Locally Advanced Breast Cancer Research Articles

Systematic Evaluation of HLA-G 3'Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome.

Despite major improvements in diagnostics and therapy in early as well as in locally advanced breast cancer (LABC), metastatic relapse occurs in about 20% of patients, often explained by early micro-metastatic spread into bone marrow by disseminated tumor cells (DTC). Although neoadjuvant chemotherapy (NACT) has been a successful tool to improve overall survival (OS), there is growing evidence that various environmental factors like the non-classical human leukocyte antigen-G (HLA-G) promotes cancer invasiveness and metastatic progression. HLA-G expression is associated with regulatory elements targeting certain single-nucleotide polymorphisms (SNP) in the HLA-G 3’ untranslated region (UTR), which arrange as haplotypes. Here, we systematically evaluated the impact of HLA-G 3’UTR polymorphisms on disease status, on the presence of DTC, on soluble HLA-G levels, and on therapy and disease outcome in non-metastatic LABC patients. Although haplotype frequencies were similar in patients (n = 142) and controls (n = 204), univariate analysis revealed that the UTR-7 haplotype was related to patients with low tumor burden, whereas UTR-4 was associated with tumor sizes >T1. Furthermore, UTR-4 was associated with the presence of DTC, but UTR-3 and UTR-7 were related to absence of DTC. Additionally, increased levels of soluble HLA-G molecules were found in patients carrying UTR-7. Regarding therapy and disease outcome, univariate and multivariate analysis highlighted UTR-1 or UTR-2 as a prognostic parameter indicative for a beneficial course of disease in terms of complete response towards NACT or progression-free survival (PFS). At variance, UTR-4 was an independent risk factor for a reduced OS besides already known parameters. Taken into account the most common HLA-G 3’UTR haplotypes (UTR-1–UTR-7, UTR-18), deduction of the UTR-1/2/4 haplotypes to specific SNPs revealed that the +3003C variant, unique for UTR-4, seemed to favor a detrimental disease outcome, while the +3187G and +3196G variants, unique for UTR-1 or UTR-2, were prognostic parameters for a beneficial course of disease. In conclusion, these data suggest that the HLA-G 3’UTR variants +3003C, +3187G, and +3196G are promising candidates for the prediction of therapy and disease outcome in LABC patients.

Prognostic value of pre-treatment inflammatory markers in patients with locally advanced breast cancer (LABC) from Saudi Arabia

Prognostic value of pre-treatment inflammatory markers in patients with locally advanced breast cancer (LABC) from Saudi Arabia

Angiogenesis versus Metabolic Imaging in Locally Advanced Breast Cancer Patients - A Comparative Study.

Purpose:The comparison of angiogenesis imaging (Ga-68-DOTA-Arginine-Glycine-Aspartic Acid [RGD]) positron emission tomography/computed tomography [PET/CT]) with metabolic imaging (F-18 fluorodeoxyglucose [FDG] PET/CT) in primary staging and response assessment to neoadjuvant chemotherapy (NACT) in locally advanced breast cancer (LABC) patients.Methods:In this prospective study, 85 female patients with LABC were subjected to two PET/CT studies (Ga-68-DOTA-RGD2 and F-18 FDG) within 1 week of each other. Thirty patients had repeat studies 4 weeks after completing eight cycles of NACT. Response assessment was done by RECIST 1.1 criteria.Results:Ga-68-DOTA-RGD2 and F-18 FDG uptake in the primary tumor were seen in all patients. Ipsilateral axillary and internal mammary lymph nodes were detected in 77 (90.5%) versus 80 (94.1%) and 22 (25.8%) versus 27 (31.7%) patients on Ga-68-DOTA-RGD2 and F-18 FDG scans, respectively. Ipsilateral supra-clavicular lymph nodes and skeletal lesions were noted in 17 (20%) versus 21 (24.7%) patients and 23 (27.0%) versus 24 (28.2%) patients on Ga-68-DOTA-RGD2 versus F-18 FDG studies, respectively. However, the Ga-68-DOTA-RGD2 did not show uptake in F-18 FDG avid liver lesions (LLs) in 10 patients, adrenal lesion in one patient, mediastinal lymph nodes in 2 patients, lung nodules, and pleural soft-tissue deposits, each in one patient. In response assessment, 23 and 25 patients had concordance with RECIST1.1 criteria on F-18 FDG and Ga-68-DOTA-RGD2 scans, respectively. However, there were discordant results in four patients on Ga-68-DOTA-RGD2 scan and two patients on F-18 FDG scans.Conclusion:Metabolic imaging is better in primary staging and chemotherapy response assessment than angiogenesis imaging in LABC patients. The latter may miss the metastatic soft-tissue deposits, adrenal, and LLs.

