Statin use, HMGCR expression, and breast cancer survival – The Malmö Diet and Cancer Study

AbstractStatins, commonly used to treat hypercholesterolemia, have also been proposed as anti-cancer agents. The identification of a predictive marker is essential. The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR), which is inhibited by statins, might serve as such a marker. Thorough antibody validation was performed for four different HMGCR antibodies. Tumor expression of HMGCR (#AMAb90619, CL0260, Atlas Antibodies, Stockholm, Sweden) was evaluated in the Malmö Diet and Cancer Study breast cancer cohort. Statin use and cause of death data were retrieved from the Swedish Prescribed Drug Register and Swedish Death Registry, respectively. Breast cancer-specific mortality (BCM) according to statin use and HMGCR expression were analyzed using Cox regression models. Three-hundred-twelve of 910 breast cancer patients were prescribed statins; 74 patients before and 238 after their breast cancer diagnosis. HMGCR expression was assessable for 656 patients; 119 showed negative, 354 weak, and 184 moderate/strong expressions. HMGCR moderate/strong expression was associated with prognostically adverse tumor characteristics as higher histological grade, high Ki67, and ER negativity. HMGCR expression was not associated with BCM. Neither was statin use associated with BCM in our study. Among breast cancer patients on statins, no or weak HMGCR expression predicted favorable clinical outcome. These suggested associations need further testing in larger cohorts.

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Survival impact of primary tumor resection in de novo metastatic breast cancer patients (GEICAM/El Alamo Registry)

Scientific Reports ◽

10.1038/s41598-019-55765-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Sara Lopez-Tarruella ◽

M. J. Escudero ◽

Marina Pollan ◽

Miguel Martín ◽

Carlos Jara ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Patients ◽

Primary Tumor ◽

Cox Regression ◽

De Novo ◽

Histological Grade ◽

Tumor Resection ◽

Metastatic Breast ◽

Breast Cancer Patients

AbstractThe debate about surgical resection of primary tumor (PT) in de novo metastatic breast cancer (MBC) patients persists. We explored this approach’s outcomes in patients included in a retrospective registry, named El Álamo, of breast cancer patients diagnosed in Spain (1990–2001). In this analysis we only included de novo MBC patients, 1415 of whom met the study’s criteria. Descriptive, Kaplan-Meier and Cox regression analyses were carried out. Median age was 63.1 years, 49.2% of patients had single-organ metastasis (skin/soft tissue [16.3%], bone [33.8%], or viscera [48.3%]). PT surgery (S) was performed in 44.5% of the cases. S-group patients were younger, had smaller tumors, higher prevalence of bone and oligometastatic disease, and lower prevalence of visceral involvement. With a median follow-up of 23.3 months, overall survival (OS) was 39.6 versus 22.4 months (HR = 0.59, p < 0.0001) in the S- and non-S groups, respectively. The S-group OS benefit remained statistically and clinically significant regardless of metastatic location, histological type, histological grade, hormone receptor status and tumor size. PT surgery (versus no surgery) was associated with an OS benefit suggesting that loco-regional PT control may be considered in selected MBC patients. Data from randomized controlled trials are of utmost importance to confirm these results.

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ALDH1 Expression and Vasculogenic Mimicry Are Positively Associated with Poor Prognosis in Patients with Breast Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000493227 ◽

2018 ◽

Vol 49 (3) ◽

pp. 961-970 ◽

Cited By ~ 7

Author(s):

Peng Xing ◽

Huiting Dong ◽

Qun Liu ◽

Tingting Zhao ◽

Fan Yao ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Cox Regression ◽

Histological Grade ◽

Vasculogenic Mimicry ◽

Disease Free Survival ◽

Breast Cancer Patients ◽

Double Positive ◽

The Status ◽

Aldh1 Expression

Background/Aims: This study aimed to explore the prognostic value of aldehyde dehydrogenase 1 (ALDH1) expression and vasculogenic mimicry (VM) in patients with breast cancer. Methods: ALDH1 expression and the presence of VM were examined by immunohistochemistry and CD31/PAS double staining, respectively, using formalin-fixed paraffin-embedded tissues from 202 breast cancer patients. The mean follow-up period ranged from 15 to 115 months. The Kaplan-Meier method was used to plot survival curves. Prognostic values were assessed by multivariate analysis using the Cox regression model. Results: ALDH1 expression was strongly associated with VM (P = 0.005). ALDH1 expression was positively correlated with histological grade (P = 0.011). Both ALDH1 expression and VM were negatively related to the status of the estrogen receptor and progesterone receptor and were statistically increased in triple-negative breast cancer. Patients with ALDH1 expression or VM displayed poorer disease-free survival (DFS) and overall survival (OS) than ALDH1-negative or VM-negative patients, with the worst OS and DFS observed in ALDH1/VM-double-positive patients. ALDH1-positive and VM-positive were independent survival risk factors for DFS and OS. Conclusion: ALDH1 expression and VM are correlated with the survival rate of patients with breast cancer. ALDH1 and VM, either alone or together, are prognostic factors in patients with breast cancer.

