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Purpose: Increased insight in tumor biology has revealed that not all young women are at high risk of disease recurrence. Therefore, in some patients extent of treatment could probably be safely scaled down. We aimed to evaluate the risk of breast cancer (BC) relapse according to the 70-gene signature (70-GS) result in relation to young age, in early-stage BC patients enrolled in the MINDACT trial. Patients and Methods: The analyzed population consisted of enrolled BC patients in the MINDACT trial with available clinical (C), as per a modified version of Adjuvant!Online, and genomic (G), according to the 70-GS, risk assessments and known age (n=6693). Patients were categorized in three age groups; 55 years (post-menopausal). Clinicopathological and treatment characteristics as well as gene expression were compared for the different age groups further split by corrected risk groups (C-low/G-low, C-low/G-high, C-high/G-low, C-high/G-high). Subsequently, the 5-year distant metastasis-free survival according to risk category was calculated. Results: The study included 1100 patients 55 years of age (50%). Median age of the young group was 41 (25.8-45.0) years. The young age group had a higher frequency of lymph node involvement (25% vs. 22% and 19%), poorly differentiated tumors (42% vs. 26% and 27%), ER-negative tumors (20% vs. 11% and 11%) and triple negative molecular IHC subtype (16% vs. 9% ad 8%). Median tumor size was the same across the 3 age groups (17mm). Of the 1100 young patients, 61% were C-high while the 70-GS assessed 48% as G-high. Overall, 31% were CL/GL (vs. 43% in other age groups), 9% CL/GH, 21% CH/GL and 40% CH/GH (vs. 24% and 25%). In the discordant risk groups, chemotherapy (CT) allocation when randomized to no chemo occurred in 5% of young women as compared to 3% and 1% in the older age groups. Reason for non-compliance was 50/50 between patient refusal and PI decision. Overall, the 5-year DMFS was 94.1% (95% CI 92.4-95.4) in 55. For the young patients, 5-year DMFS was 98.3% for the CL/GL (96.0-99.3), 97.4% in CL/GH (90.0-99.4), 95.5% in CH/GL (91.6-97.7) and 89.2% in CH/GH (85.6-92.0). In the older two age groups (45-55 and >55), the 5-year DMFS rates were 97.8% (96.5.98.6) and 97.2% (96.2-98.0) for CL/GL, 93.9% (88.8-96.7) and 94.5% (91.0-96.7) for CL/GH, 94.5% (92.0-96.3) and 95.4% (93.5-96.8) for CH/GL and 92.0% (89.2-94.1) and 90.4% (88.0-92.4) for CH/GH, respectively. With 9 events in the Conclusion: The use of the 70-GS reduces the proportion of patients characterized as high risk as compared to traditional clinical risk assessment (48% vs. 61%). Outcome was comparable for the 3 age categories with a very good 5-year DMFS of 95-98% in all GL groups. Performing the 70-GS provides clinically relevant information concerning the prognosis for young early-stage BC patients categorized as CH. These results add important new data to the limited available evidence on genomic expression in young BC patients. Citation Format: Aalders K, Genbrugge E, Poncet C, Kuijer A, Pistilli B, Piccart M, Tryfonidis K, van Dalen T, Cardoso F, van 't Veer L, Rutgers E. Young age and the risk of disease recurrence as assessed by the 70-gene signature – an analysis from the EORTC 10041/BIG 03-04 MINDACT trial [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 P1-07-08.

Purpose In Dutch guidelines gene expression profiles (GEP) are indicated in estrogen receptor positive early breast cancer patients in whom benefit of chemotherapy (CT) is controversial based on traditional prognostic factors alone. Aim of the current study is to assess the use and impact of GEP on administration of adjuvant CT in breast cancer patients who have according to national guidelines a clear indication to either use or withhold adjuvant chemotherapy (clinical high or low risk). Methods Clinical low- and high risk patients, according to Dutch breast cancer guidelines, diagnosed between 2011-2014 were selected from the Netherlands Cancer Registry (NCR). Influence of GEP use and GEP test result on CT administration was assessed with logistic regression. Results Overall, 26,425 patients were identified; 4.8% of patients with clinical low- risk (444/ 9,354), 7.5% of the patients with a clinical high-risk (1,281/ 17,071) received a GEP. GEP use was associated with a significantly increased odds of CT administration in clinical low-risk patients (OR=2.12 95%CI: 1.44-3.11). In clinical high-risk patients GEP use was associated with a decreased frequency of CT administration (OR=0.55, 95%CI: 0.48-0.63). Adherence to the GEP result was higher in clinical high-risk patients with a discordant GEP result as compared to clinical low-risk patients with a discordant GEP result: 71.7% vs. 52.2%, respectively. Conclusion GEP is frequently used outside the indicated area and significantly influenced the administration of adjuvant CT, although adherence to the test-result was limited. Citation Format: Schreuder K, Kuijer A, Rutgers EJTh, Smorenburg CH, Van Dalen T, Siesling S. Impact of gene-expression profiling in patients with early breast cancer when applied outside the guideline directed indication area [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 P3-08-09.

