Background: Axillary lymph node staging techniques (e.g., sentinel lymph node biopsy, MARI = Marking Axillary lymph nodes with Radioactive Iodine seeds, and TAD = targeted axillary dissection) after primary systemic therapy (PST) are associated with low false negative rates. This observation has stimulated the use of tailored axillary treatment, including the omission of axillary lymph node dissection (ALND). However, robust data on the oncologic outcomes following tailored axillary treatment after PST are lacking, especially in patients with extensive nodal disease. In this study, we present the axillary recurrence rate, disease free survival and overall survival of node positive breast cancer patients with >3 suspicious axillary lymph nodes treated according to the MARI-protocol.

Background Subgroup analyses of randomized, controlled trials (RCTs) using high dose chemotherapy (HD) with autologous stem cell support (autoSCT) reveal a potential benefit of HD in patients with triple negative breast cancer (TNBC) and in tumors harboring features of HRD (Vollebergh et al, 2011). The phase III part of the neo-TN RCT, compared neo-adjuvant HD with conventional treatment (CONV) in BRCA1-like TNBC. Methods Patients with cT2-3N0-3M0 TNBC with HRD were randomized between HD or CONV after 3 courses of 2-weekly doxorubicin/cyclophosphamide (ddA60C600). CONV treatment consisted of another 3xddAC, or in case of an unfavorable response on MRI a switch to 3 cycles capecitabine800BID14-7/docetaxel75; after an amendment all patients switched to 3xcarboplatinAUC6/paclitaxel80weekly. The HD regimen consisted of a 4th course ddAC and 2 courses of cyclophosphamide3000d1/carboplatin400d1,2/ thiotepa250d2 both followed by autoSCT. Primary outcome was the Neo-adjuvant Response Index (NRI), secondary outcomes included overall (OS) and recurrence free survival (RFS). Results From 2010 to 2016, 122 patients were randomized (intention-to-treat). Median follow-up is 45 months. There was no significant difference in NRI between HD and CONV (mean NRI 0.78 versus 0.72, range 0-1, p = 0.41 Wilcoxon test). An NRI of > 0.7 was strongly associated with good prognosis (RFS of 97% [95%CI 93%-100%] versus 67% [95%CI 55%-82%] at 4 years). See Table for 4-years OS and RFS comparing HD with CONV. There were no treatment related deaths. However, 7 out of 55 patients who actually received HD did not complete HD mainly because of infections or allergic reactions. Table . 187P HD % (95%CI) CONV % (95%CI) HR (95%CI) p-value All (n = 122) 4-yrs OS 4-yrs RFS 92 (85-99) 92 (85-99) 79 (69-91) 78 (68-89) 0.43 (0.15-1.23) 0.41 (0.15-1.07) 0.12 0.07 Stage III only (n = 35) 4-yrs OS 93 (81-100) 60 (39-93) 0.14 (0.02-1.14) 0.07 Conclusions No significant efficacy differences were found between HD and CONV. The NRI is of prognostic value. Whether the HD regimen is promising, especially in very high risk BRCA1-like TNBC [HR = 0.14], requires additional data including a comparison with platinum treatment in all control arm patients. Clinical trial identification NCT01057069. Legal entity responsible for the study The authors. Funding The Dutch Cancer Foundation (KWF) and by the Schumacher Kramer Foundation. Disclosure S.C. Linn: Research grant / Funding (self), research support for patients fees in D-Care study: Amgen; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Cergentis; Research grant / Funding (self): Genentech; Advisory / Consultancy: IBM; Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (institution), patients fees in TEAM 2b study: Pfizer; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Roche; Research grant / Funding (institution): Tesaro; Speaker Bureau / Expert testimony, Fee for teaching, paid to institution: Bayer. All other authors have declared no conflicts of interest.

Background: With the advent of targeted neoadjuvant therapies such as trastuzumab and pertuzumab as well as the indivualized chemotherapy regimens, increasing rates of pathologic complete response (pCR) are achieved. In triple negative and Her2-positive subtypes, pCR rates as high as 40–75% are described. In case of a pCR, no residual invasive tumour cells are present. In these patients, surgical resection of (part of) the original tumour area is not likely to contribute to locoregional control, and is performed solely to confirm the absence or presence of residual tumour. Previous studies already investigated whether surgery can be omitted in patients with a clinical complete response, which was defined by the absence of palpable tumour and/or absence of residual tumour on mammography and/or ultrasound. Results however showed a higher rate of local recurrences. The current higher pCR rates and modern imaging modalities such as MRI lead to a renewed and justified interest to downsize locoregional treatment following PST. Therefore, we propose the MICRA trial: Minimally Invasive Complete Response Assessment of the breast after primary systemic treatment using multiple biopsies, to select a group of patients in whom surgery of the breast can be omitted.

