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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.

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.

Purpose Gene-expression profiles increasingly are used in addition to conventional prognostic factors to guide adjuvant chemotherapy (CT) decisions. The Dutch guideline suggests use of validated gene-expression profiles in patients with estrogen receptor (ER) –positive, early-stage breast cancer without overt lymph node metastases. We aimed to assess the impact of a 70-gene signature (70-GS) test on CT decisions in patients with ER-positive, early-stage breast cancer. Patients and Methods In a prospective, observational, multicenter study in patients younger than 70 years old who had undergone surgery for ER-positive, early-stage breast cancer, physicians were asked whether they intended to administer adjuvant CT before deployment of the 70-GS test and after the test result was available. Results Between October 1, 2013, and December 31, 2015, 660 patients, treated in 33 hospitals, were enrolled. Fifty-one percent of patients had pT1cN0, BRII, HER2-Neu-negative breast cancer. On the basis of conventional clinicopathological characteristics, physicians recommended CT in 270 (41%) of the 660 patients and recommended withholding CT in 107 (16%) of the 660 patients. For the remaining 43% of patients, the physicians were unsure and unable to give advice before 70-GS testing. In patients for whom CT was initially recommended or not recommended, 56% and 59%, respectively, were assigned to a low-risk profile by the 70-GS (κ, 0.02; 95% CI, -0.08 to 0.11). After disclosure of the 70-GS test result, the preliminary advice was changed in 51% of patients who received a recommendation before testing; the definitive CT recommendation of the physician was in line with the 70-GS result in 96% of patients. Conclusion In this prospective, multicenter study in a selection of patients with ER-positive, early-stage breast cancer, 70-GS use changed the physician-intended recommendation to administer CT in half of the patients.

Background Tracheomalacia is a condition that may result in acute life-threatening events. Aortopexy has become a generally accepted mode of treatment, although the impact of a thoracotomy is considerable. With the advent of minimal invasive surgery the impact of such a procedure may be greatly reduced. This study evaluates the outcome of thoracoscopic aortopexy for tracheomalacia. Methods Retrospective analysis of a database containing all patients with thoracoscopic aortopexy. Based on symptomatology, on indication 24 h pH study and/or rigid tracheo-bronchoscopy were carried out to confirm the diagnosis. A three-trocar technique was used on the left side together with intra-operative flexible tracheoscopy through the tube. Follow-up continued for the duration of the study. Results Between January 2002 and December 2012, 16 patients presented with severe tracheomalacia. Fourteen of them had a history of esophageal atresia. Age at time of aortopexy varied from 2 weeks to 12 months. All procedures were performed thoracoscopically without intra-operative complications. In five children, there was a recurrence of symptoms within 2-4 weeks for which a re-thoracoscopic aortopexy was carried out successfully. With a follow-up of 6 months to 10 years all patients are thriving and are without incidents. Conclusion This is the largest single-center series of thoracoscopic aortopexy for tracheomalacia so far. All procedures were completed successfully without complications. Although recurrences occur, as in open surgery, the ultimate results are satisfactory. In an era of minimal invasive surgery the thoracoscopic approach is feasible and safe, even in redo-procedures.