PURPOSE: gene-expression profiles, such as the 70-gene signature (70-GS), are increasingly used as adjunct to conventional clinicopathological prognostic factors to guide adjuvant chemotherapy (CT) decisions. The Dutch guideline suggests use of validated gene-expression profiles in estrogen-receptor (ER) positive (+) early stage breast cancer patients without overt lymph node metastases. We aimed to assess the impact of the 70-GS on CT decisions in ER+ early stage breast cancer patients. PATIENTS AND METHODS: In this prospective observational multicenter study physicians were asked for their opinion whether to administer or omit adjuvant CT before deployment and after obtaining the test result of the 70-GS in this guideline delineated group of patients. RESULTS: Between January 1 2013 And December 31 2015 660 patients, treated in 31 hospitals, were enrolled. Based on the clinicopathological postoperative findings physicians would administer CT in 41%, withhold CT in 16% of patients and refrained from formulating an advice in the remaining 43% of patients letting their recommendation depend on the result of the 70-GS. Estimated 5-year survival benefit of CT administration was 0.8%, 0.6% and 0.7% respectively (p 0,585). The 70-GS result hardly varied in relation to the initial advice of the physician: 56% and 59% had a low-risk profile in patients in whom CT was recommended or discommended respectively (r =0.021, Table 1). In 51% of patients in whom a pre-test recommendation was formulated incorporation of the 70-GS test result changed the initial advice. Adherence to the test result was high for the three groups (range 94-97%). Table 1. Concordance between pre-test CT recommendation of the oncologist and the 70-gene signature (GS) test result. 70-GS test resultPre-test CT recommendationno. patientsLow RiskHigh RiskNo CT10763 (59%)44 (41%)CT270152 (56%)118 (44%)Depends on 70-GS result283174 (61%)109 (39%)Note. Agreement between pre-test oncologist CT recommendation and the 70-GS test result: Pearsons r = -0,031 95%CI (-0,11 – 0,045). Table 2. CT recommendation before vs. after obtaining the 70-GS test result and the actual administration of CT. Post-test CT recommendationAdherence to test result*Actual administered CTAdherence to test result*Pre-test CT recommendationno. patientsNo CTCT%No CTCT%No CT10769 (65%)38 (35%)94%73 (68%)34 (32%)91%CT207156 (58%)114 (42%)97%162 (60%)108 (40%)90%Depends on 70-GS result283173 (61%)110 (39%)95%185 (65%)98 (35%)91%*Percentage of patients in whom the post-test recommendation/actual administered CT was in line with the 70-GS test result (i.e. no CT in case of a low-risk profile and CT in case of a high-risk profile. Note. Change in CT recommendation in patients with a CT or no CT pre-test recommendation McNemar's chi-square test p < 0.001 and p < 0.001 for actual administered CT CONCLUSION: guideline-directed use of the 70-GS in Dutch ER+ early breast cancer patients influenced CT treatment decision in the majority of patients. The physician's tentative CT advice was not associated with the 70-GS test-result. Citation Format: Kuijer A, Straver M, Elias S, Smorenburg C, Wesseling J, Linn S, Rutgers E, Siesling S, van Dalen T. Impact of 70-gene signature use on adjuvant chemotherapy decisions in early breast cancer patients: Results of the prospective symphony triple A study [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 P6-09-03.

Background Breast cancer treatment is a multimodality effort to optimize outcome as well as to achieve the optimal cosmetic result. Various treatment strategies can be used for the latter goal: upfront breast conserving surgery (BCS), BCS after neoadjuvant therapy (NAC), and ablative surgery combined with immediate breast reconstruction. The rate of BCS is frequently used as a quality and trend indicator. The aim of the present study was to analyse the combined efforts expressed as the rate of breast contour preserving procedures (BCPP) and compare it to the rate of BCS. Material and methods All invasive M0 female breast cancer patients diagnosed and operated in one of the 89 hospitals in the Netherlands between January 2011 – December 2015 were selected from the national NABON Breast Cancer Audit. BCPP (defined as 'primary BCS', 'BCS after NAC', or 'ablative surgery combined with an immediate reconstruction') was calculated for the years of diagnosis, age groups ( Results A total of 61,309 patients were identified. The rate of upfront BCS remained stable during the study period (52%), while the BCPP rate increased over the years (63% to 71%) due to an equal increase in the proportions of patients receiving NAC with BCS and undergoing ablative surgery with immediate breast reconstruction. While upfront BCS (with and without NAC) rates increased with age (30% in patients aged The rate of BCS varied between hospitals in the Netherlands: 37% to 77%. Although BCPP is more often performed compared to BCS, the variation between hospitals remained (47% to 88%). Table. Percentage of patients treated with Breast Conserving Surgery (BCS), BCS after neo-adjuvant therapy and immediate breast reconstruction with ablative surgery resulting in total percentages of Breast Contour Preserving Procedures (BCPP). BCSBCSAblative surgeryBCPP Neo-adjuvant +IBR + Year of Diagnosis 201153%4%6%63%201253%4%7%64%201352%6%8%67%201452%8%9%69%201552%9%11%71%Age Group Conclusions While the rate of BCS remained stable over recent years, the rate of BCPP has increased significantly. Including immediate reconstruction into the BCPP rate annihilates observed age-dependent differences of the BCS-rates, while institutional differences remained. All in all, combining different treatment strategies into one parameter (BCPP) provides a more appropriate measure of maintaining the breast contour than BCS alone. Citation Format: van Bommel A, Spronk P, Vrancken Peeters M-J, Mureau M, Siesling S, Smorenburg C, van Dalen T. The concept of breast contour preserving surgery as parameter in breast cancer surgery [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 P3-13-12.

