Endobronchial Ultrasonography to Assess and Evaluate Tracheobronchial Tree Invasion in cT4b Esophageal Cancer Patients Treated with Definitive Chemoradiotherapy: Assessment of Resectability.

BACKGROUND: In cT4b esophageal cancer, accurate assessment of tracheobronchial tree invasion after definitive chemoradiotherapy (dCRT) aids in the selection of patients for whom an oncologic radical esophagectomy can be achieved. The current report aimed to determine the accuracy of endobronchial ultrasound in assessing tumor invasion in the tracheobronchial tree after dCRT in patients with cT4b esophageal cancer. METHODS: Esophageal cancer patients with suspicion of tracheobronchial tree invasion on the diagnostic contrast-enhanced computed tomography (CT) who underwent a staging endobronchial ultrasonography (EBUS) were eligible for inclusion in this study. To assess the accuracy of the EBUS in assessing tumor ingrowth in the tracheobronchial tree after dCRT, patients who had an EBUS during restaging and underwent surgery were included in the final analysis. RESULTS: The final analysis included 26 patients. For 18 (90%) of 20 patients in whom the anatomy of the tracheobronchial tree was restored on the restaging EBUS and tumor invasion was considered to be absent, a radical esophagectomy was achieved. In six patients, persistent ingrowth was observed during the restaging EBUS. For these patients, the EBUS was repeated after a median of 9 weeks. Tumor invasion was considered to be absent in four patients, and a radical resection was achieved in three of these patients. CONCLUSION: The EBUS provides valuable information on the assessment of tracheobronchial tree invasion in cT4b esophageal cancer patients after dCRT. This information could aid in the proper selection of patients who benefit from a curative but highly invasive esophagectomy.

Effect of a prediction tool and communication skills training on communication of treatment outcomes: a multicenter stepped wedge clinical trial (the SOURCE trial).

Background: For cancer patients to effectively engage in decision making, they require comprehensive and understandable information regarding treatment options and their associated outcomes. We developed an online prediction tool and supporting communication skills training to assist healthcare providers (HCPs) in this complex task. This study aims to assess the impact of this combined intervention (prediction tool and training) on the communication practices of HCPs when discussing treatment options. Methods: We conducted a multicenter intervention trial using a pragmatic stepped wedge design (NCT04232735). Standardized Patient Assessments (simulated consultations) using cases of esophageal and gastric cancer patients, were performed before and after the combined intervention (March 2020 to July 2022). Audio recordings were analyzed using an observational coding scale, rating all utterances of treatment outcome information on the primary outcome-precision of provided outcome information-and on secondary outcomes-such as: personalization, tailoring and use of visualizations. Pre vs. post measurements were compared in order to assess the effect of the intervention. Findings: 31 HCPs of 11 different centers in the Netherlands participated. The tool and training significantly affected the precision of the overall communicated treatment outcome information (p = 0.001, median difference 6.93, IQR (-0.32 to 12.44)). In the curative setting, survival information was significantly more precise after the intervention (p = 0.029). In the palliative setting, information about side effects was more precise (p < 0.001). Interpretation: A prediction tool and communication skills training for HCPs improves the precision of treatment information on outcomes in simulated consultations. The next step is to examine the effect of such interventions on communication in clinical practice and on patient-reported outcomes. Funding: Financial support for this study was provided entirely by a grant from the Dutch Cancer Society (UVA 2014-7000).

Safety and Feasibility of Robot-Assisted Minimally Invasive Esophagectomy (RAMIE) with Three-Field Lymphadenectomy and Neoadjuvant Chemoradiotherapy in Patients with Resectable Esophageal Cancer and Cervical Lymph Node Metastasis.

