Sevilay Altintas

Prognostic significance of oncogenic markers in ductal carcinoma in situ of the breast: a clinicopathologic study.

Abstract:  Ductal carcinoma in situ (DCIS) is a heterogeneous malignant condition of the breast with an excellent prognosis. Until recently mastectomy was the standard treatment. As the results of the National Surgical Adjuvant Breast and Bowel Project‐17 trial and the introduction of the Van Nuys Prognostic Index (VNPI) less radical therapies are used. Objectives are to identify clinicopathologic and biologic factors that may predict outcome. Cases of DCIS diagnosed in two Belgian University Centers were included. Paraffin‐embedded material and Hematoxylin and Eosin stained slides of DCIS cases were reviewed and tumor size, margin width, nuclear grade, and comedo necrosis were assessed. Molecular markers (estrogen receptor, progesterone receptor, HER1‐4, Ki67, and c‐myc) were assayed immunohistochemically. Applied treatment strategies were correlated with the prospective use of the VNPI score. Kaplan–Meier survival plots were generated with log‐rank significance and multiple regression analysis was carried out using Cox proportional hazards regression analysis; 159 patients were included with a median age of 54 years (range 29–78); 141 had DCIS and 18 DCIS with microinvasion. The median time of follow‐up was 54 months (range 5–253). Twenty‐three patients developed a recurrence (14.5%). The median time to recurrence was 46 months (range 5–253). Before the introduction of the VNPI, 37.5% of the DCIS patients showed a recurrence while thereafter 6.7% recurred (p < 0.005). Two recurrences occurred in the VNPI group I (7.1%); seven in the VNPI group II (8.5%) (median time to recurrence 66.3 months) and 14 in the VNPI group III (28.5%) (median time to recurrence 40.2 months) (disease‐free survival [DFS]: p < 0.05). A Cox proportional hazards regression analysis indicated that tumor size, margin width, pathologic class, and age were independent predictors of recurrence, but none of the studied molecular markers showed this. Overexpression of HER4 in the presence of HER3 was found to be associated with a better DFS (p < 0.05). This study confirms the value of the VNPI score and questions the benefit of an aggressive approach in the low‐risk DCIS lesions. Independent predictors for recurrence included size, margin width, pathologic class, and age, but none of the molecular markers were part of it. Overexpression of HER4 in the presence of HER3 was associated with a better DFS.

Low CD10 mRNA expression identifies high-risk ductal carcinoma in situ (DCIS).

Purpose Optimal management of breast ductal carcinoma in situ (DCIS) is controversial, and many patients are still overtreated. The local death of myoepithelial cells (MECs) is believed to be a pre-requisite to tumor invasion. We thus hypothesized that loss of CD10 expression, a MEC surface peptidase, would signify basement membrane disruption and confer increased risk of relapse in DCIS. The aim of our study was to retrospectively evaluate the prognostic value of CD10 in DCIS. Experimental Design CD10 expression was evaluated by quantitative RT-PCR and immunohistochemistry using paraffin-embedded samples of normal breast tissue (n = 11); of morphologically normal ducts associated with DCIS (n = 10); and of DCIS without an invasive component (n = 154). Results CD10 immunostaining was only observed in MECs in normal tissue and in DCIS. Normal tissue showed high mRNA expression levels of CD10, whereas DCIS showed a variable range. After a median follow-up of 6 years, DCIS with CD10 expression below the levels observed in normal tissue (71%) demonstrated a higher risk of local relapse (HR = 1.88; [95CI:1.30–2.70], p = 0.001) in univariate analysis. No relapse was observed in patients expressing high CD10 mRNA levels (29%) similar to the ones observed in normal tissue. In multivariate analysis including known prognostic factors, low CD10 mRNA expression remained significant (HR = 2.25; [95%CI:1.24–4.09], p = 0.008), as did the recently revised Van Nuys Prognostic Index (VNPI) score (HR = 2.03; [95%CI:1.23–3.35], p = 0.006). Conclusion The decrease of CD10 expression in MECs is associated with a higher risk of relapse in DCIS; this knowledge has the potential to improve DCIS management.

