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PURPOSE Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. PATIENTS AND METHODS Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC. RESULTS Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates ( P < .0001) and 3-year overall survival (OS) rates ( P < .0001). TNBC was associated with increased risk for visceral metastases ( P = .0005), lower risk for bone recurrence ( P = .027), and shorter postrecurrence survival ( P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival ( P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC ( P < .0001). CONCLUSION Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.

Purpose:A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC.Patients and Methods:In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers.Results:Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders.Conclusions:The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.

Supplementary Table from A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer

Supplementary Figure from A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer

Purpose: A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC. Patients and Methods: In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. Results: Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. Conclusions: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.

Summary Background HER2-positive breast cancers usually contain large amounts of T-cell infiltrate. We hypothesised that trastuzumab resistance in HER2-positive breast cancer could be mediated by immune mechanisms. We assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer. Methods We did this single-arm, multicentre, phase 1b–2 trial in 11 centres based in five countries. Eligible participants were women aged 18 years or older, who had advanced, histologically confirmed, HER2-positive breast cancer; documented progression during previous trastuzumab-based therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a formalin-fixed, paraffin-embedded metastatic tumour biopsy for central assessment of programmed cell death 1 ligand 1 (PD-L1) status. In phase 1b, we enrolled patients with PD-L1-positive tumours in a 3 + 3 dose-escalation of intravenous pembrolizumab (2 mg/kg and 10 mg/kg, every 3 weeks) plus 6 mg/kg of intravenous trastuzumab. The primary endpoint of the phase 1b study was the incidence of dose-limiting toxicity and recommended phase 2 dose; however, a protocol amendment on Aug 28, 2015, stipulated a flat dose of pembrolizumab of 200 mg every 3 weeks in all Merck-sponsored trials. In phase 2, patients with PD-L1-positive and PD-L1-negative tumours were enrolled in parallel cohorts and received the flat dose of pembrolizumab plus standard trastuzumab. The primary endpoint of the phase 2 study was the proportion of PD-L1-positive patients achieving an objective response. This trial is registered in ClinicalTrials.gov, number NCT02129556, and with EudraCT, number 2013-004770-10, and is closed. Findings Between Feb 2, 2015, and April 5, 2017, six patients were enrolled in phase 1b (n=3 received 2 mg/kg pembrolizumab, n=3 received 10 mg/kg pembrolizumab) and 52 patients in phase 2 (n=40 had PD-L1-positive tumours, n=12 had PD-L1-negative tumours). The data cutoff for this analysis was Aug 7, 2017. During phase 1b, there were no dose-limiting toxicities in the dose cohorts tested. Median follow-up for the phase 2 cohort was 13·6 months (IQR 11·6–18·4) for patients with PD-L1-positive tumours, and 12·2 months (7·9–12·2) for patients with PD-L1-negative tumours. Six (15%, 90% CI 7–29) of 40 PD-L1-positive patients achieved an objective response. There were no objective responders among the PD-L1-negative patients. The most common treatment-related adverse event of any grade was fatigue (12 [21%] of 58 patients). Grade 3–5 adverse events occurred in 29 (50%) of patients, treatment-related grade 3–5 adverse events occurred in 17 (29%), and serious adverse events occurred in 29 (50%) patients. The most commonly occurring serious adverse events were dyspnoea (n=3 [5%]), pneumonitis (n=3 [5%]), pericardial effusion (n=2 [3%]), and upper respiratory infection (n=2 [3%]). There was one treatment-related death due to Lambert-Eaton syndrome in a PD-L1-negative patient during phase 2. Interpretation Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1-positive population and be done in less heavily pretreated patients. Funding Merck, International Breast Cancer Study Group.

Reconfigurable wireless networks, such as ad hoc or wireless sensor networks, do not rely on fixed infrastructure. Nodes must cooperate in the multi-hop routing process. This dynamic and open nature make reconfigurable networks vulnerable to routing attacks that could degrade significantly network performance. Intrusion detection systems consist of a set of techniques designed to identify hostile behavior. In this paper, there are several approaches for intrusion detection in reconfigurable network routing such as collaborative, statistical, or machine learning-based techniques. In this paper, we introduce a new approach to intrusion detection for reconfigurable network routing based on linear systems theory. Using this approach, we can discriminate routing attacks by considering the system's z-plane poles. The z-plane can be thought of as a two dimensional feature space that arises naturally. It is independent of the number of network attack detection metrics and does not require extra dimensionality reduction. Two different host-based intrusion detection techniques, inspired by this new linear systems perspective, are presented and analyzed through a case study. The case study considers the effects of attack severity and node mobility to the attack detection performance. High attack detection accuracy was obtained without increasing packet overhead for both techniques by analyzing locally available information.