BACKGROUND: In the West, patients with cervical lymph node metastasis of resectable esophageal cancer at diagnosis are generally precluded from curative treatment. This study prospectively explored the safety and feasibility of neoadjuvant chemoradiotherapy followed by robot-assisted minimally invasive esophagectomy (RAMIE) with three-field lymphadenectomy for these patients. METHODS: Between 2015 and 2021, patients with resectable thoracic esophageal cancer and cervical lymph node metastasis were recruited nationwide in the Netherlands. Patients without interval metastasis following neoadjuvant chemoradiotherapy and good physical condition underwent RAMIE with bilateral three-field lymphadenectomy. Safety was predefined as ≤50% Clavien-Dindo grade ≥3b postoperative complications. RESULTS: Neoadjuvant chemoradiotherapy was administered to 29 patients (19 (66%) adenocarcinoma and 10 (34%) squamous cell carcinoma). After restaging, nine (31%) patients were excluded (interval metastasis, clinical deterioration, or withdrawn consent). RAMIE was performed in 20 patients (R0-rate 95%). A median of 42 [range 21-71] lymph nodes were resected of which 13 [range 2-35] were cervical. Only 1 (5%) patient had an unexpected contralateral cervical lymph node metastasis. Complications grade ≥3b occurred in 50%. Most frequent complications of any grade were recurrent laryngeal nerve palsy (45%) and pneumonia (40%). Overall survival at 1 year was 85% and quality of life at 6 months was comparable to esophageal cancer patients treated with curative intent. CONCLUSIONS: RAMIE with three-field lymphadenectomy following neoadjuvant chemoradiotherapy for patients with resectable esophageal cancer presenting with cervical lymph node metastasis is feasible in a Western population. Because contralateral cervical metastasis is rare, a unilateral neck dissection would suffice in the majority of cases. CLINICAL TRIAL: gov Identifier: NCT02426879. Dutch trial register Identifier: NTR 4552.

Clinical implementation and feasibility of long-course fractionated MR-guided chemoradiotherapy for patients with esophageal cancer: An R-IDEAL stage 1b/2a evaluation of technical innovation.

Purpose: This R-Ideal stage 1b/2a study describes the workflow and feasibility of long-course fractionated online adaptive MR-guided chemoradiotherapy with reduced CTV-to-PTV margins on the 1.5T MR-Linac for patients with esophageal cancer. Methods: Patients with esophageal cancer scheduled to undergo chemoradiation were treated on a 1.5T MR-Linac. Daily MR-images were acquired for online contour adaptation and replanning. Contours were manually adapted to match the daily anatomy and an isotropic CTV-to-PTV margin of 6 mm was applied. Time was recorded for all individual steps in the workflow. Feasibility and patient tolerability were defined as on-table time of ≤60 min and completion of >95% of the fractions on the MR-Linac, respectively. Positioning verification and post-treatment MRIs were retrospectively analyzed and dosimetric parameters were compared to standard non-adaptive conventional treatment plans. Results: Nine patients with esophageal cancer were treated with chemoradiation; eight patients received 41.4 Gy in 23 fractions and one received 50.4 Gy in 28 fractions. Four patients received all planned fractions on the MR-Linac, whereas for two patients >5% of fractions were rescheduled to a conventional linac for reasons of discomfort. A total of 183 (86%) of 212 scheduled fractions were successfully delivered on the MR-Linac. Three fractions ended prematurely due to technical issues and 26 fractions were rescheduled on a conventional linac due to MR-Linac downtime (n = 10), logistical reasons (n = 3) or discomfort (n = 13).The median time per fraction was 53 min (IQR = 3 min). Daily adapted MR-Linac plans had similar target coverage, whereas dose to the organs-at-risk was significantly reduced compared to conventional treatment (26% and 12% reduction in mean lung and heart dose, respectively). Conclusion: Daily online adaptive fractionated chemoradiotherapy with reduced PTV margins is moderately feasible for esophageal cancer and results in better sparing of heart and lungs. Future studies should focus on further optimization and acceleration of the current workflow.

CTV-to-PTV margin assessment for esophageal cancer radiotherapy based on an accumulated dose analysis.