It is well established that flame front speed is an important factor influencing sinter productivity, sinter quality and fuel rate. In this work, the effect of suction, coke addition and mix moisture on flame front speed was studied in a pilot-scale sinter pot and also using a recently developed theoretical model. Airflow through the bed has a large influence on flame front speed. It was found that increasing sintering airflow rate will lead to increased flame front speed, but the increases become smaller at higher airflow rates. Sinter pot test results showed that increasing coke addition decreased green bed permeability and increased flame front temperature, which resulted in increased flame front resistance and decreased flame front speed. Studies also showed that green bed properties are sensitive to sinter mix moisture level. The changes in green bed properties further influence the flame front properties.

The high-temperature behaviour of reducing ferrous materials is quantified using a laboratory softening and melting test. Using a combination of standard, non-standard and quenched tests supported by optical image analysis this work has highlighted some important differences in behaviour between lump, pellets and sinter as well as between the lump ores and the pellets. One lump ore is denser than the other and there is also a denser pellet. In both cases, the denser ore/pellet is also higher in silica content. Densification of the ferrous bed leads to reduced bed permeability. Studies indicate that densification can happen through two mechanisms. Results show that material density and silica content are two key factors causing increased bed densification. Material density influences reduction efficiency and wustite levels while silica influences the level of fayalite formed. Fayalite is formed by reactions between wustite and silica. Results also show that the behaviour of fluxed sinter is superior to ore and acid pellets because lime preferentially reacts with silica to form dicalcium silicate, a high melting temperature compound. Studies using mixtures of fluxed sinter and lump ore indicate that blast furnace burdens can easily accommodate 20% ore.

The performance of a sinter machine and the quality of the ensuing product are strongly dependent on the processes occurring in the descending flame front. As it is not possible to measure flame front properties in a sintering bed directly, embedded thermocouples are used to provide information in this area. Through making some assumptions, it is possible to assess flame front properties using the obtained thermocouple profiles. Flame front speed, thickness and maximum temperature are identified as important parameters. The total heat transferred to the material from the flame front is a function of these parameters. Experimental results show that increasing flame front speed decreases residence time, maximum temperatures and total heat transferred to the bed. Only indicative trends can be obtained because of the variability in thermocouple results, which are inherent in the experimental technique. Coke combustion efficiency also depends on flame front speed.

Iron ore sintering is the most popular process used to produce a suitable feed for the blast furnace. With changing iron ore supplies and composition, steel mills have to continually adjust the blended ore mix composition to the sinter plant. To help decision making in this area, and also obtain increased understanding of the process to allow improvements in sintering operations, laboratory-scale sinter pot tests are conducted. The use of a pot for routine testing and for research is discussed. When used as a research tool, the experimental approach used to simulate a plant will have to be modified to facilitate the interpretation of results. Airflow rate through a bed is a critical parameter and this paper highlights the important relationship between post- and pre-ignition airflow rates and also the effect of changing bed suction and coke level in the sinter mix.

The generation of sufficient melt of appropriate properties is essential for the transformation of a blended sinter mix bed into a bed composed of large discrete sinter particles. For a chosen sinter mix, melt properties are determined by the quantity of heat transferred from the moving flame front and the chemical properties of the bed. Temperature-time profiles from embedded thermocouples are used to assess the transferred heat. From considerations of melt initiation and solidification temperatures, a critical sintering reaction area in the profiles is defined. The area is about three times the flame front area as it includes high temperature regions outside the front. It represents the total amount of heat available to the material in the partially molten state. Reasonable correlations are obtained between this area and the tumble strength of the sinter product. Temperature-time profiles are quite variable and strong correlations cannot be expected.