Multiobjective Optimization of Microwave Phased Array Excitation for Targeted Tissue Heating With Reduced Channel Power in Hyperthermia Treatment Planning

The multiobjective genetic algorithm (MOGA) is proposed for determining phased array (PA) excitation to selectively heat the tumor with minimal healthy tissue hotspot. Power absorption indicators, such as mean specific absorption rate (SAR) in tumor target (SAR <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">targ</sub> ), hotspot to tumor quotient (HTQ), average power absorption ratio (aPA ratio), and 50% iso-SAR tumor coverage (TC <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">50</sub> ), were combined in pairs as an objective function in MOGA. Coupled electromagnetic (EM) and thermal simulations of the heterogeneous breast with locally advanced breast cancer (LABC) were used for evaluating MOGA and single-objective GA (SOGA)-based treatment plans; 25 LABC patient models with varying breast (144.66–1339.3 cc) and tumor (10.53–88.88 cc) volumes and tumor location were employed. The treatment plans were assessed using aforementioned SAR indicators, steady-state thermal metrics in tumors, healthy tissue hotspots in the hyperthermia range (40 °C–44 °C), and channel power consumption of the PA. Among the treatment plans, MOGA with [1/SAR <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">targ</sub> , HTQ] <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">obj</sub> yielded 104.63% rise in SAR <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">targ</sub> across patients with thermal metrics comparable to SOGA with HTQ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">obj</sub> [state of the art (SoA)]. MOGA with [1/SAR <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">targ</sub> , HTQ] <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">obj</sub> required only 50.5% channel power compared to the SoA, as the tumor was efficiently heated without wasting power in the healthy tissues. This is a significant contribution to developing an affordable PA system.

Significance of Neutrophil-Lymphocyte Ratio and Trombocyte-Lymphocyte Ratio in Predicting Complete Pathological Response in Patients with Local Advanced Breast Cancer

Significance of Neutrophil-Lymphocyte Ratio and Trombocyte-Lymphocyte Ratio in Predicting Complete Pathological Response in Patients with Local Advanced Breast Cancer

BECN1 protein expression is associated with poor survival in triple negative locally advanced breast cancer.

The role that Beclin 1 (BECN1) plays in the development and progression of cancer mediated by autophagy, as well as its differential expression in breast cancer cell lines and mammary tumor tissue according to the molecular subtype, has been demonstrated. The objective of this study was to evaluate the association of BECN1 cytoplasmic expression with clinical and pathologic response, recurrence, disease-free survival (DFS) and overall survival (OS) in patients with locally advanced breast cancer (LABC), according to immunophenotype. 64 patients with non-triple negative LABC and 20 patients with triple negative LABC who received preoperative chemotherapy were included in an observational, analytical and retrospective study to evaluate the cytoplasmic expression of BECN1 protein by immunohistochemistry in microarrays of breast cancer tissue obtained before treatment. Association between BECN1 and clinicopathological characteristics, clinical and pathologic response to preoperative chemotherapy and recurrence, were analyzed using Chi-square or Fisher's exact test. Postoperative DFS and OS were assessed by Kaplan-Meir curves, and the difference according to BECN1 expression was evaluated using the log-rank test. The bivariate analysis was performed using the Cox Proportional Hazards Model. A p-value of < 0.05 was considered statistically significant. BECN1 staining revealed positive expression in 62.5% of patients with non-triple negative and 60.0% with triple negative LABC. No association was observed between BECN1 expression and clinical or pathological response or recurrence. An association of the BECN1 expression with lower OS in triple negative breast cancer was found (HR = 5.19; 95% CI 1.12-24.02; p = 0.035). Results showed an association of the cytoplasmic expression of BECN1 with a lower OS, which could be a poor prognostic biomarker in triple negative LABC.

