Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance

Breast cancer has been shown to live in the tumor microenvironment, which consists of not only breast cancer cells themselves but also a significant amount of pathophysiologically altered surrounding stroma and cells. Diverse components of the breast cancer microenvironment, such as suppressive immune cells, re-programmed fibroblast cells, altered extracellular matrix (ECM) and certain soluble factors, synergistically impede an effective anti-tumor response and promote breast cancer progression and metastasis. Among these components, stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways, whereas the ECM features biochemical and biomechanical changes. However, triple-negative breast cancer (TNBC), the most aggressive subtype of this disease that lacks effective therapies available for other subtypes, is considered to feature a unique microenvironment distinct from that of other subtypes, especially compared to Luminal A subtype. Because these changes are now considered to significantly impact breast cancer development and progression, these unique alterations may serve as promising prognostic factors of clinical outcome or potential therapeutic targets for the treatment of TNBC. In this review, we focus on the composition of the TNBC microenvironment, concomitant distinct biological alteration, specific interplay between various cell types and TNBC cells, and the prognostic implications of these findings.

MUC1-positive circulating tumor cells and MUC1 protein predict chemotherapeutic efficacy in the treatment of metastatic breast cancer

Chemotherapy plays an important role in the treatment of metastatic breast cancer. It is important to monitor chemotherapeutic efficacy, to find a simple and efficient tool to guide treatment, and to predict the efficacy of treatment in a timely and accurate manner. This study aimed to detect mucin-1 (MUC1) - positive circulating tumor cells and MUC1 protein in the peripheral blood of patients with metastatic breast cancer and to investigate their relationship to chemotherapeutic efficacy. MUC1 mRNA was detected in the peripheral blood of 34 patients with newly diagnosed metastatic breast cancer by reverse transcription- polymerase chain reaction. The positive rates of MUC1 mRNA were 88.2% before chemotherapy and 70.6% after chemotherapy, without a significant difference (P = 0.564); MUC1 mRNA expression before chemotherapy had no correlation with treatment effectiveness (P = 0.281). The response rate of MUC1 mRNA -negative patients after first-cycle chemotherapy was significantly higher (P = 0.009) and the progression-free survival (PFS) was clearly longer than those of MUC1 mRNA-positive patients (P = 0.095). MUC1 protein in peripheral blood plasma was detected by an ELISA competitive inhibition assay. The patients with decreased MUC1 protein after chemotherapy had a significantly longer PFS than those with elevated MUC1 protein (P = 0.044). These results indicate that the outcomes of MUC1 mRNA - negative patients after chemotherapy are better than those of MUC1 mRNA-positive patients. In addition, patients with decreased expression of MUC1 protein have a better PFS.

High Expression of p300 in Human Breast Cancer Correlates with Tumor Recurrence and Predicts Adverse Prognosis

Objective：Transcriptional coactivator p300 has been shown to play a variety of roles in the transcription process and mutation of p300 has been found in certain types of human cancers.However,the expression dynamics of p300 in breast cancer （BC） and its effect on BC patients＇ prognosis are poorly understood.Methods：In the present study,the methods of tissue microarray and immunohistochemistry （IHC） were used to investigate the protein expression of p300 in BCs.Receiver operating characteristic （ROC） curve analysis,Spearman＇s rank correlation,Kaplan-Meier plots and Cox proportional hazards regression model were utilized to analyze the data.Results：Based on the ROC curve analysis,the cutoff value for p300 high expression was defined when the H score for p300 was more than 105.High expression of p300 could be observed in 105/193 （54.4%） of BCs,in 6/25 （24.0%） of non-malignant breast tissues,respectively （P=0.004）.Further correlation analysis showed that high expression of p300 was positively correlated with higher histological grade,advanced clinical stage and tumor recurrence （P0.05）.In univariate survival analysis,a significant association between high expression of p300 and shortened patients＇ survival and poor progression-free survival was found （P0.05）.Importantly,p300 expression was evaluated as an independent prognostic factor in multivariate analysis （P0.05）.Conclusion：Our findings provide a basis for the concept that high expression of p300 in BC may be important in the acquisition of a recurrence phenotype,suggesting that p300 high expression,as examined by IHC,is an independent biomarker for poor prognosis of patients with BC.