Abstract Background and aim of the study: A.The ongoing Preoperative Accelerated Partial Breast Irradiation (PAPBI) trial (NCT01024582) is based on the rationale that three-dimensional conformal external-beam radiation (3D-CRT) leads to more dose homogeneity compared with brachy-or intraoperative radiotherapy (RT). By irradiating preoperatively this can lead to more accurate tumor delineation and smaller irradiated volumes. As the tumor remains in situ during irradiation, more precise delivery of the radiation dose is guaranteed with CT cone beam linear accelerators, avoiding the uncertainties of the original tumor position in the operation cavity as is the case in postoperative RT. Tumor excision 6 weeks after RT removes the high dose volume tissue and can lead to better cosmesis. B. By assessing tumor response to radiotherapy, an additional goal of the study is to develop a gene expression profile that predicts breast cancer radiosensitivity. This gene signature of breast radiosensitivity would further design optimal treatment strategies for individual breast cancer patients treated with BCT. Inclusion citeria: Patients 60 years or older with a cT< = 3cm, ductal carcinoma (no in situ component), unifocal on mammogram and MRI, pN0(sn) (sentinel node procedure before RT), will be treated by preoperative RT (CTV = GTV + 2 cm, 10 × 4 Gy IMRT/VMAT over two weeks). Six weeks after pre-operative RT, a wide local excision will be performed. Skin toxicity and fibrosis is scored using EORTC/RTOG criteria. Patients are followed during RT and on a 3-monthly basis. Cosmesis is scored and photographs are taken for analysis (BCCT.core project score). To study radiosensit ivity, gene expression profiling from RNA and DNA isolated from biopsies (mRNA gene expression profiles, the miRNA expression profiles and the DNA copy number changes) taken of the tumor before radiotherapy and at time of surgery will be correlated with response to radiotherapy, defined as pathologic response at the time of the lumpectomy. Response of the tumor will be evaluated by MRI scan and PET (before radiotherapy and before surgery) and classical pathology. Endpoint : The main objective is to investigate the impact of a short fractionated schedule given preoperatively on cosmesis and breast fibrosis. Therefore, it is anticipated that the percentage of moderate or severe fibrosis will decrease from 27% as found in the boost arm of the EORTC boost-no boost trial to 15% (Collette et al EJC 2008). The total sample size of 120 patients will provide in excess of 80% power to detect the difference between the null hypotheses (a rate of fibrosis of 27%) and the alternative hypothesis (a rate of fibrosis of 15%) with an exact binomial test at 0.05 2-sided significance level. In addition, the 2-sided 95% confidence interval for the proportion of patients without local recurrence will extend 0.035 from the observed proportion for an expected proportion of 96%. An additional objective is to build a classifier (genomic or proteomic or any kind of molecular signature) to identify responders and non-responders. A total of 120 patients will be included in the study. The main analysis will include 60 patients in the training set and 60 in the validation set. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-1-03.

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.

610 Background: Magnetic Resonance Imaging (MRI) of the breast shows superior ability to visualize the extent of invasive breast cancer compared to conventional breast imaging. Nonetheless, MRI may under- or overestimate the extent of invasive disease, and the ability of MRI to depict components of disease around the primary invasive tumor is not well established. The purpose of this study was to precisely correlate MRI findings with histopathologic findings in breast cancer patients and to establish the incidence and quantity of surrounding MRI occult disease in breast cancer patients that are scheduled for breast-conserving therapy (BCT). METHODS Patients were prospectively included if they had biopsy-proven invasive breast cancer and the choice of treatment was BCT after pre-operative MRI. Pathology findings were spatially reconstructed and correlated with preoperative MRI. Tumors were stratified by absence or presence of an extensive intraductal component (EIC- or EIC+). The largest diameter of the MRI-visible lesion was compared with the largest diameter of the primary invasive tumor at pathology. Distances (mm) between the edge of the MRI-visible lesion and surrounding subclinical tumor foci (i.e., DCIS, invasive foci) were measured. At various distances from the edge of the MRI-visible tumor, the incidence of disease was determined. RESULTS 53 patients with 54 breast tumors were included. 42 tumors were EIC- and 12 were EIC+. The mean size (± SD) of the primary invasive tumor was 18.1 ± 7.5 mm on MRI and 19.5 ± 8.2 mm on pathology (Pearson's correlation coefficient: 0.75). The MRI-visible lesion was larger than or equal to the primary invasive tumor on pathology in 21 (39%) cases. Underestimation of the primary invasive tumor occurred up to 7 mm from the edge of the MRI-visible lesion. Beyond 10 mm, subclinical tumor foci were found in 48% off all tumors, in 36% and 92% of EIC- and EIC+ tumors (p < 0.001). Beyond 20 mm these rates were 19%, 7% and 67%, respectively (p < 0.001). CONCLUSIONS Disease around MRI-visible lesions may be more extensive than assumed prior to treatment, especially in EIC+ tumors. This may have consequences for treatment margins in MRI-guided therapy of localized breast cancer. No significant financial relationships to disclose.