Effect of Inflammatory Markers on the Pathologic Complete Response in the Neoadjuvan Treatment of HER-2 Positive Local Advanced Breast Cancer

Effect of Inflammatory Markers on the Pathologic Complete Response in the Neoadjuvan Treatment of HER-2 Positive Local Advanced Breast Cancer

A Study Protocol for Assessment of Outcomes of Adjuvant versus Neoadjuvant Chemotherapy in Stage-IIIA of Breast Cancer

Background: Locally advanced breast cancer (LABC) includes stage III along with stage IV breast cancer and consists of operable and inoperable advanced breast cancer and metastatic disease. LABC is among the most common breast malignancies with increasing incidence now a days. In India, it accounts for 30-35% of all cases. The use of neo-adjuvant chemotherapy (NACT) for the treatment of LABC offers benefits like initiation of early systemic treatment, the drugs can be delivered via intact vasculature, the tumours can be down staged which helps to convert inoperable tumours into operable tumours and renders tumours suitable for breast conserving surgery (BCS). This study is aimed to compare the outcomes of neoadjuvant and adjuvant chemotherapy using taxane based drugs for locally advanced breast cancers.&#x0D; Methodology: This was an observational study will be undertaken in AVBRH. Total 40 patients will be enrolled in the study. Confirmed patients of breast malignancy either by FNAC or true cut histopathology with advanced breast malignancy confirmed on FNAC or true cut histopathology and planned for neo-adjuvant chemotherapy will be included in the study. For all the patients HER2, PR and ER status will be checked via immunohistopathology. Data will be analysed with appropriate statistical tests.&#x0D; Results: We expect neoadjuvant chemotherapy to have better surgical outcomes compared to neoadjuvant chemotherapy. &#x0D; Conclusion: Neoadjuvant paclitaxel based chemotherapy can be a better option for patients undergoing BCS (breast conserving surgery).

Positive ROS (Reactive Oxygen Species) Modulator Engineered Device Support Skin Treatment in Locally Advanced Breast Cancer (LABC) Enhancing Patient Quality of Life.

The development of research in genetic and biochemical fields has made it possible to investigate certain metabolic aspects of the microenvironment of chronic skin lesions, including altered cell signalling, highlighting its importance in determining the blockage of repair processes. The purpose of this prospective observational study is to evaluate the efficacy of a medical device consisting of a polyester scaffold enriched with an oleic matrix with controlled release of ROS in the management of LABC skin lesions. During the period from October 2018 to March 2020, 20 patients with locally advanced breast cancer were enrolled and ten were treated with the devices abovementioned. After 30 days of treatment all patients treated reported a general improvement in local conditions with reduction in ulceration area, exudate and odour. The results suggest that the application of these devices even in particular conditions (healthy and neoplastic tissue) does not lead to the onset of negative effects due to the release of ROS, though their role in tissue repair requires further study to fully understand their potential and increase the fields of application of the device by exploiting its modulation capabilities.

