Breast Cancer Treatment Protocols Research Articles

Abstract PO2-12-11: Ocular Toxicity of Tamoxifen in Patients with Breast Cancer

Abstract Background: The latest recommendations in breast cancer treatment protocols with tamoxifen indicate that it should be used from five to 10 years. It depends mainly on the cumulative dose of the drug in the body. Despite its multiplicity, the various studies conducted on this subject did not reach conclusive results. Objectives: This research aims to study retinopathy associated with hormonal treatment of breast cancer using tamoxifen. Methods: A cross-sectional study was conducted at Al-Mouwasat University Hospital on a sample of 130 eyes according to (G-Power) with a statistical power of 95%. The participants were briefed on the research and consented on the ethical considerations. Then, the patients who entered the study were interrogated, clinically examined, and were asked about their medical history, the time of breast cancer diagnosis along with the details about the treatment protocols they underwent or currently undergoing. The refractive errors were measured with an automatic refractive device, then they were examined on the slit lamp to investigate the refractory media, then the corrected and uncorrected visual acuity were taken. Finally, after ensuring that the inclusion criteria were met and excluding those who fulfil one or more of the exclusion criteria, optical coherence tomography was performed using SD-OCT technique to measure and review the retinal thickness map in circles of 1-3-6 mm, respectively, to notice possible changes on it. Results: We found that the use of tamoxifen irrespective to cumulative dose leads to increase in the macula thickness values in the upper and lower sectors within the 3 mm circle, and to significant decrease in the macula thickness values in the upper and lower sectors within the 6 mm circle, in addition to decrease in nasal sector thickness within the circles of 3 and 6 mm. Conclusion: We conclude that the difference between people treated with tamoxifen and those not treated with it is not limited to the occurrence of crystals deposition in the macular area or the presence of a cavity in the central macula (with or without typical cystic macular edema), but rather to existence of macula thickness differences unrelated to the cumulative dose of the drug, whether by increase or decrease in thickness of the upper, lower and nasal segments. Citation Format: Husain Alhouz, Arwa Azmeh, Maher Saifo. Ocular Toxicity of Tamoxifen in Patients with Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-12-11.

Neoadjuvant radiotherapy in ER+, HER2+, and triple-negative -specific breast cancer based humanized tumor mice enhances anti-PD-L1 treatment efficacy.

Pre-operative radiation therapy is not currently integrated into the treatment protocols for breast cancer. However, transforming immunological "cold" breast cancers by neoadjuvant irradiation into their "hot" variants is supposed to elicit an endogenous tumor immune defense and, thus, enhance immunotherapy efficiency. We investigated cellular and immunological effects of sub-lethal, neoadjuvant irradiation of ER pos., HER2 pos., and triple-negative breast cancer subtypes in-vitro and in-vivo in humanized tumor mice (HTM). This mouse model is characterized by a human-like immune system and therefore facilitates detailed analysis of the mechanisms and efficiency of neoadjuvant, irradiation-induced "in-situ vaccination", especially in the context of concurrently applied checkpoint therapy. Similar to clinical appearances, we observed a gradually increased immunogenicity from the luminal over the HER2-pos. to the triple negative subtype in HTM indicated by an increasing immune cell infiltration into the tumor tissue. Anti-PD-L1 therapy divided the HER2-pos. and triple negative HTM groups into responder and non-responder, while the luminal HTMs were basically irresponsive. Irradiation alone was effective in the HER2-pos. and luminal subtype-specific HTM and was supportive for overcoming irresponsiveness to single anti-PD-L1 treatment. The treatment success correlated with a significantly increased T cell proportion and PD-1 expression in the spleen. In all subtype-specific HTM combination therapy proved most effective in diminishing tumor growth, enhancing the immune response, and converted non-responder into responder during anti-PD-L1 therapy. In HTM, neoadjuvant irradiation reinforced anti-PD-L1 checkpoint treatment of breast cancer in a subtype -specific manner. According to the "bench to bedside" principle, this study offers a vital foundation for clinical translating the use of neoadjuvant irradiation in the context of checkpoint therapy.