The Value of the Van Nuys Prognostic Index in Ductal Carcinoma In Situ of the Breast: A Retrospective Analysis

Abstract:  The Van Nuys Prognostic Index 1996 (VNPI), based upon tumor size, pathological grade and tumor margins, is a guideline for the treatment of ductal carcinoma in situ (DCIS). It was thought to strongly decrease overtreatment. In 2003, age was added to the index as a fourth prognostic factor. We examined changes in treatment modality after applying the VNPI retrospectively and investigated if the addition of age to the Index causes a shift in treatment. The influence of each prognostic factor on disease‐free survival (DFS) was calculated. We performed a retrospective file study of DCIS patients treated between 1985 and 2003 at the University Hospital, Antwerp. Patients were assigned a Van Nuys Score 1996 and 2003. The influence of tumor size, pathological grade, tumor margins and age on DFS was calculated with the Kaplan–Meier method and the log‐rank test. We identified 104 DCIS cases with a median follow‐up of 36 months. Twelve patients showed recurrence (11.5%), of whom seven were invasive (58%). Seventeen of the 29 women diagnosed before 1997 were undertreated according to the VNPI 1996 and six of them showed recurrence. The remaining three recurrences were correctly treated. Seventy‐five patients diagnosed after 1997 were all treated according to the VNPI 1996 and only three had a recurrence. The introduction of age caused no significant shift in treatment modalities. Significant differences in DFS were seen between large (>41 mm) and small (<15 mm) tumors (p = 0.0074), old (>60 years) and young (<40 years) patients (p = 0.024) and Van Nuys Subgroup 2 and 3 (p = 0.04). Tumor margins and pathological grade showed no significant difference in DFS. The VNPI can be a useful tool in the treatment of DCIS. However, this Index is not evidence‐based, using a relatively small retrospective series of patients. The validity of the modified VNPI must be prospectively confirmed with large numbers of DCIS patients.

Fine Tuning of the Van Nuys Prognostic Index (VNPI) 2003 by Integrating the Genomic Grade Index (GGI): New Tools for Ductal Carcinoma In Situ (DCIS)

Abstract:  Ductal carcinoma in situ (DCIS) is considered a heterogeneous premalignant condition of the breast with a certain probability for progressing to malignancy. There is no standard of care. The updated Van Nuys Prognostic Index (VNPI) 2003 is a clinical tool in treatment decision making. This study assessed the prognostic value of the VNPI after integration of proliferative biomarkers (GGI and Ki‐67). DCIS samples were divided into three VNPI subgroups (low risk [score 4–6], intermediate risk [score 7–9], high risk [score 10–12]) based on nuclear grade ± necrosis, tumor size, margin width, and age. Nuclear grade was substituted by the genomic grade index (GGI) to generate the VNPI‐GGI and combined with the Ki‐67 to generate the VNPI‐Ki67. Disease‐free survival was calculated by Kaplan–Meier survival plots with log‐rank significance. Multiple regression analysis was carried out using Cox proportional hazard regression analysis. A total of 88 cases (median age 54 years) with representative tissue were identified out of 168 DCIS patients. Median follow‐up was more than 5 years. Ten patients developed an ipsilateral recurrence of whom nine were invasive: six patients were classified in the VNPI subgroup 2 and three patients in the VNPI subgroup 3. One non‐invasive recurrence (DCIS) was classified in the VNPI subgroup III. A statistical association was observed between a high VNPI score and a higher risk of recurrence (HR = 7.72 [95% CI 1.01–58.91], p = 0.049). Ki‐67 did not improve the prognostic value of VNPI (HR = 6.5, [95% CI 0.80–53.33], p = 0.08). In contrast, the VNPI‐GGI could identify more accurately high‐risk DCIS patients with early relapses within 5 years (HR = 18.14 [95% CI 1.75–188], p = 0.015). GGI incorporated into the VNPI improved its prognostic value for DCIS, especially for identifying early relapses. This method should be validated and incorporated in future prospective clinical DCIS trials.