Locally advanced breast cancer

Locally advanced breast cancer (LABC) is defined here as inoperable breast adenocarcinoma without distant metastases. Patients with LABC require a multidisciplinary approach. Given the risk of distant metastasis, staging exams are necessary. The incidence of LABC (stages IIIB and IIIC) has decreased in recent years. LABC has rarely been investigated separately: patients with LABC have participated both in clinical trials of palliative and of neoadjuvant therapy. Most trials did not analyze responses and long-term outcomes independently; thus, the treatment of patients with LABC is extrapolated from studies of patients with less or more advanced disease. Pathologic confirmation and molecular profiling are essential for the choice of neoadjuvant chemotherapy. Preoperative endocrine therapy may be considered in certain clinical situations; the addition of a CDK4/6 inhibitor is being investigated. HER2 positive LABCs are targeted with anti-HER2 agents combined with chemotherapy. PD-1 and PD-L1 antibodies in ‘triple-negative’ LABC are promising. Excellent responses to neoadjuvant therapy enable conservative surgery in many patients; however, inflammatory breast cancer may still indicate mastectomy. Postoperative radiotherapy is usually indicated. Target volumes include breast/chest wall, axillary, supraclavicular and internal mammary nodal basins. Preoperative radiation therapy can be useful in patients without response to systemic therapies. Palliative surgery for poor responders after neoadjuvant systemic and radiation therapy can be considered. Multidisciplinary teams can optimize local control and prevent relapses. However, modest improvement in survival was achieved between 2000 and 2014 underscoring the unmet need in patients with LABC who will benefit from specific research efforts in this disease entity.

Radiomics in predicting recurrence for patients with locally advanced breast cancer using quantitative ultrasound.

Background: The purpose of the study was to investigate the role of pre-treatment quantitative ultrasound (QUS)-radiomics in predicting recurrence for patients with locally advanced breast cancer (LABC).Materials and Methods: A prospective study was conducted in patients with LABC (n = 83). Primary tumours were scanned using a clinical ultrasound device before starting treatment. Ninety-five imaging features were extracted-spectral features, texture, and texture-derivatives. Patients were determined to have recurrence or no recurrence based on clinical outcomes. Machine learning classifiers with k-nearest neighbour (KNN) and support vector machine (SVM) were evaluated for model development using a maximum of 3 features and leave-one-out cross-validation.Results: With a median follow up of 69 months (range 7–118 months), 28 patients had disease recurrence (local or distant). The best classification results were obtained using an SVM classifier with a sensitivity, specificity, accuracy and area under curve of 71%, 87%, 82%, and 0.76, respectively. Using the SVM model for the predicted non-recurrence and recurrence groups, the estimated 5-year recurrence-free survival was 83% and 54% (p = 0.003), and the predicted 5-year overall survival was 85% and 74% (p = 0.083), respectively.Conclusions: A QUS-radiomics model using higher-order texture derivatives can identify patients with LABC at higher risk of disease recurrence before starting treatment.

Pathological responses and survival outcomes in patients with locally advanced breast cancer after neoadjuvant chemotherapy: a single-institute experience

BackgroundPathological complete response (pCR) is a surrogate for the efficacy of neoadjuvant chemotherapy (NCT) in locally advanced breast cancer (LABC). We analyzed the predictive clinical factors for pathological responses and survival outcomes in a cohort of Egyptian patients.MethodsWe evaluated the medical records of patients with breast cancer who received NCT in our academic institute. Survival curves were estimated with the Kaplan-Meier method. Cox proportional models were used for multiple regression analysis.ResultsOur cohort included 368 patients with a median age of 48 years (range 21–70). The median follow-up time was 3 years. The clinical tumor stage (T3–4) represented 58%, with 80% having positive axillary nodes. The luminal subgroup prevailed by 68%. The objective response rate (ORR) reached 78%, and 16% of patients achieved pCR. The clinical node stage and optimal chemotherapy were associated with higher ORR (p = 0.035 and p = 0.001, respectively). Predictors of pCR were clinical T-stage (p = 0.026), high Ki-67 index > 20 (p = 0.05), and receiving optimal chemotherapy (p = 0.014). The estimated 3-year disease free-survival (DFS) was 53%. Receptor status, achieving ORR, and pCR were associated with better DFS with hazard ratios of 0.56, p = 0.008; 0.38, p = 0.04; and 0.28, p = 0.007, respectively.ConclusionsLuminal tumors still draw benefit from neoadjuvant chemotherapy in terms of clinical response and breast conservative surgery. Treatment escalation to those who did not achieve pCR requires more investigation, given a higher recurrence rate in real-world experience.

Machine Learning Frameworks to Predict Neoadjuvant Chemotherapy Response in Breast Cancer Using Clinical and Pathological Features.

