Understanding the Role of Estrogen Receptor Status in PRODH/POX-Dependent Apoptosis/Survival in Breast Cancer Cells

It has been suggested that activation of estrogen receptor α (ER α) stimulates cell proliferation. In contrast, estrogen receptor β (ER β) has anti-proliferative and pro-apoptotic activity. Although the role of estrogens in estrogen receptor-positive breast cancer progression has been well established, the mechanism of their effect on apoptosis is not fully understood. It has been considered that ER status of breast cancer cells and estrogen availability might determine proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis. PRODH/POX is a mitochondrial enzyme that converts proline into pyrroline-5-carboxylate (P5C). During this process, ATP (adenosine triphosphate) or ROS (reactive oxygen species) are produced, facilitating cell survival or death, respectively. However, the critical factor in driving PRODH/POX-dependent functions is proline availability. The amount of this amino acid is regulated at the level of prolidase (proline releasing enzyme), collagen biosynthesis (proline utilizing process), and glutamine, glutamate, α-ketoglutarate, and ornithine metabolism. Estrogens were found to upregulate prolidase activity and collagen biosynthesis. It seems that in estrogen receptor-positive breast cancer cells, prolidase supports proline for collagen biosynthesis, limiting its availability for PRODH/POX-dependent apoptosis. Moreover, lack of free proline (known to upregulate the transcriptional activity of hypoxia-inducible factor 1, HIF-1) contributes to downregulation of HIF-1-dependent pro-survival activity. The complex regulatory mechanism also involves PRODH/POX expression and activity. It is induced transcriptionally by p53 and post-transcriptionally by AMPK (AMP-activated protein kinase), which is regulated by ERs. The review also discusses the role of interconversion of proline/glutamate/ornithine in supporting proline to PRODH/POX-dependent functions. The data suggest that PRODH/POX-induced apoptosis is dependent on ER status in breast cancer cells.

Analyzing the Estrogen Receptor Status of Liver Metastases with [18F]-FES-PET in Patients with Breast Cancer

Background: Positron emission tomography (PET) with 16α-[18F]-fluoro-17β-estradiol ([18F]-FES) can visualize estrogen receptor (ER) expression, but it is challenging to determine the ER status of liver metastases, due to high physiological [18F]-FES uptake. We evaluated whether [18F]-FES-PET can be used to determine the ER status of liver metastases, using corresponding liver biopsies as the gold standard. Methods: Patients with metastatic breast cancer (n = 23) were included if they had undergone a [18F]-FES-PET, liver metastasis biopsy, CT-scan, and [18F]-FDG-PET. [18F]-FES-PET scans were assessed by visual and quantitative analysis, tracer uptake was correlated with ER expression measured by immunohistochemical staining and the effects of region-of-interest size and background correction were determined. Results: Visual analysis allowed ER assessment of liver metastases with 100% specificity and 18% sensitivity. Quantitative analysis improved the sensitivity. Reduction of the region-of-interest size did not further improve the results, but background correction improved ER assessment, resulting in 83% specificity and 77% sensitivity. Using separate thresholds for ER+ and ER– metastases, positive and negative predictive values of 100% and 75%, respectively, could be obtained, although 30% of metastases remained inconclusive. Conclusion: In the majority of liver metastases, ER status can be determined with [18F]-FES-PET if background correction and separate thresholds are applied.

EP.TH.275The role of amino acid transporters SLC1A5 and SLC3A2 in primary breast cancer in older women

