Van Nuys Prognostic Index Research Articles

Ipsilateral tumor recurrence risk in women with ductal carcinoma in situ: application of the Van Nuys Prognostic Index and the Memorial Sloan Kettering Cancer Center nomogram.

To apply the Van Nuys Prognostic Index (VNPI) and the Memorial Sloan Kettering Cancer Center (MSKCC) ductal carcinoma in situ (DCIS) nomogram to DCIS patients with known long-term outcomes. A retrospective review was performed of consecutive patients diagnosed with DCIS from 2007 to 2014. Included patients underwent breast-conserving surgery (BCS) and were followed with imaging for at least five years. For each patient, the VNPI and MSKCC nomogram risk estimates were determined. In addition, variables used in both models were compared between women with and without recurrences using the Wilcoxon signed-rank test and the Pearson's chi-squared test. Over the eight-year period, 456 women (average age 57 years, range 30-87) underwent BCS for DCIS. Thirty-one (6.8%) experienced an ipsilateral recurrence. The average VNPI scores were 7 (range 5-9) and 7 (range 4-10) for women with and without a recurrence (p = 0.14), respectively, with 4-6, 7-9, and 10-12 being the low, moderate, and high-risk groups, respectively. Per the MSKCC nomogram, the average five-year recurrence risks were 5% (range 1-12%) and 4% (range 1-38%) for women with and without a recurrence (p = 0.09), respectively. The recurrence risk-related variables were younger patient age, need for one or more re-excision surgeries, and use of endocrine therapy for 0 to less than five years after surgery. Ipsilateral tumor recurrence risk estimates based on the VNPI and MSKCC nomogram are similar between women with DCIS who did and did not have a recurrence, suggesting that more robust prognostic models are needed.

Comparison of conventional clinical models and a multigene assay to assess DCIS risk in a prospective single center study.

e12578 Background: Ductal carcinoma in situ (DCIS) is a preinvasive breast cancer typically excised and treated with adjuvant therapy. While there is consensus that this results in overtreatment, there is little agreement on who may avoid radiation or endocrine therapy. Two freely available prediction models, Van Nuys Prognostic Index (VNPI) and Memorial Sloan Kettering Nomogram (MSK-N), are commonly used to identify low-risk DCIS based on standard clinicopathological features. Oncotype DCIS is a newer commercially available tissue-based multigene assay also used to assess risk, but its use is limited due to cost and unclear value over VNPI and MSK-N. We sought to compare these tests’ agreement in determining DCIS ipsilateral breast recurrence (IBR) risk and potential to de-escalate therapy. Methods: In this subanalysis from a prospective single center clinical trial, we analyzed 38 patients with newly diagnosed pure DCIS confirmed at excision. Each risk assessment tool presents risk in a different manner. Oncotype DCIS provides multiple assessments: a raw score (0-100), a DCIS Score Category (low, intermediate, high), and a Refined Score incorporating clinical features (10-year IBR risk). The VNPI calculates a raw score (4-12) and assigns a risk category (low, intermediate, high). MSK-N calculates a 10-year IBR risk. The tests were dichotomized as low vs. not-low risk categories using these thresholds: DCIS Score Category = low, DCIS Refined Score ≤ 10% IBR risk, VNPI risk category = low, MSK-N ≤ 10% IBR risk. Agreement of the 4 models (DCIS Score Category, DCIS Refined Score, VNPI, MSK-N) were compared using Spearman’s rank correlation for continuous data; percent agreement and Cohen’s kappa (k) were used to compare categorized data. Results: There was poor agreement of continuous risk assessments across the 4 models, with only VNPI and DCIS Refined Score showing significant but moderate correlation (r = 0.53, p = 0.001; others ranged r = 0-0.27, p > 0.1). The number of cases identified as low-risk for each assay was DCIS Score Category = 14 (37%), DCIS Refined Score = 3 (8%), VNPI = 1 (3%), and MSK-N = 0. Percent agreement of low vs. not-low risk categorizations between DCIS Refined Score, VNPI, and MSK-N was 92-97%, but each assay classified 3 or fewer cases as low-risk and kappa was not significant (k = 0-0.48, p > .1). DCIS Score Category demonstrated 63-71% agreement with the other 3 assays (k = 0-0.26). Only 1 case was classified as low-risk DCIS on multiple tests. Conclusions: DCIS risk models have poor agreement for determining IBR risk. DCIS Score Category initially identified many low-risk lesions; however, inclusion of clinical features to create a Refined Score decreased this substantially, providing very few additional low-risk cases for de-escalation over VNPI or MSK-N. Additional studies are needed to determine precise IBR rates when these models are used for adjuvant therapy decision-making. Clinical trial information: NCT03495011 .

Predictors of residual disease after breast conservation surgery for ductal carcinoma in situ: A retrospective study.

