Factor In Breast Cancer Patients Research Articles

Prognostic Factors in Breast Cancer Patients with Brain Metastases: Retrospective Analysis

Background: Breast cancer is first cause of cancer-related deaths and it is estimated that 15% of breast cancer patients will develop brain metastases (BM). Its incidence differs according to many factors like molecular subtypes and burden and duration of systemic disease. Triple negative disease is an aggressive subtype with lifetime BM incidence of 25-46%. Survival of patients with BM is generally poor and affected by molecular subtypes, patient's performance, number and burden of visceral metastasis and resectability of brain lesions. Aim: This analysis aimed at evaluating the prognostic factors in breast cancer patients with BM. Methods: We retrospectively reviewed breast cancer patients' files treated at a single institute between January 2010 and December 2014. From 2095 files reviewed, 32 had BM. The clinico-epidemiological, pathological, treatment received and survival data were extracted and analysed. Results: Median age at BM diagnosis was 49.5 years (range 27-69). Median time from breast cancer diagnosis to BM diagnosis was 16 months (95% CI: 13.23-18.77). Postmenopausal women represented 59% of patients and 56% of them had a good performance status (ECOG 1-2). The majority of patients had grade II disease and invasive ductal carcinoma (65.6% and 81.3%, respectively). The tumor subtype was hormone receptor positive/HER2-neu negative in 25%, triple negative in 25% and HER2-neu positive in 50%. More than 2/3 of patients presented with signs of increased intracranial tension. Seven (22%) patients had single BM lesion, 22 (69%) had multiple lesions and 3 (9%) had concomitant leptomeningeal metastases. Three (9%) patients underwent brain metastatectomy. The median progression free survival was 4.5 months (95% CI: 3.58-5.42) and was significantly longer among patients who underwent metastatectomy (p=0.023) and those with hormone receptor-positive disease (p=0.007). The median overall survival was 6.5 months (95% CI: 4.23-9.77) and was significantly longer in patients with better performance status (ECOG 1), hormone receptor-positive disease, low number of metastatic sites and brain metastatectomy (p=0.037, 0.045, Conclusion: Brain metastases in breast cancer patients is an indicator of short survival which is influenced by tumor subtype, performance status, burden of systemic disease and ability to perform metastatectomy.

Promoter epigenetics of APC gene and its implication in sporadic breast cancer patients from South Indian population

BackgroundThe adenomatous polyposis coli (APC) gene is a tumor suppressor gene associated with both familial and sporadic cancer, whose protein plays an important role in the WNT signal transduction pathway. WNT signaling is a key developmental pathway involved in embryonic development, cell differentiation, cell proliferation and tissue maintenance in adults. APC protein acts as an antagonist of the WNT signaling pathway by binding and regulating the β-catenin protein. Impaired APC gene function usually leads to a lack of degradation of β-catenin, which could cause uncontrolled cell growth and lead to tumorigenic transformation. APC gene may be inactivated by aberrant DNA methylation of CpG islands in their promoter regions. ObjectiveHence the present study was designed to determine the role of promoter methylation of APC genes in sporadic breast cancer patients from South Indian population. MethodsDNA methylation analyses of APC gene was performed by methylation-specific polymerase chain reaction (MSP).·Fifty biopsy samples of breast tumor and their corresponding non-malignant portions as controls were studied comparatively. APC mRNA expression analysis was also done using real time PCR. ResultsThirty eight percent (38%) cancerous tissue samples (19/50) showed promoter hypermethylation in APC gene; however, none of normal tissues showed promoter hypermethylation. The difference in methylation frequency between cancerous and normal tissue was statistically significant (p = 0.0001). APC promoter methylation was positively associated with lymph node involvement (p = 0.048), APC Promote hyper methylation and decreased mRNA expression was significantly associated (p = 0.0034). Lower APC-mRNA expression was associated with patient's age above 50 years (p = 0.044). ConclusionIn conclusion, our data showed that promoter hypermethylation of APC gene was a prognostic factor in breast cancer patients from South Indian population. The loss of APC gene function usually leads to an accumulation of β-catenin, which may promote tumorigenesis.