Introduction: Historically, young breast cancer patients proved to have a poorer prognosis regarding survival and locoregional recurrence. Over the last two decades, the survival of breast cancer patients has improved substantially, while at the same time locoregional recurrence rates decreased. The diminishing recurrence rates in the overall breast cancer population and acknowledgement of tumor biology and intrinsic subtypes in relation to age, raise the question whether the historically high locoregional recurrence risk in young women has decreased over a time where systemic treatment has evolved, particularly for the aggressive tumor types that occur frequently in young women. The aim of this study was to evaluate contemporary local and regional recurrence rates in very young breast cancer patients in relation to tumor biology in the shape of intrinsic subtypes. Methods: Women Results: A total of 1,000 patients were identified. The overall 5-year LR and RR rates were 3.5% and 3.7% respectively and a decreasing trend for both rates was observed over time. Overall 5-year local, regional and distant recurrence rates over time in breast cancer patients Intrinsic subtype proved to be a prognostic factor for both LR and RR (P=0.0556 and P=0.0141, respectively). Particularly HR-/HER2+ tumors were associated with high LR and RR rates. Patients with lymph node metastases at time of diagnosis had a higher RR-risk in both the total population (P=0.0349) as well as within the different intrinsic subtypes, although only significantly in the triple negative group (P=0.0401). Type of surgery did not influence the rate of LR and RR in this study. Conclusions: Overall, the LR and RR rates in very young breast cancer patients were relatively low and decreased over time. The higher recurrence rates in this population were associated with the presence of more aggressive intrinsic subtypes. We emphasize that tumor biology should guide decision-making towards optimal treatment in this specific population. Although longer follow-up is needed, especially for this very young patient population, the results of this study provide important insight in the locoregional recurrence risks for this historically high-risk population. Citation Format: Aalders KC, Postma EL, Strobbe LJ, van der Heiden-van der Loo M, Sonke GS, Boersma LJ, van Diest PJ, Siesling S, van Dalen T. Contemporary local and regional recurrence rates in very young breast cancer patients. [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 P5-08-01.

Introduction Neo-adjuvant chemotherapy (NAC) is increasingly used in breast cancer to enable less extensive surgery and monitor the response to systemic therapy. Little is known about local recurrence (LR) in patients who received NAC. However, this information is important when deciding on optimal local treatment in these patients, especially since NAC is increasingly being offered to patients with smaller tumors. The aim of this study is to assess the contemporary rates of local breast cancer recurrence in patients that received NAC. Methods All women treated with NAC for primary invasive breast cancer in the years 2003-2008 were selected from the Netherlands Cancer Registry. The first event within five years after NAC was included for analyses. The 5-year local (LR) recurrence rate was calculated using Kaplan Meier estimates and the prognostic value of various clinicopathological and treatment factors was evaluated. Results A total of 2,457 patients were identified of whom 43% had cT1-2, 25% cT3 and 29% cT4 tumors. Two-thirds of the patients had metastatic lymph node involvement and 85% received adjuvant radiotherapy. The overall 5-year risk of LR was 6.7% and decreased from 2003-2008. Table 1. Overall 5-year rate of local breast cancer recurrence in 2,457 breast cancer patients that received neo-adjuvant chemotherapy in the period 2003-2008. Local recurrencea NRate2003N=412309.6%2004N=429288.0%2005N=549398.1%2006N=604234.7%2007N=406164.7%2008N=489245.5%TotalN=2,4571606.7%aLocal recurrence defined as ipsilateral in-breast recurrence or new primary Rates represent Kaplan Meier estimates The LR-rate was lower in hormone receptor positive (HR+) than HR-negative (HR-) tumors (3.3% vs. 12.9%) and increased with larger residual tumor size (from 1.2% in ypT0 to 13.0% in ypT3 and 16.1% in ypT4 tumors). The LR-rate also increased with the ypN-stage (4.1% in ypN0, 5.7% in ypN1 and 11.3% in ypN>1 patients) and was lower following breast-conserving surgery (BCS) than after mastectomy (4.8% vs. 7.2%). Currently, we are working on the multivariate analyses, which will be available at the San Antonio Breast Cancer Symposium. Conclusions The rate of LR in patients treated with NAC has decreased over time. This will most likely be caused by enhanced imaging and radiotherapy techniques, as well as by increased insight in tumor biology resulting in improvements in both the development and application of systemic treatment modalities. Multivariate analyses will have to provide further insight into the risk of developing LR in patients treated with NAC, as well as into the prognostic value of different clinicopathological factors. Citation Format: Aalders KC, Sonke GS, van der Heiden-van der Loo M, Boersma LJ, van Diest PJ, Siesling S, van Dalen T. Contemporary risk of local breast cancer recurrence after neo-adjuvant chemotherapy: Results of a population-based cohort study. [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 P5-08-36.