Neoadjuvant chemotherapy (NAC) is used to treat locally advanced breast cancer (LABC) and high-risk early breast cancer (BC). Pathological complete response (pCR) has prognostic value depending on BC subtype. Rates of pCR, however, can be variable. Predictive modeling is desirable to help identify patients early who may have suboptimal NAC response. Here, we test and compare the predictive performances of machine learning (ML) prediction models to a standard statistical model, using clinical and pathological data. Clinical and pathological variables were collected in 431 patients, including tumor size, patient demographics, histological characteristics, molecular status, and staging information. A standard multivariable logistic regression (MLR) was developed and compared with five ML models: k-nearest neighbor classifier, random forest (RF) classifier, naive Bayes algorithm, support vector machine, and multilayer perceptron model. Model performances were measured using a receiver operating characteristic (ROC) analysis and statistically compared. MLR predictors of NAC response included: estrogen receptor (ER) status, human epidermal growth factor-2 (HER2) status, tumor size, and Nottingham grade. The strongest MLR predictors of pCR included HER2+ versus HER2- BC (odds ratio [OR], 0.13; 95% CI, 0.07 to 0.23; P < .001) and Nottingham grade G3 versus G1-2 (G1-2: OR, 0.36; 95% CI, 0.20 to 0.65; P < .001). The area under the curve (AUC) for the MLR was AUC = 0.64. Among the various ML models, an RF classifier performed best, with an AUC = 0.88, sensitivity of 70.7%, and specificity of 84.6%, and included the following variables: menopausal status, ER status, HER2 status, Nottingham grade, tumor size, nodal status, and presence of inflammatory BC. Modeling performances varied between standard versus ML classification methods. RF ML classifiers demonstrated the best predictive performance among all models.

Impact of Preoperative vs Postoperative Radiotherapy on Overall Survival of Locally Advanced Breast Cancer Patients

BackgroundThe treatment for locally advanced breast cancer (LABC) is a severe clinical problem. The postoperative radiotherapy is a conventional treatment method for patients with LABC, whereas the effect of preoperative radiotherapy on outcome of LABC remains controversial. This study aimed to examine and compare the overall survival (OS) in patients with LABC who underwent preoperative radiotherapy or postoperative radiotherapy.MethodsThis retrospective cohort study included 41,618 patients with LABC from the National Cancer Database (NCDB) between 2010 and 2014. We collected patients’ demographic, clinicopathologic, treatment and survival information. Propensity score was used to match patients underwent pre-operative radiotherapy with those who underwent post-operative radiotherapy. Cox proportional hazard regression model was performed to access the association between variables and OS. Log-rank test was conducted to evaluate the difference in OS between groups.ResultsThe estimated median follow-up of all included participants was 69.6 months (IQR: 42.84-60.22); 70.1 months (IQR: 46.85-79.97) for postoperative radiotherapy, 68.5 (IQR: 41.13-78.23) for preoperative radiotherapy, and 67.5 (IQR: 25.92-70.99) for no radiotherapy. The 5-year survival rate was 80.01% (79.56-80.47) for LABC patients who received postoperative radiotherapy, 64.08% (57.55-71.34) for preoperative radiotherapy, and 59.67% (58.60-60.77) for no radiotherapy. Compared with no radiation, patients receiving postoperative radiotherapy had a 38% lower risk of mortality (HR=0.62, 95%CI: 0.60-0.65, p<0.001), whereas those who received preoperative radiotherapy had no significant survival benefit (HR=0.88, 95%CI: 0.70-1.11, p=0.282). Propensity score matched analysis indicated that patients treated with preoperative radiotherapy had similar outcomes as those treated with postoperative radiotherapy (AHR=1.23, 95%CI: 0.88-1.72, p=0.218). Further analysis showed that in C0 (HR=1.45, 95%CI: 1.01-2.07, p=0.044) and G1-2 (AHR=1.74, 95%CI: 1.59-5.96, p=0.001) subgroup, patients receiving preoperative radiotherapy showed a worse OS than those who received postoperative radiotherapy.ConclusionsPatients with LABC underwent postoperative radiotherapy had improved overall survival, whereas no significant survival benefit was observed in patients receiving preoperative radiotherapy. Preoperative radiotherapy did not present a better survival than postoperative radiotherapy for LABC patients.