Abstract P3-07-06: TRIM44 is a possible poor prognostic factor for breast cancer patients and positively regulates NF-κB signaling pathway

Abstract [Background] Many of the tripartite motif (TRIM) proteins, like Efp/TRIM25 which was identified by our group previously (Nature 417, 871-875, 2002), function as E3 ubiquitin ligases, and are thought to be involved in various physiological and pathological processes such as immunity and oncogenesis. In regard to tripartite motif containing 44 (TRIM44), which is an atypical TRIM family protein lacking RING finger domain, some evidences suggest that it is implicated in the progression of several human malignancies. But its pathophysiological significance in breast cancer remains unknown. [Methods] In the present study, immunohistochemical analysis using anti-TRIM44 antibody was performed in clinical breast cancer tissues from 129 patients with the approval of institutional ethical committees (approval number: 845). We then explored the pathophysiological role of TRIM44 in breast cancer by modulating TRIM44 expression in MCF-7 and MDA-MB-231 breast cancer cells. [Results] TRIM44 strong immunoreactivity was significantly associated with nuclear grade, distant disease-free survival and overall survival of the breast cancer patients. With multivariate analysis it was shown that the TRIM44 status was an independent prognostic factor for distant disease-free survival and overall survival. The proliferation of MCF-7 and MDA-MB-231 cells was significantly decreased by siRNA-mediated TRIM44 knockdown. TRIM44 knockdown also suppressed migration of MDA-MB-231 cells. Microarray analysis and qRT-PCR revealed that TRIM44 knockdown upregulated CDK19 (Cyclin Dependent Kinase 19), which is reported to be a tumor suppressor gene, whereas downregulated MMP1 (Matrix Metallopeptidase 1) in MDA-MB-231 cells. Notably, TRIM44 knockdown impaired nuclear factor-kappa B (NF-κB)-mediated transcriptional activity stimulated by tumor necrosis factor α (TNFα). Moreover, TRIM44 knockdown substantially attenuated the TNFα-dependent phosphorylation of p65 subunit of NF-κB and IκBα in both MCF-7 and MDA-MB-231 cells. [Discussion] Our clinical study showed that prognosis of breast cancer patients is correlated with the immunoreactivity detected by anti-TRIM44 antibody. This result suggested that expression of TRIM44 protein could be used as a potential biomarker of breast cancer. We demonstrated that NF-κB signaling pathway is modulated by TRIM44. Since NF-κB augmentation is shown to be related to aggressive character of breast cancer, stimulation of NF-κB signaling with TRIM44 might be underlying mechanism of poor prognosis. Our in vitro study showed TRIM44 knockdown caused attenuated proliferation and migration of breast cancer cells, raising the possibility of TRIM44 as a potential therapeutic target for breast cancer. These findings provide new clues to develop alternative effective strategies for breast cancer management. Citation Format: Kawabata H, Azuma K, Ikeda K, Sugitani I, Kinowaki K, Fujii T, Osaki A, Saeki T, Horie-Inoue K, Inoue S. TRIM44 is a possible poor prognostic factor for breast cancer patients and positively regulates NF-κB signaling pathway [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-07-06.

Abstract P1-07-13: Obesity is associated with poor prognosis of Japanese breast cancer, especially in ER positive/HER2 negative subtype, which tendency is prominent