Breast cancer as photodynamic therapy target: Enhanced therapeutic efficiency by overview of tumor complexity

Photodynamic therapy is a minimally invasive and clinically approved procedure for eliminating selected malignant cells with specific light activation of a photosensitizer agent. Whereas interstitial and intra-operative approaches have been investigated for the ablation of a broad range of superficial or bulky solid tumors such as breast cancer, the majority of approved photodynamic therapy protocols are for the treatment of superficial lesions of skin and luminal organs. This review article will discuss recent progress in research focused mainly on assessing the efficacies of various photosensitizers used in photodynamic therapy, as well as the combinatory strategies of various therapeutic modalities for improving treatments of parenchymal and/or stromal tissues of breast cancer solid tumors. Cytotoxic agents are used in cancer treatments for their effect on rapidly proliferating cancer cells. However, such therapeutics often lack specificity, which can lead to toxicity and undesirable side effects. Many approaches are designed to targettumors. Selective therapies can be established by focusing on distinctive intracellular(receptors, apoptotic pathways, multidrug resistance system, nitric oxidemediated stress) and environmental(glucose, pH) differences between tumor and healthy tissue. A rational design of effective combination regimens for breast cancer treatment involves a better understanding of the mechanisms and molecular interactions of cytotoxic agents that underlie drug resistance and sensitivity.

Tumor infiltrating lymphocytes in triple negative breast cancer receiving neoadjuvant chemotherapy

AIM To determine influence of neoadjuvant-chemotherapy(NAC) over tumor-infiltrating-lymphocytes(TIL) intriple-negative-breast-cancer(TNBC).METHODS TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de Enfermedades Neoplasicas from 2005 to 2010. Immunohistochemistry staining for CD3, CD4, CD8 and FOXP3 was performed in tissue microarrays(TMA) sections. Evaluation of H/E in full-face and immunohistochemistry in TMA sections was performed in pre and post-NAC samples. STATA software was used and P value < 0.05 was considered statistically significant. RESULTS Higher TIL evaluated in full-face sections from pre-NAC tumors was associated to pathologic-complete-response(pCR)(P = 0.0251) and outcome(P = 0.0334). TIL evaluated in TMA sections showed low level of agreement with full-face sections(ICC = 0.017-0.20) and was not associated to pCR or outcome. TIL in post-NAC samples were not associated to response or outcome. PostNAC lesions with pC R had similar TIL levels than those without pCR(P = 0.6331). NAC produced a TIL decrease in full-face sections(P < 0.0001). Percentage of TIL subpopulations was correlated with their absolute counts. Higher counts of CD3, CD4, CD8 and FOXP3 in pre-NAC samples had longer disease-free-survival(DFS). Higher counts of CD3 in pre-NAC samples had longer overallsurvival. Higher ratio of CD8/CD4 counts in pre-NAC was associated with pCR. Higher ratio of CD4/FOXP3 counts in pre-NAC was associated with longer DFS. Higher counts of CD4 in post-NAC samples were associated with pCR.CONCLUSION TIL in pre-NAC full-face sections in TNBC are correlated to longer survival. TIL in full-face differ from TMA sections, absolute count and percentage analysis of TIL subpopulation closely related.

Pattern response of dendritic cells in the tumor microenvironment and breast cancer

Breast cancer(BC) is the most common malignant neoplasm and the cause of death by cancer among women worldwide. Its development, including malignancy grade and patient prognosis, is influenced by various mutations that occur in the tumor cell and by the immune system's status, which has a direct influence on the tumor microenvironment and, consequently, on interactions with non-tumor cells involved in the immunological response. Among the immune response cells, dendritic cells(DCs) play a key role in the induction and maintenance of anti-tumor responses owing to their unique abilities for antigen cross-presentation and promotion of the activation of specific lymphocytes that target neoplasic cells. However, the tumor microenvironment can polarize DCs, transforming them into immunosuppressive regulatory DCs, a tolerogenicphenotype which limits the activity of effector T cells and supports tumor growth and progression. Various factors and signaling pathways have been implicated in the immunosuppressive functioning of DCs in cancer, and researchers are working on resolving processes that can circumvent tumor escape and developing viable therapeutic interventions to prevent or reverse the expression of immunosuppressive DCs in the tumor microenvironment. A better understanding of the pattern of DC response in patients with BC is fundamental to the development of specific therapeutic approaches to enable DCs to function properly. Various studies examining DCs immunotherapy have demonstrated its great potential for inducing immune responses to specific antigens and thereby reversing immunosuppression and related to clinical response in patients with BC. DCbased immunotherapy research has led to immense scientific advances, both in our understanding of the antitumor immune response and for the treatment of these patients.