Machine learning analysis of breast cancer treatment protocols and cycle counts: A case study at Mohammed vi hospital, Morocco

This paper presents a new study of predicting patients' breast cancer treatment protocol and the corresponding treatment cycle based on machine learning algorithms. The data used were collected at Mohammed VI Hospital in Morocco, and it contains patient information with two targets (protocol and treatment cycle).After preparing the data and testing several machine learning algorithms, two models were developed: The first one, based on Gradient Boosting Classifier algorithm, successfully classified patient treatment protocols with an overall accuracy of 64 % across all categories and an impressive 94 % accuracy for the mode category, widely adopted in the hospital. The second model, based on Random Forest Regressor algorithm, which integrates the results of the first model during the training, predicted the treatment cycle of patients with a Root Mean Square Error (RMSE) score of 0.050 and a Mean Absolute Percentage Error (MAPE) score of 0.020. Furthermore, feature importance analysis was performed to highlight the importance of variables, and show the positive influence of some variables on the models.Finally, this study can help doctors quickly make decisions about the treatment needed for each patient and also gives an idea of which molecules should exist in the hospital stock based on the patient's treatment cycle predicted.

MRI-Based Kinetic Heterogeneity Evaluation in the Accurate Access of Axillary Lymph Node Status in Breast Cancer Using a Hybrid CNN-RNN Model.

Accurate evaluation of the axillary lymph node (ALN) status is needed for determining the treatment protocol for breast cancer (BC). The value of magnetic resonance imaging (MRI)-based tumor heterogeneity in assessing ALN metastasis in BC is unclear. To assess the value of deep learning (DL)-derived kinetic heterogeneity parameters based on BC dynamic contrast-enhanced (DCE)-MRI to infer the ALN status. Retrospective. 1256/539/153/115 patients in the training cohort, internal validation cohort, and external validation cohorts I and II, respectively. 1.5 T/3.0 T, non-contrast T1-weighted spin-echo sequence imaging (T1WI), DCE-T1WI, and diffusion-weighted imaging. Clinical pathological and MRI semantic features were obtained by reviewing histopathology and MRI reports. The segmentation of the tumor lesion on the first phase of T1WI DCE-MRI images was applied to other phases after registration. A DL architecture termed convolutional recurrent neural network (ConvRNN) was developed to generate the KHimage (kinetic heterogeneity of DCE-MRI image) score that indicated the ALN status in patients with BC. The model was trained and optimized on training and internal validation cohorts, tested on two external validation cohorts. We compared ConvRNN model with other 10 models and the subgroup analyses of tumor size, magnetic field strength, and molecular subtype were also evaluated. Chi-squared, Fisher's exact, Student's t, Mann-Whitney U tests, and receiver operating characteristics (ROC) analysis were performed. P < 0.05 was considered significant. The ConvRNN model achieved area under the curve (AUC) of 0.802 in the internal validation cohort and 0.785-0.806 in the external validation cohorts. The ConvRNN model could well evaluate the ALN status of the four molecular subtypes (AUC = 0.685-0.868). The patients with larger tumor sizes (>5 cm) were more susceptible to ALN metastasis with KHimage scores of 0.527-0.827. A ConvRNN model outperformed traditional models for determining the ALN status in patients with BC. 3 TECHNICAL EFFICACY: Stage 2.

Phase 1/2 Study of the Timing and Efficacy of 3 mg Peg-GCSF in Neo/Adjuvant Dose Dense Breast Cancer Treatment Protocols.