PURPOSE: This study aimed to assess the smallest clinical target volume (CTV) to planned target volume (PTV) margins for esophageal cancer radiotherapy using daily online registration to the bony anatomy that yield full dosimetric coverage over the course of treatment. METHODS: 29 esophageal cancer patients underwent six T2-weighted MRI scans at weekly intervals. An online bone-match image-guided radiotherapy treatment of five fractions was simulated for each patient. Multiple conformal treatment plans with increasing margins around the CTV were created for each patient. Then, the dose was warped to obtain an accumulated dose per simulated fraction. Full target coverage by 95% of the prescribed dose was assessed as a function of margin expansion in six directions. If target coverage in a single direction was accomplished, then the respective margin remained fixed for the subsequent dose plans. Margins in uncovered directions were increased in a new dose plan until full target coverage was achieved. RESULTS: The smallest set of CTV-to-PTV margins that yielded full dosimetric CTV coverage was 8 mm in posterior and right direction, 9 mm in anterior and cranial direction and 10 mm in left and caudal direction for 27 out of 29 patients. In two patients the curvature of the esophagus considerably changed between fractions, which required a 17 and 23 mm margin in right direction. CONCLUSION: Accumulated dose analysis revealed that CTV-to-PTV treatment margins of 8, 9 and 10 mm in posterior & right, anterior & cranial and left & caudal direction, respectively, are sufficient to account for interfraction tumor variations over the course of treatment when applying a daily online bone match. However, two patients with extreme esophageal interfraction motion were insufficiently covered with these margins and were identified as patients requiring replanning to achieve full target coverage.

Salvage Robot-Assisted Minimally Invasive Esophagectomy (RAMIE) for T4b Esophageal Cancer After Definitive Chemoradiotherapy.

BACKGROUND: Patients  with esophageal cancer  that invades adjacent structures (cT4b) are precluded from surgery and usually treated with definitive chemoradiotherapy (dCRT). dCRT might result in sufficient downstaging to enable a radical resection, possibly improving survival. This study aimed to assess the perioperative and oncologic outcomes of a salvage robot-assisted minimally invasive esophagectomy (RAMIE) in patients with cT4b esophageal cancer after dCRT. METHODS: Between June 2012 and November 2019, patients who underwent a RAMIE with a gastric conduit reconstruction after completion of dCRT for cT4b esophageal carcinoma were identified from a prospectively maintained surgical database at the University Medical Center Utrecht. RESULTS: In total, 24 patients with a histopathologically confirmed T4b adenocarcinoma or squamous cell carcinoma of the esophagus were included. The adjacent organs involved were the tracheobronchial tree (67%), aorta (21%) or both (13%). No conversions or major intraoperative complications were observed. A radical resection was achieved in 22 patients (92%), and a pathologic complete response was observed in 13 (54%) patients. Postoperative grade 2 or higher complications occurred in 20 patients (83%). The disease-free survival at 24 months was 68% for the patients in whom a radical resection was achieved. CONCLUSION: In patients with cT4b esophageal cancer treated with dCRT followed by a salvage RAMIE, a radical resection rate of 92% was achieved, with acceptable complications and promising survival rates. These results demonstrate the feasibility of a curative surgical treatment for patients with initially irresectable esophageal cancer but underscore the importance of a proper preoperative patient selection.

Online adaptive MR-guided radiotherapy for rectal cancer; feasibility of the workflow on a 1.5T MR-linac: clinical implementation and initial experience.