PURPOSE: A decade ago intrinsic biological breast cancer subtypes have been identified which have proven to be of clinical importance in terms of outcome and response to systemic treatment. The aim of the current study is to assess concordance between breast cancer subtypes determined by local immunohistochemistry (IHC) assessment of estrogen receptor (ER), progesterone receptor (PR) and Her2-receptor status and microarray based molecular subtyping in a subset of ER+ early stage breast cancer patients. PATIENTS AND METHODS: In this prospective observational multicenter study information on local pathology assessment and BluePrint/TargetPrint results were obtained in ER+ Dutch early stage breast cancer patients in whom a 70-gene profile (MammaPrint) was used as they were enrolled in clinical trial based on the existence of controversy regarding the additional value of adjuvant CT. Local IHC assessment of ER, PR and Her2 status were compared with microarray based assessment (TargetPrint/BluePrint) of these characteristics. Reclassification of ER and PR overexpression was assessed by a McNemars test and by Spearman correlation. Furthermore, concordance between the clinical subtypes based on local pathology (Luminal-type: ER+/PR+/Her2-; Her2-type: Her2+ disease) and molecular subtyping was assessed. RESULTS: Between January 2013 And December 2015 660 patients, treated in 31 hospitals, were enrolled. In 564 (85%) BluePrint and/or TargetPrint was performed in addition to the 70-GS. The majority of patients had ER+/Her2- disease and TargetPrint reclassified 1% (n = 7) of patients as ER-negative (r = 0,250, p Table 1. Concordance between immunohistochemistry and TargetPrint. TargetPrint result (ER, PR and Her2 resp.) ImmunohistochemistryPositiveNegativeOverall discordance (%)p-value*Estrogenreceptor status Positive557 (99%)6 (1%) Negativen.a.n.a.1%n.a.Progesterone receptor status Positive474 (96%)18 (4%) Negative22 (31%)49 (69%)7%0,636Her2 receptor status Positive3 (30%)7 (70%) Negative4 (3%)546 (97%)2%0,549Equivocal0 (0%)3 (1%) * P-value represents results of the McNemar test.). Based on IHC 545 (98%) patients were regarded as luminal-type and the remaining 2% as Her2-type. BluePrint reclassified 2% of the clinical luminal-type patients: 4 (1%) patients were reclassified as basal-type and 3 (0%) patients as Her2-type. Of the clinical Her2-type patients 80% (n=8) was reclassified by BluePrint as molecular luminal-type. Table 2. Concordance between clinical subtyping and molecular subtyping according to BluePrint. BluePrint resultClinical SubtypeNo. ptsLuminalBasalHer2Luminal545539 (99%)4 (1%)3 (0%)Her2108 (80%)02 (20%)Note. Overall discordance 3%. Conclusion: In the current study we observe a high concordance between microarray-based assessment of ER, PR and Her2 and local pathology in Dutch ER+ early stage breast cancer patients. In the small subset of ER+ patients who are considered candidates for 70 GS use and who have HER2+ tumors by IHC molecular typing of HER2 status is of additional value. Citation Format: Kuijer A, Straver M, Elias S, Smorenburg C, Wesseling J, Linn S, Rutgers E, Siesling S, van Dalen T. Concordance of local immunohistochemistry with TargetPrint microarray based assessment of ER, PR and Her2 and BluePrint molecular subtyping in the Symphony Triple A study [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 P1-03-04.

Background: Randomised controlled trials have shown that breast conserving therapy (conserving surgery with radiation therapy, BCT) has equal overall survival (OS) rates as mastectomy without radiation therapy (MAST) in early stage breast cancer. However, 10-year disease-free survival (DFS) in a population-based study was not investigated before. The aim of this study was to compare 10-year OS and DFS after BCT with MAST in Dutch women with early stage breast cancer. Methods: Data of all women diagnosed with primary invasive T1-2N0-1M0 stage breast cancer between 1 January 2000 and 31 December 2004, treated with either BCT or MAST, were selected from the Netherlands Cancer Registry. Multivariable Cox proportional hazard analysis was performed to estimate 10-year OS, stratified for T and N stage. Ten-year DFS was determined in a subgroup of patients diagnosed in 2003, of which an active follow-up was conducted registering all recurrent events within 10 years. Multiple imputation was performed to account for missing data. Results: Of in total 37,207 patients, 21,734 patients (58.4%) received BCT and 15,473 patients (41.6%) received MAST. The subcohort of 2003 consisted of 7,552 patients, with similar distributions of treatments and characteristics. In the total cohort, 10-year OS was 76.8% (99% CI: 76.1-77.5%) after BCT and 59.7 (99% CI: 58.7-60.7%) after MAST. After correction for confounding, 10-year OS was better after BCT than after MAST (HRadjusted: 0.79 [99% CI 0.75-0.83]). In the 2003 cohort, 10-year DFS was 83.6% (99% CI: 82.5-84.7%) after BCT and 81.5% (99% CI: 79.6-83.4%) after MAST. After correction for confounding, 10-year DFS was comparable for both treatments (HRadjusted 0.91 [99% CI 0.77-1.07]). All results were similar for all subgroups (Table). In the 2003 cohort, 11.0% of the patients experienced distant metastases (DM) after BCT compared to 14.7% after MAST (p Table. Adjusted hazard ratios of breast-conserving surgery with radiation therapy vs. mastectomy on 10-year overall and disease-free survival in T1-2N0-1 staged breast cancer patients n10-year OS [99% CI]10-year DFS [99% CI]Overall cohort MAST15,47311BCT21,7340.79 [0.75-0.83]0.91 [0.79-1.07]Subgroups T1N0 MAST6,09211BCT18,8600.80 [0.74-0.87]0.81 [0.62-1.08]T1N1 MAST2,18511BCT3,7410.80 [0.69-0.92]1.02 [0.64-1.63]T2N0 MAST4,17411BCT3,1650.79 [0.70-0.88]0.99 [0.72-1.35]T2N1 MAST3,02211BCT2,0600.77 [0.67-0.88]0.82 [0.58-1.15]All hazard ratios are adjusted for all relevant confounders. Abbreviations: MAST = mastectomy; BCT = breast conserving surgery with post-operative radiation therapy; OS = overall survival; DFS = disease-free survival Conclusion: BCT showed substantially improved OS compared to MAST. However, while DFS was similar, patients treated with BCT less often developed RR and DM. Although residual factors might explain part of the difference in recurrences, we hypothesise that radiation therapy might largely be responsible for better OS by eliminating residual tumour cells. Citation Format: van Maaren MC, de Munck L, de Bock GH, Jobsen JJ, van Dalen T, Poortmans P, Linn SC, Strobbe LJA, Siesling S. Higher 10-year overall survival after breast conserving therapy compared to mastectomy in early stage breast cancer: A population-based study with 37,207 patients. [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 S3-05.