Abstract Introduction: Body mass index (BMI) is defined as a poor prognostic factor in breast cancer patients in western countries. Since the percentage of the overweight differs between Asian and western breast cancer patients, we do not know if breast cancer prognosis in Asia is related to obesity, the same as in western countries. Therefore, we have investigated the association between BMI and the prognosis of Japanese breast cancer patients. Patients and Methods: This study is a retrospective analysis of the 1,924 primary Japanese female breast cancer patients with clinical stage I through III disease to have undergone surgery between January 2004 and December 2013 at the Hokkaido Cancer Center. The data of BMI were at the time of diagnosis, and stratified into 2 groups as non-Obese (BMI < 25 kg/m2), Obese (BMI ≥ 25 kg/m2). The overall survival (OS) and disease-free survival (DFS) were compared between two BMI groups using the Kaplan-Meier method and Cox hazards model. Results: The number of non-Obese group was 1,353 (70.3%) and Obese group was 571 (29.7%) of the 1,924 patients. Six hundred and thirty two patients were in premenopausal (32.8%), 1,289 were in postmenopausal (67.0%) and 3 were unknown. The median follow-up period was 73 months. Breast cancer recurred in 239 patients (12.2%), and 204 patients died. There were 110 cases of breast cancer-related death, 48 cases of non-breast cancer death, and 46 cases of unknown as the cause of death. Patients in Obese group had shown significantly poorer OS (adjusted hazard ratio (HR) = 1.68, 95% confidence interval (CI) = 0.45 to 0.79) and DFS (HR = 1.46, 95% CI = 1.16 to 1.82). As investigating by subtype analysis, a high BMI in ER positive/HER2 negative patients was associated with a significantly worse OS (HR = 2.04, 95% CI = 1.42 to 2.92) and significantly worse DFS (HR = 1.61, 95% CI = 1.23 to 2.11). On the other hand, there was no significant interaction found between the BMI and OS or DFS in ER negative/HER2 negative patients and HER2 positive patients. Subsequently, when analysis was limited to ER positive HER2 negative, there was a difference in the degree of association between obesity and prognosis due to the difference in menopause status. In premenopausal patients with ER positive/HER2 negative cancer, Obese group had significantly poorer OS (HR = 2.83, 95%CI = 1.32 to 5.88) and significantly poorer DFS (HR = 2.41, 95%CI = 1.41 to 3.99). In postmenopausal patients, Obese group patients had significantly poorer OS (HR = 1.71, 95%CI = 1.11 to 2.58) and poorer DFS (HR = 1.35, 95%CI = 0.98 to 1.86), however. The relevance was not so large compared with that in premenopausal patients. Conclusion: Among Japanese breast cancer patients, Obese (BMI ≥ 25 kg/m2) was one of poor prognostic factors. Specifically, obesity was associated as an extremely strong prognostic factor in ER positive/HER2 negative premenopausal patients. Since hormone therapy has been practiced in almost all ER positive breast cancers, the relationship between hormonal therapy susceptibility and obesity is noticed not only in western patients but also in Asian patients. Citation Format: Sato M, Terai S, Tachikawa H, Maeda H, Yamamoto M, Tomioka N, Watanabe K, Takahashi M. Obesity is associated with poor prognosis of Japanese breast cancer, especially in ER positive/HER2 negative subtype, which tendency is prominent [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-13.

Overexpression of TACC3 in Breast Cancer Associates With Poor Prognosis.

Increasing evidences suggest that transforming acidic coiled-coil protein 3 (TACC3) is associated with various types of human cancer. However, the expression of TACC3 in breast cancer tissues remains largely unknown. To identify whether TACC3 can serve as a biomarker for the diagnosis and prognosis of breast cancer, quantitative polymerase chain reaction, western blotting, and immunohistochemistry staining were utilized to detect the expression of TACC3. The mRNA and protein levels of TACC3 in breast cancer samples were novelty higher compared with nontumorous breast tissues. Immunohistochemistry results revealed TACC3 expression was significantly correlated to lymphoid nodal metastasis (P=0.035) and HER-2 status (P=0.021). The patients with high expression of TACC3 had a significantly poor prognosis compared with patients with low expression (P=0.017), especially in the patients with pathological tumor size 2-4 status (P=0.028). Furthermore, multivariate analysis indicated that TACC3 expression was an independent prognostic factor for breast cancer patients (P=0.029). This study, first, suggested TACC3 might be an important molecular marker for diagnosis and prognosis of breast cancer.

Prognostic influence of Korean public medical insurance system on breast cancer patients.

PurposeTo investigate the prognostic influence of Korean public medical insurance system on breast cancer patients.MethodsData of 1,068 patients with primary invasive breast cancer were analyzed. Korean public medical insurance status was classified into 2 groups: National Health Insurance and Medical Aid. Kaplan-Meier estimator and Cox proportional hazards model were used for survival analysis.ResultsThe Medical Aid group showed worse prognoses compared to the National Health Insurance group both in overall survival (P = 0.001) and recurrence-free survival (P = 0.006). The Medical Aid group showed higher proportion of patients with tumor size > 2 cm (P = 0.022), more advanced stage (P = 0.039), age > 50 years (P = 0.003), and low education level (P = 0.003). The Medical Aid group showed higher proportion of patients who received mastectomy (P < 0.001) and those who received no radiation therapy (P = 0.013). The Medical Aid group showed a higher rate of distant recurrence (P = 0.014) and worse prognosis for the triple negative subtype (P = 0.006). Medical insurance status was a significant independent prognostic factor in both univariate analysis and multivariate analysis.ConclusionThe Medical Aid group had worse prognosis compared to the National Health Insurance group. Medical insurance status was a strong independent prognostic factor in breast cancer. Unfavorable clinicopathologic features could explain the worse prognosis for the Medical Aid group. Careful consideration should be given to medical insurance status as one of important prognostic factors for breast cancer patients.