BACKGROUND AND PURPOSE: Daily online adaptation of the clinical target volume (CTV) using MR-guided radiotherapy enables margin reduction of the planning target volume (PTV). This study describes the implementation and initial experience of MR-guided radiotherapy on the 1.5T MR-linac and evaluates treatment time, patient compliance, and target coverage, including an initial assessment of margin reduction. MATERIALS AND METHODS: Patients were treated on a 1.5T MR-linac (7MV, FFF). At each fraction a 3D T2 weighted (T2w) MR-sequence was acquired on which the CTV was adapted after a deformable registration of the contours from the pre-planning CT scan. Based on the new contours a full online replanning was done after which a new 3D T2w MR-sequence was acquired for position verification. A 5 field Intensity Modulated Radiotherapy (IMRT) plan was delivered. RESULTS: Forty-three patients with rectal cancer were treated with 25 Gy in 5 fractions of which 18 with reduced margins. In total, 204 of 215 fractions were delivered on the MR-linac all of which obtained a clinically acceptable treatment plan. Median in-room time per fraction was 48 min (interquartile range 8). No fractions were canceled or interrupted because of patient intolerance. CTV coverage after margin reduction was good on all post-treatment scans but one due to passing gas. CONCLUSION: MR-guided radiotherapy using daily full online recontouring and replanning on a 1.5T MR-linac for rectal cancer is feasible and currently takes about 48 min per fraction.

Technical feasibility of magnetic resonance fingerprinting on a 1.5T MRI-linac.

Hybrid MRI-linac (MRL) systems enable daily multiparametric quantitative MRI to assess tumor response to radiotherapy. Magnetic resonance fingerprinting (MRF) may provide time efficient means of rapid multiparametric quantitative MRI. The accuracy of MRF, however, relies on adequate control over system imperfections, such as eddy currents and [Formula: see text], which are different and not as well established on MRL systems compared to diagnostic systems. In this study we investigate the technical feasibility of gradient spoiled 2D MRF on a 1.5T MRL. We show with phantom experiments that the MRL generates reliable MRF signals that are temporally stable during the day and have good agreement with spin-echo reference measurements. Subsequent in-vivo MRF scans in healthy volunteers and a patient with a colorectal liver metastasis showed good image quality, where the quantitative values of selected organs corresponded with the values reported in literature. Therefore we conclude that gradient spoiled 2D MRF is feasible on a 1.5T MRL with similar performance as on a diagnostic system. The precision and accuracy of the parametric maps are sufficient for further investigation of the clinical utility of MRF for online quantitatively MRI-guided radiotherapy.

3-Dimensional target coverage assessment for MRI guided esophageal cancer radiotherapy.

PURPOSE: This study aimed to quantify the coverage probability for esophageal cancer radiotherapy as a function of a preset margin for online MR-guided and (CB)CT-guided radiotherapy. METHODS: Thirty esophageal cancer patients underwent six T2-weighted MRI scans, 1 prior to treatment and 5 during neoadjuvant chemoradiotherapy at weekly intervals. Gross tumor volume (GTV) and clinical target volume (CTV) were delineated on each individual scan. Follow-up scans were rigidly aligned to the bony anatomy and to the clinical target volume itself, mimicking two online set-up correction strategies: a conventional CBCT-guided set-up and a MR-guided set-up, respectively. Geometric coverage probability of the propagated CTVs was assessed for both set-up strategies by expanding the reference CTV with an isotropic margin varying from 0 mm to 15 mm with an increment of 1 mm. RESULTS: A margin of 10 mm could resolve the interfractional changes for 118 out of the 132 (89%) analyzed fractions when applying a bone-match registration, whereas the CTV was adequately covered in 123 (93%) fractions when the registration was directly performed at the CTV itself (soft-tissue registration). Closer analyses revealed that target coverage violation predominantly occurred for distal tumors near the junction and into the cardia. CONCLUSION: Online MR-guided soft-tissue registration protocols exhibited modest improvements of the geometric target coverage probability as compared to online CBCT-guided bone match protocols. Therefore, highly conformal target irradiation using online MR-guidance can only be achieved by implementing on-table adaptive workflows where new treatment plans are daily generated based on the anatomy of the day.

Diagnostic performance of MRI for assessment of response to neoadjuvant chemoradiotherapy in oesophageal cancer.