In this work, the channel characterization in terms of large-scale propagation, small-scale propagation, statistical and interference analysis of Fifth-Generation (5G) Millimeter Wave (mmWave) bands for wireless networks for 28, 30 and 60 GHz is presented in both an outdoor urban complex scenario and an indoor scenario, in order to consider a multi-functional, large node-density 5G network operation. An in-house deterministic Three-Dimensional Ray-Launching (3D-RL) code has been used for that purpose, considering all the material properties of the obstacles within the scenario at the frequency under analysis, with the aid of purpose-specific implemented mmWave simulation modules. Different beamforming radiation patterns of the transmitter antenna have been considered, emulating a 5G system operation. Spatial interference analysis as well as time domain characteristics have been retrieved as a function of node location and configuration. Project RTI2018-095499-B-C31, funded by Ministerio de Ciencia, Innovación y Universidades, Gobierno de España (MCIU/AEI/FEDER, UE).

Flame spread over liquids is of high importance because of its relation to fire hazards in liquid fuel spillages. Aviation fuels mixed with nanoparticles are rising as promising higher performance fuels for high-end applications. Fire safety characterization of aviation fuels mixed with nanoparticles is paramount to the successful implementation of these new fuels in the aerospace/aviation industry. In this paper, measurements of the flame spread rate on top of a fuel pool of Jet A mixed with carbon nanoparticles are reported. Multi-Walled Carbon Nanotubes (MWCNT) with a nominal diameter of 30–50 nm were added in concentrations varied between 2 g/L and 6 g/L. Jet A temperature was varied between 30oC to 100oC, and a Nd:YAG laser was used to ignite the fuel-air mixture established over the liquid fuel pool. Flame spread rate was observed to decrease with increased nanoparticle concentration for all temperatures. Reductions in the flame spread rate up to 50% were observed which are relevant for fire safety of liquids fuels.

9115 Background: The introduction of immunotherapy has altered the treatment paradigm for metastatic non-small cell cancer (mNSCLC). Unfortunately, many patients with mNSCLC have limited or no benefit from immune checkpoint inhibitors (ICIs). A variety of approaches have been explored to augment the efficacy of ICIs. Our study’s aim was to determine whether the addition of stereotactic body radiation therapy (SBRT) and intratumoral injection of the oncolytic virus ADV/HSV-tk (adenovirus-mediated expression of herpes simplex virus thymidine kinase) to a monoclonal antibody targeting programmed cell death-1 (PD-1) would improve the ICI’s efficacy in the treatment of mNSCLC. Methods: In this single-arm, open-label phase II study, patients with mNSCLC (squamous or non-squamous) who were ICI-naive or who were previously treated with a maximum of one line of therapy that included an ICI received an intratumoral injection of ADV/HSV-tk (5 x 1011 vp) followed by SBRT (30 Gy in 5 fractions) to the same tumor. An anti-PD-1 agent (pembrolizumab 200 mg IV every 3 weeks or nivolumab 240 mg IV every 2 weeks) was then given for up to 24 months (pembrolizumab) or 12 months (nivolumab), or until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A secondary endpoint was clinical benefit rate (CBR). Results: A total of 35 patients were enrolled, with 28 (80%) receiving pembrolizumab and 7 (20%) receiving nivolumab; 14 (40%) had previous ICI therapy while 21 (60%) were ICI-naive. The ORR and CBR were 28.5% and 61.9% in the ICI-naive group, and 14.2% and 64.2% in the group that previously received an ICI, respectively. Grade 3 or higher toxicity was seen in five patients (26.3%) in the ICI-naive group and in one patient (7.1%) in the previously ICI-treated group. No treatment-related deaths were observed. Conclusions: The addition of SBRT and intratumor injection of ADV/HSV-tk to anti-PD-1 therapy in mNSCLC resulted in a CBR of over 60% for both ICI-naive and previously ICI-treated patients without the use of chemotherapy. The combination was able to reinstitute sensitivity to ICIs in patients previously treated with an ICI, and also benefited some patients whose tumors did not express PD-L1. These findings should be further explored in a larger study population. Clinical trial information: NCT03004183. [Table: see text]