Real World Data of Response of Trastuzumab Based Chemotherapy in Locally Advanced HER2 Positive Breast Cancer from a Developing Country

Background: Data regarding pathologic response of Trastuzumab based chemotherapy in locally advanced HER2 positive breast cancer in neoadjuvant setting is scarce. Methods: A retrospective analysis was conducted from January 2014 to January 2019 at a tertiary cancer care centre in North India and 81 breast cancer patients who underwent neoadjuvant chemotherapy were included. The clinical and pathologic characteristics, response, toxicity and survival data was collected, collated and analyzed. Results: The most commonly observed tumor characteristics at baseline were clinical stage T4 (72.8%), nodal stage N2 (40.7%), invasive ductal carcinoma on histology (98.8%), grade 3 (66.7%) and hormone receptor negativity (54.3%). In terms of post treatment characteristics, a higher incidence of partial response (55.6%), post treatment tumor stage ypT0 (45.7%), nodal status ypN0 (54.3%), absence of extracapsular invasion (77.8%) and absence of pathologic complete response (pCR, 63%) were observed. pCR was attained in 30 patients and was most commonly associated with clinical tumor stage T4 (26/30), nodal stage N2-N3 (19/30), grade 3 (21/30) and hormone receptor negativity (20/30). Altogether, 19.75% had grade 3/4 adverse events. At 6 years, 86% v/s 61% patients were disease free (p=0.037) and 93% v/s 79% patients (p=0.181) were alive in the pCR and no pCR groups, respectively. Conclusion: Even in locally advanced breast cancer (LABC), Trastuzumab had good response in terms of pCR and survival outcomes. Thus, one can be encouraged to use this single HER2 blockade if dual blockade is not feasible in HER2 positive LABC in the neoadjuvant setting.

Changes in Ki67 expression and clinical response to neoadjuvant chemotherapy in locally advanced breast cancer (LABC)

Background: Locally Advanced Breast Cancer (LABC) is still the most common stage found in breast cancer patients in Indonesia. Neoadjuvant Chemotherapy (NAC) is the initial therapy and the main pillar of LABC treatment. NAC could provide less extensive surgery and improve patient’s overall survival to those who achieve a complete pathological response. Ki67 expression is a tumor biomarker representing tumor cell proliferation and has been extensively investigated as a promising predictive and prognostic factor in breast cancer. This study aims to examine the association between Ki67 expression with clinical response of NAC.Methods: The study was designed as a case-control study in breast cancer patients who received standard anthracycline-based NAC. Clinical and immunohistochemical characteristics before and after NAC were obtained retrospectively. Changes in Ki67 and NAC responses were analyzed. Data were analyzed using SPSS version 23 for WindowsResults: A total of 66 subjects were analyzed. About 33 subjects were in good clinical response and 33 subjects were in poor clinical response. Chi-square analysis showed that no significant differences were found in the pre-treatment Ki67 expression between good and poor clinical response group, whereas a low post-treatment Ki67 expression (Ki67 &lt;20%) was correlated with a good clinical response to NAC (p=0.027). Further analysis also showed that a decrease of Ki67 expression greater than 12.5% after treatment was significantly correlated with good clinical response (p=0.007; OR=4.67; 95%CI=1.45-15.08). In multivariate analysis, a decrease in Ki67 was significantly correlated to response in NAC (p=0.037).Conclusion: Decreased in Ki67 greater than 12.5% was correlated with good clinical response of Anthracycline-based NAC in LABC.