Background The increasing use of primary systemic treatment (PST) for patients with breast cancer enables more breast conserving surgery. In addition, PST converts node-positive into node-negative disease in 20-40% of patients. However, the current guidelines still recommend axillary lymph node dissection (ALND) for clinical node-positive disease (cN+), even if it became node-negative after PST, since false-negative rates of sentinel lymph node biopsy after PST range from 5-30%. Recently, an alternative technique has been introduced to stage the axilla after PST: the MARI-procedure (sensitivity 97%; FNR 7%), in which a tumour-positive lymph node is marked with a radioactive iodine seed before the start of PST and selectively removed after PST. In the present study, we propose a new strategy for treatment of the axilla in cN+ patients by combining results of the pre-PST PET/CT with the post-PST MARI-procedure. Material and methods All patients who received a MARI-procedure from July 2014 until May 2016 were included. Before the start of PST a PET/CT was performed for axillary staging and the detection of distant metastasis. A radioactive iodine seed was placed in a proven tumour-positive axillary lymph node (MARI-node), after which PST was given according to Dutch national guidelines. At our institute, we have implemented a protocol in which results of the pre-PST PET/CT and the post-PST MARI-procedure determine the type of axillary treatment. Patients with 1-3 positive axillary lymph nodes (ALNs) on PET/CT and a tumour-negative MARI-node receive no further axillary treatment. Patients with ≤3 positive ALNs on PET/CT and a tumour-positive MARI-node receive axillary radiotherapy, as well as patients with >3 positive ALNs on PET/CT and a tumour-negative MARI-node. An ALND is only performed in patients with >3 positive ALNs on PET/CT and a tumour-positive MARI-node. Results In total 168 patients received a PET/CT and a MARI procedure, of whom 43% were hormone receptor positive, 28% triple negative and 29% Her2-positive. One hundred and eight patients (64%) showed ≤ 3 and 60 patients (36%) >3 suspected ALNs on PET/CT before the start of PST. The axillary pathologic complete response was 39%. In 134 patients (80%) an ALND was omitted; of these patients 94 (56%) were treated with axillary radiotherapy and 40 patients (24%) received no further axillary treatment. In 34 patients (20%) an ALND was performed (Table 1). The median number of positive additional nodes at ALND was 5 (range 0-16). During a median follow-up of 6 months there were no local recurrences. Axillary treatmentSuspective ALNs on PET/CTOutcome MARIAxillary Treatment NoneRadiotherapyALND + Radiotherapy≤3Negative40-- Positive-68->3Negative-26- Positive--34Total409434ALN: axillary lymph nodes; ALND: axillary lymph node dissection; MARI: Marking the Axilla with Radioactive Iodine Seeds Conclusion Combining pre-PST axillary staging with PET/CT and post-PST staging with use of the MARI-procedure results in a reduction of 80% of axillary lymph node dissections in breast cancer patients with clinical node-positive disease. Citation Format: van der Noordaa MEM, Straver M, van Duijnhoven FH, Groen E, Stokkel M, Vrancken Peeters M-JTFD. Selective elimination of axillary surgery after primary systemic treatment in clinically node-positive breast cancer patients by combining PET/CT and the MARI procedure (marking the axilla with radioactive iodine seeds) [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 P2-01-07.

Background: An important benefit of neoadjuvant chemotherapy (NAC) is the increase in breast-conserving surgery. At present the response of axillary lymph node metastases to chemotherapy is not assessed accurately, since SN biopsy either before or after NAC will not provide an accurate answer. Therefore a reliable axilla-conserving therapy is not yet a benefit. We developed a new surgical technique to evaluate the axillary nodal response by Marking of the Axillary lymph node with Radioactive Iodine seeds (= the MARI procedure) Method: Prior to NAC, tumor positive axillary lymph nodes were marked with a Iodine-125 seed under ultrasound guidance (the MARI node). After NAC, the marked lymph node was selectively removed with the use of a gamma-detection probe. A complementary axillary lymph node dissection was performed to assess whether the pathological response in the marked node was indicative for the pathological response in the additional lymph nodes. Results: In 44 patients who were scheduled for NAC the MARI procedure was attempted. In 42 patients the tumor-positive axillary lymph node was successfully marked with a radioactive Iodine-125 seed. Two patients appeared to have overt distant metastasis and did not undergo complete axillary dissection. Thus, in 40 patients the MARI node was selectively removed after NAC. In all these patients a complementary axillary lymph node dissection was performed. In 24 patients the MARI node contained a macrometastasis after NAC. In 4 patients only isolated tumor cells (ITC) were present in the MARI node. In 24 of these 28 patients further nodal involvement was found. More importantly: in 12 patients (=30%) no residual tumor was present in the MARI node (pathological complete response= pCR) and 10 of them also showed a pCR in the complementary axillary lymph node dissection. In one patient a macrometastasis, and in one, ITC were found in one of the additional nodes. Conclusion: In this study we present the first results of a new surgical technique to assess the response of metastatic lymph nodes in the context of NAC for breast cancer; the MARI procedure. We conclude that marking tumor-positive lymph nodes before NAC and selectively removing them after NAC is feasible. Moreover we report that this MARI node is indicative for the response to NAC in the other axillary nodes: in 30% of the treated patients an axillary pCR was found which was correctly indicated by a negative MARI node in all but one patient. Thus the MARI procedure will enable us to select patients in which axillary lymph node dissection can be avoided after NAC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-06.