K.G.A. Gilhuijs

Reduction in the number of sentinel lymph node procedures by preoperative ultrasonography of the axilla in breast cancer

Currently, breast cancer patients without clinically suspicious lymph nodes are candidates for sentinel lymph node procedures (SLNPs). The aims of this study were to investigate whether preoperative axillary ultrasonography and fine-needle aspiration cytology (FNA) can reduce the number of the more time-consuming SLNPs, and to identify a subset of quantitative nodal features to predict metastatic involvement. 268 axillae were ultrasonographically examined. FNA was performed on suspicious nodes (smallest diameter > or =5 mm or atypical cortex appearance). SLNP was omitted if a tumour-positive node was found on FNA. Length, width, maximum cortex thickness and appearance of cortex and hilus were ultrasonographically established. In 93 axillae (35%), at least one node was detected with ultrasound. FNA was performed once per axilla on 66 nodes; 37 (56%) contained tumour cells. 31% of all tumour-positive axillae (macro-+micrometastases) was found by ultrasound and FNA (37/121). 41% of all axillae containing macrometastases was found by ultrasound and FNA (36/87). SLNPs were reduced by 14% (37/268). Maximum cortex thickness is the main feature to predict metastatic involvement (area under Receiver Operating Characteristic (ROC) curve (A(Z))=0.87).

Neoadjuvant chemotherapy adaptation and serial MRI response monitoring in ER-positive HER2-negative breast cancer.

Background:Changing the neoadjuvant chemotherapy regimen in insufficiently responding breast cancer is not a standard policy. We analysed a series of patients with ‘luminal’-type breast cancer in whom the second half of neoadjuvant chemotherapy was selected based on the response to the first half.Methods:Patients with oestrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2−) breast cancer received three courses of neoadjuvant dose-dense doxorubicin and cyclophosphamide (ddAC). Three further courses of ddAC were administered in case of a ‘favourable response’ on the interim magnetic resonance imaging (MRI) and a switch to docetaxel and capecitabine (DC) was made in case of an ‘unfavourable response’, using previously published response criteria. The efficacy of this approach was evaluated by tumour size reductions on serial contrast-enhanced MRI, pathologic response and relapse-free survival.Results:Two hundred and forty-six patients received three courses of ddAC. One hundred and sixty-four patients (67%) had a favourable response at the interim MRI, with a mean tumour size reduction of 31% after the first three courses and 34% after the second three courses. Patients with unfavourable responsive tumours had a mean tumour size reduction of 12% after three courses and received three courses of DC rather than ddAC. This led to a mean shrinkage of 27%.Conclusion:The tumour size reduction of initially less responsive tumours after treatment adaptation adds further evidence that a response-adapted strategy may enhance the efficacy of neoadjuvant chemotherapy.

Abstract P4-02-07: Association between computer-derived features of the ipsilateral breast on DCE-MRI and the 70-gene signature in patients with invasive breast cancer

Introduction Molecular assays such as the 70-gene signature are increasingly used as prognostic indicators to select chemotherapy in individual patients. These assays are typically derived from postoperative excision specimens and require several weeks to complete. Earlier assessment of the results of such assays could open up new therapeutic options in subgroups of patients, potentially avoiding overtreatment of early breast cancer. Although molecular assays may be derived from biopsied tissue, tumor heterogeneity may cause uncertainty. Dynamic contrast-enhanced MRI (DCE-MRI) depicts some of the hallmarks of cancer that are tested by these molecular essays. The goal of this study was to investigate the association between the postoperatively derived 70-gene signature and computer-derived DCE-MRI features of the ipsilateral breast prior to surgery. Material and Methods Sixty-nine patients with node-negative invasive breast cancer were enrolled between 2003 and 2006. These patients received a preoperative MRI in study setting and a postoperative 70-gene signature assay. Association between preoperative features and the 70-gene signature was evaluated using a computer prediction model combining clinical features and automatically extracted MRI features. The clinical features were age at diagnosis and largest tumor diameter on MRI. The MRI features were rate of contrast uptake in the tumor, rate of wash-out, tumor volume, and two features from the intramammary blood vessel tree (total length and mean rate of contrast uptake). The features were transformed into an orthogonal feature set using principal component analysis. Association with the 70-gene signature (positive or negative indication for systemic therapy) was evaluated using binary logistic regression. Model performance was measured using the area under the receiver operating characteristics curve (AUC) after bootstrap validation using 200 iterations. Two operating points were examined: one to predict a positive 70-gene signature with high certainty (i.e., at high positive-predictive value (PPV)) and one to predict a negative signature with high certainty (i.e., at high negative-predictive value (PPV)). Results The average patient age at diagnosis was 48 years (range: 32-58). The median largest tumor diameter on MRI was 17 mm (range: 5-40). The 70-gene signature was positive in 29/69 (42%) patients. The computer prediction model achieved an AUC of 0.72 after bootstrap validation. At high PPV, 10/29 (34.5%) positive 70-gene signatures were identified preoperatively at the expense of 2/40 (5.0%) false-positive. The PPV was 10/12 (83.3%). At high NPV, 12/40 (30.0%) negative 70-gene signatures were identified at the expense of 1/29 (3.5%) false-negative signature. The NPV was 12/13 (92.3%). Conclusion Computer-derived DCE-MRI features from the ipsilateral breast in combination with clinical parameters show potential to preoperatively assess a negative outcome of the 70-gene signature in approximately one-third of the total patient group. Citation Format: van der Velden BHM, Schmitz AMTh, Loo CE, Gilhuijs KGA. Association between computer-derived features of the ipsilateral breast on DCE-MRI and the 70-gene signature in patients with invasive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-02-07.

