Real-World Use of Highly Sensitive Liquid Biopsy Monitoring in Metastatic Breast Cancer Patients Treated with Endocrine Agents after Exposure to Aromatase Inhibitors.

Endocrine-resistant, hormone receptor-positive, and HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) is largely governed by acquired mutations in the estrogen receptor, which promote ligand-independent activation, and by truncal alterations in the PI3K signaling pathway, with a broader range of gene alterations occurring with less prevalence. Circulating tumor DNA (ctDNA)-based technologies are progressively permeating the clinical setting. However, their utility for serial monitoring has been hindered by their significant costs, inter-technique variability, and real-world patient heterogeneity. We interrogated a longitudinal collection of 180 plasma samples from 75 HR+/HER2- mBC patients who progressed or relapsed after exposure to aromatase inhibitors and were subsequently treated with endocrine therapy (ET) by means of highly sensitive and affordable digital PCR and SafeSEQ sequencing. Baseline PIK3CA and TP53 mutations were prognostic of a shorter progression-free survival in our population. Mutant PIK3CA was prognostic in the subset of patients receiving fulvestrant monotherapy after progression to a CDK4/6 inhibitor (CDK4/6i)-containing regimen, and its suppression was predictive in a case of long-term benefit with alpelisib. Mutant ESR1 was prognostic in patients who did not receive concurrent CDK4/6i, an impact influenced by the variant allele frequency, and its early suppression was strongly predictive of efficacy and associated with long-term benefit in the whole cohort. Mutations in ESR1, TP53, and KRAS emerged as putative drivers of acquired resistance. These findings collectively contribute to the characterization of longitudinal ctDNA in real-world cases of HR+/HER2- mBC previously exposed to aromatase inhibitors and support ongoing studies either targeting actionable alterations or leveraging the ultra-sensitive tracking of ctDNA.

A common variant SNP rs1937810 in the MPP7 gene contributes to the susceptibility of breast cancer in the Chinese Han population.

BACKGROUND: Breast cancer (BC) is common cancer caused by environmental factors and genetic ones. Previous evidence has linked gene MAGUK P55 Scaffold Protein 7 (MPP7) to BC, despite that there has been no research evaluating the relationship between MPP7 genetic polymorphisms and BC susceptibility. We aimed to investigate the potential association of the MPP7 gene with the susceptibility to BC in Han Chinese individuals. METHODS: In total, 1390 patients with BC and 2480 controls were enrolled. For genotyping, 20 tag SNPs were chosen. The serum levels of protein MPP7 were measured in all subjects using an enzyme-linked immunosorbent assay. Genetic association analysis was performed in both genotypic and allelic modes, and the relationship between BC patients' clinical features and genotypes of relevant SNPs was examined. The functional implications of significant markers were also evaluated. RESULTS: After adjusting for Bonferroni correction, SNP rs1937810 was found to be significantly associated with the risk of BC (p = 1.19 × 10-4 ). The odds ratio of CC genotypes in BC patients was 49% higher than in controls (1.49 [1.23-1.81]). Serum MPP7 protein levels were significantly higher in BC patients than in controls (p < 0.001). The protein level of the CC genotype was the highest, and that of the CT and TT genotypes decreased in turn (both p < 0.001). CONCLUSIONS: Our results linked SNP rs1937810 to the susceptibility of BC and the clinical features of BC patients. This SNP is also proved to be significantly related to the serum level of protein MPP7 in both BC patients and controls.

SERUM LEPTIN LEVEL IN BREAST CANCER.

Leptin is a polypeptide which is mostly produced in white fat tissue and is an important proinflammatory, proangiogenic, proinvasive and mitotic factor. There is ever more evidence suggesting the key role of leptin in the occurrence of breast cancer. The aim of the study was to investigate serum leptin levels in patients with benign breast tumors, as well as in various breast cancer phenotypes, taking into account leptin levels connected to menopausal status and body mass index (BMI). The study included 97 patients having their breast tumor surgically removed. Serum leptin level was determined by ELISA method in all study patients. Study results showed that significantly more women, regardless of having malignant or benign tumors, were postmenopausal and had a significantly higher level of leptin compared to the premenopausal group. The highest level of leptin was recorded in the group of postmenopausal obese women compared to other postmenopausal women but also compared to premenopausal women. According to BMI alone, obese women had a significantly higher level of leptin regardless of the type of tumor. The most significant differences in leptin levels observed through BMI were found in the Luminal B1 group. In conclusion, serum leptin level was shown to be a good diagnostic parameter suggesting a higher possibility of breast cancer development.

