Abstract Background An important advantage of neoadjuvant systemic therapy (NST) in breast cancer patients is down-sizing of the primary tumor. However, many patients with T3 tumors are treated with mastectomy regardless of response to NST. In this study, we evaluated predictive characteristics for positive margins and local control in T3 breast cancer patients who underwent breast-conserving therapy (BCT) after NST. Methods This single institution study included all clinical T3 breast cancer patients (determined by contrast-enhanced magnetic resonance imaging [MRI]) who underwent breast conserving surgery (BCS) after NST between 2000-2015. Clinical T3 was defined as a breast tumor >50mm on MRI pre-NST. Patient, tumor and treatment characteristics were recorded, as well as response on MRI and final pathology. The local recurrence probability was estimated with the Kaplan-Meier method. Predictive characteristics for positive margins in patients undergoing BCS were analyzed using Fishers exact test. Results In total, 115 T3 patients were identified. Patient, tumor and MRI findings are presenting in the table. Median tumor size was 60 mm on MRI pre-NST (range 51-120 mm) and 4 mm after NST (range 0-58 mm). Overall pathologic complete response was 19%: 5% in HR+/HER2- patients, 32% in HR-/HER2+ patients and 40% in TN patients. After initial BCS, 73 patients had negative margins (63.5%), 18 focally positive margins (15.7%) and 24 more than focally positive margins (20.9%). Patients with HR+/HER2- tumors (52%) were more likely to have positive margins than patients with HR-/HER2+ and TN tumors (21% and 19%, p=0.002). In addition, positive margins rate was higher in patients with lobular carcinoma compared to patients with ductal carcinoma (57 vs 32%, p=0.031). Presence of non-mass enhancement on pre-NST MRI was predictive for positive margins (52% in patients with and 25% in patients without non-mass enhancement, p=0.003). Of patient with positive margins, 15 underwent radiotherapy with boost, 6 underwent re-excision and 21 underwent mastectomy. Finally, 94/115 patients were treated with BCT (82%). Of these patients, two had a local recurrence after a median follow-up of 6.5 years (6-year local recurrence probability 2.6% (95%-CI 0-7%). Conclusion In this series, BCT after NST was successful in 82% of patients with T3 breast cancer and local control in this group was excellent. The positive margin rate after BCS was higher in patients with HR+ tumors, lobular carcinoma and tumors with non-mass enhancement on MRI pre-NST. BCT should always be considered in T3 cancers after NST. CharacteristicTotal (n=115)Positive margins (focally+ >focally), n=42(%)p-valueHistology 0.031Ductal9229(32) Lobular2313(57) Subtype 0.002HR+/HER2-6132(52) HER2+347(21) TN203(15) MRI morphology of mass pre-NST 0.948Unifocal288(29) Multifocal4012(33) Multicentric134(31) Only non-mass enhancement34 MRI non-mass enhancement before NST 0.003Absent6516(25) Present5026(52) MRI response after NST 0.952rCR5218(35) non-rCR6221(38) Missing1 Citation Format: van der Noordaa ME, Vrancken Peeters M-JM, Ioan I, Loo CE, van Urk J, van Werkhoven E, Voorthuis R, Wiersma T, Groen E, Rutgers ET, van Duijnhoven FH. Breast conserving therapy after neoadjuvant systemic therapy in patients with T3 breast cancer is feasible [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 P3-13-02.

Abstract 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.

Abstracts: Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX 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.

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.