Correlation between Serum Interleukin-6 Levels and Clinical Response to Anthracycline-Based Neoadjuvant Chemotherapy Regimen in Locally Advanced Breast Cancer Patients

Background: Neoadjuvant chemotherapy is the initial therapy and the main pillar of treatment for locally advanced breast cancer (LABC). Currently, there is marker that widely accepted as a predictive factor for chemotherapy response in LABC. Elevated serum interleukin-6 (IL-6) levels and tumor sites have been proposed as prognostic markers for breast cancer. In this study, we aimed to examine the association between serum IL-6 levels with clinical response after the administration of neoadjuvant chemotherapy. Methods: This study is an observational analytic study with a cohort prospective character to determine the relationship between IL-6 serum levels and clinical response to anthracycline-based neoadjuvant chemotherapy in locally advanced breast cancer (LABC) patients at Dr. Soetomo General Hospital during April 2021 to September 2021 with a total sample of 38 patients. Results: Fourteen patients (77.8%) had a positive response in the low IL-6 level group and 4 patients (22.2%) had a negative response. In high IL-6 level group, 4 patients (40%) had a positive response and 16 patients (80%) had a negative response. The cut off of 15.495 pg/mL was used as cut off value for IL-6 to predict the clinical response to chemotherapy. The sensitivity, specificity, PPV, NPV, and accuracy of IL-6 to predict the clinical response after chemotherapy were 80.0%, 77.8%, 80.0%, 77.8%, and 78.9%, respectively. Conclusion: There is a relationship between serum IL-6 levels and clinical response to anthracycline-based neoadjuvant chemotherapy regimens in locally advanced breast cancer (LABC) patients. Keywords: interleukin-6, clinical response, locally advanced breast cancer.

LncRNA BCAR4 expression predicts the clinical response to neoadjuvant chemotherapy in patients with locally advanced breast cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is an important treatment for locally advanced breast cancer (LABC). However, there are no effective biomarkers to predict the efficacy. Therefore, there is an urgent need for new biomarkers to predict the response of LABC to NAC. LncRNA BCAR4 has been detected in a variety of malignant tumor tissues and used as a new biomarker for diagnosis and prognosis. However, LncRNA BCAR4 predicts the response of LABC to NAC is unclear.OBJECTIVE: Explore the predictive effect of LncRNA BCAR4 on the efficacy of NAC for LABC in three different evaluation systems.METHODS: First, the TCGA database was used to analyze the expression of LncRNA BCAR4 in 33 kinds of malignant tumors, and further explore its expression in breast cancer and its impact on the survival and prognosis of breast cancer. Furthermore, quantitative methods were used to measure the expression level of LncRNA BCAR4 in cancer tissues of 48 LABC patients, and the correlation between LncRNA BCAR4 and clinicopathological status and response to NAC under the evaluation system of 3, RECIST1.1, Miller-Payne (MP) score and whether it reaches pCR,was analyzed.RESULTS: TCGA data analysis found that LncRNA is highly expressed in a variety of malignant tumor tissues, including breast cancer. And relatively low expression, the shorter the overall survival time of high expression patients. The high expression of LncRNA BCAR4 is related to the size of the tumor, and there are differences in expression between stage I and other stages, but there is no obvious correlation with the positive lymph node and hormone receptor status. Among the three evaluation systems, only in the RECIST 1.1 evaluation system LncRNA BCAR4 has a predictive effect on NAC for LABC. The expression of LncRNA BCAR4 has no significant correlation with clinical stage, Ki-67% and hormone receptor status, and has no significant correlation with whether patients with locally advanced breast cancer obtain pCR during neoadjuvant chemotherapy.CONCLUSION: LncRNA BCAR4 is highly expressed in LABC tissues and may be an effective marker for predicting the efficacy of NAC for LABC.

Ten Fraction Adjuvant Hypofractionated Radiotherapy in Node Positive Breast Cancer: 3 Year-Follow-Up of a Phase II Toxicity Study