Aims Breast cancer in older women has more favourable biology, compared to younger women. Increased glutamine metabolism is a hallmark of cancer. The prognostic role of amino acid transporters involved with glutamine flux, SLC1A5 and SLC3A2, has been shown in breast cancer in younger women. This study aimed to investigate the role of SLC1A5 and SLC3A2 in breast cancer in older women as possible prognostic markers. Methods Surgical specimens were obtained from an existing series of 1,758 older women (≥70 years) with primary breast cancer, treated in a single institution with long-term (37+ years) follow-up. Of this cohort, 813 had primary surgical treatment. As part of previous work, it was possible to construct good quality tissue microarrays (TMAs) in 575 cases. Immunohistochemical staining for SLC1A5 and SLC3A2 was performed. H-score was considered as a continuous variable as well as using positivity cut-offs of ≥ 45 for SLC1A5 and ≥15 for SLC3A2, using X-tile software. Association between H-score and tumour size, grade, ER status, local-recurrence-free-survival (LRFS), overall survival (OS) and breast-cancer-specific-survival (BCSS) was investigated. Results No correlation was seen between neither marker and LRFS, OS, or BCSS in older women with breast cancer. Both markers were associated with high tumour grade and negative ER status (both p < 0.001). Conclusions These findings are contrary to those found in younger women, where these amino acid transporters are associated with shorter BCSS. This may suggest that breast cancer in older women is less reliant on glutamine metabolism, which is consistent with an overall less aggressive phenotype.

Low pan-immune-inflammation-value predicts better chemotherapy response and survival in breast cancer patients treated with neoadjuvant chemotherapy

Blood-based biomarkers reflect systemic inflammation status and have prognostic and predictive value in solid malignancies. As a recently defined biomarker, Pan-Immune-Inflammation-Value (PIV) integrates different peripheral blood cell subpopulations. This retrospective study of collected data aimed to assess whether PIV may predict the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in Turkish women with breast cancer. The study consisted of 743 patients with breast cancer who were scheduled to undergo NAC before attempting cytoreductive surgery. A pre-treatment complete blood count was obtained in the two weeks preceding NAC, and blood-based biomarkers were calculated from absolute counts of relevant cell populations. The pCR was defined as the absence of tumor cells in both the mastectomy specimen and lymph nodes. Secondary outcome measures included disease-free survival (DFS) and overall survival (OS). One hundred seven patients (14.4%) had pCR. In receiver operating characteristic analysis, optimal cut-off values for the neutrophile-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte (PLR), PIV, and Ki-67 index were determined as ≥ 2.34, ≥ 0.22, ≥ 131.8, ≥ 306.4, and ≥ 27, respectively. The clinical tumor (T) stage, NLR, MLR, PLR, PIV, estrogen receptor (ER) status, human epidermal growth factor receptor-2 (HER-2) status, and Ki-67 index were significantly associated with NAC response in univariate analyses. However, multivariate analysis revealed that the clinical T stage, PIV, ER status, HER-2 status, and Ki-67 index were independent predictors for pCR. Moreover, the low PIV group patients had significantly better DFS and OS than those in the high PIV group (p = 0.034, p = 0.028, respectively). Based on our results, pre-treatment PIV seems as a predictor for pCR and survival, outperforming NLR, MLR, PLR in predicting pCR in Turkish women with breast cancer who received NAC. However, further studies are needed to confirm our findings.

Breast cancer risk factors in relation to molecular subtypes in breast cancer patients from Kenya

Background Few studies have investigated risk factor heterogeneity by molecular subtypes in indigenous African populations where prevalence of traditional breast cancer (BC) risk factors, genetic background, and environmental exposures show marked differences compared to European ancestry populations. Methods We conducted a case-only analysis of 838 pathologically confirmed BC cases recruited from 5 groups of public, faith-based, and private institutions across Kenya between March 2012 to May 2015. Centralized pathology review and immunohistochemistry (IHC) for key markers (ER, PR, HER2, EGFR, CK5-6, and Ki67) was performed to define subtypes. Risk factor data was collected at time of diagnosis through a questionnaire. Multivariable polytomous logistic regression models were used to determine associations between BC risk factors and tumor molecular subtypes, adjusted for clinical characteristics and risk factors. Results The median age at menarche and first pregnancy were 14 and 21 years, median number of children was 3, and breastfeeding duration was 62 months per child. Distribution of molecular subtypes for luminal A, luminal B, HER2-enriched, and triple negative (TN) breast cancers was 34.8%, 35.8%, 10.7%, and 18.6%, respectively. After adjusting for covariates, compared to patients with ER-positive tumors, ER-negative patients were more likely to have higher parity (OR = 2.03, 95% CI = (1.11, 3.72), p = 0.021, comparing ≥ 5 to ≤ 2 children). Compared to patients with luminal A tumors, luminal B patients were more likely to have lower parity (OR = 0.45, 95% CI = 0.23, 0.87, p = 0.018, comparing ≥ 5 to ≤ 2 children); HER2-enriched patients were less likely to be obese (OR = 0.36, 95% CI = 0.16, 0.81, p = 0.013) or older age at menopause (OR = 0.38, 95% CI = 0.15, 0.997, p = 0.049). Body mass index (BMI), either overall or by menopausal status, did not vary significantly by ER status. Overall, cumulative or average breastfeeding duration did not vary significantly across subtypes. Conclusions In Kenya, we found associations between parity-related risk factors and ER status consistent with observations in European ancestry populations, but differing associations with BMI and breastfeeding. Inclusion of diverse populations in cancer etiology studies is needed to develop population and subtype-specific risk prediction/prevention strategies.