Breast-conserving therapy is the standard of care for ductal carcinoma in situ (DCIS). Debate on what constitutes a satisfactory margin persists. This study aimed to identify predictors of residual disease at re-excision. This is a population-based retrospective cohort study of women with DCIS who underwent a lumpectomy between 2007 and 2017 in Manitoba, with close (≤2 mm) or positive margins that led to re-excision. The DCIS re-excision rate was 29.3% for 1001 patients. 63.2% of patients were found to have residual disease on re-excision. On univariable analysis, the size, margin status, number of positive margins, type of second surgery, and Van Nuys Prognostic Index score were associated with residual disease on re-excision. The size of DCIS and the number of positive margins remained statistically significant on multivariable analysis. Re-excision should be rationalized by considering the predictors of residual disease in conjunction with other factors.

Assessment of the usefulness of prognostic Van Nuys Prognostic Index in the treatment in ductal carcinoma in situ in 15-year observation

Ductal carcinoma in situ, a marginal fraction of the mammary gland diseases, is recognized in 25% of breast cancers detected with mammographic screening. The aim of the study was to assess the prognostic value of Van Nuys Prognostic Index, serving to determine the method of treatment according to the recurrence risk. From the 737 of cases of DCIS detection patients treated in our department in the years 1996–2011. The remaining 525 patients whose treatment began from excision of local DCIS and whose further course of treatment was determined after histopathological examination, who were left for observation, treated with lumpectomy and radiotherapy or mastectomy, were qualified for the assessment of mentioned index (Online Appendix 1- Figure S1). The 5-, 10- and 15- year disease recurrence-free survival for the group of 525 patients was 88%, 74% and 62%, respectively. The percentage of 5-, 10- and 15-year disease recurrence-free survival in patients treated in compliance with the VNP Index in individual risk groups did not differ in a statistically significant way. In the low-risk group the percentage of recurrences after local excision, after 5, 10 and 15 years of observation amounted to 8.8%, 22.8% and 28.8%. In patients from this group, the recurrence risk after breast conserving treatment and mastectomy was 2% and 0%, respectively. VNP Index is not an optimal tool for patients with DCIS. It can be helpful only in some clinically difficult cases as one of methods of assessing the risk of recurrence.

Risk Stratification of Ductal Carcinoma In Situ and Texture Analysis of Contrast-Enhanced Breast Magnetic Resonance Imaging.

The aim of this study was to investigate whether texture analysis of contrast-enhanced T1 weighted images could predict risk of ductal carcinoma in situ (DCIS). The study included 185 DCIS lesions that were classified as either low risk or non-low risk using surgical pathology records. All magnetic resonance imaging texture analyses were performed using postprocessing software, and texture-derived parameters were extracted. The sphericity, compactness, and spherical disproportion were significantly different in the low-risk and non-low risk groups using the Van Nuys Prognostic Index (mean ± SD, 0.479 ± 0.189 vs 0.414 ± 0.176, 0.161 ± 0.159 vs 0.112 ± 0.134, and 2.569 ± 1.434 vs 2.934 ± 1.374, respectively; P < 0.05). In the univariate analyses, sphericity (odds ratio, 7.091; 95% confidence interval, 1.236-40.666; P = 0.028) and compactness (odds ratio, 9.267; 95% confidence interval, 1.125-76.360; P = 0.039) were significantly associated with a high probability of being low risk according to the Van Nuys Prognostic Index. Whole-lesion texture analysis may be helpful in identifying patients classified as having low-risk DCIS before surgery.

Abstract PS17-21: Characterization of the immune microenvironment in ductal carcinoma in situ of the breast