Background: Pembrolizumab monotherapy did not significantly improve overall survival (OS) as second- or third-line treatment for metastatic TNBC vs chemotherapy in the randomized, open-label, phase 3 KEYNOTE-119 study (NCT02555657; N = 622). However, the benefit of pembrolizumab compared with chemotherapy appeared to be greater with increasing PD-L1 expression as quantified by combined positive score (CPS; defined as the number of PD-L1–staining cells [tumor cells, lymphocytes, macrophages] divided by the total number of viable tumor cells, multiplied by 100). In the current exploratory analysis, we aimed to determine whether expression of PD-L1 on tumor cells contributes to the value of PD-L1 as a predictive biomarker in metastatic TNBC.Methods: Patients with centrally confirmed TNBC and 1 or 2 prior systemic treatments for metastatic disease were enrolled in KEYNOTE-119. Patients were randomly assigned 1:1 to pembrolizumab 200 mg Q3W or investigator’s choice of single-agent chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). PD-L1 expression in tumor samples was assessed using PD-L1 IHC 22C3 pharmDx and quantified per tumor proportion score (TPS; defined as the percentage of PD-L1–expressing tumor cells [partial or complete membrane staining] relative to total number of tumor cells) and CPS. Quantitative immune cell density (QID) was defined as CPS minus TPS. QID isolates immune cells but may be truncated when TPS is high. The ability of each scoring method (TPS, CPS, and QID) to predict objective response rate (ORR) with pembrolizumab, including receiver operating characteristics (ROC) analysis, and OS hazard ratios (HRs; pembrolizumab vs chemotherapy) was evaluated.Results: Tumor samples were available for 601 patients (pembrolizumab, 309; chemotherapy, 292) in KEYNOTE-119. ORR was 9.7% (30/309) with pembrolizumab and 11.3% (33/292) with chemotherapy when PD-L1 expression status was not considered. In the pembrolizumab arm, the area under the ROC curve (AUROC; 95% CI) was 0.69 (0.58-0.80) for tumor samples scored for CPS, 0.66 (0.55-0.77) for QID, and 0.55 (0.46-0.64) for TPS. ROC analysis is shown in the Table. At each cutoff, QID had lower estimated sensitivity (ie, missed responders) and a lower Youden Index compared with CPS. The number of missed responders (of 30 total in the pembrolizumab arm) for QID relative to CPS were 2, 5, 5, 6, 2, and 2 at cutoffs of 1, 10, 20, 30, 40, and 50, respectively. Across all practical cutoffs, the OS HR tended to be slightly smaller for CPS than QID. At cutoffs corresponding to the upper percentiles of 10, 20, 40, and 60, OS HRs were 0.497, 0.658, 0.758, and 0.850, respectively, for CPS vs 0.572, 0.712, 0.814, and 0.863, respectively, for QID. QID appeared to be orthogonal to TPS (r = -0.03 for all 601 observations; r = -0.04 after eliminating 7 potentially truncated values).Conclusions: Trends estimated using KN119 suggest that tumor cell expression is an important component of PD-L1 as a predictive biomarker of pembrolizumab efficacy in metastatic TNBC. In this exploratory analysis, when immune cells alone were used to measure PD-L1 expression, a meaningful number of responders was missed and OS benefit trended toward higher HR estimates. Tumor and immune cell PD-L1 expression may represent distinct (presumably negative modulatory) mechanisms. Table. ROC AnalysisCutoffCPS SensCPS SpecCPS YICPS PrevQID SensQID SpecQID YIQID PrevTPS SensTPS SpecTPS YITPS Prev010011001100110.8330.3660.1990.6540.7670.4160.1820.6020.3000.7890.0890.220100.5670.7170.2840.3110.4000.8140.2140.2070.2000.8920.0920.117200.5000.8490.3490.1840.3330.9250.2580.1000.1670.9320.0990.078300.3670.8920.2590.1330.1670.9570.1240.0550.1000.9430.0430.061400.2000.9350.1350.0780.1330.9860.1190.0260.0670.9530.0200.049500.2000.9570.1570.0580.1330.9930.1260.0190.0670.9680.0340.036 Citation Format: Eric P. Winer, Oleg Lipatov, Seock-Ah Im, Anthony Goncalves, Eva Muñoz-Couselo, Keun Seok Lee, Zbigniew Nowecki, Peter Schmid, Kenji Tamura, Laura Testa, Isabell Witzel, Shoichiro Ohtani, Stephanie Hund, Karina Kulangara, Vassiliki Karantza, Jaime A. Mejia, Junshui Ma, Petar Jelinic, Lingkang Huang, Kenneth Emancipator, Javier Cortes. Contribution of tumor and immune cells to PD-L1 as a predictive biomarker in triple-negative breast cancer (TNBC): Analysis from KEYNOTE-119 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD14-04.

Mas alla de la comprension y analisis de un contexto critico donde las demandas sociales superan la posibilidad de oferta gubernamental, la gestion fundamental de los gerentes sociales es la accion dirigida a la participacion comunitaria que junto a les decisiones institucionales dinamicen el proceso de politicas publicas, acompanado de la transformacion de subjetividades para la modificacion finalmente de unas condiciones objetivas hacia el desarrollo humano. Abstract Beyond the understanding and analysis of a critical context where social demands exceed the possibility of government supply, the fundamental management of social managers is the action aimed at community participation that, together with institutional decisions, stimulate the public policy process, accompanied by the transformation of subjectivities for the final modification of objective conditions towards human development.