Amol PatelBackground Peg-GCSF has similar efficacy at a dose of 60 µg/kg and 100 µg/kg. The conventional 6 mg SC dose was based on the maximum tolerable dose. In Japan, 3.6 mg dose was approved on the basis of dose finding studies. Peg-GCSF is an integral part of dose-dense chemotherapy protocols. Dose finding and scheduling study of peg-GCSF have not been conducted in Indian patients. Materials and Methods We conducted two-center phase 1/2 clinical study addressing the timing and efficacy of peg-GCSF in Indian breast cancer patients (CTRI no: 2021/07/034751). Three groups of timing administration were studied, namely 1, 6, and 24 hours post chemotherapy. The phase 2 part was the expansion of the best timing group. The primary objective was dose density, which was defined as receiving chemotherapy on < 3 days of scheduled date. Adriamycin/epirubicin cyclophosphamide (AC/EC) was administered q2 weeks. The total leucocyte (TLC) and absolute neutrophil (ANC) kinetics were studied. Other outcomes were incidence of grade 4 neutropenia, febrile neutropenia (FN), and requirement of additional doses of G-CSF. Bone pain, fever, and myalgia were studied for adverse effects. Results From November 20 to December 21, 36 patients were enrolled. Patient characteristics are depicted in Table 1. Initially, three patients received the peg-GCSF in each timing group. One patient in each 1-hour and 6 hours needed G-CSF support for maintaining the dose density. The 24-hour group was carried to phase 2 part. Dose density was maintained in 97% of patients. None of the patient in 24-hour group had FN. Also, 4/30 patients had grade 4 neutropenia and required an additional dose of GCSF. Grade 3 or 4 bone pain was not noticed by any of the patients. During the first cycle, the mean ANC (cells/μL) was 5284, 20704, 3010, 6954 on D0, D + 3, D + 7, and D + 13, respectively (Fig. 1A-TLC and 1B-ANC). The mean ANC (cells/μL) rise on D + 3 in cycles 1, 2, 3, 4 was 23810, 29209, 32428,22455, respectively. Conclusion Dose density of AC/EC breast cancer protocol is maintained with peg-GCSF 3 mg. Post chemotherapy 24-hour timing of peg-GCSF administration remains as the standard. A phase 3 trial of 6 mg versus 3 mg is warranted.

The Safe Use of 125I-Seeds as a Localization Technique in Breast Cancer during Pregnancy

Introduction: Some aspects of the treatment protocol for breast cancer during pregnancy (PrBC) have not been thoroughly studied. This study provides clarity regarding the safety of the use of 125I-seeds as a localization technique for breast-conserving surgery in patients with PrBC. Methods: To calculate the exposure to the fetus of one 125I-seed implanted in a breast tumor, we developed a model accounting for the decaying 125I-source, time to surgery, and the declining distance between the 125I-seed and the fetus. The primary outcome was the maximum cumulative fetal dose of radiation at consecutive gestational ages (GA). Results: The cumulative fetal dose remains below 1 mSv if a single 125I-seed is implanted at a GA of 26 weeks. After a GA of 26 weeks, the fetal dose can be at a maximum of 11.6 mSv. If surgery takes place within two weeks of implantation from a GA of 26 weeks, and one week above a GA of 32 weeks, the dose remains below 1 mSv. Conclusion: The use of 125I-seeds is safe in PrBC. The maximum fetal exposure remains well below the threshold of 100 mSv, and therefore, does not lead to an increased risk of fetal tissue damage. Still, we propose keeping the fetal dose as low as possible, preferably below 1 mSv.

Towards Patient-Specific Optimization of Neoadjuvant Treatment Protocols for Breast Cancer Based on Image-Guided Fluid Dynamics.

This study establishes a fluid dynamics model personalized with patient-specific imaging data to optimize neoadjuvant therapy (i.e., doxorubicin) protocols for breast cancers. Ten patients recruited at the University of Chicago were included in this study. Quantitative dynamic contrast-enhanced and diffusion weighted magnetic resonance imaging data are leveraged to estimate patient-specific hemodynamic properties, which are then used to constrain the mechanism-based drug delivery model. Then, computer simulations of this model yield the subsequent drug distribution throughout the breast. By systematically varying the dosing schedule, we identify an optimized regimen for each patient using the maximum safe therapeutic duration (MSTD), which is a metric balancing treatment efficacy and toxicity. With an individually optimized dose (range = 12.11-15.11 mg/m2 per injection), a 3-week regimen consisting of a uniform daily injection significantly outperforms all other scheduling strategies (P < 0.001). In particular, the optimal protocol is predicted to significantly outperform the standard protocol (P < 0.001), improving the MSTD by an average factor of 9.93 (range = 6.63 to 14.17). A clinical-mathematical framework was developed by integrating quantitative MRI data, advanced image processing, and computational fluid dynamics to predict the efficacy and toxicity of neoadjuvant therapy protocols, thus enabling the rational identification of an optimal therapeutic regimen on a patient-specific basis. Our clinical-computational approach has the potential to enable optimization of therapeutic regimens on a patient-specific basis and provide guidance for prospective clinical trials aimed at refining neoadjuvant therapy protocols for breast cancers.