Incorporating Anti-VEGF Pathway Therapy as a Continuum of Care in Metastatic Colorectal Cancer

Opinion statementMetastatic cancer was previously treated with distinctive lines of chemotherapy regimens upon disease progression or toxicity, yet the choices of therapy are actually interrelated, with the selection of a first-line regimen in part determining the choices available for subsequent treatment. Lately the therapeutic approach based on separate lines of treatment, tends to be replaced from a perspective strategical approach, that of the “continuum of care”. This strategy targets to an improved overall survival, improved of quality of life and minimization of toxicity through upfront design of treatment selection and sequencing, exposure to all available drugs and minimization of unnecessary treatment. Anti-VEGF treatment has a well-documented role in this approach. Bevacizumab should be included in upfront treatment regimens for all mCRC patients independently of RAS status, unless contraindicated. Upfront bevacizumab could be combined with all available regimens since the optimal choice of backbone chemotherapy is yet to be defined. In RAS wild-type population, when metastasectomy is the target, an anti-EGFR combination is also a valid approach. Maintenance with bevacizumab and fluoropyrimidines should be considered upon intolerance of induction treatment and/or disease stabilization; maintenance with bevacizumab monotherapy should be avoided. In highly selected patients, complete treatment cessation could be also an option. Continuation with bevacizumab upon first progression and switch of the “backbone” chemotherapy is a validated approach. Patients progressing after first-line oxaliplatin regimen including bevacizumab combinations could be treated with an aflibercept–irinotecan combination. When no more options are available, regorafenib monotherapy should be the following choice. Combinations of anti-VEGF and anti-EGFR treatment have no place in this approach and are not indicated.

A non-randomized comparison of gemcitabine-based chemoradiation with or without induction chemotherapy for locally advanced squamous cell carcinoma of the head and neck.

BackgroundConcomitant chemotherapy and radiotherapy (chemoradiation; CRT) is the standard treatment for locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). CRT improves local control and overall survival (OS) when compared to radiotherapy (RT) alone. Induction chemotherapy (IC) reduces the risk of distant metastases (DM) and improves OS by 5% with the use of cisplatin/infusional 5 fluorouracil (PF) in meta-analysis. Adding a taxane to PF in the IC regimen confers a better outcome. Sequential treatment (ST) of IC followed by CRT is therefore under active investigation in multiple phase III trials.MethodsWe compared the outcome of two cohorts of patients (pts) with LA-SCCHN treated at our institution with CRT (n = 27) or ST (n = 31), respectively. CRT consisted of GEM 100 mg/m2 weekly + conventional RT (70 Gy); ST consisted of the same CRT preceded by platinum-based IC.ResultsResponse to IC: complete 8 (26%), partial 20 (65%), stable 1, progressive 1, not evaluable 1. Median follow up of the surviving pts: for CRT 73 months, for ST 51 months. Median time to distant metastasis (TDM) was for CRT 23.6 months, for ST not reached. Median OS was for CRT 20.2 months, for ST 40.2 months. Cox regression analysis, taking into account age, T and N stage and tumor site, showed a hazard ratio with ST of 1.190 for time to locoregional failure (p = 0.712), 0.162 for TDM (p = 0.002), and 0.441 for overall survival (OS) (p = 0.026).ConclusionTDM and OS were found significantly longer in the ST cohort without a reduced locoregional control. Notwithstanding the limitations of a non-randomized single-center comparison, the results are in line with very preliminary data of randomized comparisons suggesting an improved outcome with ST.