BACKGROUND: Patients with a pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) for oesophageal cancer may benefit from non-surgical management. The aim of this study was to determine the diagnostic performance of visual response assessment of the primary tumour after nCRT on T2-weighted (T2W) and diffusion-weighted (DW) MRI. METHODS: Patients with locally advanced oesophageal cancer who underwent T2W- and DW-MRI (1·5 T) before and after nCRT in two hospitals, between July 2013 and September 2017, were included in this prospective study. Three radiologists evaluated T2W images retrospectively using a five-point score for the assessment of residual tumour in a blinded manner and immediately rescored after adding DW-MRI. Histopathology of the resection specimen was used as the reference standard; ypT0 represented a pCR. Sensitivity, specificity, area under the receiver operating characteristic (ROC) curve (AUC) and interobserver agreement were calculated. RESULTS: Twelve of 51 patients (24 per cent) had a pCR. The sensitivity and specificity of T2W-MRI for detection of residual tumour ranged from 90 to 100 and 8 to 25 per cent respectively. Respective values for T2W + DW-MRI were 90-97 and 42-50 per cent. AUCs for the three readers were 0·65, 0·66 and 0·68 on T2W-MRI, and 0·71, 0·70 and 0·70 on T2W + DW-MRI (P = 0·441, P = 0·611 and P = 0·828 for readers 1, 2 and 3 respectively). The κ value for interobserver agreement improved from 0·24-0·55 on T2W-MRI to 0·55-0·71 with DW-MRI. CONCLUSION: Preoperative assessment of residual tumour on MRI after nCRT for oesophageal cancer is feasible with high sensitivity, reflecting a low chance of missing residual tumour. However, the specificity was low; this results in overstaging of complete responders as having residual tumour and, consequently, overtreatment.

ypT0N+ status in oesophageal cancer patients: Location of residual metastatic lymph nodes with regard to the neoadjuvant radiation field.

INTRODUCTION: A subset of oesophageal cancer patients has residual nodal disease despite complete pathologic response of the primary tumour after neoadjuvant chemoradiation and resection. The aim of this study was to determine the exact location of metastatic nodes with regard to the neoadjuvant radiation field and to assess progression-free (PFS) and overall survival (OS) in this group of patients. MATERIALS AND METHODS: From January 2010 to January 2017, complete tumour responders (ypT0) after neoadjuvant chemoradiotherapy and oesophagectomy were identified from a prospective database and grouped according to residual nodal disease (ypT0N + or ypT0N0). Radiation fields were analysed for location of the metastatic nodes and PFS and OS were determined. RESULTS: In a total of 192 patients, 53 complete responders (ypT0) were identified. Of those, 11 patients (20.8%) were ypT0N+ with a total of 12 metastatic nodes: 8 (66.7%) located within the neoadjuvant radiation field and 4 (33.3%) located outside this field. Although not statistically significant, 1- and 2-year PFS were worse in ypT0N + patients (ypT0N+ 64.3% vs. ypT0N0 84.4%; ypT0N+ 48.2% vs. ypT0N0 80.7%, respectively; p = 0.051), just as 1- and 2-year OS rates, however, to a lesser extent (ypT0N+ 75.0% vs. ypT0N0 76.3%; ypT0N+ 75.0% vs. ypT0N0 72.9%, respectively; p = 0.956). CONCLUSION: Most ypT0N + lymph nodes are located within the neoadjuvant radiation field. Although a small heterogeneous population was included, this might be due to an inadequate response to neoadjuvant chemoradiotherapy leading to a trend towards worse PFS and OS in ypT0N + patients. Larger studies need to validate our findings.

Preoperative image-guided identification of response to neoadjuvant chemoradiotherapy in esophageal cancer (PRIDE): a multicenter observational study.