Circulating Tumor Cells in Metastatic Breast Cancer:Monitoring Response to Chemotherapy and Predicting Progression-Free Survival

Objective:The purpose of this study is to explore RT-PCR method to set up the examination platform for detecting circulating tumor cells(CTC) in peripheral blood from metastatic breast cancer patients.The primary endpoint is to find out the correlation of existence of CTC with clinical responses and progression-free survival(PFS).Methods:The breast cancer cell line MCF-7 was serially diluted into the peripheral blood from 45 healthy donors to set up the sensitivity of RT-PCR assay.The expression of CK19 mRNA was amplified from both 49 patients and 45 healthy donors respectively.The CK19 protein quantity from plasma was measured by competitive inhibition ELISA assay.Results:The sensitivity of RT-PCR could reach 1/106?107 white blood cells with specificity of 95.6%.The objective response rate(ORR) of patients with CK19 mRNA-negative undertaken one cycle chemotherapy was significantly higher than those with positive(P0.0001).PFS among CK19 mRNA-negative patients was also increased,although there was no significance(P=0.098).The results of ELISA assay showed that CK19 protein was decreased significantly after one cycle chemotherapy,which gave rise to a little higher ORR(P=0.015) and increased PFS(P=0.016).Conclusion:Patients with unamplified CK19 mRNA after one cycle chemotherapy could achieve better radiographic evaluation and increased PFS,which was showed to be of consistency with the CK19 protein assay among the patients treated.

Combined peripheral natural killer cell and circulating tumor cell enumeration enhance prognostic efficiency in patients with metastatic triple-negative breast cancer

Objective：Triple-negative breast cancer（TNBC）is a heterogeneous disease with poor prognosis.Circulating tumor cells（CTCs）are a promising predictor for breast cancer prognoses but their reliability regarding progression-free survival（PFS）is controversial.We aim to verify their predictive value in TNBC.Methods：In present prospective cohort study,we used the Pep@MNPs method to enumerate CTCs in baseline blood samples from 75 patients with TNBC（taken at inclusion in this study）and analyzed correlations between CTC numbers and outcomes and other clinical parameters.Results：Median PFS was 6.0（range：1.0–25.0）months for the entire cohort,in whom we found no correlations between baseline CTC status and initial tumor stage（P=0.167）,tumor grade（P=0.783）or histological type（P=0.084）.However,among those getting first-line treatment,baseline CTC status was positively correlated with ratio of peripheral natural killer（NK）cells（P=0.032）,presence of lung metastasis（P=0.034）and number of visceral metastatic site（P=0.037）.Baseline CTC status was predictive for PFS in first-line TNBC（P=0.033）,but not for the cohort as a whole（P=0.118）.This prognostic limitation of CTC could be ameliorated by combining CTC and NK cell enumeration（P=0.049）.Conclusions：Baseline CTC status was predictive of lung metastasis,peripheral NK cell ratio and PFS in TNBC patients undergoing first-line treatment.We have developed a combined CTC-NK enumeration strategy that allows us to predict PFS in TNBC without any preconditions.

Presence of circulating tumor cells is associated with metabolic-related variables in postoperative patients with early-stage breast cancer