Background Obtaining tumor free resection margins is essential in patients undergoing breast conserving surgery. Several risk factors associated with positive margins are described in literature. We developed a prediction model to predict positive resection margins in patients undergoing breast conserving surgery of non-palpable lesions. Methods A total of 576 patients with non-palpable invasive breast cancer underwent breast conserving surgery at five different hospitals in the Netherlands. A prediction model for positive resection margins was built using multivariate regression analysis and internally validated by bootstrapping. Results Positive resection margins were present in 69/576 (12%) patients. Factors associated with positive margins included microcalcifications on mammography (OR 1.8, 1.0-3.2), tumor not visible on ultrasound (OR 2.6, 1.2-5.6), presence of DCIS (OR 2.3, 1.3-4.0), multifocality (OR 3.5, 1.0-12.1), caudal location in the breast (OR 1.9, 1.1-3.5), and invasive tumor size (OR 1.83, 1.6-2.7). Together, these factors were able to moderately discriminate between patients with positive versus negative margins (area under the ROC 0.71, 95% CI 0.648 – 0.780). After internal validation the discrimination was slightly lower with an AUC of 0.694. Prevalence of positive margins was 5.2% in the highest risk quintile versus 26.3% in the lowest quintile. Conclusion A model predicting positive resection margins after breast conserving surgery in non-palpable breast cancer was built. This model is moderately able to differentiate between women with high versus low risk of positive margins, and may be useful for surgical planning (eg. preoperative MRI) and informing of patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-15-03.

Background: The effectiveness of intraoperative ultrasound (IOUS) for preoperative localization of non-palpable breast cancers within the operation theatre has not been studied extensively. In this prospective cohort study, we compared margin status, re-excision rate and excised volume of IOUS to guidewire localization (GWL). Methods: A total of 258 consecutive patients with non-palpable invasive breast cancer underwent breast conserving surgery between 1999–2010. GWL was performed in 138 (54%) and IOUS in 120 (46%) patients. Tumour dimensions, resection volume, margin status and re-excision rates were compared by means of multivariate regression analysis. Calculated resection ratios, i.e. indicating the amount of excess tissue resection, were calculated by dividing the total resection volume by the optimal resection volume (the tumor diameter plus a 1.0 cm margin) and compared between the groups. Results: The groups were similar in terms of age, histological subtype and presence of DCIS. Lesions in the IOUS group were larger (1.24 vs. 0.98 cm), while lesions in the GWL group consisted more often of microcalcifications only (19% vs. 3%). Tumour free resection margins were obtained in more than 93% of patients (93.5% with GWL vs. 93.3% with IOUS, P = .958) and re-excision was performed in 11.0% of patients undergoing GWL and 12.5% of patients undergoing IOUS (P = .684). In both groups, resection volumes were similar, but IOUS led to more optimal tissue resection (calculated resection ratio 4.33 vs 3.30, P = .018). After adjustment for tumor diameter, radiological findings and presence of DCIS, the difference in calculated resection volumes was no longer significant. Conclusion: For localization of non-palpable breast cancer, IOUS is a reliable alternative to GWL, as it achieves similar results in terms of complete tumour removal, re-excision rate and excised volume. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-14-08.