Survival Time and Prognostic Factors for Breast Cancer among Women in North-East Peninsular Malaysia

Background:Breast cancer is the most common malignant disease and the leading cause of cancer death among women globally. This study aimed to determine the median survival time and prognostic factors for breast cancer patients in a North-East State of Malaysia.Methods:This retrospective cohort study was conducted from January till April 2017 using secondary data obtained from the state’s cancer registry. All 549 cases of breast cancer diagnosed from 1st January 2007 until 31st December 2011 were selected and retrospectively followed-up until 31st December 2016. Sociodemographic and clinical information was collected to determine prognostic factors.Results:The average (SD) age at diagnosis was 50.4 (11.2) years, the majority of patients having Malay ethnicity (85.8%) and a histology of ductal carcinoma (81.5%). Median survival times for those presenting at stages III and IV were 50.8 (95% CI:25.34, 76.19) and 6.9 (95% CI:3.21, 10.61) months, respectively. Ethnicity (Adj. HR for Malay vs non-Malay ethnicity=2.52; 95% CI: 1.54, 4.13; p<0.001), stage at presentation (Adj. HR for Stage III vs Stage I=2.31; 95% CI: 1.57, 3.39; p<0.001 and Adj. HR for Stage IV vs Stage I=6.20; 95%CI: 4.45, 8.65; p<0.001), and history of surgical treatment (Adj. HR for patients with no surgical intervention=1.95; 95%CI: 1.52, 2.52; p<0.001) were observed to be the statistically significant prognostic factors associated with death caused by breast cancer.Conclusion:The median survival time among breast cancer patients in North-East State of Malaysia was short as compared to other studies. Primary and secondary prevention aimed at early diagnosis and surgical management of breast cancer, particularly among the Malay ethnic group, could improve treatment outcome.

Combined Let-7a and H19 Signature: A Prognostic Index of Progression-Free Survival in Primary Breast Cancer Patients.

PurposeThe long non-coding RNA H19, a conservatively imprinted gene, acts as a molecular sponge for the let-7 family, which has been identified as a set of tumor suppressors. However, the combined prognostic value of H19 and let-7a signature in breast cancer patients remains unclear.MethodsIn this research we assessed the prognostic value of the combined H19 and let-7a signature in breast cancer patients by retrospectively reviewing that data of 79 patients who underwent neoadjuvant chemotherapy; we also investigated the expression and function of H19 in breast cancer cell lines in vitro. Survival data were calculated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate survival analyses were conducted using the Cox proportional hazards regression method. As determined using X-tile, the optimal cutoff value for the risk score to assess progression-free survival (PFS) based on the combined signature was –0.1.ResultsPatients with an overall positive treatment response had higher let-7a and lower H19 levels. In addition, let-7a expression was negatively correlated with H19 expression. Patients with a risk score of >–0.1 had shorter overall survival and PFS. In vitro data showed that chemoresistant cell lines exhibit higher H19 and lower let-7a levels and knockdown H19 restores paclitaxel sensitivity.ConclusionOur results suggest that the combined let-7a and H19 signature is a novel prognostic factor for breast cancer patients treated with neoadjuvant chemotherapy.

Caspase-3 over-expression is associated with poor overall survival and clinicopathological parameters in breast cancer: a meta-analysis of 3091 cases.

Caspase-3 is a vital executioner molecule during the apoptotic process. Numerous studies have revealed the close association of caspase-3 expression and breast cancer. Nevertheless, the prognostic value of caspase-3 expression for patients with breast cancer remains uncertain. To thoroughly analyze the prognostic effect of caspase-3 expression on the clinicopathological features and survival of breast cancer, we conducted this meta-analysis. With various search strategies, electronic databases were comprehensively searched. A total of 3091 patients from 21 studies were ultimately obtained. The analysis results indicated that increased expression of caspase-3 had a negative influence on the overall survival (OS) of breast cancer (HR = 1.73, 95%CI 1.12–2.67, P = 0.014). Subgroup analyses based on race revealed that the value of caspase-3 for evaluating patients’ OS was more useful in Asian patients (HR = 3.16, 95%CI 1.20–8.15, P = 0.020), and subgroup analyses based on study analytical methods revealed that caspase-3 was a risk factor for breast cancer patients in multivariate overall survival analyses (HR = 1.67, 95%CI 1.02–2.75, P = 0.044). As for the relationship between caspase-3 expression and breast cancer subtype as well as progression, caspase-3 might serve as a risk factor for the progestogen receptor (PR) and human epidermal growth factor receptor-2 (HER-2) subtypes (OR = 1.44, 95%CI 1.09–1.89, P = 0.010; OR = 1.76, 95%CI 1.18–2.62, P = 0.050, respectively) of breast cancer. However, no evidence showed that increased expression of caspase-3 was statistically correlated with tumor differentiation state (low/moderate or high), tumor TNM stage (I-II/III-IV) or lymph node metastasis (–/+). In conclusion, this meta-analysis revealed that increased caspase-3 expression was significantly associated with worse prognosis and two subtypes of breast cancer. More prospective studies are urgently needed to define the prognostic value of caspase-3 expression in patients with breast cancer.