BACKGROUND: Nearly one third of patients undergoing neoadjuvant chemoradiotherapy (nCRT) for locally advanced esophageal cancer have a pathologic complete response (pCR) of the primary tumor upon histopathological evaluation of the resection specimen. The primary aim of this study is to develop a model that predicts the probability of pCR to nCRT in esophageal cancer, based on diffusion-weighted magnetic resonance imaging (DW-MRI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET-CT). Accurate response prediction could lead to a patient-tailored approach with omission of surgery in the future in case of predicted pCR or additional neoadjuvant treatment in case of non-pCR. METHODS: The PRIDE study is a prospective, single arm, observational multicenter study designed to develop a multimodal prediction model for histopathological response to nCRT for esophageal cancer. A total of 200 patients with locally advanced esophageal cancer - of which at least 130 patients with adenocarcinoma and at least 61 patients with squamous cell carcinoma - scheduled to receive nCRT followed by esophagectomy will be included. The primary modalities to be incorporated in the prediction model are quantitative parameters derived from MRI and 18F-FDG PET-CT scans, which will be acquired at fixed intervals before, during and after nCRT. Secondary modalities include blood samples for analysis of the presence of circulating tumor DNA (ctDNA) at 3 time-points (before, during and after nCRT), and an endoscopy with (random) bite-on-bite biopsies of the primary tumor site and other suspected lesions in the esophagus as well as an endoscopic ultrasonography (EUS) with fine needle aspiration of suspected lymph nodes after finishing nCRT. The main study endpoint is the performance of the model for pCR prediction. Secondary endpoints include progression-free and overall survival. DISCUSSION: If the multimodal PRIDE concept provides high predictive performance for pCR, the results of this study will play an important role in accurate identification of esophageal cancer patients with a pCR to nCRT. These patients might benefit from a patient-tailored approach with omission of surgery in the future. Vice versa, patients with non-pCR might benefit from additional neoadjuvant treatment, or ineffective therapy could be stopped. TRIAL REGISTRATION: The article reports on a health care intervention on human participants and was prospectively registered on March 22, 2018 under ClinicalTrials.gov Identifier: NCT03474341 .

Management of resectable esophageal and gastric (mixed adeno)neuroendocrine carcinoma: A nationwide cohort study.

INTRODUCTION: The aim of this study is to provide insight in accuracy of diagnosing, current treatment and survival in patients with resectable esophageal and gastric neuroendocrine- and mixed adenoneuroendocrine carcinomas (NEC, MANEC). METHODS: All patients with esophageal or gastric (MA)NEC, who underwent surgical resection between 2006 and 2016, were identified from the Dutch national registry for histo- and cytopathology (PALGA). Patients with a neuroendocrine tumor lower than grade 3 were excluded. Data on patients, treatment and outcomes were retrieved from the patient records. Diagnosis by endoscopic biopsy was compared with diagnosis by resection specimen. Kaplan Meier survival analysis was performed. RESULTS: A total of 49 patients were identified in 25 hospitals, including 21 patients with esophageal (MA)NEC and 26 patients with gastric (MA)NEC on resection specimen. Biopsy diagnosis of (MA)NEC was correct in 23/27 patients. However, 20/47 patients with definitive diagnosis of (MA)NEC, were misdiagnosed on biopsy. Neoadjuvant therapy was administered in 13 (62%) esophageal (MA)NECs and 12 (46%) gastric (MA)NECs. Survival curves were similar with and without neoadjuvant therapy. One (4.8%) esophageal (MA)NEC and 4 (15%) gastric (MA)NECs died within 90 days postoperatively. For esophageal (MA)NEC the median overall survival (OS) after surgery was 37 months and 1-, 3- and 5-year OS were 71%, 50% and 35%, respectively. For gastric (MA)NEC, the median OS was 23 months and 1-, 3- and 5-year OS were 62%, 50% and 39%, respectively. CONCLUSION: Localized esophageal and gastric (MA)NEC are often misdiagnosed on endoscopic biopsies. After resection, long-term survival was achieved in respectively 35% and 39% of patients.