P5-10-02: Relevance of Magnetic Resonance Imaging To Predict Disease-Free Survival after Neoadjuvant Chemotherapy of Breast Cancer.

Purpose : To explore the relevance of magnetic resonance imaging (MRI) to predict disease free survival (DFS) after neoadjuvant chemotherapy (NAC) of breast cancer. Patients and Methods Between July 2000 and December 2007, MRI examinations were performed in 188 women before, during and after NAC in the context of a single-institution review board approved study. Patients were consecutively included after informed consent. Interpretation of MRI was revised by an experienced breast MR radiologists and included assessment of lesion morphology, changes in morphology, size, and contrast uptake kinetics (initial and late enhancement). MRI features and known prognostic markers of breast cancer (age, tumor response at pathology, tumor size at baseline, immunohistochemistry-derived breast cancer subtype (triple-negative; HER2−positive or ER-positive/HER2−negative)) were correlated with DFS. Multivariate Cox regression analysis was used with forward LR feature selection. Kaplan Meier curves were obtained to explore the impact of relevant associations. Results : Follow-up data were available of 184 women. The median follow-up time was 57,6 months (range 32,4 — 125). In 30 women events were found (26 breast cancer related deaths; 29 distant metastasis and 12 local/regional recurrences). At multivariate analysis, only breast cancer subtype (p=0.004) and largest diameter of late enhancement at MRI after NAC (p=0.006) retained prognostic value in favour of response at final pathology, age and tumor size at baseline. Cumulative survival at 60 months (kaplanmeier curves) was 70%, 86.7%, and 89.7% for triple-negatives, HER2−positive and ER-positive/HER2−negative subtypes [figure 1], respectively, and 88.5%, 81.4 % and 55.1% for absence of washout/plateau after NAC, between 0 and 30 mm washout/plateau, and ≥ 30 mm washout/plateau, respectively [figure 2]. Conclusions MRI after NAC in conjunction with breast cancer subtype has potential as complementary predictor for DFS. Larger diameters of residual late enhancement at MRI after NAC are associated with inferior DFS at 60 months. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-10-02.

P3-14-06: Combined Use of 18F-FDG PET/CT and MRI To Monitor Breast Cancer Response during Neoadjuvant Chemotherapy.

Background and aim : Contrast-enhanced breast magnetic resonance imaging (MRI) is commonly used for the evaluation of the therapeutic effect of neoadjuvant chemotherapy (NAC). A recent study demonstrated the relevance of breast cancer subtype with regard to the accuracy of MRI to predict response during NAC. The role of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (FDG PET/CT) is under investigation, and varying results have been reported. MRI and 18 F-FDG PET/CT, visualize different functional characteristics of the tumor (perfusion and glucose metabolism), but it is unclear if they complement one another to monitor response to NAC, and whether breast cancer subtype plays an independent role. Method and material : The study group consisted of 65 women with stage II or III breast cancer and measurable FDG tumor uptake, who were treated with NAC and participated in an ongoing MRI/FDG PET/CT study. MRI and FDG PET/CT scans were acquired prior to and during treatment, using prone patient positioning. Written informed consent was obtained. Prior to the start of NAC a biopsy was taken and tumors were divided into three subtypes, using immunohistochemistry: human epidermal growth factor receptor 2 (HER2) amplified (HER2+) (N=18), estrogen receptor positive/HER2 non-amplified (ER+/HER2−) (N=29), and triple negative (TN) tumors (N=18). MRI interpretation included lesion morphology at baseline, changes in morphology, tumor size, and contrast uptake kinetics (initial and late enhancement). At FDG PET/CT the maximum standardized uptake value (SUV max ) at baseline and during treatment was obtained. Tumor response at pathology was stratified to “incomplete response” (substantial presence of vital invasive tumor cells) and “favourable response” (complete absence of invasive residual tumor or only a small number of scattered tumor cells). Appropriate statistical analyses including T-tests, multivariate logistic regression and receiver operating characteristic (ROC) curves were employed to indentify factors associated with incomplete response at pathology. The following imaging and clinical features were candidates for forward feature selection in the multivariate analysis: lesion morphology, largest tumor diameter, pattern of reduction, absolute and relative change in largest tumor diameter at initial and at late enhancement during NAC, SUV max at baseline; absolute and relative change in SUV max during NAC; breast cancer subtype; chemotherapy regimen, and age. Results : At pathology after NAC, 32 tumors (49 %) showed favourable response and 33 (51 %) had residual disease. At multivariate analysis, breast cancer subtype, relative change in the diameter of late enhancement on MRI and relative change in SUV max on FDG PET/CT were independent markers of tumor response at final pathology. The area under the ROC curve increased from 0.86 for MRI alone to 0.94 (p Conclusion : MRI and FDG PET/CT show complementary potential to predict response during NAC, in addition to breast cancer subtype. Ackowledgement: This study was supported by the Center for Translational Molecular Medicine, project Breast CARE (grant ***03O-104). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-06.