Danmarks status ved FN i New York

Denne artikel analyserer Danmarks status relativt til de tre største nordiske konkurrenter ved FN i New York: Norge, Sverige og Finland. FN er siden 2001 blevet nedprioriteret af gentagne danske regeringer, og undersøgelsen forsøger vha. en statusteoretisk analyseramme at afdække, om disse ændringer har haft konsekvenser for Danmarks status internt i den nordiske kreds. Fra et dansk perspektiv er status særligt relevant i øjeblikket, da Danmark i 2024 planmæssigt skal vejes på FN’s mest markante statusvægt: Valget til FN’s Sikkerhedsråd. Analysen konkluderer, at Danmarks relative status siden 2001 overordnet er faldet på de to undersøgte felter – det udviklingspolitiske og militære område. Der er derfor brug for en ændret strategi og et fornyet fokus såfremt sandsynligheden for at blive valgt til Sikkerhedsrådet i tilfælde af kampvalg skal højnes.

Breast Cancer Risk factors in Relation to Molecular Subtypes in Breast Cancer Patients from Kenya.

BackgroundFew studies have investigated risk factor heterogeneity by molecular subtypes in indigenous African populations where prevalence of traditional breast cancer (BC) risk factors, genetic background, and environmental exposures show marked differences compared to European ancestry populations. MethodsWe conducted a case-only analysis of 838 pathologically confirmed BC cases recruited from 5 groups of public, faith-based and private institutions across Kenya between March 2012 to May 2015. Centralized pathology review and immunohistochemistry (IHC) for key markers (ER, PR, HER2, EGFR, CK5-6, and Ki67) was performed to define subtypes. Risk factor data was collected at time of diagnosis through a questionnaire. Multivariable polytomous logistic regression models were used to determine associations between BC risk factors and tumor molecular subtypes, adjusted for clinical characteristics and risk factors.ResultsThe median age at menarche and first pregnancy were 14 and 21 years, median number of children was 3 and breastfeeding duration was 62 months per child. Distribution of molecular subtypes for luminal A, luminal B, HER2-enriched, and Triple Negative (TN) breast cancers was 34.8%, 35.8%, 10.7%, and 18.6%, respectively. After adjusting for covariates, compared to patients with ER positive tumors, ER negative patients were more likely to have higher parity (OR=2.03, 95% CI= (1.11, 3.72), p=0.021, comparing ≥5 to <2 children) and younger age at first pregnancy (ORtrend=0.77, 95% CItrend=0.61, 0.98, Ptrend=0.032, comparing older to younger age). Compared to patients with luminal A tumors, luminal B patients were more likely to have lower parity (OR=0.45, 95% CI= 0.23, 0.87, p=0.018, comparing ≥5 to <2 children); HER2-enriched patients were less likely to be obese (OR=0.36, 95% CI=0.16, 0.81, p=0.013) or older age at menopause (OR=0.38, 95% CI=0.15, 0.997, p=0.049). Body mass index (BMI), either overall or by menopausal status, did not vary significantly by ER status. Overall, cumulative or average breastfeeding duration did not vary significantly across subtypes. Conclusions In Kenya, we found associations between parity-related risk factors and ER status consistent with observations in European ancestry populations, but differing associations with BMI and breastfeeding. Inclusion of diverse populations in cancer etiology studies are needed to develop population and subtype specific risk prediction/prevention strategies.