Abstract Background Ductal carcinoma in situ (DCIS) is considered a low-risk disease of the breast. Current increases in its incidence have resulted in many women either being under- or over-treated due to our limited findings on independent prognostic and predictive biomarkers. The Van Nuys Prognostic Index, based on tumor size, margin status, grade and age, is one tool used in treatment decisions. Patients with a low score show no significant benefit from radiotherapy, in contrast to those with an intermediate score, while patients with high scores should be considered for mastectomy. In contrast, for invasive ductal carcinoma (IDC) of the breast there is a strong consensus for the prognostic and predictive value of tumor infiltrating lymphocytes (TIL). As very little is known about TIL in DCIS, the goal of this study is to fully characterize the immune infiltrate and compare it to IDC, examine differences in the balance between effector and regulatory subpopulations and potentially discover new biomarkers for risk stratification. Material and Methods Fourteen patients were prospectively enrolled at the St. Luc hospital in Brussels, including 4 pure DCIS, 5 mixt DCIS and IDC, and 5 normal breast tissues. Formalin-fixed paraffin-embedded sections were stained with three fluorescent multiplex immunohistochemistry (mIHC) panels that combined antibodies to CD45, CD4, CD8, CD20, FOXP3, CD68, GZMB, PD-1, Ki67 and cytokeratin. InForm® Tissue Finder™ software and PhenoptrReports (Akoya Biosciences®) were employed for TIL quantification and spatial distribution. Freshly resected DCIS tissues were used to isolate tumor-infiltrating CD4 and CD8 T cells for single cell RNAseq analysis to determine the T cell clonotypes present (A. Devaux’s poster) Results Our analyses reveal the DCIS stroma has a significant immune infiltrate dominated by CD4+ helper T cells and B cells (140 and 115 cells/mm2, respectively) followed by CD8+ cytotoxic T cells (72 cells/mm2), regulatory T cells (Treg) (27 cells/mm2) and to a lesser extent macrophages (23 cells/mm2). The immune pattern in DCIS is similar to IDC except there are fewer macrophages in the tumor areas and Treg increase in the stroma. Tumor areas are generally less infiltrated than the stroma but some DCIS cells are in direct contact with T cells and macrophages. Spatial distribution analysis within a radius of 30 μm confirms that Treg are in close proximity to the DCIS cells and in the proximity of CD4+ helper and CD8+ cytotoxic T cells. Moreover, proliferating GZMB+ cells, mainly CD8+ cytotoxic T cells, were observed in direct contact with DCIS cells. Only one patient out of 4 had PD1+ TIL in the stroma. A comparison of pure and mixt DCIS reveals lower stromal infiltration by T and B cells in the former, which is also associated with an increase in macrophages. Finally, the abundance of stromal TIL was frequently organized in tertiary lymphoid structures (TLS), composed by a B cell follicle surrounded by a T cell zone containing both CD4+ helper and CD8+ cytotoxic T cells. TLS were characterized by the presence of proliferating B cells and PD1high T follicular helper cells. FOXP3+ and GZMB+ cells were also observed in the T cell zone. Conclusions Examination of the immune infiltrate in DCIS shows an abundance of helper T cells, B cells and active cytotoxic T cells in association with stromal TLS. These observations reveal an active tumor immune microenvironment in DCIS and suggest that the immune response plays an active role in DCIS pathogenesis. Citation Format: Soizic Garaud, Alix Devaux, Anais Boisson, Céline Naveaux, Pierre Coulie, Ahmad Awada, Karen Willard-Gallo. Characterization of the immune microenvironment in ductal carcinoma in situ of the breast [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-21.

A Comparison of Predicted Ipsilateral Tumor Recurrence Risks in Patients With Ductal Carcinoma in Situ of the Breast After Breast-Conserving Surgery by Breast Radiation Oncologists, the Van Nuys Prognostic Index, the Memorial Sloan Kettering Cancer Center DCIS Nomogram, and the 12-Gene DCIS Score Assay

PurposeTo compare ipsilateral breast event (IBE) risks in patients with ductal carcinoma in situ of the breast (DCIS) post-lumpectomy, as estimated by breast radiation oncologists, the Van Nuys Prognostic Index, the Memorial Sloan Kettering Cancer Center (MSKCC) DCIS nomogram, and the 12-gene Oncotype DX DCIS score assay. Methods and MaterialsConsecutive DCIS cases treated with lumpectomy from November 2011 to August 2014 with available DCIS score results were identified. Three radiation oncologists independently estimated the 10-year IBE risk. The Van Nuys Prognostic Index and MSKCC nomogram 10-year IBE risk estimates were generated. Differences and correlations between the IBE estimates and clinicopathologic factors were evaluated. ResultsNinety-one patients were identified for inclusion. Forty-eight percent would have been ineligible for the E5194 study. The mean risk of IBE from the DCIS score assay was 12.4%, compared with a range of 18.9% to 26.8% from other sources. The mean IBE risk from the DCIS score assay was lower regardless of E5194 eligibility. The MSKCC nomogram and DCIS score assay risk estimates were weakly correlated with each other (P = .23) and were each moderately correlated with the other risk estimates (P = .41-.56). When applying the radiation oncologists’ treatment recommendations based on their proposed risk cutoffs, evaluating risk according to the DCIS score assay led to the highest proportion of patients recommended excision alone. ConclusionsIBE risk estimates for this general community cohort of DCIS cases vary significantly among commonly available clinical predictive tools and individual radiation oncologist estimates. Surgical margins and tumor size continue to factor prominently in radiation oncologist decision algorithms. The differences found between the IBE risk estimate methods suggests that they are not interchangeable and the methods that rely on clinicopathologic features may tend to overestimate risk.

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

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. 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). 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. 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.

Validation of the Van Nuys Prognostic Index in 737 patients with ductal carcinoma in situ (DCIS) treated at Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.

e12603 Background: To assess the value of the Van Nuys Prognostic Index (VNPI) used in Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO) to select the most adequate method of the treatment of DCIS patients. Methods: The database covered 737 subsequent DCIS patients treated in MSCNRIO in the years 1996 -2011. The results of the treatment with and without compliance with the VNPI index were compared. Results: In the group of 737 patients 66 (9%) failures were reported. There were 4 (0.5%) deaths due to DCIS progression. After 15 years of observation of patients treated in compliance with VNPI, the percentage of failures after local excision (4-6 VNPI points), breast conserving treatment (7-9 VNPI points) and mastectomy (10-12 VNPI points) was 29%, 21% and 9%, respectively. No differences in the overall survival was observed. In patients with 4-6 VNPI points the percentage of recurrences in the group treated in compliance with the VNPI (without radiotherapy) was 29% while in the group treated without compliance with the VNPI (with radiotherapy) - 2%. Conclusions: The Van Nuys prognostic index (VNPI) does not seem to be an ideal tool in patients with DCIS. It shows too high percentage of recurrences in the low risk group (VNPI of 4, 5 or 6 points), treated exclusively with a sparing surgery. Almost all patients after surgical excision should be irradiated.