In silico pathway analysis in cervical carcinoma reveals potential new targets for treatment

An in silico pathway analysis was performed in order to improve current knowledge on the molecular drivers of cervical cancer and detect potential targets for treatment. Three publicly available Affymetrix gene expression data-sets (GSE5787, GSE7803, GSE9750) were retrieved, vouching for a total of 9 cervical cancer cell lines (CCCLs), 39 normal cervical samples, 7 CIN3 samples and 111 cervical cancer samples (CCSs). Predication analysis of microarrays was performed in the Affymetrix sets to identify cervical cancer biomarkers. To select cancer cell-specific genes the CCSs were compared to the CCCLs. Validated genes were submitted to a gene set enrichment analysis (GSEA) and Expression2Kinases (E2K). In the CCSs a total of 1,547 probe sets were identified that were overexpressed (FDR < 0.1). Comparing to CCCLs 560 probe sets (481 unique genes) had a cancer cell-specific expression profile, and 315 of these genes (65%) were validated. GSEA identified 5 cancer hallmarks enriched in CCSs (P < 0.01 and FDR < 0.25) showing that deregulation of the cell cycle is a major component of cervical cancer biology. E2K identified a protein-protein interaction (PPI) network of 162 nodes (including 20 drugable kinases) and 1626 edges. This PPI-network consists of 5 signaling modules associated with MYC signaling (Module 1), cell cycle deregulation (Module 2), TGFβ-signaling (Module 3), MAPK signaling (Module 4) and chromatin modeling (Module 5). Potential targets for treatment which could be identified were CDK1, CDK2, ABL1, ATM, AKT1, MAPK1, MAPK3 among others. The present study identified important driver pathways in cervical carcinogenesis which should be assessed for their potential therapeutic drugability.

Preoperative ultrasound staging of the axilla make’s peroperative examination of the sentinel node redundant in breast cancer: saving tissue, time and money

OBJECTIVE To evaluate the role of preoperative axillary staging with ultrasound (US) and fine needle aspiration cytology (FNAC). Can we avoid intraoperative sentinel lymph node (SLN) examination, with an acceptable revision rate by preoperative staging? DESIGN This study is based on the retrospective data of 336 patients that underwent US evaluation of the axilla as part of their staging. A FNAC biopsy was performed when abnormal lymph nodes were visualized. Patients with normal appearing nodes on US or a benign diagnostic biopsy had removal of the SLNs without intraoperative pathological examination. We calculated the sensitivity, specificity and accuracy of US/FNAC in predicting the necessity of an axillary lymphadenectomy. Subsequently we looked at the total cost and the operating time of 3 models. Model A is our study protocol. Model B is a theoretical protocol based on the findings of the Z0011 trial with only clinical preoperative staging and in Model C preoperative staging and intraoperative pathological examination were both theoretically done. sentinel node, staging, ultrasound, preoperative axillary staging, FNAC, axilla RESULTS: The sensitivity, specificity and accuracy are respectively 0.75 (0.66-0.82), 1.00 (0.99-1.00) and 0.92 (0.88-0.94). Only 26 out of 317 (8.2%) patients that successfully underwent staging needed a revision. The total cost of Model A was 1.58% cheaper than Model C and resulted in a decrease in operation time by 9,46%. The benefits compared with Model B were much smaller. CONCLUSION Preoperative US/FNAC staging of the axillary lymph nodes can avoid intraoperative examination of the sentinel node with an acceptable revision rate. It saves tissue, reduces operating time and decreases healthcare costs in general.

Decreased CD10 Expression Is Associated with a Higher Risk of Relapse in Ductal Carcinoma In Situ (DCIS).