Comparison of TNF-α and IL-19 concentrations at different stages of breast cancer.

This study investigated the alteration of tumour necrosis factor (TNF-α) and interleukin-19 (IL-19) at different clinical disease stages, lymph node metastasis, and ductal carcinoma in women with breast cancer. Serum samples were collected from 90 individuals with an age range of 25-61 years. These individuals were divided into a control group (healthy people), consisting of 31 individuals, and a breast cancer patients (BCP) group, consisting of 59 individuals. The pathological data (tumour stage, lymph node metastasis, and ductal carcinoma) was obtained from the medical record of patients and confirmed by experienced histopathology. Enzyme-linked immunosorbent assay (ELISAs) technology was used to measure the serum concentrations of IL-19 and TNF-α. The results showed significant differences (P≤0.002) in the mean of BMI, interleukin-19, and TNF-α in BCP compared to controls, while the age factor did not play an important role. The stages of breast cancer caused clear differences in the levels of TNF-α and IL-19. According to the findings, BCPs had a greater level of TNF-α in lymph node metastases than healthy persons. The concentration of serum IL-19 in BCP with lymph node metastasis was significantly different in non-lymph node metastasis patients and healthy people. Additionally, BCP with ductal carcinoma showed significant differences in the mean levels of IL-19 and TNF-α in comparison with healthy people.

The role of interleukin­7 serum level as biological marker in breast cancer: a cross­sectional, observational, and analytical study.

BACKGROUND: The important role that the immune system plays in malignant diseases is well known. The action of interleukin-7 (IL-7) as a cytokine has been observed in many cellular processes, both in normal cells of the immune system and in some cancer cells. The aim of this study has been to explore whether there is any elevation of interleukin-7 serum levels in early invasive breast cancer (EIBC) patients in comparison with healthy controls. In addition, the correlation between the IL-7 serum level and the histopathological characteristics of the tumor has been evaluated. METHODS: This cross-sectional, observational, and analytical study included 213 consecutive patients with EIBC (113 from Croatia and 100 from Kosovo) and 62 healthy participants as the control group (30 from Croatia and 32 from Kosovo). Blood samples have been taken from patients confirmed with breast cancer (BC) by biopsy, prior to surgical intervention and other oncological treatments, as well as from healthy participants. A serum IL-7 level has been measured, using the "Sandwich" ELISA Immunoenzyme test. In addition, after the surgical intervention, histopathological specimen examinations and immunohistochemistry have been performed and analyzed. The differences in the distribution of the numerical variables have been analyzed with the Mann-Whitney U test and Kruskal-Wallis ANOVA test. Correlations have been tested with Pearson coefficients. A P-value < 0.05 has been accepted as statistically significant. RESULTS: The serum level of IL-7 in EIBC patients was significantly higher than in control cases (P 0.001). Patients with invasive lobular carcinoma (ILC) seem to have a lower IL-7 serum level compared to other histological subtypes, and the difference has been significant (P = 0.043). There has been no correlation between IL-7 serum level and histopathological characteristics of the tumor, with neither age nor menopausal status of the patients. CONCLUSIONS: Noting the significant increase in the IL-7 serum level in the EIBC patients as compared to the healthy control group, the use of IL-7 as a potential diagnostic indicator for BC, as well as in the follow-up of the patients after treatment, can be assumed. The lack of correlation with tumor size, lymph node metastasis, and all other histopathological characteristics of the tumor questions its use as a prognostic indicator.

Evaluation of miRNA-21-5p and miRNA-10b-5p levels in serum-derived exosomes of breast cancer patients in different grades.