Abstract P5-18-02: A quantitative centrosomal amplification score (CAS) predicts local recurrence in ductal carcinoma in situ

Abstract Background: About 60-80% of ductal carcinoma in situ (DCIS) cases are high-grade (HG) DCIS with an elevated risk of local recurrence (LR) even after a lumpectomy. Patients are often under or over treated due to the lack of accurate recurrence risk prediction models. Current prognostic models such as OncotypeDX and Van Nuys Prognostic Index (VNPI) lack consistency and are limited to a specific subset of patients. Here in this study, we show that the extent of centrosome amplification (CA) in a DCIS lesion can predict the risk of LR after lumpectomy. CA refers to presence of supernumerary or large centrosomes and is a characteristic of pre-invasive lesions, and breast tumors, and promotes erroneous mitoses and chromosomal instability. Methods: We have pioneered a semi-automated pipeline that integrates immunofluorescence confocal microscopy with digital image analysis and yields a quantitative Centrosomal Amplification Score (CAS) for each patients' tumor sample by evaluating severity and frequency of centrosomal aberrations therein. To this end, we first immunofluorescently stained centrosomes in formalin fixed paraffin embedded resection samples from DCIS patients (discovery cohort n=133 and a validation cohort n=119) using an antibody against γ-tubulin, and co-stained nuclei with DAPI. Next, we imaged the slides and processed the raw 3D image data using IMARIS Biplane 8.2 3D volume rendering software. Finally, we calculated centrosome numbers and volume in ˜250 cells from each patient sample. Using a mathematical algorithm, we generated a composite CAS score for each patient sample by integrating the numerical (CASi) and structural (CASm) aberrations. Results: We found that DCIS patients with recurrence exhibited higher CAS. Intriguingly, higher CAS was also associated with greater risk of developing ipsilateral breast events [Hazard ratio (HR) =7.58 for discovery cohort and HR=5.8 for validation cohort, p&amp;lt;0.0001] which remained significant (HR=8.5 for discovery and HR=3.39, p&amp;lt;0.0001) after accounting for the confounding factors like age, tumor size, comedo necrosis and radiotherapy. Kaplan Meir survival analysis indicated that high CAS was associated with poor recurrence-free survival (RFS) (p&amp;lt;0.001). For the high and low CAS groups, the 5-year risk of recurrence was 87.5% and 12.5% respectively (p&amp;lt;0.001). In our discovery cohort, a head-to-head comparison of the ability of VNPI and CAS to predict recurrence illuminated that CAS was able to stratify the DCIS group in recurrence and recurrence-free group with much higher significance (p&amp;lt;0.0001) than the Van Nuys Prognostic Index (VNPI) (HRs for CAS- 8.8 vs. VNPI 0.959). Finally, the Harrell's concordance index using SAS PROC PHREG tests yielded that the probability of a patient with poorer/lower RFS to be in the high CAS group is 76.2%. Conclusion: Our data compellingly show that CAS quantifies the risk of recurrence in DCIS patients with the highest concordance and provides a novel and innovative tool to tailor their treatment based on their risk profile. Citation Format: Mittal K, Kaur J, Wei G, Toss MS, Osan RM, Janssen EA, Søiland H, Rakha EA, Rida PC, Aneja R. A quantitative centrosomal amplification score (CAS) predicts local recurrence in ductal carcinoma in situ [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-18-02.

Should radiotherapy be succeed tumorectomy in patients with low risk ductal carcinoma in situ (DCIS) when using Van Nuys Prognostic Index based treatment?

e12561Background: Selecting patients with low risk DCIS in whom radiotherapy could be safely omitted is still debatable. The Van Nuys Prognostic Index (VNPI) which analyses 4 prognostic factors hel...

