DCIS with specifically involved genes, supporting a model in which different histological grades of DCIS are associated with distinct genomic changes that progress to IDC in different routes. These high grade DCIS specific genes may be potential targets for treatment and/or predict progression.

Project description:BackgroundBreast ductal carcinoma in situ (DCIS) represent approximately 20% of screen-detected breast cancers. The overall risk for DCIS patients treated with breast-conserving surgery stems almost exclusively from local recurrence. Although a mastectomy or adjuvant radiation can reduce recurrence risk, there are significant concerns regarding patient over-/under-treatment. Current clinicopathological markers are insufficient to accurately assess the recurrence risk. To address this issue, we developed a novel machine learning (ML) pipeline to predict risk of ipsilateral recurrence using digitized whole slide images (WSI) and clinicopathologic long-term outcome data from a retrospectively collected cohort of DCIS patients (n = 344) treated with lumpectomy at Nottingham University Hospital, UK.MethodsThe cohort was split case-wise into training (n = 159, 31 with 10-year recurrence) and validation (n = 185, 26 with 10-year recurrence) sets. The sections from primary tumors were stained with H&E, then digitized and analyzed by the pipeline. In the first step, a classifier trained manually by pathologists was applied to digital slides to annotate the areas of stroma, normal/benign ducts, cancer ducts, dense lymphocyte region, and blood vessels. In the second step, a recurrence risk classifier was trained on eight select architectural and spatial organization tissue features from the annotated areas to predict recurrence risk.ResultsThe recurrence classifier significantly predicted the 10-year recurrence risk in the training [hazard ratio (HR) = 11.6; 95% confidence interval (CI) 5.3-25.3, accuracy (Acc) = 0.87, sensitivity (Sn) = 0.71, and specificity (Sp) = 0.91] and independent validation [HR = 6.39 (95% CI 3.0-13.8), p < 0.0001;Acc = 0.85, Sn = 0.5, Sp = 0.91] cohorts. Despite the limitations of our cohorts, and in some cases inferior sensitivity performance, our tool showed superior accuracy, specificity, positive predictive value, concordance, and hazard ratios relative to tested clinicopathological variables in predicting recurrences (p < 0.0001). Furthermore, it significantly identified patients that might benefit from additional therapy (validation cohort p = 0.0006).ConclusionsOur machine learning-based model fills an unmet clinical need for accurately predicting the recurrence risk for lumpectomy-treated DCIS patients.

Dataset Information

A Quantitative Centrosomal Amplification Score Predicts Local Recurrence of Ductal Carcinoma In Situ.

Publications

A Quantitative Centrosomal Amplification Score Predicts Local Recurrence of Ductal Carcinoma <i>In Situ</i>.

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