BACKGROUND & OBJECTIVES: Tumor cells have various effects and dominance over other healthy cells. Cancer cells alter the cell program in healthy cells by secreting exosomes containing microRNAs involved in epithelial-mesenchymal transition (EMT). They can migrate to distant organs and establish a pre-metastatic niche. The purpose of this study was to determine the expression of miRNA-21-5p and miRNA-10b-5p, both of which are involved in EMT, in breast cancer-derived exosomes of various grades in order to identify new biomarkers involved in breast cancer progression. METHODS: In this study, a blood sample was taken from 60 patients with grades I, II, or III breast cancer, as well as twenty healthy individuals as a control group. The exosomes were then purified from serum samples, and their relative expression of miRNA-21-5p and miRNA-10b-5p was determined using the real-time PCR method. RESULTS: miRNA-21-5p expression was significantly increased in patients with breast cancer grades I, II, and III compared to the control group (p < 0.01), (p < 0.0001) and (p < 0.0001), respectively, as was miRNA-10b-5p expression in patients with breast cancer grades I, II, and III compared to the control group (p < 0.0001), (p < 0.0001) and (p < 0.0001), respectively. CONCLUSION: Our results show that both microRNAs increase as cells lose their differentiation and become more invasive, which is evidence of cancer progression. Hence, both microRNAs may have the potential to be used alone or in combination with other biomarkers for the diagnosis and prognosis of breast cancer.

Hypermethylation of TMEM240 predicts poor hormone therapy response and disease progression in breast cancer.

BACKGROUND: Approximately 25% of patients with early-stage breast cancer experience cancer progression throughout the disease course. Alterations in TMEM240 in breast cancer were identified and investigated to monitor treatment response and disease progression. METHODS: Circulating methylated TMEM240 in the plasma of breast cancer patients was used to monitor treatment response and disease progression. The Cancer Genome Atlas (TCGA) data in Western countries and Illumina methylation arrays in Taiwanese breast cancer patients were used to identify novel hypermethylated CpG sites and genes related to poor hormone therapy response. Quantitative methylation-specific PCR (QMSP), real-time reverse transcription PCR, and immunohistochemical analyses were performed to measure DNA methylation and mRNA and protein expression levels in 394 samples from Taiwanese and Korean breast cancer patients. TMEM240 gene manipulation, viability, migration assays, RNA-seq, and MetaCore were performed to determine its biological functions and relationship to hormone drug treatment response in breast cancer cells. RESULTS: Aberrant methylated TMEM240 was identified in breast cancer patients with poor hormone therapy response using genome-wide methylation analysis in the Taiwan and TCGA breast cancer cohorts. A cell model showed that TMEM240, which is localized to the cell membrane and cytoplasm, represses breast cancer cell proliferation and migration and regulates the expression levels of enzymes involved in estrone and estradiol metabolism. TMEM240 protein expression was observed in normal breast tissues but was not detected in 88.2% (67/76) of breast tumors and in 90.0% (9/10) of metastatic tumors from breast cancer patients. QMSP revealed that in 54.5% (55/101) of Taiwanese breast cancer patients, the methylation level of TMEM240 was at least twofold higher in tumor tissues than in matched normal breast tissues. Patients with hypermethylation of TMEM240 had poor 10-year overall survival (p = 0.003) and poor treatment response, especially hormone therapy response (p < 0.001). Circulating methylated TMEM240 dramatically and gradually decreased and then diminished in patients without disease progression, whereas it returned and its levels in plasma rose again in patients with disease progression. Prediction of disease progression based on circulating methylated TMEM240 was found to have 87.5% sensitivity, 93.1% specificity, and 90.2% accuracy. CONCLUSIONS: Hypermethylation of TMEM240 is a potential biomarker for treatment response and disease progression monitoring in breast cancer.

Platelet-Derived miR-126-3p Directly Targets AKT2 and Exerts Anti-Tumor Effects in Breast Cancer Cells: Further Insights in Platelet-Cancer Interplay.

Among the surrounding cells influencing tumor biology, platelets are recognized as novel players as they release microvesicles (MVs) that, once delivered to cancer cells, modulate signaling pathways related to cell growth and dissemination. We have previously shown that physiological delivery of platelet MVs enriched in miR-126 exerted anti-tumor effects in different breast cancer (BC) cell lines. Here, we seek further insight by identifying AKT2 kinase as a novel miR-126-3p direct target, as assessed by bioinformatic analysis and validated by luciferase assay. Both ectopic expression and platelet MV-mediated delivery of miR-126-3p downregulated AKT2 expression, thus suppressing proliferating and invading properties, in either triple negative (BT549 cells) or less aggressive Luminal A (MCF-7 cells) BC subtypes. Accordingly, as shown by bioinformatic analysis, both high miR-126 and low AKT2 levels were associated with favorable long-term prognosis in BC patients. Our results, together with the literature data, indicate that miR-126-3p exerts suppressor activity by specifically targeting components of the PIK3/AKT signaling cascade. Therefore, management of platelet-derived MV production and selective delivery of miR-126-3p to tumor cells may represent a useful tool in multimodal therapeutic approaches in BC patients.