Abstract P4-15-12: Evaluating the significance of the Van Nuys prognostic index for the management of ductal carcinoma in situ – one center's experience

Abstract Aim: This was to assess the treatment outcomes of ductal carcinoma of the breast (DCIS) based on the Van Nuys Prognostic Index. Material and Methods: 634 consecutive patients with DCIS were treated at the Warsaw Cancer Center, Poland between 1996 and 2008 based on the VNPI score. Tumorectomy without radiotherapy (T) was performed in 123 (20%) patients, breast conserving treatment (BCT) in 206 (32%) and mastectomy (M) in 305 (48%). Disease-free survival (DFS) and overall survival (OS) were analysed within 3 groups and a multivariate analysis was performed to determine the most important factor affecting local relapse. Results: 5-year, 10-year and 15-year DFS in the M group were respectively 98%, 97% and 97% whilst 5-year, 10-year and 15-year DFS in the BCT group were respectively 91%, 87% and 80%. 5-year, 10-year and 15-year DFS in the T group were respectively 92%, 73% and 67%. Local recurrence was observed in 54 patients. In 40% cases this was noninvasive and in 60 % invasive. Only 4 of 54 patients with recurrence died due to breast cancer. 5-year, 10-year and 15-year OS in the M group were respectively 96%, 92% and 89%. 5-year, 10-year and 15-year OS in the BCT group were respectively 99%, 94% and 85%. 5-year, 10-year and 15-year OS in the T group were respectively 95%, 90% and 73% (p=0.422). Tumor size assessed by mammography was the only variable affecting DFS. Conclusions: Treatment outcomes of DCIS based on the Van Nuys Prognostic Index are comparable with those cited the literature, however, the recurrence rate in the T group seems to be very high. This group requires that new risk factors be sought for prior to taking a treatment decision. Citation Format: Niwinska A, Galecki J, Nagadowska M, Piechocki J, Kunkiel M, Jagiello-Gruszfeld AI, Nowecki Z. Evaluating the significance of the Van Nuys prognostic index for the management of ductal carcinoma in situ – one center's experience [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-15-12.

Abstract P5-11-02: Predicting local recurrence in patients treated for ductal carcinoma in situ of the breast (DCIS)

Abstract Background: Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of precursor, non-invasive breast lesions. Currently we lack accurate tools to stratify DCIS patients according to inherent risk of in breast tumour recurrence (IBTR) or progression to invasive breast cancer (IBC).Most DCIS patients are treated by breast-conversing surgery (BCS), followed by whole-breast radiotherapy (RT) for the majority of high-grade DCIS. The aim of this study was to identify novel biomarkers which predict recurrence after BCS +/- RT. Methods: A single institution study of 466 consecutive patients (median age 61, range 35-94) with DCIS treated by BCS between 2000 and 2010 was carried out. 271 patients with grade 3 DCIS received RT and 155 with grade 1/2 DCIS did not receive RT. For biomarker discovery, a case-control matched series of 200 patients (mean age = 61, range = 36-84) from the above audit that met the following criteria was selected: · 120 with low/intermediate-grade DCIS treated with BCS alone: 30 have recurred, 90 patients matched 3:1 have not recurred by 10 years. · 80 with high-grade DCIS treated by BCS plus RT: 20 have recurred, 60 patients matched 3:1 have not recurred by 10 years. Median follow-up was 7.4 years. RNA has been extracted and Affymetrix Clariom S whole-genome analysis has been performed and is currently being analysed. Results: In the cohort of 466 patients, 271 patients with high grade DCIS had BCS plus RT. Actuarial IBTR and IBC-IBTR in this group were 10% and 4% at 5 years and 18% and 6% at 10 years, respectively. 155 patients with low/intermediate grade DCIS had BCS alone. Actuarial overall IBTR and IBC-IBTR in this group were 6% and 2% at 5 years and 13% and 2% at 10 years respectively. In the high-grade, RT treated group, lesion size (P&amp;lt;0.001, P=0.003), presence of comedo necrosis (P=0.018, P=0.025) and the Van Nuys Prognostic Index (VNPI) (P=0.02, P=0.004) were significantly associated with overall IBTR and DCIS-IBTR. No factor was significantly associated with IBS-IBTR in the high grade group and no factor predicted for any IBTR in the low/intermediate group. Full genomic analysis of the 240 patient case-control matched cohort is underway and will be presented. Discussion: · This is the first DCIS biomarker discovery study using whole genome analysis and the matched cohort design looking separately at BCS + RT for high-grade DCIS and BCS only for low/intermediate grade DCIS. · Clinical parameters alone may have insufficient sensitivity to identify high-grade, RT-treated patients at risk of developing IBC-IBTR. · While recurrence rates in the low/intermediate grade DCIS group are lower than in the high-grade group, some patients do recur and there is a need to develop new tools which can identify low grade patients with a sufficiently high risk of recurrence to warrant additional treatment. Citation Format: Martinez-Perez C, Turnbull AK, Ekatah GE, Arthur LM, Fernando A, Sims AH, Thomas JS, Dixon JM. Predicting local recurrence in patients treated for ductal carcinoma in situ of the breast (DCIS) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-11-02.

Will oncotype DX DCIS testing guide therapy? A single-institution correlation of oncotype DX DCIS results with histopathologic findings and clinical management decisions.