P2-09-06: Relevance of Breast Cancer Subtypes in Response Monitoring with 18F-FDG PET/CT during Neoadjuvant Chemotherapy.

Background - Neoadjuvant chemotherapy (NAC) is increasingly applied in stage II and III breast cancer. Response monitoring with magnetic resonance imaging (MRI) has been shown valuable, but knowledge of the breast cancer subtype is essential for correct interpretation of response assessment.(Loo et al, J Clin Oncol 29:660–6, 2011) The aim of the present study was to evaluate the relevance of breast cancer subtype for 18F-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET/CT) markers for monitoring of therapy response during NAC. Methods - Evaluation included 94 women with primary stage II or III breast cancer and measurable (quantifiable) FDG tumor uptake. FDG PET/CT scans were performed before and after six weeks of NAC using similar prone patient positioning. FDG uptake of the primary tumor was quantified using maximum standardized uptake values (SUVmax). Tumors were divided into three subtypes using immunohistochemistry: human epidermal growth factor receptor 2 (HER2) positive, estrogen receptor (ER) positive/HER2 negative and triple negative. Tumor response was assessed as presence of residual tumor in the surgery specimen (no response or partial response) or absence thereof (near complete or complete response). Multivariate regression analysis and receiver operating characteristic (ROC) analyses were employed to determine significant associations. Results - A (near) complete response at pathology was observed in 16 (73%) of 22 HER2 positive tumors, 5 (12%) of 43 ER positive/HER2 negative tumors and 20 (69%) of 29 triple negative tumors. In the multivariate regression analysis for the whole group, (near) complete response in the surgery specimen was significantly associated with relative reduction of SUVmax of the tumor between both scans and breast cancer subtype (area under the curve of the ROC curve 0.88 [95% confidence interval 0.81−0.95], p Conclusion - Knowledge of the breast cancer subtype appears relevant for the assessment of response to NAC with FDG PET/CT. Response monitoring with FDG PET/CT may predict a pathological response adequately in ER positive/HER2 negative and triple negative tumors, but seems less accurate in HER2 positive tumors. The reasons for these differences need to be elucidated in further investigations. Disclosure - This study was performed within the framework of CTMM, the Center for Translational Molecular Medicine (www.ctmm.nl), project Breast CARE (grant 030–104). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-06.

Accuracy of MRI in selecting patients for breast conserving therapy after neoadjuvant chemotherapy.

Abstract #4006 Introduction: Accurate assessment of the extent of residual breast cancer is crucial for the surgical planning after neoadjuvant chemotherapy (NAC). Compared to conventional imaging, MRI shows superior ability to monitor tumor response. Nonetheless, controversy exists about the precision of MRI to visualize disease extent after NAC. The aim of this study was to determine which variables influence the accuracy of MRI.
 Methods: Retrospective analysis of 130 patients treated with NAC. Contrast-enhanced MRI studies were performed on a 1.5-T scanner with a dedicated breast coil before, during and after NAC. The outcome parameters were the accuracy of the estimation of tumor size on final MRI and the accuracy in predicting the ability to perform breast conserving therapy (BCT). Tumor size on the final MRI was therefore compared to residual tumor size on pathology. Discrepancy Results: In 61/130 patients (47%) the difference between size on MRI and size on pathology was >10 mm. In 50% (n=32) this discrepancy between pathology and MRI would lead to different surgical treatment. Based on the MRI indication for BCT, 19 patients would have unjustly undergone BCT (disease extent at MRI 30 mm). In 13 patients MRI alone would have led to mastectomy (extent >30 mm) while the actual extent at pathology was Conclusions: The results show the strengths and limitations in monitoring tumor response with MRI. For preoperative assessment the final MRI should be evaluated with the knowledge of the baseline MRI and the molecular and histological subtype. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4006.