Energy homeostasis genes modify the association between serum concentrations of IGF-1 and IGFBP-3 and breast cancer risk.

Breast cancer is a multifactorial disease in which the interplay among multiple risk factors remains unclear. Energy homeostasis genes play an important role in carcinogenesis and their interactions with the serum concentrations of IGF-1 and IGFBP-3 on the risk of breast cancer have not yet been investigated. The aim of this study was to assess the modifying effect of the genetic variation in some energy homeostasis genes on the association of serum concentrations of IGF-1 and IGFBP-3 with breast cancer risk. We analyzed 78 SNPs from 10 energy homeostasis genes in premenopausal women from the 4-Corner's Breast Cancer Study (61 cases and 155 controls) and the Mexico Breast Cancer Study (204 cases and 282 controls). After data harmonization, 71 SNPs in HWE were included for interaction analysis. Two SNPs in two genes (MBOAT rs13272159 and NPY rs16131) showed an effect modification on the association between IGF-1 serum concentration and breast cancer risk (Pinteraction < 0.05, adjusted Pinteraction < 0.20). In addition, five SNPs in three genes (ADIPOQ rs182052, rs822391 and rs7649121, CARTPT rs3846659, and LEPR rs12059300) had an effect modification on the association between IGFBP-3 serum concentration and breast cancer risk (Pinteraction < 0.05, adjusted Pinteraction < 0.20). Our findings showed that variants of energy homeostasis genes modified the association between the IGF-1 or IGFBP-3 serum concentration and breast cancer risk in premenopausal women. These findings contribute to a better understanding of this multifactorial pathology.

Serum-Based lncRNA ANRIL, TUG1, UCA1, and HIT Expressions in Breast Cancer Patients.

Breast cancer is a heterogeneous disease and is the most common and prevalent form of malignancy diagnosed in women. lncRNAs are found to be frequently dysregulated in cancer, and its expression plays a critical role in tumorigenesis. The study included 100 histopathologically confirmed, newly diagnosed untreated patients of invasive ductal carcinoma (IDC) of breast cancer patients and 100 healthy subjects. After blood collection, the serum was separated and total RNA was extracted, cDNA was synthesized using 100 ng of total RNA, and lncRNA (ANRIL, TUG1, UCA1, and HIT) expression was analyzed. Increased ANRIL (3.83-fold), TUG1 (7.64-fold), UCA1 (7.82-fold), and HIT (3.31-fold) expressions were observed in breast cancer patients compared to healthy controls. Relative expression of lncRNAs UCA-1 (p = 0.010) and HIT-1 (p < 0.0001) was significantly elevated in patients with advanced breast cancer stage compared to those with early-stage disease. While lncRNA TUG-1 expression was found to be higher in patients with early-stage tumors than those with advanced-stage tumors (p = 0.06), lncRNA ANRIL showed increased expression in patients with PR positive status (p = 0.04). However, we found a significant difference in lncRNA HIT expression in HER-2 positive breast cancer patients compared to HER-2 negative breast cancer patients (p = 0.005). An increase in the expression of serum lncRNAs ANRIL (p < 0.0001), UCA-1 (p = 0.004), and HIT (p < 0.0001) was observed in the distant organ metastatic breast cancer patients. In the ROC curve concerning lymph node involvement, the sensitivity and specificity of lncRNA HIT were 68% and 58%, respectively (p value = 0.007). In the ROC curve w.r.t. stages of disease, the sensitivity and specificity of lncRNA HIT were 80% and 50%, respectively (p value < 0.0001). Better sensitivity and specificity were observed for lncRNA HIT (sensitivity 91% and specificity 78%; p value < 0.0001) and ANRIL (sensitivity 70% and specificity 60%; p value < 0.0001) w.r.t distant organ metastases.