Green self-assembled lactoferrin carboxymethyl cellulose nanogels for synergistic chemo/herbal breast cancer therapy

The current treatment protocols for breast cancer have shifted from single agent therapies to combinatorial approaches that offer synergistic efficacies and reduced side effects. Self-assembled nanogels comprising natural polysaccharides and functional proteins provide an intelligent platform for the targeted co-delivery of therapeutic molecules. Herein, we report the fabrication of self-assembled nanogels utilizing hydrophilic biocompatible proteins, lactoferrin (Lf), and polysaccharide carboxy methyl cellulose (CMC), for the combined delivery of the antimetabolite pemetrexed (PMT) and the herbal polyphenol honokiol (HK). PMT was conjugated to LF via an amide bond. The conjugate was then electrostatically assembled into CMC under optimized conditions to form nanogels (Lf-CMC NGs). An inclusion complex of HK with hydroxypropyl-β-cyclodextrin was then encapsulated in the prepared Lf-CMC NGs with an entrapment efficiency of 66.67%. The dual drug-loaded cross-linked Lf-CMC NGs exhibited a particle size of 193.4 nm and zeta potential of − 34.5 mV and showed a sustained release profile for both drugs. PMT/HK-loaded Lf-CMC NGs were successfully taken up by MDA-MB-231 breast cancer cells and demonstrated superior in vitro cytotoxicity, as elucidated by a low combination index value (CI=0.17) and a higher dose reduction index (DRI) compared to those of the free drugs. An in vivo antitumor study using an Ehrlich ascites tumor (EAT) mouse model revealed the robust efficacy of PMT/HK-loaded Lf-CMC NGs in inhibiting tumor growth, which was ascribed to the reduced expression level of VEGF-1, elevated protein expression level of caspase-3, and suppressed Ki-67 protein level in the tumor tissue (P ˂0.05). In conclusion, our green fabricated self-assembled dual-loaded nanogels offer a promising biocompatible strategy for targeted combinatorial breast cancer therapy.

Abstract 222: Towards patient-specific optimization of neoadjuvant treatment protocols for breast cancer based on image-based fluid dynamics

Abstract Introduction: Standard-of-care neoadjuvant therapeutic regimens are based on clinical trials designed to identify treatment protocols at the population level, which cannot capture the unique characteristics of individual patients. Moreover, it is impossible for clinical trials to experimentally evaluate all the possible treatment combinations and dosing strategies. Mechanism-based, mathematical modeling can potentially address this critical barrier to achieving truly personalized treatment. In this contribution, we present preliminary results using a fluid dynamics model personalized with a patient's imaging data to optimize a drug injection protocol in breast cancer. Methods: Nine breast cancer patients are included in this study. MRI data are acquired, processed, and used to estimate hemodynamics and imported to our drug delivery model. By varying the dosing schedule, the model predicts varying dynamics of drug distribution throughout the breast. We define an objective function, MSTD, balancing the treatment efficacy and toxicity, and use it to optimize the injection protocol for each patient. The injection schedules tested include: (a) single injection on day 1 of each 3-week cycle; double injections of half the total dose each at (b) day 1 and 2, (c) day 1 and 3, (d) day 1 and 5, and (e) day 1 and 8 within each 3-week cycle. The doses tested vary from 0 to 100 μg/ml of maximal plasma concentration. Improvement ratio of the optimal protocol to a standard protocol, 10 μg/ml via schedule (a), is measured. Results: The optimal protocol and improvement are reported for each patient in Table 1. Conclusion: Our modeling system can efficiently solve the personalization of drug injection protocol as an optimal control problem. Different patients have different optimal treatment protocols, each of which is predicted to outperform the standard protocol. Table 1.Optimal injection protocol for individual patientsPatientOptimal scheduleOptimal dose (μg/ml)Improvement ratio1(e)8.891.492(e)6.071.823(e)5.882.124(e)7.362.415(e)5.193.266(e)5.203.377(e)5.703.598(e)4.103.079(e)4.593.49NCI U01CA142565, U01CA174706, R01CA218700, R01CA172801, U24CA226110, P30CA014599. CPRIT RR160005. Citation Format: Chengyue Wu, David A. Hormuth, Federico Pineda, Gregory S. Karczmar, Thomas E. Yankeelov. Towards patient-specific optimization of neoadjuvant treatment protocols for breast cancer based on image-based fluid dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 222.