Given the increased detection rates of ductal carcinoma in situ (DCIS) and the limited overall survival benefit from adjuvant breast irradiation after breast-conserving surgery, there is interest in identifying subsets of patients who have low rates of ipsilateral breast tumor recurrence such that they might safely forgo radiation. The Oncotype DCIS score is a reverse transcription-PCR (RT-PCR)-based assay that was validated to predict which DCIS cases are most likely to recur. Clinically, these results may be used to assist in selecting which patients with DCIS might safely forgo radiation therapy after breast-conserving surgery; however, little is currently published on how this test is being used in practice. Our study examines traditional histopathologic features used in predicting DCIS risk with Oncotype DCIS results and how these results affect clinical decision-making at our academic institution. Histopathologic features and management decisions for 37 cases with Oncotype DCIS results over the past 4 years were collected. Necrosis, high nuclear grade, biopsy site change, estrogen receptor and progesterone receptor positivity <90% on immunohistochemistry, and Van Nuys Prognostic Index score of 8 or greater were significant predictors of an intermediate-high recurrence score on multivariate regression analysis (P<0.02). Low Oncotype DCIS scores and low nuclear grade were associated with lower rate of radiation therapy (P<0.008). There were seven cases (19%) with Oncotype DCIS results that we considered unexpected in relation to the histopathologic findings (ie, high nuclear grade with comedonecrosis and a low Oncotype score, or hormone receptor discrepancies). Overall, pathologic features correlate with Oncotype DCIS scores but unexpected results do occur, making individual recommendations sometimes challenging.

Postoperative radiotherapy after DCIS: Useful for whom?

The number of patients with ductal carcinoma in situ (DCIS) increases with more widely used screening mammography programs. DCIS accounts for approximately 20% of all new breast cancer diagnoses in these programs and the natural course of this heterogeneous group of pre-invasive lesions is not fully known. Better definition of subgroups benefitting from radiotherapy and knowledge on the natural course of DCIS are important issues for the future management of DCIS.Four large randomized trials have studied the effects of postoperative radiotherapy after breast conserving surgery in patients with wider spectrum of DCIS and all of them have shown radiotherapy to halve the risk of ipsilateral events, however, without any significant effect on breast cancer mortality.SweDCIS is one of these four randomized trials (n = 1046) and with 20 years follow-up the relative risk reduction for an ipsilateral event was 37.5% and the absolute reduction was 12%. For an in-situ ipsilateral event the absolute reduction was 10% and for an invasive ipsilateral event the reduction was 2%. The reduction of new events in the SweDCIS was most evident during the first decade after treatment.In RTOG 9804 patients in a good-risk subset of DCIS were randomized to radiotherapy or not and with seven years of follow-up the ipsilateral local failure rate was 0.9% and 6.7% in the two arms, respectively.Radiotherapy to the conserved breast may also give long-term side effects in a small proportion of the patients, in which experience of breast pain is the most common, reported in about 10% of the patients. With modern radiotherapy techniques the dose to the heart can be restricted to low levels and meta-analyses from the randomized DCIS trials showed no difference in non-breast cancer mortality.Several factors in different trials have shown to influence the risk for an ipsilateral event: age, size, grade, necrosis, clear margin, and detected on mammography or not. But identification of subgroups without relative efficacy of radiotherapy has been challenging to find. The Van Nuys prognostic index and the nomogram from the Memorial Sloan-Kettering take several of these factors into account. These and genomic assays may help to optimize the treatments of patients with DCIS. Still, radiotherapy after breast conserving surgery is the standard of care for a majority of DCIS patients. For some low risk DCIS patients accepting a slight increased risk of an ipsilateral event it is reasonable to omit radiotherapy after close communication with the patient about pros and cons of radiotherapy.

Abstract P1-11-02: A comparison of models (physician, the Van Nuys prognostic index, the Memorial-Sloan-Kettering Cancer Center DCIS nomogram)to predict ipsilateral breast events in patients with ductal carcinoma in situ (DCIS) of the breast after breast-conserving surgery failed to replicate results of the oncotype DCIS recurrence score