Preliminary results using a kit to measure tamoxifen and metabolites concentrations in capillary blood samples from women with breast cancer.

The aim of the study was to compare 3 blood sampling methods, including capillary blood sampling, for determining Tamoxifen (TAM), Z-endoxifen (END), and 4-hydroxytamoxifen (4HT) concentrations. High performance liquid chromatography-mass spectrometry was used to quantify concentrations of TAM, END, and 4HT in plasma, venous blood, and capillary blood samples of 16 participants on TAM therapy for breast cancer. The rhelise kit was used for capillary sampling. Calibration curves using 13C-labeled analogs of TAM, END, and 4HT as internal standards were used for quantifications. A capillary sampling kit was used successfully for all participants. Mean TAM concentrations did not differ significantly in the 3 types of samples. Mean END and 4HT concentrations did differ significantly between capillary and venous blood samples, possibly related to photodegradation in the internal standards prior to use or degradation products with chromatographic retention times similar to the metabolites. TAM, END, and 4HT concentrations were relatively stable when stored for 14 days at 8 °C and 20 °C. Therapeutic drug monitoring of TAM using an innovative kit and capillary blood sampling is feasible. Preliminary data from this study will aid in developing a multicenter, randomized clinical trial of personalized TAM dose monitoring and adjustments, with the goal of enhancing the quality-of-life and outcomes of patients with breast cancer.Clinical Trial Identification: EudraCT No 2017-000641-44.

Diagnostic Value of Nonacid Nucleic Blood Tumor Marker Panels in Early Diagnosing Breast Cancer: A Systematic Review and Network Meta-Analysis.

This study is aimed at determining the best nonacid nucleic blood tumor marker panels in terms of sensitivity, specificity, and accuracy in order to detect breast cancer in early stages (I, II, and III) among eligible women for breast cancer screening. PubMed, Web of Science, Embase, Scopus, and Cochrane were systematically reviewed to assess nonacid nucleic blood tumor marker panels' diagnostic value in women, both healthy and patient (before any anticancer treatment), for detecting breast cancer. A network meta-analysis was carried out using a Bayesian network meta-analysis to estimate combined odd ratio (OR) and 95% CI credible interval for presenting the results. Rankograms plot was drawn to rank the diagnostic value of different panels. Of the 2358 titles initially identified, 9 studies and 8 panels were included in the network meta-analysis. Panels A (MMP-9/TIMP-1) and K (TF1+TF2+TF3) had the highest sensitivity in early stages, as panel A with OR = 11.61 and 95% CI (1.49-102.5) demonstrated a better function than mammography. Panels H (CA 15.3 + IL-18) and A (MMP-9/TIMP-1) had the highest specificity in early stages, but no significant difference with mammography. Panels A (MMP-9/TIMP-1) and H (CA 15.3 + IL-18) had the highest accuracy in early stages, as they significantly exhibited a higher function than mammography with OR = 6.87 and 95% CI (2.07-31.35) as well as OR = 3.44 and 95% CI (1.15-11.07), respectively. Panel A including MMP-9/TIMP-1 in early stages demonstrated a higher diagnostic value for breast cancer than the rest of the panels.

Comparison of Her2/Neu Oncoprotein in Serum and Tissue Samples in Women with Breast Cancer.