Abstract PS4-36: Non-invasive evaluation of chemoresistance in breast cancers using circulating tumor associated cells

Abstract Background: Despite the development of Checkpoint Inhibitor Treatments (Immunotherapy) and Targeted anticancer agents, cytotoxic (chemotherapy) agents remain the mainstay of breast cancer treatments. However, treatment failure is often encountered in breast cancers owing to innate or acquired chemoresistance. Real time monitoring of inherent or incipient chemoresistance is an unmet need to minimize or prevent treatment failures and improve outcomes. However, prior efforts to determine chemoresistance have used tumor tissue or explants and are hence not suitable for repetitive monitoring. We present findings from a large cohort perspective observational study which shows that Circulating Tumor Associated Cells (CTACs) be isolated in sufficient numbers from peripheral blood and can be profiled in vitro for chemoresistance characteristics. Methods: 15 ml of peripheral blood was obtained from 1410 breast cancer patients, of whom 719 were treatment naïve and 691 had received prior systemic therapies. Matched tumor tissue was obtained by a biopsy (post-blood collection) in a subset of 68 cases. Peripheral blood mononuclear cells (PBMCs) were isolated from all blood samples and treated with an epigenetically activating treatment medium which exerts selective cytotoxicity towards non-malignant hematolymphoid cells and allows survival of apoptosis resistant malignant CTACs, which were defined as cells which were EpCAM+, PanCK+ and CD45+/-. Viable Tumor Derived Cells (TDCs) were harvested from biopsied tumor tissue (N=68). CTACs and TDCs were treated in vitro with cytotoxic chemotherapy agents that are used in Standard of Care (SoC) treatment protocols for breast cancer as single agents or in combinations. In 68 cases, concordance in Chemoresistance Profiles (CRP) was determined between CTACs and corresponding TDCs. In 681 pretreated cases, CRP of CTACs evaluated cumulative (innate and acquired) resistance following prior exposure to chemotherapy agents. In 685 therapy naïve cases, CRP of CTACs evaluated innate chemoresistance towards chemotherapy agents. Results: Among the 68 paired samples of CTACs and TDCs, there were 733 unique combinations of CTAC-TDC-drug, among which 366 pairs (50%) were concordant for chemo-resistance, 336 pairs (46%) were concordant for absence of resistance, and 31 pairs (4%) showed absence of concordance leading to a cumulative concordance of 96% in CRP between TDC and CTACs. Among the 681 pretreated cases, resistance towards ≥1 anticancer agents was observed in 67% of the samples. Among the 685 therapy naïve cases, resistance towards ≥1 anticancer agents was observed in 39% of the samples. Conclusion: The present study shows that sufficient CTACs can be harvested from peripheral blood for meaningful non-invasive chemoresistance profiling and that the resistance profiles of CTACs are concordant with that of tumor tissue. The present approach can identify innate as well as acquired chemoresistance and can guide selection of appropriate therapies. This approach can facilitate real time monitoring of chemoresistance and therapeutic course correction to minimize the risk of treatment failures. Citation Format: Darshana Patil, Dadasaheb Akolkar, Sanket Patil, Vishakha Mhase, Sachin Apurwa, Sushant Pawar, Rutuja Bhave, Mahesh Ukade, Samruddhi Raut, Harshal Bodke, Shabista Khan, Raja Dhasarathan, Vineet Datta, Stefan Schuster, Cynthe Sims, Jatinder Bhatia, Chirantan Bose, Ajay Srinivasan, Rajan Datar. Non-invasive evaluation of chemoresistance in breast cancers using circulating tumor associated cells [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 PS4-36.

Acquired immune deficiency of cancer: Evaluation of NK cell number as a predictor of overall survival in breast cancer.