Introduction: Female breast cancer patients carrying a BRCA1/2 mutation have an increased risk of second primary breast and ovarian tumors. Rapid genetic counseling and testing (RGCT) may aid in making informed decisions about therapeutic and preventive surgery and adjuvant treatment. Little is known about the effects of RGCT on treatment decisions and psychosocial well-being. We have performed a randomized controlled trial to investigate these issues. Methods: Newly diagnosed breast cancer patients from 12 Dutch hospitals with at least a 10% risk of carrying a BRCA1/2 mutation were randomized to an intervention group (RGCT) or a usual care control group (ratio 2:1). Study outcomes included uptake of RGCT, choice of type of surgery, cancer risk perception, cancer-specific distress, quality of life and decisional satisfaction. Assessments took place at study entry, and at 6 and 12 months follow-up. Results: Between 2008 and 2010, 271 patients were recruited, of whom 3 subsequently withdrew. The remaining 268 patients were randomized to the intervention (n = 181) or control (n = 87) group. Complete questionnaire data were available for 250 (93%) and 243 (91%) patients at 6 and 12 months follow-up, respectively. Of the 181 women in the intervention group, 180 (98%) underwent genetic counseling after a median of 4 days. One-hundred thirteen (63%) of them opted for accelerated DNA test procedures, of whom 72 underwent rapid testing (results available in Conclusion: The uptake of rapid genetic counseling among high-risk breast cancer patients was high, and the majority of patients underwent accelerated DNA-testing procedures. However, RGCT did not have a significant effect on choice of type of primary surgery. In part, this may be explained by the fact that surgeons and patients often did not wait for DNA test results before primary surgery. Conclusions regarding the psychosocial impact of RGCT will be presented at the time of the conference. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-11-01.

Background The value of magnetic resonance imaging (MRI) for patients with breast cancer remains under debate. Breast MRI may contribute to the planning of local therapy, but also bears the risk of overtreatment. We analyzed the use of MRI and its impact on surgical treatment and risk of detecting contralateral breast cancer in the Netherlands. Patients and methods All patients who underwent primary surgery for stage I-III invasive breast cancer in the years 2011-2013 were identified through the Netherlands Cancer Registry. The following data were documented: year of diagnosis, hospital type and volume, age at diagnosis, clinical T and N stage, histological type and grade, presence of multifocality in resection specimen, hormone receptor status, HER2 status and use of MRI. We analyzed whether MRI use was related to type of surgery (primary or secondary mastectomy or breast conserving surgery), surgical margin involvement, and diagnosis of synchronous contralateral breast cancer. Results MRI was performed in 10,819 (29,8%) out of 36,333 patients newly diagnosed with invasive breast cancer and treated with primary surgery in the years 2011-2013 in the Netherlands. Use of MRI did not clearly increase in this period. In the multivariate analysis, patients younger than 50 years of age compared to patients aged 70 years or older (OR 6.34, 95% CI 5.86-6.87), patients with lobular breast cancer compared to those with ductal carcinoma (OR 3.46; 95% CI 3.23-3.70) and patients with multifocal tumors compared to those without multifocality (OR 2.30, 95% CI 2.15-2.45) were more likely to undergo MRI. Hospital volume (150) was only marginally related to MRI use (OR 0.93; 95% CI 0.87-0.99). Patients with invasive breast cancer undergoing MRI were more likely to undergo primary mastectomy than those without MRI (OR 1.21; 95% CI 1.15-1.28), but the subgroup with invasive lobular cancer undergoing MRI were less likely to undergo primary mastectomy (OR 0.85; 95% CI 0.75-0.98). A significantly lower risk of positive surgical margins was seen in patients with lobular breast cancer and breast conserving surgery who had undergone MRI as compared to those without MRI (OR 0.58, 95% CI 0.44-0.78) and, consequently, also a lower risk of secondary mastectomy (OR 0.60, 95% CI 0.41-0.87). Risk of positive surgical margins was not reduced by MRI use in patients with invasive ductal carcinoma (OR 0.91; 95% CI 0.77-1.07). Patients who underwent MRI were almost four times more frequently diagnosed with contralateral breast cancer, compared to those in whom MRI was not performed (OR 3.60, 95% CI 3.06-4.24). Conclusion Breast MRI was significantly more often used in younger patients, patients with lobular and/or multifocal breast cancer. Interestingly, MRI use was associated with less primary and secundary mastectomies in lobular invasive breast cancer, in contrast to an increased number of primary mastectomies in patients with invasive ductal cancer. MRI was further associated with an almost fourfold higher incidence of contralateral breast cancer. Citation Format: Tjan-Heijnen VC, Lobbes MB, Vriens IJ, van Bommel AC, Nieuwenhuijzen GA, Smidt ML, Boersma LJ, van Dalen T, Smorenburg CH, Siesling S, Voogd AC. Only in lobular breast cancer MRI use is associated with a lower risk of positive surgical margins and a reduced number of mastectomies. A real-world analysis in The Netherlands. [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 P4-02-01.