BACKGROUND AND OBJECTIVES: Human Epidermal Growth Factor Receptor 2 (HER2/neu) is one of the most extensively studied proto-oncogens in breast cancer patients.  Accurate and timely assessment of the HER2/neu over expression is pivotal for the identification of breast cancer patients that could benefit from HER2-targeted therapy.  The present study was undertaken to investigate the diagnostic utility of serum HER2/neu testing by chemiluminescent immunoassay (CLIA) in breast cancer patients and compare it with the immunohistochemistry (IHC) method of HER2/neu expression. METHODS: Serum sample and tissue/paraffin block was collected from 52 patients with breast cancer before start of any anticancer regimen or hormonal therapy.  The tissue specimens were processed in Histopathology lab. Sections were immunostained with anti -estrogen receptor (ER) , anti -progesteron receptor (PR) and anti HER2/neu receptor  mouse monoclonal antibodies.) Serum HER2/neu was estimated using the chemiluminiscent immunoassay using 15ng/ml as the cut off. RESULTS: Out of 52 patients with breast cancer, serum HER2/neu was found elevated in 25(48.1%) patients and remaining 27(51.9%) showed normal serum HER2/neu concentrations. On IHC HER2/neu score was 3+ in 9(17.3%), 2+ in 10(19.2%), 1+ in 1(1.9%); while 32(61.5%) showed no HER2/neu expression.  31(59.6%) patients were ER positive and 28(53.8%) were PR positive. There was a significant correlation (P<0.001) of serum HER2 concentration with tissue expression of HER2/neu and Histological tumor grade. Serum HER2/neu levels showed a negative correlation with ER status (P=0.047) but no correlation with PR status. CONCLUSION: The result showed that the elevated serum HER2/neu was correlated with the IHC expression of HER2/neu in tissue and the histological grade of the tumor.  Findings suggest that post initial tissue diagnosis (IHC HER2/neu), serum HER2 assay may supplement subsequent tissue tests to monitor disease status and response to therapy.

Prognostic Value of Tumor Infiltrating Lymphocytes in Locally Advanced HER2 Enriched Breast Cancer.

PURPOSE: We aim to study the association between stromal tumor infiltrating lymphocytes (TILs) level and disease free survival (DFS) in a group of ER and PR negative, HER2+ locally advanced breast cancer patients who underwent curative intent surgery. METHODS: This is a retrospective cohort study including 66 locally advanced hormone receptor-negative; HER2+ breast cancer patients presented between 2013 and 2015 at NCI-Cairo, Egypt. Enrolled patients had at least clinically T3 and/or node positive disease either clinically or radiologically. Metastatic workup included CT and bone scans or PET-CT. Patients with hormone receptor positive, HER2 negative, inadequate paraffin block and who lost follow up before or immediately after curative surgery were excluded. Patients were followed from breast surgery till relapse date for a minimum of 36 months. TILs and CD8 antigen were assessed on paraffin-embedded blocks using immunohistochemistry. RESULTS: Patients with a median age of 52 years presented with clinical T3 stage (53%) and N1 stage (61%). Modified radical mastectomy was performed in 79%. Only 41% received neoadjuvant chemotherapy and 56% received trastuzumab. TILs were 50, 17 and 33% for absent, intermediate and extensive groups and CD8+ lymphocytes were present in 80% of cases. At the end of follow-up period, 23 patients (35%) were found to have disease recurrence either loco-regional (22%) or distant (78%). TILs were 14, 4 and 5% for absent, intermediate and extensive respectively; while CD8+ lymphocytes were absent in 6% and present (≥1%) in 17%. Higher DFS was recorded for patients with extensive TILs level only who received trastuzumab. CONCLUSION: High TILs is good prognosis in HER2 enriched breast cancer provided that patients received HER2 directed therapy. Moreover, CD8+ lymphocytes are highly representative and maybe used as an alternative for TILs. We recommend considering TILs and specifically CD8+ as one of the risk factors that predict prognosis of HER2+ breast cancer.

Evaluation of Serum MicroRNAs (miR-9-5p, miR-17-5p, and miR-148a-3p) as Potential Biomarkers of Breast Cancer.

BACKGROUND: MicroRNAs (miRNAs) play important roles in the initiation and progression of cancers. The purpose of the present study was to evaluate the use of serum miRNA biomarkers in the early diagnosis of breast cancer. METHODS: The expression levels of miR-9-5p, miR-17-5p, and miR-148a-3p were analyzed by quantitative reverse transcription-polymerase chain reaction in 49 patients with newly diagnosed breast cancer and 49 healthy controls. The associations between miR-9-5p, miR-17-5p, and miR-148a-3p levels and clinicopathological parameters were also analyzed. Regression analysis and sensitivity and specificity analyses were used to determine the diagnostic efficacy of the miRNAs. RESULTS: Serum levels of miR-9-5p and miR-148a-3p were significantly higher in breast cancer patients than in healthy controls (both P < 0.05), but miR-17-5p levels were not different between the two groups (P = 0.996). Serum miR-9-5p levels were markedly higher in patients with human epidermal growth factor receptor 2- (HER2-) positive breast cancer than in those with HER2-negative breast cancer (P = 0.049). Serum levels of miR-9-5p and miR-148a-3p were positively correlated with the presence of breast cancer, and both miRNAs had high sensitivity and specificity for the diagnosis of breast cancer. CONCLUSIONS: These findings provide evidence that serum miR-9-5p and miR-148a-3p levels may be used as noninvasive biological markers for the clinical diagnosis of breast cancer.