High expression of PALB2 predicts poor prognosis in patients with advanced breast cancer.

PALB2 mutation is associated with increased breast cancer risk; however, PALB2 mutation is rare in sporadic breast cancer cases and little is known about PALB2 expression in breast cancer. Here, we evaluated the prognostic effects of PALB2 with tissue microarray specimens of 117 female breast cancer patients, and determined the potential underlying mechanisms in cell models. In immunohistochemical analysis, we found increased expression of PALB2 in breast cancer tissues compared with the adjacent normal ductal epithelium (P < 0.001). Higher PALB2 scores were positively associated with histological grade and higher PALB2 expression was found in patients that were Her‐2 negative compared with those that were positive (P < 0.05). Interestingly, higher expression of PALB2 was significantly associated with poorer overall survival (P < 0.01) in patients with stage III or nearby lymph node metastasis (N1, N2 or N3). In vitro studies found that PALB2 may promote the migration and invasion of MDA‐MB‐231 cells through E‐cadherin suppression and NF‐κB activation. In conclusion, these results suggest that PALB2 expression levels may serve as a novel prognostic factor for breast cancer patients.

MiR‑455‑5p promotes cell invasion and migration in breast cancer.

MicroRNA (miR)‑455‑5p has been identified as a biomarker for various types of cancer and may therefore be involved in the regulation of cancer development and progression. However, the specific role and function of miR‑455‑5p in breast cancer remains unclear. The present study explored the expression levels and function of miR‑455‑5p in breast cancer. The results from reverse transcription‑quantitative polymerase chain reaction analysis revealed that miR‑455‑5p was significantly upregulated in breast cancer. Clinically, increased expression of miR‑455‑5p predicted a poor survival rate and miR‑455‑5p was identified as one of the independent prognostic factors for breast cancer patients. Furthermore, results from wound healing and Transwell assays revealed that miR‑455‑5p accelerated invasiveness and migration capabilities of breast cancer cells. In addition, programmed cell death 4 was identified as a downstream target of miR‑455‑5p and its expression was observed to be negatively regulated by miR‑455‑5p. Overall, miR‑455‑5p may function as an oncogene in breast cancer, and may therefore be used as a prognostic marker for breast cancer patients.

Proteomic profiling of breast cancer metabolism identifies SHMT2 and ASCT2 as prognostic factors

BackgroundBreast cancer tumors are known to be highly heterogeneous and differences in their metabolic phenotypes, especially at protein level, are less well-understood. Profiling of metabolism-related proteins harbors the potential to establish new patient stratification regimes and biomarkers promoting individualized therapy. In our study, we aimed to examine the relationship between metabolism-associated protein expression profiles and clinicopathological characteristics in a large cohort of breast cancer patients.MethodsBreast cancer specimens from 801 consecutive patients, diagnosed between 2009 and 2011, were investigated using reverse phase protein arrays (RPPA). Patients were treated in accordance with national guidelines in five certified German breast centers. To obtain quantitative expression data, 37 antibodies detecting proteins relevant to cancer metabolism, were applied. Hierarchical cluster analysis and individual target characterization were performed. Clustering results and individual protein expression patterns were associated with clinical data. The Kaplan-Meier method was used to estimate survival functions. Univariate and multivariate Cox regression models were applied to assess the impact of protein expression and other clinicopathological features on survival.ResultsWe identified three metabolic clusters of breast cancer, which do not reflect the receptor-defined subtypes, but are significantly correlated with overall survival (OS, p ≤ 0.03) and recurrence-free survival (RFS, p ≤ 0.01). Furthermore, univariate and multivariate analysis of individual protein expression profiles demonstrated the central role of serine hydroxymethyltransferase 2 (SHMT2) and amino acid transporter ASCT2 (SLC1A5) as independent prognostic factors in breast cancer patients. High SHMT2 protein expression was significantly correlated with poor OS (hazard ratio (HR) = 1.53, 95% confidence interval (CI) = 1.10–2.12, p ≤ 0.01) and RFS (HR = 1.54, 95% CI = 1.16–2.04, p ≤ 0.01). High protein expression of ASCT2 was significantly correlated with poor RFS (HR = 1.31, 95% CI = 1.01–1.71, p ≤ 0.05).ConclusionsOur data confirm the heterogeneity of breast tumors at a functional proteomic level and dissects the relationship between metabolism-related proteins, pathological features and patient survival. These observations highlight the importance of SHMT2 and ASCT2 as valuable individual prognostic markers and potential targets for personalized breast cancer therapy.Trial registrationClinicalTrials.gov, NCT01592825. Registered on 3 May 2012.