The aim of this review is to explore the methodologies employed to assess the exposure of children to air pollutants, in particular traffic emissions, at school, and how these methodologies influence the assessment of the impact of this exposure on the children’s health. This involves four main steps: the measurement of air quality at school level, the association between measured air quality and children’s exposure, the association between children’s exposure and health; and source identification. The comparative advantages and disadvantages of the methods used at each of these steps are discussed. Air quality in schools can be measured at three scales: broad scale, across several city blocks using remote monitors; school-based scale, through ground-level monitors installed within the schools or their immediate surroundings (i.e. only a few metres outside the school); and personal exposure scale using portable monitors attached to a sample of children. Although studies have reported high exposure to PAHs (polycyclic aromatic hydrocarbons), submicrometre ( Associating air quality measurements at the broad and medium scale with children’s exposure is challenging: there is spatial and temporal heterogeneity in the distribution of air quality within a school, indoor measurements can often exceed outdoor measurements; and exposure in the classroom is affected by the penetration of outdoor pollutants, wall absorption, emissions from furniture and other materials, level and length of occupancy, and quality of ventilation. This is further exacerbated by the fact that children move around during their school day. Quantifying the contribution of school exposure with observed health symptoms presents further challenges. In addition to ascertaining the impact of non-school-based exposures and co-morbidities, the air pollutant dose intake is affected by daily patterns of physical and traffic activity during and outside school hours which make it difficult to compare the contribution of school-based and non-school-based exposures to the health effect under investigation. Finally, there is strong evidence that low socioeconomic level is highly correlated with the proximity of the school to pollution sources, yet this area of socioeconomic research has been largely unexplored in the assessment of traffic emission exposure.

Ambient aerosols play an important role in atmospheric processes affecting the human and natural environments. They affect air quality, reduce visibility, and induce climate change by directly scattering and/or absorbing the incoming solar radiation (Charlson et al., 1992; Kim et al., 2006), or indirectly by acting as cloud condensation nuclei (Hobbs, 1993). Aerosol particles are emitted from a variety of anthropogenic and natural sources either directly into the atmosphere or as secondary particles by gas-to-particle formation process. There is growing interest in studying and analysing the mechanisms of formation of secondary particles. The development of new instruments during the 1990s to measure the particle size distribution of nanoparticles (

Purpose: The clinical outcome for patients with breast cancer is influenced by the metastatic competence of the cancer and its sensitivity to endocrine therapy and chemotherapy. A molecular marker may be prognostic of outcome or predictive of response to therapy, or a combination of both. Experimental Design: We examined separately the prognostic and predictive values of tau mRNA expression in estrogen receptor (ER)–positive primary breast cancers in three patient cohorts. We used gene expression data from 209 untreated patients to assess the pure prognostic value of tau, data from 267 patients treated with adjuvant tamoxifen to assess predictive value for endocrine therapy, and data from 82 patients treated with preoperative paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide (paclitaxel/FAC) to assess predictive value for chemotherapy response. Wilcoxon rank sum test was used to compare tau expression between different outcome groups. Results: Higher tau mRNA expression showed borderline nonsignificant association with better prognosis in the absence of systemic adjuvant therapy. Higher tau mRNA expression was significantly associated with no recurrence (at 5 and 10 years, P = 0.005 and P = 0.05, respectively) in patients treated with tamoxifen, indicating a predictive value for endocrine therapy. Tau expression was significantly lower in patients who achieved pathologic complete response to paclitaxel/FAC chemotherapy (P < 0.001). Conclusion: This study suggests that high tau mRNA expression in ER-positive breast cancer indicates an endocrine-sensitive but chemotherapy-resistant disease. In contrast, low tau expression identifies a subset of ER-positive cancers that have poor prognosis with tamoxifen alone and may benefit from taxane-containing chemotherapy.

Particle number size distribution data in the range from 0.015 to 0.630 mm were collected over a 5-year period in the central business district (CBD) of Brisbane, Australia. Particle size distribution was summarised by total number concentration and number median diameter (NMD) as well as the number concentration of the 0.015–0.030 (N15–30), 0.030–0.050 (N30–50), 0.050–0.100 (N50–100), 0.100–0.300 (N100–300) and 0.300–0.630 (N300–630) mm size classes. Morning (6:00–10:00) and afternoon (16:00–19:00) measurements, the former representing fresh traffic emissions (based on the local meteorological conditions) and the latter well-mixed emissions from the CBD, during weekdays were extracted and the respective monthly mean values were estimated for time series analysis. For all size fractions, average morning concentrations were about 1.5 higher than in the afternoon whereas NMD did not vary between the morning and afternoon. The trend and seasonal components were extracted through weighted linear regression models, using the monthly variance as weights. Only the morning measurements exhibited significant trends. During this time of the day, total particle number increased by 105.7% and the increase was greater for larger particles, resulting in a shift in NMD by 7.9%. Although no seasonal component was detected the evidence against it remained weak due to the limitations of the database.