2531 Background: Preoperative chemotherapy is increasingly employed to treat primary breast cancer, allowing an ‘in vivo chemosensitivity test’. Markers which predict a pathological complete response are urgently needed to refine this strategy. This study was conducted to evaluate the use of gene expression profiling to predict response to neoadjuvant anthracycline- or taxane-based chemotherapy. Methods: Patients with operable or locally advanced HER2-negative breast cancer received preoperative chemotherapy: either dose- dense doxorubicin and cyclophosphamide (ddAC) or capecitabine and docetaxel (CD). Core needle biopsies were taken before treatment and gene expression profiling was performed using 35k oligo microarrays. Results: Gene expression profiles were obtained from pretreatment biopsies of 63 tumors. 27% of the patients achieved a (near) pathologic complete remission (pCR), 40% of the patients had a partial remission and 33% of the patients did not respond to chemotherapy. Based on the gene expression profiles, tumors were assigned to the previously identified “molecular subtypes” luminal, basal-like or ERBB2-like (Sorlie et al., PNAS 98: 10869, 2001). 13 out of 25 patients with a basal-like tumor (52%) achieved a complete remission, whereas for the luminal tumors a pCR was only obtained in 2 out of 29 patients. Using four published gene expression classifiers of response to chemotherapy, a reasonable separation between responders and non-responders could be observed for two of these. We also performed exploratory supervised classification analyses on our dataset to identify a novel classifier. This resulted in a classifier for response to therapy irrespective of the chemotherapy regimen used and a second classifier specifically associated with response to ddAC chemotherapy. We will perform validation of these classifiers in samples from patients that are currently being enrolled in the study. Conclusions: Basal-like tumors have a better response to neoadjuvant chemotherapy as compared to other tumor types. The identification of robust gene expression signatures for better response prediction may require larger patient groups and should probably be established separately for each of the molecular subtypes of breast cancer. No significant financial relationships to disclose.

In iron ore sintering, granule deformation and compaction can be responsible for significant losses in bed voidage and green bed permeability. In this study, uniaxial compression tests have been used to examine the bed strength of granulated single and binary iron ore sinter mixes. The results show that at low moistures, bed strength is dependent on the granule layer mass to nuclei mass ratio. For binary iron ore sinter mixes, bed strength was found to increase as levels of Channel Iron ore were increased. Permeability-moisture curves for a series of single ore sinter mixes were recorded to examine the key parameters that affect this relationship. The results confirmed that the porosity of the ore pore size distribution and contact angle all affect the shape or width of the curves and the moisture at maximum permeability. The height of the curves is determined by bed voidage and the granule size distribution. This study has demonstrated that provided sufficient water is available during granulation, both Channel Iron and Marra Mamba ores granulate well, forming packed beds with permeability and strength comparable with or higher than those formed from less porous Brockman and Itabirite ores.

20005 Background: Neoadjuvant chemotherapy is increasingly employed in operable breast cancer. Our initial studies on a cDNA array platform failed to identify gene expression patterns predicting response to neoadjuvant chemotherapy in breast cancer patients (J Clin Oncol 23:3331, 2005). Now we included more patients and used oligo microarrays. Methods: Patients with operable or locally advanced breast cancer were included in a randomized phase II study or received neoadjuvant chemotherapy off protocol. All except 7 patients began chemotherapy with 3 courses of dose-dense adriamycin and cyclophosphamide (ddAC) and response was evaluated by MRI. Patients with a response and a HER2-positive tumor were then randomized between either 3 additional courses of ddAC or six weekly courses of carboplatin, paclitaxel and trastuzumab (CPT). Patients without response were switched to CPT. Patients with HER2-negative tumors were randomized between 3 courses of either ddAC or capecitabine and docetaxel (CD). After evaluation, patients without response were switched to the alternative treatment arm. From all patients 14G core needle biopsies were taken before treatment and total RNA was isolated. Amplified mRNA was labeled and hybridized to 35k human oligo microarrays from our microarray facility. Results: So far, 77 patients have been included into the study. From 48 of these, good quality RNA from tissue with >50% tumor cells was isolated. 43 patients had received ddAC as initial chemotherapy; 32 of these had not been switched to another regimen. In a training set containing 11 pathological complete remissions (pCR) and 9 non-responders (NR) we could separate these groups by using 20 genes in a supervised classification and a 9-step cross validation. These results could be validated in an independent set of 11 samples (6 pCR, 5 NR). From 10 out of 11 samples, response status could be predicted correctly, independent from the treatment regimen. Although ER-positive tumors have a lower pCR rate than ER-negative ones, the steroid hormone receptors were not present in the classifier. Conclusions: We conclude that it should be possible to identify a reliable gene expression profile associated with response to adriamycin based neoadjuvant chemotherapy in breast cancer. No significant financial relationships to disclose.