CLINICAL AND EXPERT EVALUATION OF PERSISTENT DISTURBANCES OF FUNCTIONS IN BREAST CANCER

There is proposed clinical expert and quantitative evaluation of persistent disorders of body functions with taking into account the TNM classification and prognostic factors in breast cancer patients.

Characteristics and prognosis of breast cancer after liver or kidney transplantation.

Immunoediting is crucial in cancer development and progression. This study compared the characteristics and prognosis of post-transplant breast cancer (PTBC) patients receiving immunosuppressants and general breast cancer patients. Data from the Asan Medical Center Breast Cancer (AMCBC), kidney transplantation, and liver transplantation databases recorded during 1989-2013 were retrospectively analyzed. Four controls of AMCBC cohort per one case of PTBC cohort were selected based on tumor size, lymph node metastasis, and age. After a median of 61 and 90.8months after liver and kidney transplantation, respectively, 8 and 16 patients were diagnosed with breast cancer, respectively (p=0.178). Mean age at breast cancer diagnosis was 51.9 (±8.7) and 45.2 (±4.5) years in liver and kidney transplantation patients, respectively. Age at diagnosis was significantly younger in kidney transplantation patients than in general breast cancer patients (45.2±4.5 vs. 48.5±10.1years; p=0.008). Cancer was detected via asymptomatic screening in 41.7% of the PTBC cohort but 30.6% of the control cohort (p=0.241). In the PTBC cohort, 7 (29.2%) patients had stage 0 breast cancer compared with 1704 (9.7%) in the control cohort (p=0.022); 22 (91.7%) patients had lymph node-negative cancer compared with 11,704 (66.8%) in the control cohort (p=0.01). Estrogen receptor, progesterone receptor, and HER2 positivity did not differ between cohorts. Immunosuppressant use was not a poor prognostic factor for breast cancer patients. Age at breast cancer diagnosis was younger in patients who received kidney transplants; the subtype and prognosis of breast cancer were comparable with that in the general cohort. Immunosuppressants do not adversely affect breast cancer prognosis.

TRIM44 Is a Poor Prognostic Factor for Breast Cancer Patients as a Modulator of NF-κB Signaling.

Many of the tripartite motif (TRIM) proteins function as E3 ubiquitin ligases and are assumed to be involved in various events, including oncogenesis. In regard to tripartite motif-containing 44 (TRIM44), which is an atypical TRIM family protein lacking the RING finger domain, its pathophysiological significance in breast cancer remains unknown. We performed an immunohistochemical study of TRIM44 protein in clinical breast cancer tissues from 129 patients. The pathophysiological role of TRIM44 in breast cancer was assessed by modulating TRIM44 expression in MCF-7 and MDA-MB-231 breast cancer cells. TRIM44 strong immunoreactivity was significantly associated with nuclear grade (p = 0.033), distant disease-free survival (p = 0.031) and overall survival (p = 0.027). Multivariate analysis revealed that the TRIM44 status was an independent prognostic factor for distant disease-free survival (p = 0.005) and overall survival (p = 0.002) of patients. siRNA-mediated TRIM44 knockdown significantly decreased the proliferation of MCF-7 and MDA-MB-231 cells and inhibited the migration of MDA-MB-231 cells. Microarray analysis and qRT–PCR showed that TRIM44 knockdown upregulated CDK19 and downregulated MMP1 in MDA-MB-231 cells. Notably, TRIM44 knockdown impaired nuclear factor-kappa B (NF-κB)-mediated transcriptional activity stimulated by tumor necrosis factor α (TNFα). Moreover, TRIM44 knockdown substantially attenuated the TNFα-dependent phosphorylation of the p65 subunit of NF-κB and IκBα in both MCF-7 and MDA-MB-231 cells. TRIM44 would play a role in the progression of breast cancer by promoting cell proliferation and migration, as well as by enhancing NF-κB signaling.