Purpose We developed a multigene predictor of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil-doxorubicin-cyclophosphamide (T/FAC) chemotherapy and assessed its predictive accuracy on independent cases. Patients and Methods One hundred thirty-three patients with stage I-III breast cancer were included. Pretreatment gene expression profiling was performed with oligonecleotide microarrays on fine-needle aspiration specimens. We developed predictors of pCR from 82 cases and assessed accuracy on 51 independent cases. Results Overall pCR rate was 26% in both cohorts. In the training set, 56 probes were identified as differentially expressed between pCR versus residual disease, at a false discovery rate of 1%. We examined the performance of 780 distinct classifiers (set of genes + prediction algorithm) in full cross-validation. Many predictors performed equally well. A nominally best 30-probe set Diagonal Linear Discriminant Analysis classifier was selected for independent validation. It showed significantly higher sensitivity (92% v 61%) than a clinical predictor including age, grade, and estrogen receptor status. The negative predictive value (96% v 86%) and area under the curve (0.877 v 0.811) were nominally better but not statistically significant. The combination of genomic and clinical information yielded a predictor not significantly different from the genomic predictor alone. In 31 samples, RNA was hybridized in replicate with resulting predictions that were 97% concordant. Conclusion A 30-probe set pharmacogenomic predictor predicted pCR to T/FAC chemotherapy with high sensitivity and negative predictive value. This test correctly identified all but one of the patients who achieved pCR (12 of 13 patients) and all but one of those who were predicted to have residual disease had residual cancer (27 of 28 patients).

Gastric cancer (GC) is often diagnosed at an advanced stage and consequently remains the third most common cause of cancer-related death worldwide. Early detection and surgical intervention has been found to reduce GC-associated mortality, yet an efficient and cost-effective screening program still does not exist. Several proteins including Lgr5, CD44 and CD133 have been found to be upregulated during the H. pylori-associated Correa pathway of carcinogenesis, and have the potential to act as biomarkers for early detection. The tools of mathematical oncology facilitate the development of models capable of both reproducing and predicting the increase in expression of these markers, and thus the patient-specific progression of disease. These predictions can allow the identification of optimal screening times to minimize the risk of undetected malignant transformation. Here, we present a combined mathematical-statistical approach to identifying such optimal screening times in a manner which is both biomarker-independent and H.pylori status-independent, thus allowing improved generalizability and the potential for broader application in the clinical setting. Logistic regression models are developed for each biomarker of interest (Lgr5, CD133, CD44) to determine the likelihood of a patient being either early in the Correa pathway (gastritis or metaplasia) or late in the pathway (dysplasia or carcinoma) based on current age, sex and biomarker-positive cell fraction obtained from immunohistochemical staining of biopsy tissue samples. Calibrated models for all three biomarkers were able to accurately classify disease stage as determined by pathology report in more than 85% of an initial cohort of 59 patients. Mathematical models describing the temporal evolution of the expression of each marker of interest are then defined based on clinical data. Coupled with the statistical tool for identifying the likelihood of being at each stage of disease for all combination of input parameters, this framework can forecast time to a clinically-significant endpoint such as the development of dysplasia or adenocarcinoma for future patients, allowing the suggestion of screening times at which the likelihood of progression reaches a certain threshold. The results suggest that for 13 out of 16 patients in our initial test cohort (81%), models independently developed using three different markers all recommend similar follow-up screening times, showing promise for the general applicability and robustness of such a tool. Citation Format: Heiko Enderling, Rachel Walker, Jose Pimiento, Jaime Mejia, Domenico Coppola. Computational modeling to suggest patient-specific screening schedules for early detection of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4544. doi:10.1158/1538-7445.AM2017-4544

Background. Up to 80% of patients in the early stages of gastric cancer are asymptomatic, making early diagnosis and hence effective treatment challenging. The poor prognosis of patients with late diagnoses clearly necessitates the identification of markers for early detection and the development of streamlined screening protocols. This is particularly crucial in high-risk populations, for example regions in which Helicobacter Pylori infection and associated chronic inflammation, responsible for over 70% of gastric cancers worldwide, is prevalent. At present, an efficient and personalized program for early detection does not exist. Methods. Specific biomarkers for the progression of gastric cancer have been identified in preliminary studies, including CD44, Lgr5 and CD133. In retrospective tissue samples incremental increases in expression of these markers was observed during the progression from normal gastric tissue to precancerous histologic lesions such as intestinal metaplasia and ultimately dysplasia and carcinoma. We developed a mechanistic mathematical model capable of simulating these marker-positive population dynamics, calibrated using the existing clinical data. The predictive capability of the model is validated by comparison of simulated to actual marker expression patterns in an independent test cohort of endoscopic gastric biopsies taken at sequential points during individual patients’ disease progression. Results. Based on clinically obtainable, patient-specific tissue conditions, the computational model can simulate the dynamics of marker-positive cells and, when calibrated and validated with clinical data from specific patient populations, may forecast disease progression and suggest optimal screening schedules for individual patients. Conclusions. The tools of mathematical oncology have the potential to directly inform clinical screening protocols. Verified prognostic factors for disease progression can be incorporated into mathematical models to improve diagnostic accuracy and allow clinically-actionable screening optimization. This can guide personalized screening schedules according to current marker expression on a case-by-case basis to achieve more efficient prognosis and reduced healthcare costs. Citation Format: Rachel Walker, Jaime Mejia, Heiko Enderling, Jose M. Pimiento, Domenico Coppola. Cross-disciplinary methods for personalizing screening modalities for early gastric cancer intervention. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1523.