e13003 Background: Cancer specialists, be they molecular geneticists or oncology clinicians, now accept the fact that a cancer results after a deleterious mutation in the apoptosis program AND failure of the immune system, innate (non-specific) and adaptive (specific), to eliminate the now abnormal transformed cell and it's progeny. Just as the acquired immune deficiency syndrome existed as a syndrome BEFORE the HIV virus was described, the disease AIDS/HIV was designated because the virus explained the syndrome and made HIV/AIDS a disease. We believe cancer works the same way. Cancer is a failure of surveillance by the immune system which leads to a disease, one we have described as AIDS/cancer (J Immunol May 1, 2019, 202, 1S, 182.79). Methods: Commercially available laboratory analysis of peripheral blood (Quest Diagnostics) and standard treatment protocols for breast cancer. Results: The immune system can be evaluated with samples of peripheral blood where cell subsets, antibody levels, etc. are measurable. Here we present results from over 200 unselected breast cancer patients, independent of Stage. All patients were treated with standard protocols. The initial number of NK cells in peripheral blood, but not other cell subsets or immunoglobulin levels, are a, and likely the, most significant predictor for survival. Kaplan Meier survival analysis, done when 20% of the entire population had died, showed that none of the patients in the upper quartile for NK cell number had died. Survival differences, comparing the top 50% vs. bottom 50% in initial NK number. were also highly significant (P &lt; 0.05). Conclusions: We conclude that the innate immune system, reflected as numbers of NK cells in the blood are the most significant predictor of survival.

Молекулярно-генетический полиморфизм рака молочной железы

Breast cancer occupies a leading position worldwide in the structure of oncological diseases in terms of morbidity and mortality. The life expectancy of patients has increased significantly due to the development of modern treatment methods such as targeted therapy, hormone and immunotherapy. This kind of treatment became available as a result of studying the molecular genetic features of breast cancer and the emergence of new diagnostic methods for detecting molecular structures. Currently, breast cancer treatment protocols are periodically updated and changed according to the results of modern research and the emergence of a new spectrum of targeted drugs and new targets for the drugs. In this review, we summarized the achievements of modern medicine in the field of molecular genetics and the features of breast cancer pathogenesis, such as luminal types of breast cancer, androgen positive types of breast cancer, new features of Her2/neu and Ki-67 overexpression.

Evaluation of types and treatment protocols for breast cancer among Palestinian women: a retrospective study

BackgroundBreast cancer is the leading cause of cancer deaths among females in Palestine. The aims of this study were to assess the histological types of breast cancer, the stage at diagnosis, and oestrogen receptor status of women with breast cancer in the West Bank. MethodsThis retrospective study was conducted in the two major outpatient oncology clinics of the West Bank (Al-Watani Governmental Hospital in Nablus and Beit Jala Governmental Hospital). The data collection form was completed by reviewing patients' medical records. SPSS was used for data analysis. The study was approved by the Institutional Review Board of An-Najah National University and the Palestinian Ministry of Health. FindingsThe study included 400 women with an average age of 52·16 years (SD 11·56); as the number of patients with breast cancer in the country was not known, a sample size calculator was input with an estimate of breast cancer cases, as given by six oncologists. Ductal carcinoma was the most common histological type (79%; 317 of 400), followed by lobular carcinoma (15%; 60). Patients were most commonly diagnosed at stage three (27%; 106), followed by stage two (25%; 100), stage four (24%; 95), and stage one (20%; 81). Most patients (88%; 353) were not tested for BRCA1 and BRCA2 gene mutations. Among the tested patients, 5% (21) had BRCA1 or BRCA2 gene mutation. Regarding oestrogen receptor status, 249 out of 386 women (65%) for whom data were available had a positive test, and the progesterone receptor test was positive for 225 out of 385 women (58%) for whom data were available. In terms of HER2 receptor overexpression, 306 out of 381 women (80%) for whom data were available had negative test results. InterpretationThe most common type of breast cancer among Palestinian women is invasive ductal carcinoma. Approximately half of the patients were diagnosed at stage three or four, indicating that better awareness and earlier diagnosis are needed. A high percentage of patients had positive oestrogen receptor and progesterone receptor status, which makes hormone therapy an important part of treatment. FundingNone.

MBOPS: Towards A Multidimensional Business Ontology based-Premodeling System

In this paper, we propose a Multidimensional Business Ontology based-Premodeling System (MBOPS). Its knowledge-oriented core ensures an easier use and share for unambiguous business process modeling. Furthermore, the proposed (MBOPS) guarantees a good understanding level for the modelled-domain familiar designers as well as the modelled-domain non-familiar designers thanks to a Multidimensional business ontology. In order to evaluate the proposed (MBPS) and demonstrate its effectiveness, we choice the breast cancer treatment protocols as an applicative field.

Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer.