Objective：Although circulating tumor cells（CTCs）have been well-established as promising prognostic biomarkers in both early breast cancer and metastatic settings,little is known regarding the prognostic relevance of CTCs in the long-term postoperative monitoring of patients with non-metastatic breast cancer（non-MBC）.In this study,we investigated the associations of CTCs with clinicopathological features and metabolic-related variables,such as obesity and hyperglycemia.Methods：In this retrospective study,we recruited 264 patients with postoperative stage Ⅰ–Ⅲ breast cancer at Guangdong General Hospital from January 2009 to December 2015.The prevalence and number of CTCs were assessed using the Cell Search System at a median time of 19.0 months[interquartile range（IQR）,7.8–33.0]after surgery.The CTC assay results were correlated with the clinicopathological features and metabolic-related variables.A multivariate logistic regression analysis was performed to further determine the independent predictors of CTCs.Results：CTCs were detected in 10.6%of all patients.The positive rate of CTCs in patients with infiltrating ductal carcinoma was lower than that in patients with other pathological types（9.0%vs.28.6%,P=0.020）.More importantly,the presence of CTCs was correlated with blood glucose level（P=0.015）and high-density lipoprotein level（P=0.030）.The multivariate logistic regression analysis showed that the pathological type[odds ratio（OR）：1.757,95%CI：1.021–3.023;P=0.042]and blood glucose level（OR：1.218,95%CI：1.014–1.465;P=0.035）were independent predictors of the presence of CTCs.Conclusions：This study revealed potential associations between CTCs and metabolic-related factors in Chinese patients with non-MBC and supports the hypothesis that metabolic dysfunction in breast cancer patients might influence the biological activity of metastatic breast cancer,leading to a higher prevalence of CTCs.

Association between Up-regulation of Fas Ligand Expression and Apoptosis of Tumor-infiltrating Lymphocytes in Human Breast Cancer

In order to study the significance of FasL expression in immune escape of breast cancer, FasL protein expression and the number of tumor-infiltrating lymphocytes （TILs） in 40 specimens of breast cancer were detected by immunohistochemitry. The expression of FasL mRNA was measured by in situ hybridization in the consecutive tissue slices of 40 breast cancers respectively. By using terminal deoxynucleotidyl transferase-mediaed dUTP nick end labeling （TUNEL）, apoptotic cells were detected in 40 specimens of breast cancer. The expression of FasL was detected in all 40 specimens to varying degrees. In the consecutive tissue slices, the location of expression of FasL protein corresponded with that of FasL mRNA. In those with FasL extensive expression, the number of TILs was less （P〈0.05）, the apoptotic index （AI） of TILs was higher and the AI of tumor cells was lower （P〈0.01） than those with FasL weak expression respectively. The AI of TILs was correlated with that of tumor cells （r=-0.629, P〈0.01）. In conclusion, breast cancer cells can induce the apoptosis of TILs through the expression of FasL, which can counterattack the immune system. This may be a mechanism of immune evasion in breast cancer.

The Effect of Hypofractionated Radiotherapy on Tumor Control and Survival in Patients with High-Risk Breast Cancer

BACKGROUND Adjuvant radiotherapy is given following surgery in breast cancer patients. Hypofractonated radiotherapy can significantly reduce the waiting time for radiotherapy, working load on machines, patient visits to radiotherapy departments and medical costs. Material and Methods 244 patients with high-risk breast cancer (stage IIB, stage III and stage IA with any of the following criteria: lymphovascular invasion, hormonal receptor negative, young age) who underwent Breast conservative surgery (BCS) or Modified radical mastectomy (MRM) were enrolled in this study. All patients received adjuvant radiotherapy with different hypofractionation schedules either 3900 cGY/13 fractions or 4240 cGY/16 fractions or 4005 cGY/15 fractions using linear accelerator with 6 MV photon beam. Lateral/Medial tangential and Ipsilateral supraclavicular fields were employed and the ipsilateral axilla was also irradiated if required to the same dose with posteroanterior field. Patients were followed every 3 mons for the first 2 years and every 6 mons thereafter. Outcomes were analyzed in terms of tumor control and survival. Results 244 patients with high-risk breast cancer requiring postoperative radiotherapy to the intact breast or chest wall were treated. The mean age was 48 years (range 28 - 69 years). The 5-year locoregional free survival of all patients was 93.8% the local relapse reported in 15 patients (6.2%) 7 patients at site of operated scar & 8 patients at the regional lymph nodes. The median follow up period was 75 months ranged from 49 to 102 months. Distant metastasis free survival was 92.2%, the distant metastasis reported in 19 patients which represent (7.8%) of all patients, median survival is 75 months ranged from 49 to 102 months and overall survival was 88.6%. Conclusion It is concluded that hypofractionated radiotherapy is a simple and effective protocol in patients with high-risk breast cancer regarding tumor control and survival.