Post-operative loco-regional (LR) hypofractionated radiotherapy (Hypo-RT) is an attractive approach in locally advanced breast cancer (LABC). The aim of this study is to report the preliminary results of a 10 fraction hypofractionated schedule in patients (pts) with resected LABC.The present is a single arm phase II study assessing toxicity outcomes after 34 Gy/10 fxs/2 wks to the whole breast/chest wall and to the draining lymph nodes; an optional single fraction 8 Gy boost was administered with electrons to the tumor bed in patients who had undergone conservative surgery. Both acute (CTCAE v4.0) and late (LENT/SOMA) toxicities were collected. All pts but those who underwent mastectomy without reconstruction or with temporary expander were also asked to rate their cosmetic outcome according to the Harvard scale. Toxicity was assessed weekly during RT and then at each follow-up examination (1, 3, 6 months and then yearly).From February 2015 to March 2019, 59 women (median age 60 yrs, IQR: 48.3-68.8 yrs) with stage II to IIIA breast cancer who underwent axillary dissection and conservative surgery (83%) or mastectomy (17%) entered the study. One patient refused follow up immediately after the end of RT. Of the 58 evaluable pts, 56 underwent neo-adjuvant (41%) or adjuvant (59%) chemotherapy. Trastuzumab was administered concomitant with RT in all HER2 positive pts (25%). RT was delivered initially with a conformal 3D-CRT (32.8%) and then with an optimized IMRT (67.2%) technique to improve the dose distribution. A deep inspiration breath hold technique was used in compliant left-sided LABC pts (48.4%). All ptscompleted treatment as planned. At a median follow up of 42.3 months (IQR 31.4-57.2 mths), no locoregional failures have been observed. Peak acute toxicity was as follows: grade 0, 30 pts (51.7%); grade 1, 25 pts (43.1%); grade 2, 3 pts (5.2%); no grade > 2 toxicity was recorded. Regarding late toxicity, peak 2 events were found for fibrosis (1 pt, 1.7%), telangiectasia (1 pts, 1.7%); lymphedema (1 pt, 1.7%). One patient (1.7%) experienced grade 3 breast retraction. No other grade 2+ events were reported. Of eligible patients (N = 51) patient-reported cosmetic outcome was excellent, good, fair and poor in 59%, 23.5%, 11.7% and 5.8%, respectively.These preliminary data support the feasibility and tolerability of our 10-fraction fractionation schedule targeting the primary site as well as the draining lymph node stations after surgery for LABC.

Elevated Level of Nerve Growth Factor (NGF) in Serum-Derived Exosomes Predicts Poor Survival in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy.

Simple SummaryExosomes and cytokines play crucial roles in the process of tumor progression. Recent studies have reported that cytokines can be packaged into exosomes, leading to drug resistance. The aim of this study is to evaluate the potential value of cytokines in both serum and exosomes as prognostic biomarkers of long-term outcomes in patients with breast cancer treated with neoadjuvant chemotherapy. We observed significant differences in expression patterns between serum cytokines and exosomal cytokines. Elevated levels of serum IP-10, serum MMP-1, and exosomal NGF were associated with poor overall survival. In multivariate analysis, exosomal NGF was an independent prognostic factor for overall survival. These findings suggest that exosomal NGF is useful for identifying patients with poor survival outcomes.Neoadjuvant chemotherapy (NAC) is a standard treatment strategy for patients with locally advanced breast cancer (LABC). However, there are no established predictors of chemosensitivity and survival in LABC patients who undergo NAC. Many studies have demonstrated that exosomes and cytokines are important players in intercellular communication between tumors and their environments, and are involved in chemotherapy resistance. Recently, it was reported that cytokines can be packaged into exosomes, but whether exosomal cytokines serve as biomarkers in breast cancer patients is still unclear. In this study, we examined the roles of cytokines in both serum and exosomes as prognostic biomarkers for long-term outcomes in patients with breast cancer who undergo NAC. We isolated exosomes from the blood of 129 patients with early breast cancer who were receiving neoadjuvant chemotherapy between 2008 and 2011 at Samsung Medical Center. The levels of cytokines and growth factors in serum and exosomes were measured with ProcartaPlex immune-related panels. We investigated correlations between clinic-pathologic variables and patient survival, and Cox proportional hazards regression analysis was performed for prognostic evaluation. We detected significant differences in expression patterns between serum cytokines and exosomal cytokines. In both serum and exosomes, many cytokines were positively correlated with age. In univariate analysis, patients with high serum IP-10, serum MMP-1, and exosomal NGF had shorter overall survival. Exosomal NGF showed significantly poorer overall survival in multivariate analysis. These findings suggest that exosomal NGF is useful for identifying patients with poor survival outcomes.