Choline kinase (ChoK) is the first enzyme of the Kennedy pathway leading to the biosynthesis of phosphatidylcholine (PtdCho), the most abundant phospholipid in eukaryotic cell membranes. EB-3D is a novel choline kinase α1 (ChoKα1) inhibitor with potent antiproliferative activity against a panel of several cancer cell lines. ChoKα1 is particularly overexpressed and hyperactivated in aggressive breast cancer. By NMR analysis, we demonstrated that EB-3D is able to reduce the synthesis of phosphocholine, and using flow cytometry, immunoblotting, and q-RT-PCR as well as proliferation and invasion assays, we proved that EB-3D strongly impairs breast cancer cell proliferation, migration, and invasion. EB-3D induces senescence in breast cancer cell lines through the activation of the metabolic sensor AMPK and the subsequent dephosphorylation of mTORC1 downstream targets, such as p70S6K, S6 ribosomal protein, and 4E-BP1. Moreover, EB-3D strongly synergizes with drugs commonly used for breast cancer treatment. The antitumorigenic potential of EB-3D was evaluated in vivo in the syngeneic orthotopic E0771 mouse model of breast cancer, where it induces a significant reduction of the tumor mass at low doses. In addition, EB-3D showed an antimetastatic effect in experimental and spontaneous metastasis models. Altogether, our results indicate that EB-3D could be a promising new anticancer agent to improve aggressive breast cancer treatment protocols.

Pattern of distant metastasis in molecular subtypes of carcinoma breast: An institutional study.

Molecular subtypes of carcinoma breast show a particular pattern of distant metastasis, the knowledge of which can help to diagnose and intervene early in the course of the disease. The aim of this study was to investigate and establish an association between the molecular subtypes of carcinoma breast and the pattern of distant metastasis. Single arm, retrospective study. Totally 400 patients of carcinoma breast (Stage I and II) were selected who were treated between January 2010 and December 2013. All these patients were treated with the standard treatment protocol for breast cancer. The estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 (HER-2) Neu status, and Ki-67 were done, and patients were classified into luminal A/B, HER-2 enriched, luminal/HER-2, and triple-negative subtypes. All patients were followed up until December 2015, and the pattern of local failure as well as distant metastasis was correlated with the molecular subtypes. A total of 143 patients developed distant metastasis and local recurrence. Bone was the most common site of metastasis overall. It was the most common type of metastasis in luminal A/B (53.3%) and luminal-HER (57.1%). Brain metastasis was most common in HER-2-enriched subtype (30.3%), whereas liver was the most common site of metastasis in HER-2-enriched subtype (45.45%). The incidence of brain metastasis was comparatively lower in luminal A/B subtype. Local recurrence was most common in HER-2-enriched subtype. The results were statistically significant for lung metastasis and local recurrence (with P = 0.004 and 0.047, respectively). A strong association exists between the molecular subtypes and the site of distant metastasis in breast cancer which can be used for greater vigilance to detect site-specific distant metastasis beforehand.

Implementation and evaluation of an Asbru-based decision support system for adjuvant treatment in breast cancer

The domain of cancer treatment is a promising field for the implementation and evaluation of a protocol-based clinical decision support system, because of the algorithmic nature of treatment recommendations. However, many factors can limit such systems’ potential to support the decision of clinicians: technical challenges related to the interoperability with existing electronic patient records and clinical challenges related to the inherent complexity of the decisions, often collectively taken by panels of different specialists. In this paper, we evaluate the performances of an Asbru-based decision support system implementing treatment protocols for breast cancer, which accesses data from an oncological electronic patient record. Focusing on the decision on the adjuvant pharmaceutical treatment for patients affected by early invasive breast cancer, we evaluate the matching of the system's recommendations with those issued by the multidisciplinary panel held weekly in a hospital.