Usefulness of lymphocyte-to-monocyte, neutrophil-to-monocyte and neutrophil-to-lymphocyte ratios as prognostic markers in breast cancer patients treated with neoadjuvant chemotherapy.

Nowadays, neoadjuvant chemotherapy (nCT) in breast cancer is more and more standardized, not only in advanced tumours but also in those for which there is an attempt to achieve breast-conserving surgery. In literature, we can find evidences of the relationship between several types of tumours and systemic inflammatory response. Our objective is to analyse the prognostic value of blood parameters (lymphocytes, neutrophils, monocytes, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-monocyte ratio (NMR) and neutrophil-to-lymphocyte ratio (NLR) in breast cancer (BC) patients treated with nCT. A retrospective cohort of 150 breast cancer patients treated with nCT and subsequently with surgery was analysed. Data about the patients, histology, response to chemotherapy and peripheral blood values of lymphocytes, monocytes and neutrophils was collected, and used to calculate the LMR, NMR and NLR. Univariate and multivariate analyses were performed for the variables to see the relationship of the ratios to disease-free survival (DFS) and overall survival (OS). Patients with high LMR (≥5.46) and low NLR (<3.33) were associated with a lower percentage of relapse (P=0.048 and P=0.015, respectively) and, above all, NLR was associated with a better survival (P=0.024), being those factors that predict a good progress. High LMR and low NLR can be considered as favourable prognostic factors in BC patients treated with nCT.

Increased risk of recurrence associated with certain risk factors in breast cancer patients after DIEP-flap reconstruction and lipofilling-a matched cohort study with 200 patients.

Lipofilling is performed in breast cancer patients to optimize the aesthetic outcome following breast reconstruction after mastectomy. Despite its common usage worldwide, little is known about the interaction of the lipoaspirate and dormant cancer cells. Up to date, no risk factors that increase the risk for cancer recurrence have been established. This study aims to identify risk factors for lipofilling candidates after breast cancer and questions the oncological safety of lipofilling in lymph node positive disease. Matched retrospective cohort study: the disease-free survival (DFS) between 100 breast cancer patients undergoing a lipofilling after their DIEP-flap reconstruction and 100 matched control patients with no subsequent lipofilling was analyzed. Further, patients were subdivided according to risk factors, which were categorized as patient-dependent factors (PDFs) and tumor-dependent factors (TDFs). DFS and hazard ratios (HR) were compared to identify potential risk factors that may increase cancer recurrence. Median follow-up was 76.5 months from the mastectomy, and 31 months from the startpoint to the end of follow-up. Seven and eleven patients had recurrence in the lipofilling and control group, respectively, presenting with comparable DFS rates and an insignificant HR =0.57, 95% confidence interval (CI): 0.22-1.47, P=0.24. According to subgroup survival analysis, lipofilling increased the risk of recurrence in women with a positive nodal status (P=0.035) and a high-grade neoplasia (P=0.049). No general increased recurrence risk was observed between the lipofilling and control group. The subgroup analysis identified high-grade neoplasia and positive nodal status to be a risk factor for cancer recurrence. Patients with a known node positive disease have an increased risk of occult micrometastases in their lymph nodes. Further studies are necessary to clarify whether dormant breast cancer cells in form of micrometastases in the lymph nodes can be reactivated by the factors secreted by adipose derived stem cells.

A longitudinal study of diurnal cortisol patterns and associated factors in breast cancer patients from the transition stage of the end of active cancer treatment to post-treatment survivorship

ObjectivesThe aim of this study was to examine the changes in diurnal cortisol patterns and its associated factors among breast cancer patients over a 14-month follow up period. Materials and methodsA total of 85 breast cancer patients were recruited to participate in this study. Assessments were performed at baseline (T0), T1 (the 2nd month), T2 (the 5th month), T3 (the 8th month), and T4 (the 14th month). Salivary cortisol was measured and the following questionnaires were administered: BDI-II depression scale, European Organization for Research and Treatment of Cancer Core Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its breast cancer-specific complementary measure (EORTC QLQ-BR23). Patients were grouped into flat and steep groups, according to the median of the diurnal cortisol slopes at the time of the transition period. ResultsBreast cancer patients in the flatter slope group at transition period demonstrated steeper slopes over the course of recovery from treatment and those in the steeper slope group at transition period continued with steeper slopes over the course of recovery. The greater breast cancer-related symptoms (side-effects, symptoms relating to breast and arm, and hair loss) were associated with the changes in flatter diurnal cortisol slopes during14-month follow up period. ConclusionDiurnal cortisol patterns in flatter slope group at the transition period appear to have a trend of recovery with the passage of time over the course of recovery from treatment. Management of breast cancer symptoms could improve dysregulation of diurnal cortisol patterns among survivors.