Breast Cancer Hyperthermia Treatment Based on Slotted Patch Antenna at 2.45 GHz

The present work proposed a simple model for breast cancer hyperthermia treatment at 2.45 GHz. The proposed model involves nine-element antennas alongside a numerical breast comprising multiple tumors. Using a coupled EM-Thermal simulation in the CST suite, the simulated results for a single antenna showed a reflection coefficient (S11) better than -47 dB and demonstrated a bandwidth of 78 MHz. The specific absorption rate (SAR) as a function of input powers was examined inside the breast tissues, where it exhibited a promising performance higher than 3 W/kg at the tumor volume when the applied power was at a reasonable level of 1.5 W whereas it was well attained under the recommend IEEE level of 1.6 W/kg through the surrounded health tissues. Taking into consideration nine-element antennas covering the breast containing two different located tumors, the maximum temperature as a function of treatment time was presented at which a resulting temperature of 43°C was obtainable within 10 minutes, favored for hyperthermia purposes. Considering the maximum power level of 1.5 W, the potential use of applying three-element antennas, simultaneously with 0.5 W, could be achieved.

Breast Cancer Detection Based on Multi-Slotted Patch Antenna at ISM Band

The present work designed and investigated a 3D basic model for breast cancer detection at the ISM band. The model consists of two multi-slotted rectangular patch antennas and a three-layer breast phantom containing two tumors. A multi-slotted antenna was designed at 2.45 GHz using CST STUDIO SUITE 2018, where the simulated results showed a return loss better than -35 dB and attended more than 77 MHz bandwidth. The diagnosis approach is based on exploiting the electrical properties (frequency dependent) of breast tissues, i.e., mass density, relative permittivity, and conductivity. Once the proposed slotted antenna radiates electromagnetic signals toward the breast model (with and without tumors), the radiation properties in terms of the scattering parameters (S11 and S21), the electrical field, the power flow, the current density, and the power loss density were altered. As a result, the values of these radiation parameters increased when tumors were implanted inside the breast model, informing the presence of cancerous tissues. Moreover, the specific absorption rate (SAR) was estimated as a function of input powers, where the proposed antenna showed a set of low SAR values compared to the IEEE standard of 1.6 W/kg, validating its potential use for diagnosing purposes. The simulated results indicated the prospective use of two slotted antennas (in the first instance) to detect multiple tumors which could be a challenging task using a single-element antenna, where the ultimate goal is to realize a compact antenna array to detect multi-tumors.

Comparison of the effects of two typesof multileaf collimators on tumor control probabilityin radiotherapy for breast cancer after conservativesurgery based on the EUD model

Objective To compute and compare the tumor control probability(TCP) of volumetric modulated arc therapy(VMAT) for breast cancer after conservative surgery based on two types of multileaf collimator(MLC) through a retrospective planning study.Methods For a group of 9 patients diagnosed with left breast cancer,VMAT plan based on Agility MLC and beam modulator(BM) MLC were designed.The prescription dose was 50 Gy covering at least 95% of the planning target volume,2 Gy per fraction.TCPs were calculated according to dose-volume histogram(DVH) analysis.Results The TCP of the BM VMAT plan was slightly higher than that of the Agility VMAT plan(94.61% vs 94.23%) but was inferior with respect to delivery efficiency;the delivery time was reduced for Agility VMAT plan by 35% compared to BM VMAT plan.Conclusion For breast cancer radiation therapy after conservative surgery,BM VMAT plans provide slightly higher TCP while the delivery of Agility VMAT plans is significantly faster than the BM VMAT plans.

Circulating tumor cells(CTCs)in breast cancer:a diagnostic tool for prognosis and molecular analysis