Abstract P2-19-05: Oncoplastic breast conserving surgery with perforator flap in breast cancer patients

Abstract Purpose : Oncoplastic breast surgery has been used widely as a treatment protocol for breast cancer. Thoracodorsal artery perforator (TDAP) flap and intercostal artery perforator (ICAP) flap can provide adequate cover without sacrificing any muscle and allow closing of the donor sites in inconspicuous sites. Therefore, among the oncoplastic volume replacement techniques indicated using local flap that can adequately cover the volume of breast, TDAP and ICAP are especially suggested. This study describes the use of TDAP and ICAP flap techniques after breast conserving surgery. Methods : From March 2010 to August 2012, 38 patients with breast cancer received breast reconstruction. All patients who were selected had small- to moderate-sized defects on breasts, middle aged, and were not sensitive to scars. The TDAP flap is the first choice for performing the surgery, but if the perforator of the TDAP flap is not found, a dissection toward the anterior area to find an adequate perforator is made and the serratus anterior artery perforator is normally used. Otherwise after the dissection is performed more anterior, ICAP can be used. If the perforator penetrates the LD muscle, the TDAP flap can be used. The perforator that penetrates from the serratus anterior muscle is also used in the anterior area. Otherwise, ICAP can be used in partial breast reconstruction. The TDAP flap can be applied to any defect site regardless of the size of the defect area. Results : The mean age was 44.9 years and the average follow-up interval was 6 months. The average specimen weight was 98g. Complications developed in 4 cases including 3 cases of venous congestion, though self-limited, and 1 case of wound disruption on the inframammary fold suture area. Majority of the patients were satisfied with the cosmetic result. Conclusion : Thoracodorsal artery perforator flap (TDAP) and intercostal artery perforator flap (ICAP) techniques can be reliable and useful in correcting breast deformity after breast conservation surgery, especially in patients with small- to moderate-sized defects on breasts. Key Words : intercostal artery perforator flap, thoracodorsal artery perforator flap Oncoplastic surgery, ICAP, TDAP. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-19-05.

PCN122 - Prevalence, Diagnosis & Treatment Protocols For Breast Cancer In Southern Punjab

PCN122 - Prevalence, Diagnosis & Treatment Protocols For Breast Cancer In Southern Punjab

Abstract P5-05-02: The role of cellular heterogeneity on the therapeutic response of breast cancer: Clinical insights from a hybrid multiscale computational model

Abstract Background: The therapeutic control of cancer progression critically depends on the responses of the individual cells that constitute the entire tumor mass. A key reason for poor therapeutic responses is the emergence of drug resistance due to intracellular and extracellular cellular heterogeneity that seriously impair the efficacy of chemotherapy and radiation therapy. Method: We have developed a hybrid multiscale computational model of breast cancer growth and treatment that incorporates individual cell-cycle dynamics and the effects of a changing microenvironment through the oxygen dynamics to consider optimum treatment protocols for breast cancer. In this model, the internal cell-cycle dynamics determine the growth strategy of the cancer cells, making the model more biologically relevant. This also helps classify the cancer cells according to their cell-cycle state and to analyse the effect of various cell-cycle-dependent chemotherapeutic drugs. The incorporation of oxygen dynamics within this hybrid model allows study of the effects of the microenvironment in cell-cycle regulation and drug resistance due to a hypoxia-induced quiescence (G0/G1 arrest) of the cancer cells. Furthermore, the effects of radiation therapy are included in the model using a modified linear quadratic model for the radiation damage, incorporating the effects of hypoxia and cell-cycle in determining the cell based radiosensitivity. The model is then used to study various combinations of multiple doses of cell-cycle-dependent chemotherapies and radiation therapy given that radiation may work better by the partial synchronisation of cells in a radiosensitive phase of the cell-cycle. Results: Using this computational model, we have shown that the cytotoxic effect of combination therapy is very much dependent on the timing of drug delivery, the time delay between the doses of chemotherapeutic drug and cell-cycle heterogeneity. The effectiveness of the drugs is also dependent on the spatial distribution of the tumor cell mass as this greatly influences the surrounding tumor microenvironment and drug distribution. After each dose of the chemotherapeutic drug, the changing spatial dynamics of the tumor cells redistributes the tissue oxygen and subsequently delivered drug doses within the tumor. Moreover, the cell-cycle phase-based chemotherapy also helps in favor of radiation therapy through the partial synchronisation of cells in the most radiosensitive phase of the cell-cycle. Conclusions: The incorporation of the spatial distribution of the breast cancer cells along with the internal and external cellular heterogeneity is critical to optimising scheduling strategies for chemotherapy and combined chemotherapy and radiation therapy. Overall, the computational simulation results highlight the potential usefulness of the model in developing patient-specific optimal treatment strategies. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-05-02.