Abstract Purpose: To compare ipsilateral breast event (IBE) risks in patients with DCIS of the breast post-lumpectomy, as estimated by breast radiation oncologists, the Van Nuys Prognostic Index (VNPI) studies, the Memorial Sloan Kettering Cancer Center (MSK) DCIS nomogram, and the 12-gene DCIS Recurrence Score assay. Materials/Methods: 12-gene DCIS Recurrence Score of 91 DCIS lumpectomy cases were identified from our practice. Clinicopathologic factors (excluding DCIS score) were summarized for blinded review. 3 radiation oncologists independently estimated the 10-year IBE risk and rated the impact of age/menopausal status, tumor morphology, tumor span, and margin width. Corresponding VNPI and MSK nomogram estimates were generated. Differences and correlations between the IBE estimates and clinicopathologic factors were evaluated with univariate and multivariate analysis. Results: Median age was 60, 25% margins &amp;lt; 3 mm, 48% DCIS span &amp;gt; 10 mm, 48% would have been ineligible for E5194. All comparisons were initially examined for similarity (non-significant differences) and susequently tested for a significant correlation. In three possible physician comparisons only 1 (AA-CL) had similar IBE estimates and strong correlation (r=0.792). Comparison of physicians to either VNPI nomogram or MSK DCIS calculator had similar estimates with strong correlation in only 2 of 6 possible comparisons in the all cases and the E5194 eligible patient cohorts respectively; and in 1 of 6 comparisons in the E5194 ineligible cohort. The DCIS Recurrence Score showed no strong correlation in regard to similar IBE estimates for any comparisons including either physicians, VNPI nomogram or MSK DCIS calculator. Tumor size was highly correlated with all physician IBE estimates (r = 0.547 to 0.799), while margin size showed moderate to high inverse correlations (r = -0.324 to -0.619). All 3 physicians rated margin width as having the most impact on their IBE risk estimates, then tumor morphology and tumor span. Source of EstimateAll Cases (n = 91)E5194 Eligible (n = 47)E5194 Ineligible (n = 44)DCIS Score15.1%, 5.3 (14.0-16.2)14.2%, 4.8 (12.8-15.6)16.1%, 5.7 (14.3-17.8)MSK DCIS Nomogram (Rudloff et al., 2010)18.8%, 7.7 (17.2-20.4)23.4%, 18.6 (19.6-27.3)16.1%, 4.1 (14.9-17.3)21.7%, 9.4 (18.8-24.6)VNPI studies23.4%, 18.6 (19.6-27.3)15.6%, 15.5 (11.0-20.1)31.9%, 18.1 (26.4-37.4)AA18.9%, 14.1 (16.0-21.9)11.7%, 8.8 (9.1-14.3)26.6%, 14.7 (22.2-31.1)CL19.9%, 11.8 (17.5-22.4)14.5%, 6.6 (12.5-16.4)25.8%, 13.3 (21.7-29.8)DC26.8%, 13.9 (23.9-29.7)19.8%, 5.9 (18.1-21.6)34.2%, 16.1 (29.3-39.1) Conclusion: IBE risk estimates for this cohort of DCIS cases vary significantly among commonly available clinical predictive tools and individual physician estimates. Surgical margins and tumor size continue to factor prominently in physician decision algorithms. In our observations, neither the VNPI nomogram, MSK DCIS calculator nor physician IBE risk estimates have similar values with strong enough correlation to reliably replicate the DCIS Recurrence Score. Citation Format: Leonard C, Lei R, Antell A, Nowels M, Fryman S, Howell K, Dennis C. A comparison of models (physician, the Van Nuys prognostic index, the Memorial-Sloan-Kettering Cancer Center DCIS nomogram)to predict ipsilateral breast events in patients with ductal carcinoma in situ (DCIS) of the breast after breast-conserving surgery failed to replicate results of the oncotype DCIS recurrence score [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-11-02.

Ductal carcinoma in situ and ductal carcinoma in situ with microinvasion: correlation of FDG uptake with histological and biological prognostic factors.

Several studies investigated the correlation between the intensity of fluorodeoxyglucose (FDG) uptake and some histological and biological characteristics in breast cancer. Ductal carcinoma in situ (DCIS) is generally thought to be a precursor lesion of invasive breast cancer. The aim of this study was to assess the correlation between FDG uptake values on positron emission tomography/computed tomography (PET/CT) with histological and biological prognostic factors in DCIS and ductal carcinoma in situ with microinvasion (DCIS-Mi). PET/CT images for initial staging of confirmed DCIS and DCIS-Mi patients, taken between July 2004 and December 2009, were reviewed retrospectively. Maximum standardized uptake values (SUVmax) and tumor background count density ratio on PET/CT were compared with tumor characteristics. Histological and biological prognostic factors included tumor size, nuclear grade, Van Nuys Prognostic Index, estrogen receptor, progesterone receptor, HER2, and Ki-67 index. In total, 87 lesions from 83 patients (all females; mean age 51±9years) were studied. The Van Nuys Prognostic Index group was 1 in 25 lesions, 2 in 36, and 3 in 26. On statistical analysis, significant differences in SUVmax and tumor background count density ratio were seen between the Van Nuys Prognostic Index groups and according to tumor size and HER2. The correlation between SUVmax and Ki-67 was significant. However, the correlation between tumor background count density ratio and Ki-67 was not statistically significant. In DCIS and DCIS-Mi cases, significant correlations were found between increased FDG uptake and several histological and biological factors for poor prognosis (tumor size, Van Nuys Prognostic Index, and HER2).