Background: A phase I study was initiated to determine the maximum tolerated dose (MTD) of prolonged-infusion gemcitabine combined with cyclophosphamide in patients with metastatic breast carcinoma (MBC). Methods: Patients with MBC were treated with gemcitabine infusion at 10 mg/m2/min and cyclophosphamide by intravenous piggyback injection, 4 h after initiation of the infusion. We treated 3–6 patients at a particular dose level until the MTD was determined. Results: Overall, 44 patients received a total of 197 courses of therapy. Both drugs were given on days 1, 8 and 15 to 14 patients (68 courses). Delayed white blood cell recovery necessitated first protocol amendment to drop cyclophosphamide on days 8 and 15 in 9 patients (43 cycles). A second amendment was needed to drop gemcitabine on day 15 because of thrombocytopenia in 21 patients (86 courses). The dose-limiting toxicity was thrombocytopenia. The MTD of an optimal dose schedule was 800 mg/m2 gemcitabine infused at a rate of 10 mg/m2/min on days 1 and 8, and 400 mg/m2 cyclophosphamide, by intravenous piggyback injection, on day 1, 4 h after initiation of the gemcitabine infusion. Conclusions: The MTD can be given safely every 4 weeks to patients with MBC. Phase II studies are warranted to evaluate the clinical activity of this therapy.

Background: The aim of this study was to compare the extent of pathologic response in patients with HER2-positive (HER2+) breast cancer treated with standard neoadjuvant chemotherapy, with or without trastuzumab (H), according to hormone receptor (HR) status. Patients and methods: We included 199 patients with HER2+ breast cancer from three successive cohorts of neo-adjuvant chemotherapy on the basis of paclitaxel (Taxol) (P) administered weekly (w) or three weekly (3-w), followed by 5-fluorouracil (F), doxorubicin (A) or epirubicin (E), and cyclophosphamide (C). Residual cancer burden (RCB) was determined from pathologic review of the primary tumor and lymph nodes and was classified as pathologic complete response (pCR) or minimal (RCB-I), moderate (RCB-II), or extensive (RCB-III) residual disease. Results: In HR-positive (HR+) cancers, a higher rate of pathologic response (pCR/RCB-I) was observed with concurrent H + 3-wP/FEC (73%) than with 3-wP/FEC (34%, P = 0.002) or wP/FAC (47%; P = 0.02) chemotherapy alone. In HR-negative (HR−) cancers, there were no significant differences in the rate of pathologic response (pCR/RCB-I) from 3-wP/FAC (50%), wP/FAC (68%), or concurrent H + 3-wP/FEC (72%). Conclusions: Patients with HR+/HER2+ breast cancer obtained significant benefit from addition of trastuzumab to P/FEC chemotherapy; pathologic response rate was similar to that seen in HR−/HER2+ breast cancers.

Despite numerous retrospective and case-control studies, risk factors related to overall survival (OS) and recurrence-free survival (RFS) in bilateral breast cancer are still being defined. The aim of our study was to describe tumor properties, patient characteristics, and method of cancer detection for a large cohort of patients with bilateral breast cancer and to assess the associations of these factors with OS and RFS.A retrospective chart review was conducted at the University of Texas M. D. Anderson Cancer Center. Among patients with bilateral breast cancer, we compared primary versus contralateral tumors and synchronous versus metachronous cancers. Patient and second tumor characteristics were evaluated for an association with OS and RFS, as measured from diagnosis of the second tumor.Of 11,234 patients with primary breast cancer seen for an initial visit between July 1, 1997, and December 31, 2004, 771 patients (6.9%) were diagnosed with bilateral breast cancer. The 5-year OS rates based on stage of the second tumor were 87.7%, 87.7%, 69.6%, 45.1%, and 23.8% for stages 0, I, II, III, and IV, respectively (P.0001). The 5-year OS rates for second tumor detection via mammogram/prophylactic mastectomy, physical examination, and self-examination were 81.6%, 70.9%, and 65.3%, respectively (P = .01). In addition, lymphovascular invasion, nuclear grade, hormonal receptor status, and histology were significantly associated with OS and RFS (P.05). In a multivariable analysis, clinical stage and lymphovascular invasion remained significantly associated with OS (P.05).This study represents the largest single-institution review of bilateral breast cancer. Numerous second tumor characteristics were associated with survival. The results emphasize the importance of earlier detection and improved staging for contralateral breast cancer.