Metastatic breast cancer （MBC） is characterized by a combination of tumor growth, proliferation and metastatic progression and is typically managed with palliative intent. The benefit of standard systemic therapies is relatively limited and the disease is considered incurable suggesting the need to investigate the biological drivers of the various phases of the metastatic process in order to improve the selection of molecularly driven therapies. The detection, enumeration and molecular analysis of circulating tumor cells （CTCs） provide an intriguing opportunity to advance this knowledge. CTCs enumerated by the Food and Drugs Administration-cleared CellSearchTM system are an independent prognostic factor of progression- free survival （PFS） and overall survival （OS） in MBC patients. Several published papers demonstrated the poor prognosis for MBC patients that presented basal CTC count _〉5 in 7.5 mL of blood. Therefore, the enumeration of CTCs during treatment for MBC provides a tool with the ability to predict progression of disease earlier than standard timing of anatomical assessment using conventional radiological tests. During the metastatic process cancer cells exhibit morphological and phenotypic plasticity undergoing epithelial- mesenchymal transition （EMT）. This important phenomenon is associated with down regulation of epithelial marker （e.g., EpCAM） with potential limitations in the applicability of current CTCs enrichment methods. Such observations translated in a number of investigations aimed at improving our capabilities to enumerate and perform molecular characterization of CTCs. Theoretically, the phenotypic analysis of CTCs can represent a ＂liquid＂ biopsy of breast tumor that is able to identify a new potential target against the metastatic disease and advance the development and monitoring of personalized therapies.

Prognostic role of tumor budding in breast cancer

Tumor budding, defined as a small number of cancer cells observed in pathology sections detached from the main tumor mass, is a common phenomenon in cancer. It issuggested that cells in buds are in the process of actively moving away from the primary tumor in the first step of metastasis. Tumor budding has been observed in a variety of carcinomas and is best studied in colorectal cancers where it portends poor prognosis. More recently, tumor budding was found to be of prognostic significance in other cancers including breast cancer. Tumor budding in breast cancer is associated with other adverse pathologic factors, such as larger tumor size and lymphovascular invasion, but may have additional independent prognostic value. In the future, standardization of the quantification criteria for tumor budding may further aid in its adoption as a prognostic marker.

Locoregional treatment of early breast cancer with isolated tumor cells or micrometastases on sentinel lymph node biopsy

The advent of sentinel lymph-node technique has led to a shift in lymph-node staging,due to the emergence of new entities namely micrometastases(p N1mi) and isolated tumor cells [p N0(i+)].The prognostic significance of this low positivity in axillary lymph nodes is currently debated,as is,therefore its management.This article provides updates evidence-based medicine data to take into account for treatment decision-making in this setting,discussing the locoregional treatment in p N0(i+) and p N1 mi patients(completion axillary dissection,axillary irradiation with or without regional nodes irradiation,or observation),according to systemic treatment,with the goal to help physicians in their daily practice.

A Case Report of Two Primary Cancers, Breast Cancer with Adrenal Gland Metastatic and Second Primary Neuroendocrine Tumor in Colon, a Rare Case in Al-Bashir Hospital

A 68 years old female, was diagnosed as a case of right breast cancer in 2013;grade II/III according to Bloom Richardson grading, Modify radical mastectomy (MRM) was done and the pathology report showed moderately differentiated invasive ductal carcinoma (IDC), stage T3N3M0. Immunohisrochemisty (IHC) findings revealed a tumor with Triple positive. Patient refused to treat by chemotherapy. Patient was given adjuvant trastuzumab (first dose 8 mg/kg, followed by 6 mg/kg every three weeks) for the period of one year (16) cycles after which she went on regular follow up. Exemestane tab for 5 years and radiotherapy (50 gray in 25 fractions) was applying on right breast. One year and half after diagnosed primary breast cancer, patient complained from severe diarrhea 8 times per day watery contents, vomiting and suffered from lower abdominal pain. PET scan for whole body in October 2014 was done;the results showed ascending colon is highly suspicious for malignancy and moderately hypermetabolic left adrenal mass. Subtotal colectomy surgery was done, the pathology report of biopsy revealed low grade malignant neuroendocrine neoplastic lesion stage of T3N1Mo. Physician prescribed octreotide acetate 20 mg I. M monthly due to neuroendocrine lesion. In January 2016, cancer recurrence in the same right breast, IHC revealed ER+, PR&minus;, Her 2+, physician decided to change exemestane to fulvestrant 250 mg s. c for 6 cycles. Radiation therapy was applied 20 gray in 10 fractions on scar. In May 2016, CAP-CT scan result revealed two enlarged left axillary L.N and left soft tissue density adrenal mass (3.0 × 2.3). Excisional lymph node was done which revealed IDC, ER+, PR&minus;, Her 2+. Physician decided to discontinue fulvestrant and switch to exemestane 20 mg monthly. CAP-CT was done in Feb 2017;single left axillary L.N 1 cm, small hypodense lesion (spleen 4 cm), left adrenal lesion (2.2 × 2.6 cm) and osteolytic lesion were noted in iliac areas, so the physician considered those results a metastatic area from breast and prescribed lapatinib 84 tablets. Patient now onoctreotide acetate 20 mg I. M, trastuzumab 440 m, exemestane and lapatinib tablets) monthly, zoledronic acid 4 mg q 3 months, patient now still on follow up with a good condition. Conclusion: Breast cancer metastatic to left adrenal gland which is extremely rare especially when they originate from IDCs. The present case is the seventh breast cancer metastatic to the adrenal gland in the literature up to our search. Neuroendocrine tumor was happened in colon after one year and half which was a rare second primary malignancy (SPM) among female breast cancer.