Abstract P188: Transfer Time From Spoke ER Arrival to CSC Arrival in a Hub-Spoke Transfer Model of Thrombolysis for Acute Ischemic Stroke

Introduction: Acute ischemic stroke (AIS) patients who present to a spoke Emergency Room (ER) and require transfer to a comprehensive stroke center (CSC) hub face potential delays Methods: We performed a retrospective review of 269 suspected AIS patients who received intravenous tissue plasminogen activator (tPA) from July 2016 to October 2017 in our academic telestroke network. During this period, nearly all tPA patients were transferred to the CSC hub. Data was collected on patient demographics, National Institutes of Health Stroke Scale (NIHSS), door to needle time (DTN), and distance to CSC. ER-to-CSC was defined as the time from patient arrival at Spoke ER to arrival at CSC. Top volume ER status was assigned to the 4 Spoke ERs with the highest volume of tPA. Results: Among 269 AIS patients who received tPA at spoke ERs, the mean age was 65.4 years (range, 21 to 95), 49% were female, and 91.8% were white. The initial median NIHSS was 6 (range, 0 to 30) and the mean DTN was 73.1 minutes (range, 14 to 234). The mean distance from Spoke ER to CSC was 55.2 miles (range 5.8 to 125) and the mean ER-to-CSC was 2.6 hours (range 0.62 to 6.3) (Figure 1). In univariate analysis, the following factors were significantly associated with ER-to-CSC: distance (p < 0.0001), DTN (p < 0.0001), NIHSS (p 0.0007), and top volume ER status (p 0.0034). Patient sex, age, race, SBP, weight, initial NIHSS, daytime shift, and weekend status were not significantly associated with ER-to-CSC. Significant variables from the univariate analysis were included in multivariate linear regression model in which DTN (P < 0.0001), distance (P < 0.0001), and NIHSS (P 0.024) association with ER-to-CSC remained significant. Conclusions: In our series of AIS tPA patients transferred to CSC, the mean time from spoke ER arrival to CSC arrival was 2.6 hours. Factors associated with CSC arrival time include markers of ER performance (DTN), severity (NIHSS), and distance. Further study is warranted to improve transfer time in AIS.

Identification of A 10-Gene Signature To Predict Efficacy of Neoadjuvant Therapy in Patients With HER2 Positive Breast Cancer.

Background:Patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer represent a poor prognosis, which are recommended to be treated with neoadjuvant therapy (NAT). Tumor immune microenvironment, especially tumor infiltrating cells (TILs), are proved to predict the efficacy of NAT. However, validated immune-related multi-gene signatures for HER2-positive BC are still lacking.Methods:We collected gene expression arrays of pre-NAT samples from the National Center for Biotechnology Information Gene Expression Omnibus. Totally 4 studies are included in our study (n=295, no. of train=207, no. of validation=95) to construct the signature. Single Sample Gene Set Enrichment Analysis (ssGSEA)and weighted gene co-expression network analysis (WGCNA)were used to quantify immune-infiltrating components in tumor environment and to identify immune related modules. We used spline regression to evaluate non-linear effect of genes and to construct the signature.Results:Immune infiltration status was significantly related to pathological complete response (pCR) (p=0.02). We filtered 80 differential expression genes according to immune infiltration status, and identified two gene modules correlated to pCR and immune infiltration status. CCL5, CD72, PTGDS, CYTIP, PAX5, and estrogen receptor (ER)status were significantly related to pCR in linear multivariate analysis. In spline regression, non-linear aspects of MAP7, IL2RB, CD3G, PTPRC, TRAC were relevant to pCR. We constructed a signature concerning both linear and non-linear effects of genes, which was validated in 5-fold cross validation (AUC=0.81) and an external validation cohort (n=88) (AUC=0.797).Conclusions:In HER2 positive BC, immune infiltration status should be involved into consideration to make optimal regimens. A ten-gene generalized non-linear signature including ER status could predict the efficacy of NAT.