Introduction We performed gene expression analysis to identify molecular predictors of resistance to preoperative concomitant trastuzumab and paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide (T/FEC). Methods Pretreatment fine-needle aspiration specimens from 45 patients with HER-2-overexpressing stage II to IIIA breast cancer were subjected to transcriptional profiling and examined for differential expression of various genes and gene sets. The primary endpoint for tumor response was pathologic complete response (pCR). Correlations between pCR and gene expression were sought. Results The overall pCR rate was 64%. Age, nuclear grade, tumor size, nodal status, quantitative expression of estrogen and HER-2 receptor mRNA, and HER-2 gene copy number showed no correlation with pCR. Results of gene set enrichment analysis suggested that the lower expression of genes involved with CD40 signaling is associated with a greater risk of residual cancer after the preoperative chemotherapy that includes trastuzumab. Conclusion CD40 signaling may play a role in determining response to trastuzumab-plus-T/FEC therapy in patients with HER-2-overexpressing breast cancer.

Summary Background Gene expression microarrays are being used to develop new prognostic and predictive tests for breast cancer, and might be used at the same time to confirm oestrogen-receptor status and ERBB2 status. Our goal was to establish a new method to assign oestrogen receptor and ERBB2-receptor status to breast carcinoma based on mRNA expression measured using Affymetrix U133A gene-expression profiling. Methods We used gene expression data of 495 breast cancer samples to assess the correlation between oestrogen receptor ( ESR1 ) and ERBB2 mRNA and clinical status of these genes (as established by immunohistochemical [IHC] or fluorescence in-situ hybridisation [FISH], or both). Data from 195 fine-needle aspiration (FNA) samples were used to define mRNA cutoff values that assign receptor status. We assessed the accuracy of these cutoffs in two independent datasets: 123 FNA samples and 177 tissue samples (ie, resected or core-needle biopsied tissues). Profiling was done at two institutions by use of the same platform (Affymetrix U133A GeneChip). All data were uniformly normalised with dCHIP software. Findings ESR1 and ERBB2 mRNA levels correlated closely with routine measurements for receptor status in all three datasets. Spearman's correlation coefficients ranged from 0·62 to 0·77. An ESR1 mRNA cutoff value of 500 identified oestrogen-receptor-positive status with an overall accuracy of 90% (training set), 88% (first validation set), and 96% (second validation set). An ERBB2 mRNA threshold of 1150 identified ERBB2-positive status with the overall accuracy of 93% (training set), 89% (first validation set), and 90% (second validation set). Reproducibility of mRNA measurements in 34 replicate experiments was high (correlation coefficient 0·975 for ESR1 , 0·984 for ERBB2 ). Interpretation Amounts of ESR1 and ERBB2 mRNA as measured by the Affymetrix GeneChip reliably and reproducibly establish oestrogen-receptor status and ERBB2 status, respectively.

Air quality studies have indicated that particle number size distribution (NSD) is unevenly spread in urban air. To date, these studies have focussed on differences in concentration levels between sampling locations rather than differences in the underlying geometries of the distributions. As a result, the existing information on the spatial variation of the NSD in urban areas remains incomplete. To investigate this variation in a large metropolitan area in the southern hemisphere, NSD data collected at nine different locations during different campaigns of varying duration were compared using statistical methods. The spectra were analysed in terms of their modal structures (the graphical representation of the number size distribution function), cumulative distribution and number median diameter (NMD). The study found that with the exception of one site all distributions were bimodal or suggestive of bimodality. In general, peak concentrations were below 30 nm and NMDs below 50 nm, except at a site dominated by diesel trucks, where it shifted to around 50 and 60 nm respectively. Ultrafine particles (UFPs (

546 Background: Women with a personal history of breast cancer have an annual incidence of 0.5–1% and a cumulative incidence from 3–20% of subsequently developing contralateral breast cancer. Despite numerous retrospective and case-control studies, risk factors related to overall (OS) and recurrence-free survival (RFS) in BBC are still being defined. The purpose of our study was to describe tumor properties, patient characteristics, and method of cancer detection for a large cohort of BBC patients, and to assess the associations of these factors with OS and RFS. Methods: A retrospective chart review was conducted of the BCMS (Breast Cancer Management System) database at MD Anderson Cancer Center. Among BBC patients, we compared primary versus contralateral tumors and synchronous versus metachronous cancers. Patient and second tumor characteristics were evaluated for an association with OS and RFS, as measured from diagnosis of the second tumor. Results: Of 11,234 primary breast cancer patients seen for an initial visit between 7/1/1997 to 12/31/2004, 771 patients (6.9%) were diagnosed with BBC. One hundred forty nine (19.3%) patients have died, and one hundred forty eight (19%) have relapsed. Stage 0 was present in 39.4% of synchronous second tumors disease versus 20.6% of metachronous second tumors (p No significant financial relationships to disclose.