Background: For some low-volume tumour types hospital surgical volume is associated with better survival. For breast cancer there is still much debate. The aim of this study is to determine to what extent the yearly surgical hospital volume determines the mortality in invasive non-metastatic breast cancer patients. Method: Women diagnosed with primary invasive breast cancer in the period 2001-2005 were selected from the Netherlands Cancer Registry. Hospitals were grouped by their annual volume of surgery for invasive breast cancer. Cox proportional hazard models were performed including all patients with primary non-metastatic breast cancer who underwent breast surgery. Gender, age at diagnosis, morphology, grade, size (pT), number of positive lymph nodes, year of diagnosis and socio economic status (SES) were included as covariates. Follow-up was complete until the 1th of February 2013. Results: In total 58.982 patients with invasive non-metastatic breast cancer were diagnosed during the period 2001-2005. Hospitals were grouped by volume of surgery: less than 75 (n = 19), 76-100 (n = 30), 101-150 (n = 29), 150-199 (n = 9) and 200 or more (n = 14) surgeries per year. Non-metastatic patients had a 8% higher risk of death in a low volume hospitals than a hospital with >200 surgeries per year (HR 1.08, 95%CI 1.02-1.14). Cox regression multivariable analyses: the relation of the number of surgical treated invasive breast cancer per hospital per year and the mortality of patients with non-metastatic breast cancer in the Netherlands, 2001-2005Variable HR95%CINumber of operated invasive breast cancers per yearmore than 200reference 150-1991.030.98-1.09 100-1491.010.97-1.05 75-991.040.99-1.08 less than 751.081.02-1.14Corrected for age, gender, morphology, grade, pT, number of positive lymph nodes, year of diagnosis, socioeconomic status Patient and tumour characteristics like age (HR 1.05, 95%CI 1.05-1.05) and SES (lowest vs highest; HR 1.12, 95%CI 1.07-1.16), grade (low vs high, HR 1.72, 95%CI 1.63-1.82), tumour size (1-2 cm vs 2-5 cm; HR 1.46, 95%CI 1.40-1.51), and a higher number of positive lymph nodes (0 vs 1-3; HR 1.40, 95%CI 1.34-1.46 and 0 vs >10; HR 3.19, 95%CI 3.00-3.39) influenced death to a larger extend than surgical volume. Conclusion: In the Netherlands, surgical hospital volume influences risk of death marginally, and far less than patient and tumour characteristics. No differences in mortality between hospitals with a surgical volume of more than 75 were revealed for invasive non-metastatic breast cancer patients compared to hospitals with more than 200 operations. Over the more recent period of 2007-2012, only 3 hospitals had less than 75 operations on average per year, resulting in an even more comparable mortality between hospitals in future. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-19.

Background: The diagnostic work-up and treatment of axillary lymph nodes in breast cancer patients is an ongoing topic of research. The ACOSOG-Z0011 study demonstrated no additional value of complementary axillary lymph node dissection (cALND) in case of limited axillary sentinel lymph node (SLN) metastases in breast cancer patients undergoing breast conserving therapy1. It is questionable whether these results can be applied to patients undergoing a mastectomy2. Trial design: A prospective non-inferiority randomized multicenter trial was designed. Breast cancer patients with cT1-2N0 disease treated with mastectomy and limited axillary SLN metastases will be randomized for follow-up versus complementary axillary treatment. To assess the Quality of Life and morbidity benefits of this experimental treatment, 3 validated questionnaires will be used: QLQ-C30, QLQ-BR 23 and Lymph-ICF3-5. Eligibility criteria: – Women with histological confirmed cT1-2 invasive unilateral breast carcinoma– Clinical node negative: no palpable nodes in physical examination and the axillary ultrasound without signs of lymph node metastases (cyto-/histology if indicated)– Sentinel lymph node biopsy must contain at least one and a maximum of 3 (micro)metastases– Neoadjuvant systemic therapy is allowed Specific aims: Primary endpoint is the axillary recurrence rate. The number of delayed axillary dissections will be registered. Secondary endpoints are distant-disease free survival, overall survival, local recurrence, morbidity and Quality of Life. Statistical methods: Based on 5-year axillary recurrence free survival rate, a failure rate of 0.98 among controls and a true failure rate of 0.96 for study subjects are considered acceptable. Overall, 1114 patients will be included to be able to reject the null hypothesis that the failure rate for experimental and control subjects is inferior by at least 5% (D = −5%) with probability of 0.8 and alpha of 5%. Present accrual and target accrual: This study is expected to start in late 2012 after approval by the Ethical Medical Committee. References 1. Giuliano, A.E., et al., Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA, 2011. 305(6): p. 569–75. 2. Morrow, M. and A.E. Giuliano, To cut is to cure: can we really apply Z11 in practice? Ann Surg Oncol, 2011. 18(9): p. 2413–5. 3. Aaronson, N.K., et al., The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst, 1993. 85(5): p. 365–76. 4. Sprangers, M.A., et al., The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study. J Clin Oncol, 1996. 14(10): p. 2756–68. 5. Devoogdt, N., et al., Lymphoedema Functioning, Disability and Health questionnaire (Lymph-ICF): reliability and validity. Phys Ther, 2011. 91(6): p. 944–57. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-1-03.