Variation in the management of ductal carcinoma in situ in the UK: Results of the Mammary Fold National Practice Survey

IntroductionDuctal carcinoma in situ (DCIS) accounts for approximately 10% of all newly-diagnosed breast cancers in the UK. The latest national guidelines were published in 2009 and may not reflect current best practice. We aimed to explore variation in the current management of DCIS to support the need for updated guidelines. MethodsA national practice questionnaire was developed by the Mammary Fold Academic Committee (MFAC) focussing on the pre, intra and post-operative management of DCIS. Trainees at UK breast units were invited to complete the questionnaire at their multidisciplinary team meeting to provide a comprehensive picture of current national practice. Results76 of 144 UK breast units (52.8%) participated in the survey. Variation was observed in radiological pre-operative assessment with only 33/76 units (43.4%) performing routine ultrasound assessment of the tumour or axilla. There was no clear consensus regarding indications for mastectomy; multifocality (38.2%) and extensive microcalcifications (34.2%) were the most frequent indications. 34/76 units (44.7%) offered nipple sparing mastectomy. 33/76 units (43.3%) perform sentinel node biopsy in the presence of a palpable/mass lesion and 51/76 (67.1%) at the time of mastectomy. The most widely accepted pathological radial margin remained 2 mm (36.8%). The commonest factors in decision-making for radiotherapy were tumour grade (51.3%) and size (35.5%). Only 12 units (15.8%) routinely used the Van Nuys Prognostic Index. Approximately half of all breast units offer clinical long-term follow-up. DiscussionThere is marked variation in the management of DCIS in the UK. Updated evidence-based guidelines may standardise practice and improve outcomes for patients.

Comparison of Risk of Ipsilateral Breast Event After Lumpectomy for Ductal Carcinoma In Situ, As Estimated by Breast Radiation Oncologists, Van Nuys Prognostic Index, Memorial Sloan Kettering Cancer Center DCIS Nomogram, and the 12-gene DCIS Score

Quality Consortium (MROQC), a statewide assessment of breast cancer patients undergoing radiation therapy and crude rates were used for comparisons. Results: For left sided cancers, mean heart dose was 3.09 Gy. The use of a breast cup resulted in mean V20 for lung of 5.6% and V5 of 11%. Mean dose to the contralateral breast was 3.29 Gy. Twenty patients (42.5%) experienced grade 2 skin toxicity; one patient (2.1%) experienced a grade 3 skin toxicity. Moist desquamation rates: 44.7% compared to 45.5% MROQC. Moist desquamation for patients with a BMI >35 was 52.2% vs 42.8% MROQC. For a breast volume >1550cc, moist desquamation was seen in 48.6% vs 45.5% MROQC. Conclusion: Our results indicate that use of the breast cup can allow for improved dose homogeneity with similar acute toxicities as compared with patients treated without the cup while minimizing the dose to the heart and lungs. Our clinical experience shows that breast cups can be used with ease, and allow for good setup reproducibility. It appears that the slight increase in moist desquamation was associated with increased BMI. In conclusion, we recommend that use of a breast cup be considered in appropriately selected patients with large or pendulous breasts. Author Disclosure: P.R. Sevak: None. K. Aldridge: None. C. Fraser: None. C.K. Glide-Hurst: None. E.M. Walker: ACR appropriateness criteria expert panel member; ACR. RTOG Foundation advisory board member; RTOG. Breast working group; NRG. health disparities working group member; NRG. Institutional PI for NRG; NRG.

Concordance of Van-Nuys Prognostic Index, Memorial Sloan Kettering Breast Cancer nomogram and Oncotype Dx DCIS scores in prediction of ductal carcinoma in situ(DCIS) recurrence risk.

56 Background: Ductal Carcinoma in situ (DCIS) has a wide spectrum of bioagressiveness. Three models used to assess recurrence risk (RR) of DCIS include: the Van-Nuys Prognostic Index (VN), Memorial Sloan Kettering Breast Cancer Nomogram (MN) and Oncotype Dx DCIS Score (OD; Genomic Health, Redwood City, CA). The aim of our study was to evaluate the concordance between these RR models. Methods: An IRB-approved retrospective chart review was performed on 37 consecutive patients at our institution with DCIS from 12/2011-4/2015 who underwent breast conservation surgery and in whom an OD was obtained. The OD and ‘any recurrent event at 10-years’ scores were used to stratify patients into low risk (LR; OD DCIS score &lt;39/&lt;17%), intermediate risk (IR; 39-54/17-24%) and high risk (HR; &gt;54/&gt;24%), as outlined in the original OD study. The ‘10-year RR’ scores from MN were stratified using the same percentile breakdown as OD. The VN were stratified into LR (4-6), IR (7-9) and HR (&gt;9) groups based on the updated VN study’s guideline. Pathologic slides were re-reviewed by one pathologist blinded to OD score to determine size and margin width based on the protocol outlined in the original VN paper. The three scores for each patient were compared. Results: Eleven patients (29.7%) had concordance between all three scores and all were LR. In 10.8% of patients, there was no concordance between the three scores. The concordance between the OD and VN, OD and MN, and VN and MN was 64.9%, 48.6% and 35.1%, respectively. Conclusions: In evaluating RR, determining LR may have the greatest implication since this group may be the least likely to benefit from adjuvant radiotherapy. Concordance between all three models was seen only in LR patients. All patients who were LR by VN were also LR by OD and MN. Determining a VN initially may help guide additional testing. The added value of OD may be primarily in patients who are not LR by VN. The MN seems to be of limited value in this study. Larger studies assessing these relationships and their outcomes in predicting potential RR in DCIS are warranted.