10000 Background: We developed a multi-gene predictor of pathologic complete response (pCR) to preoperative weekly paclitaxel and 5-fluorouracil, doxorubicin, cyclophosphamide (T/FAC) chemotherapy and assessed its predictive accuracy on independent cases. Methods: 133 patients with stage I-III breast cancer were included. Pretreatment gene expression profiling was performed with Affymetrix U133 A chips on fine needle aspiration specimens. We developed predictors of pCR from 82 cases and assessed accuracy on 51 independent cases. Results: Overall pCR rate was 26% in both cohorts. In the training set, 56 probes (49 genes) were identified as differentially expressed between pCR versus residual disease at a false discovery rate of 1%. We examined the performance of 780 distinct classifiers (set of genes + prediction algorithm) in full cross validation. Many predictors performed equally well. A nominally best 30-probe set DLDA classifier was selected for independent validation. It showed substantially higher sensitivity (92% vs 61%), negative predictive value (96% vs 86%) and better AUC (0.877 vs 0.811) than a predictor including clinical variables (age, ER, grade). The combination of genomic and clinical information yielded the best model, AUC=0.883, sensitivity 92%, specificity 71%, PPV 52%, NPV 96%. In 31 samples, RNA was hybridized in replicate with resulting predictions that were 97% concordant. Conclusion: A 30-probe set pharmacogenomic predictor alone or in combination with ER and grade predicts response to T/FAC chemotherapy with high sensitivity and negative predictive value. This test correctly identified all but one of the patients who achieved pCR (12/13) and all but one of those who had residual cancer (27/28). No significant financial relationships to disclose.

574 Background: D is a semi-synthetic taxane with significant activity in breast cancer. D is usually administered on an every 3-weeks schedule, however, studies have demonstrated drug efficacy and a different toxicity profile when administered on a weekly basis. In this study we compared the weekly schedule versus every 3-weeks to define the safest schedule with the highest efficacy. Methods: Patients (Pts) were enrolled if they had stage IV breast cancer and had received no more than one prior chemotherapy regimen for metastatic disease. Prior treatment with D was not allowed but adjuvant paclitaxel (P) was allowed if > 12 months since the last dose. Pts were randomized to receive D at a starting dose of 75mg/m2 on day 1 or DW at a dose of 35 mg/m2/week for 3 weeks followed by 1 week of rest every 28 days. Doses could be escalated to 100 mg/m2 and 40mg/m2, respectively at the discretion of the investigator. Premedication with dexamethasone was given with each regimen. Results: From 1/2001 until 9/2004, a total of 125 pts were enrolled, 63 in the DW arm and 62 in the D arm. Thirty-nine and 10 pts had received prior anthracycline (A) and P respectively in the D arm while 32 and 11 pts had A and P in the DW arm. Median ages were 56 and 54 years in the D and DW arm, respectively. 118 pts were eligible for an efficacy analysis with a response rate of 35.6%; (95% CI, 23.6%, 49.1%) for the D arm vs 20.3%; (95% CI, 11.0%, 32.8%) for DW. There was no difference between D and DW in median PFS and OS, 5.7 vs 5.5 months (p = 0.46) and 18.3 vs 18.6 months (p = 0.34), respectively. There was a higher overall toxicity rate (grade 3 and 4) in the D arm vs DW, 88.1% vs 55.9% (p = 0.0001). There were 48 (81%) and 6 (10%) pts with grade ¾ granulocytopenia with 6 (10%) and 2 (3%) episodes of neutropenic fever in D vs DW, respectively. Grade 3/4 fatigue and myalgias were reported more often in D than DW, 15 (25%) and 8 (13.5%), and 16 (27%) and 2 (3%), respectively. Grade 3 epiphora was similar in both arms, 4 (7%) and 5 (8%) for D and DW, respectively. Conclusions: D has a higher response rate compare to DW but with a more pronounced toxicity profile. This needs to be kept in mind when making a treatment recommendation for patients with metastatic breast cancer. No difference in PFS or OS was observed between both arms. No significant financial relationships to disclose.

545 Background: We performed gene expression analysis to identify molecular predictors of resistance to preoperative concomitant trastuzumab and T/FEC chemotherapy. Methods: Pretreatment fine needle aspirations from 21 patients with HER2 amplified, stages II-III breast cancer were available for transcriptional profiling with Affymetrix U133 A chips. Results: Overall pathologic complete response (pCR) rate was 71%. Age, nuclear grade, tumor size, nodal status or quantitative estrogen and HER2 receptor mRNA expression showed no association with response in univariate and multivariate logistic regression. We tested the accuracy of a 30-gene pCR predictor that was previously developed from patients who received T/FEC only preoperative chemotherapy. This predictor was accurate in validation in T/FEC treated patients (n=51) but showed low sensitivity in patients who also received trastuzumab (sensitivity 53% versus 92%). We could not identify any differentially expressed genes between pCR (n=15) and residual disease (RD, n=6) at a false discovery rate (FDR) No significant financial relationships to disclose.