Prognostic factors in breast cancer patients evaluated by PET/CT prior to neoadjuvant chemotherapy.

e12113 Background: Neoadjuvant chemotherapy (NAC) is an important modality in breast cancer treatment. We sought to identify pre-treatment prognostic factors in patients who had positron emission tomography paired with diagnostic quality contrast-enhanced CT (PET/CT) prior to neoadjuvant chemotherapy with respect to pathologic complete response (pCR) , survival and relapse-free survival (RFS). Methods: We retrospectively analyzed 118 breast cancer patients who had pre-treatment PET/CT imaging and received NAC from 2008-2014. We collected data on molecular markers, PET/CT, pCR, survival, and disease status. Results: The median follow up was 44 months(range 7.3-101.5),median age was 51 years; 47% were stage II, 53% stage III. 52% of patients had hormone receptor (HR) positive/HER2 negative disease, 31% of tumors were HER2 positive, and 17% of tumors were triple-negative. 92.5% with HER2 positive tumors received NAC containing at least one HER2 targeted agent. Pre-treatment standard uptake value (SUV) max of the primary breast tumor showed no statistically significant relationship to survival, RFS, or pCR. PET avid (&gt;2 SUV) extra-axillary nodes such as internal mammary and supraclavicular was associated with a non-statistically significant trend towards reduced RFS (p=0.06, HR=0.13-1.06). pCR overall was 37.5% for HER2 positive tumors, 15% in triple-negative tumors, and 8% in HR positive/HER2 negative tumors. Log-rank analysis with post-hoc pairwise comparisons showed a significant difference between the RFS of triple-negative tumors and HER2 positive tumors (p=0.001), while comparison between HR positive/HER2 negative and HER2 positive was not statistically significant (p=0.11). Multivariate cox regression analysis, which included grade and stage of tumors, showed HER2 positivity to be associated with a favorable outcome (p=0.04, HR=0.22 (0.05-0.94)). Conclusions: Within this cohort, pre-treatment SUV max of the primary tumor showed no prognostic value with regard pCR or RFS. PET avid extra-axillary metastasis trended towards reduced RFS. Patients with HER2 positive tumors had the highest pCR and RFS comparable to classically favorable subgroups such as HR positive/HER 2 negative.

Epigallocatechin gallate inhibits the growth of MDA-MB-231 breast cancer cells via inactivation of the β-catenin signaling pathway.

Epigallocatechin gallate (EGCG), a major constituent of green tea, has potential as a treatment for a variety of diseases, including cancer. EGCG induces apoptosis and inhibits tumorigenesis through multiple signaling pathways in breast cancer cells. β-catenin signaling modulators could be useful in the prevention and therapy of breast cancer. However, the precise anticancer effect of EGCG through the β-catenin signaling pathway in breast cancer is unclear. The present study investigated the association between β-catenin expression and clinicopathological factors of breast cancer patients, and the effect of EGCG on β-catenin expression in breast cancer cells. β-catenin expression was analyzed according to the clinicopathological factors of 74 patients with breast cancer. All patients were females diagnosed with invasive ductal carcinoma. Western blot analysis revealed that β-catenin was expressed at higher levels in breast cancer tissue than in normal tissue. β-catenin expression was associated with lymph node metastasis (P=0.04), tumor-node-metastasis stage (P=0.03) and estrogen receptor status (P<0.01). EGCG decreased MDA-MB-231 cell viability and significantly downregulated the expression of β-catenin, phosphorylated Akt and cyclin D1. Remarkably, additive effects of LY294002 and wortmannin, two phosphatidylinositol-3 kinase inhibitors, were observed. The present results suggest that EGCG inhibits the growth of MDA-MB-231 cells through the inactivation of the β-catenin signaling pathway. Based on these promising results, EGCG may be a potential treatment for triple negative breast cancer patients.