Detection of distant interval metastases after neoadjuvant therapy for esophageal cancer with 18F-FDG PET(/CT): a systematic review and meta-analysis.

Restaging after neoadjuvant therapy aims to reduce the number of patients undergoing esophagectomy in case of distant (interval) metastases. The aim of this study is to systematically review and meta-analyze the diagnostic performance of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and 18F-FDG PET/CT for the detection of distant interval metastases after neoadjuvant therapy in patients with esophageal cancer. PubMed/MEDLINE, Embase, and the Cochrane library were systematically searched. The analysis included diagnostic studies reporting on the detection of distant interval metastases with 18F-FDG PET(/CT) in patients with esophageal cancer who received neoadjuvant therapy and both baseline staging and restaging after neoadjuvant therapy with 18F-FDG PET(/CT) imaging. The primary outcome measure was the proportion of patients in whom distant interval metastases were detected by 18F-FDG PET(/CT) as confirmed by pathology or clinical follow-up (i.e. true positives). The secondary outcome measure was the proportion of patients in whom 18F-FDG PET(/CT) restaging was false positive for distant interval metastases (i.e. false positives). Risk of bias and applicability concerns were assessed using the QUADAS-2 tool. Random-effect models were used to estimate pooled outcomes and examine potential sources of heterogeneity. Fourteen studies were included comprising a total of 1,110 patients who received baseline staging with 18F-FDG PET(/CT) imaging of whom 1,001 (90%) underwent restaging with 18F-FDG PET(/CT) imaging. Studies were generally of moderate quality. The pooled proportion of patients in whom true distant interval metastases were detected by 18F-FDG PET(/CT) restaging was 8% (95% confidence interval [CI]: 5-13%). The pooled proportion of patients in whom false positive distant findings were detected by 18F-FDG PET(/CT) restaging was 5% (95% CI: 3-9%). In conclusion,18F-FDG PET(/CT) restaging after neoadjuvant therapy for esophageal cancer detects true distant interval metastases in 8% of patients. Therefore, 18F-FDG PET(/CT) restaging can considerably impact on treatment decision-making. However, false positive distant findings occur in 5% of patients at restaging with 18F-FDG PET(/CT), underlining the need for pathological confirmation of suspected lesions.

Additional prognostic value of the 70-gene signature (MammaPrint(®)) among breast cancer patients with 4-9 positive lymph nodes.

BACKGROUND: The 70 gene-signature (MammaPrint(®)) is a prognostic profile of distant recurrence and survival of primary breast cancer (BC). BC patients with 4-9 positive nodes (LN 4-9) are considered clinically at high-risk. Herein we examined MammaPrint(®) added prognostic value in this group. PATIENTS AND METHODS: MammaPrint(®) profiles were generated from frozen tumours of patients operated from primary BC. Samples were classified as genomic Low Risk (GLR) or genomic High Risk (GHR). RESULTS: Among the 173 samples, 70 (40%) were classified as GLR and 103 (60%) as GHR. Tumours in the GHR group were significantly more often ductal carcinomas (93%), grade 3 (60%), oestrogen and progesterone-negative, Her2 positive (25%). In the GLR category, the 5-year overall survival was 97% vs. 76% for in the GHR group (p < 0.01); Distant Metastasis Free Survival (DMFS) at 5 years was 87% for GLR patients and 63% for GHR patients (p < 0.01). In the Luminal A subgroup, the genomic profile was the only independent risk factor for DM and BC specific death. CONCLUSION: In the Luminal A subgroup, MammaPrint(®) is an independent prognostic marker in BC patients with LN 4-9 and may be integrated in a selection strategy of patients candidate for more aggressive therapeutic approaches.

Additional value of the 70-gene signature and levels of ER and PR for the prediction of outcome in tamoxifen-treated ER-positive breast cancer.