Soluble forms of PD-1/PD-L immune checkpoint receptor and ligand in blood serum of breast cancer patients: association with clinical pathologic factors and molecular type of the tumor.

Results of enzyme-linked immunosorbent assay of the soluble forms of PD-1/PD-L immune checkpoint receptor and ligand (sPD-1 and sPD-L1) in pretreatment blood serum of 88 breast cancer patients at various disease stages aged 30-83 years are presented. The control group included 55 practically healthy women aged 19-82 years. Serum sPD-1 and sPD-L1 levels in breast cancer patients highly significantly (p<0.0001) differ from control and these changes are opposite: soluble receptor level is more than 6-fold decreased, while soluble ligand concentration - 5.5 fold increased. Both markers separately, as well as their ratio demonstrate very high sensitivity (94-100%) and specificity (95-100%) in relation to healthy control. No statistically significant associations of sPD-1 and sPD-L1 levels with clinical stage, individual TNM system criteria, tumor histological structure, grade, receptor status, and molecular type were established. In particular, no significant peculiarities of the markers' levels in triple negative breast cancer successfully treated with anti-PD-1/PD-L1 preparations were revealed. Long-term follow-up and dynamic studies of sPD-1 and sPD-L1serum levels in the course of treatment are required for evaluation of their independent from clinical and morphological factors prognostic significance and the possibility of application as low invasive tests for prediction and monitoring of corresponding targeted therapy efficiency.

Single nucleotide polymorphism of fatty acid desaturase gene and breast cancer risk in estrogen receptor subtype.

BACKGROUND: Breast cancer (BC) is the most common cancer of women and the second most common cancer overall globally. Data suggest that the plasma concentration of omega fatty acids (n-3 and n-6) and the impact of the genetic variant are associated with diet-related inflammatory disease, BC. This study was aimed to find an association between genetic variant rs174537 of fatty acid desaturase gene 1(FADS 1) and breast cancer estrogen receptor subtype. METHODOLOGY: Hundred and two blood samples from women were quantified for fatty acids by gas chromatography. SNP rs 174537(G > T) showed maximum variability and the strongest genetic determinant in the Genome-wide association study were genotyped using Sanger sequencing. RESULTS: The highest tertile of ALA showed a significantly reduced risk of BC compared to the lowest tertile (OR = 0.2, 95 %CL = 0.1-1.14, P = 0.03). Median values of ALA were higher in GT/TT genotype in ER +ve molecular subtype (P = 0.03) and DPA was higher in GG genotype of ER-ve molecular subtype (P = 0.037). When both the groups were put together the highest tertile of GG tertile showed significantly reduced risk of BC compared with the other lowest tertiles of GG and GT/TT genotypes (OR, 95% CL = 0.45(0.2-0.9). CONCLUSION: The high levels of arachidonic acid and low levels of n-3 fatty acids result in a pro-inflammatory milieu and that these pro-inflammatory effects might contribute to BC. We conclude that the individuals with genetically determined lower activity of FADS1(minor allele T) will derive greater advantage from n-3 FAs than those with higher FADS1 activity (G allele) and reduce the BC risk.

Application value of the treatment of breast cancer bone metastases with radioactive seed 125I implantation under CT-guidance.

BACKGROUND: To investigate the application value of the treatment of breast cancer bone metastases with radioactive seed 125I implantation under CT-guidance. METHODS: A total of 90 patients with breast cancer admitted to our hospital from January 2017 to January 2018 were selected as the research objects and were divided into control group and experimental group according to random grouping, with 45 cases in each group. Conventional treatment was used in the control group, while the treatment of radioactive seed 125I implantation under CT-guidance was used in the experimental group. The clinical efficacy, pain intensity and levels of carcinoembryonic antigen (CEA), carcinoembryonic antigen 153 (CA153), carbohydrate antigen (CA125) in the two groups were compared. RESULTS: As for the pain intensity, it was evidently lower in the experimental group after treatment than that in the control group (P < 0.05); as for the total effective rate, it was obviously higher in the experimental group after treatment than that in the control group (P < 0.05); as for the levels of CEA, CA153 and CA125, the data in the experimental group after treatment were much lower than the control group (P < 0.05). CONCLUSION: Radioactive seed 125I implantation under CT-guidance can effectively improve the effect of the treatment of breast cancer bone metastases. It has curative efficacy and it is worth promoting and using.