Background: The Van Nuys Prognostic Index (VNPI) is the most widely used tool to predict local recurrence and guide therapy for DCIS. Nevertheless, many patients are still over-treated. Pre-clinical evidence indicates myo-epithelial cell (MEC) death in DCIS is a pre-requisite to tumor invasion. In this study we hypothesized that loss of CD10, (a marker of MECs), would be a surrogate for basement membrane disruption and tumor invasion. The aim of the present study was to retrospectively evaluate the prognostic value of CD10 in pure DCIS.Methods: CD10 expression was evaluated by qRT-PCR and immuno-histochemistry (IHC) using FFPE tissues on normal samples (N=11) and two independent pure DCIS populations: a training set (N=66) and a validation set (N=88).Results: MECs were the only cells that showed CD10 staining using IHC in normal and DCIS samples. All normal breast tissue samples demonstrated high expression levels of CD10 using both IHC and RT-PCR. In contrast, DCIS samples showed a wide range of CD10 expression levels: 1/3 of DCIS expressed high CD10 levels similar to those observed in normal breast tissue (high expression), whereas 2/3 expressed CD10 at a level below normal breast tissue (low expression). DCIS tumors with low CD10 mRNA levels were significantly associated with a higher risk of local relapse (HR= 2.49; [95%CI: 1.13-5.49], p=0.02). These results were validated in an independent dataset (HR= 1.805 [95%CI: 1.11-2.92], p=0.016). Of interest, no local relapses were observed in the high CD10 expression DCIS group. In multivariate analysis, CD10 expression by qRT-PCR was significantly associated with relapse (HR= 2.25, [95%CI: 1.24-4.09], p=0.008) in addition to VNPI score (HR: 2.03; [95%CI: 1.23-3.35], p=0.006).Conclusion: Decreased expression of CD10 in DCIS is associated with a higher risk of local relapse. These promising results are currently being validated in a larger patient series. Assessment of CD10 in addition to VPNI may lead to improved treatment tailoring for women with DCIS. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2112.

Abstract P4-21-15: Trastuzumab IVversusSC: A time, motion and cost assessment in a lean operating day care oncology unit

Purpose: Primary endpoint: quantification of the active healthcare professional (HCP) time associated with the standard intravenous (IV) infusion of trastuzumab (Herceptin®) compared to the subcutaneous (SC) administration in the treatment of patients with HER2-positive early breast cancer. Secondary endpoints: quantification of the preparation and administration related costs (HCP time, consumables and drug wastage), patient chair time and the total time spent in the day care unit for both routes of administration. Patients and Methods: A local observational project was conducted in the LEAN Operating Day Care Oncology Unit of the Antwerp University Hospital (Belgian registration number: B300201525036). Independent trained observers measured the duration of each trastuzumab IV and SC related task that HCPs undertook and recorded patient time in the chair and the day care unit. The type and quantity of medical consumables used with each route of administration were also registered. A total of 105 patient episodes were recorded (40 IV, 65 SC) from October 2015 until May 2016. The recorded active HCP time corresponded to the active preparation and administration time of the medication. Total preparation and administration time was calculated as the mean sum of task times, both for IV and SC formulations. The cost of each route of administration was calculated as the mean cost of HCP time plus the mean cost of consumables used. Drug wastage that occurred with the IV formulation was also taken into account. The total active HCP time was quantified by the Hospital9s Human Resources department. Consumables were quantified using hospital pharmacy data and online sources. Patient chair time was measured as the actual time the patient spent on the chair/bed. The total time spent in the day care unit was calculated as the time between the patient9s registry and the time the patient left the hospital. Results: The mean active HCP time for preparation and administration of IV was 64 minutes compared to 14 minutes for SC. The mean cost for preparation and administration was €303,12 for IV (€33,8 of HCP time, €23,56 of consumables and €245,76 of drug wastage) versus €10,39 for SC (€7,68 of HCP time and €2,71 of consumables). Mean patient chair time and the total time spent in the day care unit for IV was 133 minutes and 165 minutes respectively, and 11 minutes and 50 minutes for SC. SC administration of trastuzumab resulted in a HCP time saving of 50 minutes (versus IV) with a total cost saving of €292,73 per administration. This leads to a potential saving of €5.269,16 over a full course of adjuvant treatment (18 cycles). Conclusion: Substituting IV with SC administration of trastuzumab leads to a substantial reduction in active HCP time. As a result the overall costs consisting of HCP time, consumables and drug wastage are also reduced. Additionally, the reduced patient chair and unit time could provide increased capacity within existing resources in a LEAN Operating Day Care Oncology Unit. Citation Format: Tjalma WAA, Van den Mooter T, Mertens T, Bastiaens V, Altintas S, Huizing MT, Trinh B, Van Dam P, Peeters M, Papadimitriou K. Trastuzumab IV versus SC: A time, motion and cost assessment in a lean operating day care oncology unit [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 P4-21-15.