Background: The ACOSOG-Z0011 study demonstrated no additional value of complementary axillary lymph node dissection in case of limited axillary sentinel lymph node (SLN) metastases in breast cancer patients undergoing breast conserving therapy1. Since axillary ultrasound can exclude advanced axillary metastatic disease pre-operative2, there is ample opportunity to evaluate whether SLN biopsies are still indicated in a selected group of breast cancer patients. Trial design: A prospective non-inferiority randomized multicenter trial was designed. Breast cancer patients with cT1-2N0 disease, with no evidence for axillary metastases on ultrasound, treated with breast conserving therapy (lumpectomy + whole breast radiotherapy), will be randomized between follow-up and SLN biopsy. If adjuvant systemic therapy is not indicated by tumor or patient characteristics, gene expression profiling may be used for evaluation. To assess Quality of Life, 3 validated questionnaires will be used: QLQ-C30, QLQ-BR 23 and Lymph-ICF3-5. Eligibility criteria: – Women with histological confirmed cT1-2 invasive unilateral breast carcinoma– Clinical node negative: no palpable nodes at physical examination and an axillary ultrasound without signs of lymph node metastases (cyto-/histology if indicated)– Neoadjuvant systemic therapy is allowed. Specific aims: Primary endpoint is the axillary recurrence rate. The number of delayed axillary dissections will be registered. Secondary endpoints are distant-disease free survival, overall survival, local recurrence, morbidity and Quality of Life. Statistical methods: Based on a 5-year axillary recurrence free survival rate: failure rate of 0.99 for controls and a true failure rate of 0.96 (as considered acceptable) for study subjects. Overall, 2086 patients will be included to be able to reject the null hypothesis that the failure rate for experimental and control subjects is inferior by at least 5% (D = −5%) with probability of 0.8 and alpha of 5%. Present accrual and target accrual: This study is expected to start in late 2012 after approval by the Ethical Medical Committee. References 1. Giuliano, A.E., et al., Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA, 2011. 305(6): p. 569–75. 2. Neal, C.H., et al., Can preoperative axillary US help exclude N2 and N3 metastatic breast cancer? Radiology, 2010. 257(2): p. 335–41. 3. Aaronson, N.K., et al., The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst, 1993. 85(5): p. 365–76. 4. Sprangers, M.A., et al., The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study. J Clin Oncol, 1996. 14(10): p. 2756–68. 5. Devoogdt, N., et al., Lymphoedema Functioning, Disability and Health questionnaire (Lymph-ICF): reliability and validity. Phys Ther, 2011. 91(6): p. 944–57. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-1-02.

IntroductionSentinel Lymphnode Biopsy (SLNB) is generally excepted as a minimal invasive technique to stage the axilla in clinically node negative breast cancer patients. Though the reported clinically overt axillary recurrences after negative SLNB is low (0-2,8%), these false negative results after SLNB remain a concern in the treatment of pN0(slnb) breast cancer patients. In this respect many have investigated factors that may influence the risk of developing an axillary recurrence, either to explain the unexpected low incidence or to try to identify subgroups of patients with higher risk of developing an axillary recurrence. Downside to many of these studies is the single-centre study design, mostly presenting small numbers of patients with relatively short follow-up making it difficult to extrapolate the results to the every-day practice.We conducted this multicentre cohort study to identify prognostic factors for developing axillary recurrences after negative SLNB.Patients and MethodsProspectively collected data from seven large volume hospitals in the Netherlands were analyzed. Patients underwent surgery including SLNB between January 2000 and December 2002. Pathological work-up of the sentinel node, local and systemic treatment, and follow-up were performed according to Dutch National guidelines. Statistical analysis was performed to test homogeneity between the institutes. Multivariate analysis was performed to identify prognostic factors. A p-value of 0,2mm) and underwent Axillary Lymphnode Dissection (ALND). In the remaining 1028 patients, 986 (61,7%) were SLN negative and 42 (2,6%) patients were found to have isolated tumor cells (i.e. metastases Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1006.

Introduction: Since the introduction of sentinel lymph node biopsy (SLNB) for staging breast cancer, lymphogenic micrometastases are commonly detected. The prognostic meaning of these small lymph node metastases and the consequences regarding the indication for adjuvant systemic treatment is under debate. Currently, robust data with a long time follow up are lacking.Method: Between January 2000 and December 2002 1411 patients with a cT1-2N0 breast carcinoma underwent surgery in seven hospitals in the Netherlands. Pathological examination of the sentinel node consisted of serial sectioning of SLN's and H&E and IHC staining. Based on the presence of lymph node metastases patients where divided into four groups: pN0 (n = 922), pN1micro (n = 103), pN1a (n = 285) and pN≥1b (n = 101). Median follow up was 77 months.Results: At the end of follow-up 184 (13.0%) patients had died. Breast cancer recurred in 244 (17.3%) patients, 165 of them having distant metastases (11.7%) patients. The 5- years overall survival was 93% for patients with pN0 disease, 94% for pN1micro, 88% for pN1a and 78% for pN≥1b (p < 0.001). The 5-years disease free survival was 87%, 90%, 85% and 72% (p < 0.001) respectively.Following adjustment for possible confounding characteristics and for adjuvant systemic treatment, overall survival was similar for pN0 en pN1micro patients and significantly worse for pN1a and pN≥1b (HR 1.18; 95% CI 0.58-2.39, HR 2.47; 95% CI 1.69-3.63, HR 4.36; 95% CI 2.70-7.04 respectively). Disease free survival was similar too in the pN0 and pN1micro group, and worse for pN1a and pN≥1b (HR 0.96; 95% CI 0.56-1.67 vs. HR 1.64; 95% CI 1.19-2.27, HR 2.95; CI 1.98-4.42). Distant metastases were more commonly observed in the pN1micro group than in the pN0 group (HR 1.22; 95% CI 0.60-2.49), but not significantly and far less than in the pN1a and pN≥1b group (HR 2.26; 95% CI 1.49-3.40, HR 3.49; 95% CI 2.12-5.77).Conclusion: After a relative long time of follow up disease free and overall survival for patients with micrometastasis in SLNs is comparable to patients without lymphogenic metastasis and more favourable than patients with macrometastasis. The presence of micrometastatic disease in the SLN is in itself not an indication for adjuvant systemic therapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 307.