Prognostic Value of Combined Lactate Dehydrogenase, C-Reactive Protein, Cancer Antigen 153 and Cancer Antigen 125 in Metastatic Breast Cancer.

BACKGROUND: Breast cancer (BC), especially metastatic BC, is one of the most lethal diseases in women. CA 125 and CA 15-3 are commonly used indicators for diagnosis and prognosis of BC. Some serological indicators, such as lactate dehydrogenase (LDH) and C-reactive protein (CRP), can also be used to assess the prognosis and progression in BC. METHODS: Univariate Cox regression analysis and LASSO regression analysis were performed to identify prognostic factors and build prognostic models. We distributed the patients into 2 groups based on the median risk score, analyzed prognosis by Kaplan-Meier curve, and screened independent prognostic factors by multivariate Cox regression analysis. RESULT: We identified 4 indicators-LDH, CRP, CA 15-3, and CA 125-related to the prognosis in BC and established a prognostic model. The high LDH group showed worse overall survival (OS) than low LDH group (P = .017; hazard ratio (HR), 1.528; 95% confidence interval (CI), 1.055-2.215). The high CRP group showed worse OS than low CRP group (P = .004; HR, 1.666; 95% CI, 1.143-2.429). The high CA153 group showed worse OS than low CA 15-3 group (P=.011; HR, 1.563; 95% CI, 1.075-2.274). The high CA 125 group showed worse OS than low CA 125 group (P = .021; HR, 1.499; 95% CI, 1.031-2.181). The area under the curve for risk score was .824, Ki-67 was .628, age was .511, and grade was .545. Risk score was found to be an independent prognostic factor using multivariate Cox regression analysis. CONCLUSION: We successfully established an optimization model by combining 4 prognosis-related indicators to assess the prognosis in patients with metastatic BC.

High score of LDH plus dNLR predicts poor survival in patients with HER2-positive advanced breast cancer treated with trastuzumab emtansine.

OBJECTIVE: To investigate the prognostic value of derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) in patients with advanced HER2 positive breast cancer treated with trastuzumab emtansine. METHODS: Fifty one patients with advanced HER2 positive breast cancer who received T-DM1 treatment in Harbin Medical University Cancer Hospital were selected. The clinical data and blood test indexes were collected, and the ROC curve determined the optimal cut-off value. Kaplan-Meier survival curve and Cox regression model was used to analyze the effect of different levels of dNLR,LDH,LNI (dNLR combined with LDH index) before and after T-DM1 treatment on the survival of patients. RESULTS: The median PFS and OS of the patients with advanced HER2 positive breast cancer who received T-DM1 treatment were 6.9 months and 22.2 months, respectively. The optimal cut-off value of LDH and dNLR before T-DM1 treatment was 244 U / L (P = 0.003) and 1.985 (P = 0.013), respectively. Higher LDH and dNLR were significantly correlated with shorter median PFS and OS (P < 0.05). The median PFS of patients with LNI (0), LNI (1) and LNI (2) were 8.1 months, 5.5 months and 2.3 months, respectively, P = 0.007. Univariate and multivariate analysis showed that LDH > 244 U / L, dNLR > 1.985, LNI > 0, ECOG ≥1 and HER-2 (IHC2 +, FISH+) before the T-DM1 treatment were the poor prognostic factors. LDH uptrend after the T-DM1 treatment also predicted poor prognosis. CONCLUSION: Serum LDH > 244 U / L and dNLR > 1.985 before the T-DM1 treatment were prognostic risk factors for patients with advanced HER2 positive breast cancer receiving T-DM1 treatment. The higher LNI score was significantly associated with shorter PFS and OS. LDH uptrend after T-DM1 treatment was also related to the poor prognosis.