BACKGROUND: Breast cancer patients with node positive disease can have an excellent outcome with tamoxifen only. It is unclear whether analysing both the 70-gene signature and hormone receptors provides superior prediction of outcome in tamoxifen-treated patients than either alone. METHODS: Three series were evaluated: 121 patients (81% node positive) received adjuvant tamoxifen, 151 patients did not receive tamoxifen (10% node positive) and 92 patients received tamoxifen for metastatic disease. The 70-gene signature was analysed using MammaPrint. Oestrogen receptor (ER) and progesterone receptor (PR) immunohistochemistry was evaluated following St. Gallen Consensus (Highly Endocrine Responsive: ER and PR ≥ 50%, Incompletely Endocrine Responsive: ER and/or PR low or either one absent). RESULTS: In patients treated with adjuvant tamoxifen, both the 70-gene signature (adjusted for Endocrine Response Categories HR 2.17, 95%CI 1.01-4.66) as well as the Endocrine Response Categories (adjusted for 70-gene signature HR 6.35, 95%CI 1.90-21.3) were associated with breast-cancer-specific-survival (BCSS). Also in patients treated with tamoxifen for metastatic disease, combined analysis of the 70-gene signature and ER/PR revealed additional value (multivariate Cox regression, p = 0.013). In patients who did not receive tamoxifen, only the 70-gene signature was associated with outcome. CONCLUSION: In the series analysed, the 70-gene signature was mainly a prognostic factor, while ER and PR levels were mainly associated with outcome after tamoxifen. Combination of these three factors may improve outcome prediction in tamoxifen-treated patients.

The 70-gene prognosis signature predicts early metastasis in breast cancer patients between 55 and 70 years of age.

BACKGROUND: The majority of breast cancer patients are postmenopausal women who are increasingly being offered adjuvant chemotherapy. Since the beneficial effect of chemotherapy in postmenopausal patients predominantly occurs in the first 5 years after diagnosis, a prognostic marker for early events can be of use for adjuvant treatment decision making. The aim of this study was to evaluate the prognostic value of the 70-gene prognosis signature for early events in postmenopausal patients. METHODS: Frozen tumor samples from 148 patients aged 55-70 years were selected (T1-2, N0) and classified by the 70-gene prognosis signature (MammaPrint) into good or poor prognosis. Eighteen percent received hormonal therapy. RESULTS: Breast cancer-specific survival (BCSS) at 5 years was 99% for the good-prognosis signature versus 80% for the poor-prognosis signature group (P = 0.036). The 70-gene prognosis signature was a significant and independent predictor of BCCS during the first 5 years of follow-up with an adjusted hazard ratio of 14.4 (95% confidence interval 1.7-122.2; P = 0.01) at 5 years. CONCLUSION: The 70-gene prognosis signature can accurately select postmenopausal patients at low risk of breast cancer-related death within 5 years of diagnosis and can be of clinical use in selecting postmenopausal women for adjuvant chemotherapy.

Daily clinical practice of fresh tumour tissue freezing and gene expression profiling; logistics pilot study preceding the MINDACT trial.

PURPOSE: The 70-gene prognosis-signature is a prognostic tool for early breast cancer analysis. In addition to scientific evidence, implementation of the signature in clinical trials and daily practice requires logistical feasibility. The aim of our study was to test logistics for gene expression profiling on fresh frozen tumour tissue in the preparation for the prospective, multinational Microarray In Node-negative Disease may Avoid ChemoTherapy (MINDACT) trial. METHODS: Sixty-four patients were included in six European hospitals. Fresh frozen tumour samples were shipped on dry ice to Agendia B.V., where RNA was isolated and subsequently hybridised on the 70-gene prognosis-signature (MammaPrint). RESULTS: Tumour samples were obtained in 60 of 64 patients. Among the 60 samples, 11 contained insufficient tumour cells (<50%) and three contained insufficient RNA quality. All 46 samples eligible for genomic profiling were successfully hybridised, and the results were reported on average within 4-5d. CONCLUSION: Gene expression profiling on fresh frozen tissue is feasible in daily clinical practice.