Detection of the <i>PIK3CA</i>Mutation in Circulating Tumor DNA as a Possible Predictive Indicator for Poor Prognosis of Early-Stage Breast Cancer

Objectives: Circulating tumor DNA (ctDNA) is shown to provide the real-time genomic information of metastatic breast cancer. This study elucidates the clinico-pathological significance of ctDNA in early-stage breast cancer using the PIK3CA mutation as an indicator. Materials and Methods: Twenty-seven primary breast cancers without metastasis were surgically resected and pathologically diagnosed at the University of Tokyo Hospital, Japan. Genomic DNA of primary tumor was extracted from formalin-fixed and paraffin-embedded specimens. ctDNA was extracted from fresh-frozen plasma from patients. The PIK3CA mutations at E542K, E545K and H1047R were examined by Sanger sequencing or droplet digital PCR in 27 tumors and pre- and post-surgery plasma. Results: The PIK3CA mutations were detected in 13 (48%) of 27 primary tumors. These mutations did not significantly correlate with specific clinico-pathological characteristics of tumors. When ctDNA was examined, 4 (33%) of 12 cases carrying the mutated PIK3CA showed the identical mutation in pre-surgery plasma and 2 (50%) of them showed the identical mutations in post-surgery plasma. Interestingly, in these 2 cases in pathological stages IIIA and IA, fractional abundance of the mutated PIK3CA alleles to the total alleles in pre-surgery ctDNA was around 1% or more and was higher than that of the other two cases without PIK3CA mutations in post-surgery ctDNA. Conclusions: The PIK3CA mutation in ctDNA is detectable even in a subset of early-stage breast cancer. Furthermore, fractional abundance of the mutated PIK3CA in pre-surgery ctDNA could provide a possible predictive indicator for tumor burden and for choosing the appropriate adjuvant treatment of breast cancer.

A Totally Absorbable Multilayer PLGA Implant Device Containing Doxorubicin Inhibited Tumor Growth and Metastasis without Systemic Toxicity in Murine Breast Cancer and an Ideal Pharmacological Paradigm for Regional Chemotherapy

We hypothesize that a cylinder implant made of multilayer Poly-lactic-co-glycolic-acid (PLGA) membrane can be a method for controlled and extended drug release. We fashioned a multilayer cylindrical implant termed STID100 that released doxorubicin for 3 weeks in an orthotopic 4T1 breast cancer model in Balb/C mice. This implant starts as a thin doxorubicin-embedded PLGA membrane, and is then rolled into a cylinder containing an air gap between the membrane layers. Its controlled sustained release delivered 2× the amount of the intravenous (IV) equivalent of doxorubicin, inhibited the primary tumor, and prevented lung metastasis. Importantly it did not cause weight loss, splenomegaly, or cardiac toxicity vs systemically administrated doxorubicin. This favorable safety profile is further substantiated by the finding of no detectable plasma doxorubicin in multiple time points during the 3-week period, and low tumor doxorubicin concentration. The implant system delivered to the specification of an ideal pharmacological paradigm might offer a better coverage of the local tumor, significantly preventing metastatic spread with less drug toxicity to many vital organs, compared to the traditional pharmacology of IV route. The profile of STID made it an attractive therapeutic alternative in metastatic tumor prevention, pain management and many other diverse clinical scenarios.