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Poor prognostic factors of post-CNS recurrence survival in breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2097 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2097-2097

Author(s):

Carlos Castaneda Altamirano ◽

Henry Leonidas Gomez ◽

Joseph A. Pinto ◽

Luis Jesus Schwarz ◽

C. E. Vigil ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Cancer Patients ◽

Cox Regression ◽

Histological Grade ◽

Performance Status ◽

Prognostic Scores ◽

Breast Cancer Patients ◽

Class Iii ◽

Ecog Performance Status

2097 Background: Survival after the onset of metastases in the central nervous system is very short. However, some variables could indicate subsets of worse prognosis. Our aim was to determine the value of clinicopathological characteristics and prognostic scores in the post-SNC recurrence survival. Methods: We evaluated a retrospective cohort of 2597 breast cancer patients treated at the Instituto Nacional de Enfermedades Neoplasicas (Lima-Peru) between 2000-2005. Clinicopathological data was retrieved, RPA and GPA brain metastases prognostic scores were constructed and phenotypes were categorized according to the IHC expression in [HR+,HER2-], [Any HR, HER2+] and Triple Negative. Survival was calculated according to the Kaplan Meier methodology and cases were stratified by variables evaluated. The log-rank or Breslow tests were used when appropriate and multivariate analysis was done by the cox regression. A P<0.05 was considered statistically significant. Results: One hundred and fifty seven cases developed CNS metastasis, from which 23 developed leptomeningeal metastases. The post recurrence CNS survival was 0.405 years. There were not differences according to phenotype (P=0.102), histological grade (P=0.647), number of brain metastases (P=0.695) and metastases volume (P=0.155). We found statistic differences in regard to leptomeningeal carcinomatosis (present, 0.249ys vs absent 0.436ys; P=0.033); CSF infiltration (present, 0.115ys vs absent, 1.044ys; P=0.022); status of primary tumor (controlled, 0.501ys vs uncontrolled, 0.263ys; P<0.001); ECOG performance status (<2, 0.504ys vs ≥2, 0.288ys; P=0.030); and time from BC diagnosis to SNC metastases (<8 moths, 0.115 vs ≥8 months, 0.425ys; P=0.023). Cox regression identifies to CSF infiltration as statistically significant (HR=9.77; P=0.025). In regard to Prognostic scores, we found differences when cases were stratified according to RPA score (Class I, 0.564ys vs Class II, 0.455ys vs Class III, 0.288ys; P=0.049) and GPA score (0-1, 0.26ys vs 1.5-3, 0.455ys vs 3.5-5, 0,564; 0.048). Conclusions: RPA and GPA scores are more accurate to identify poor survival subsets in this group of patients than other tumor features (phenotype or histology).

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The association of single nucleotide polymorphisms (SNPs) with breast density and breast cancer survival: the Malmö Diet and Cancer Study

Acta Radiologica ◽

10.1177/0284185119900436 ◽

2020 ◽

Vol 61 (10) ◽

pp. 1326-1334

Author(s):

Hanna Sartor ◽

Jasmine Brandt ◽

Felix Grassmann ◽

Mikael Eriksson ◽

Kamila Czene ◽

...

Keyword(s):

Breast Cancer ◽

Single Nucleotide Polymorphisms ◽

Breast Density ◽

Cancer Survival ◽

Cox Regression ◽

Breast Cancer Survival ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Cancer Study ◽

Diet And Cancer

Background Genetic factors are important in determining breast density, and heritable factors account for 60% of the variation. Certain single nucleotide polymorphisms (SNPs) are associated with density and risk of breast cancer but the association with prognosis is not clear. Purpose To investigate associations between selected SNPs and breast cancer survival in the Malmö Diet and Cancer Study (MDCS). Material and Methods A total of 724 unrelated women with breast cancer and registered radiological and pathological data were identified in MDCS 1991–2007, with genotyping available for 672 women. Associations among 15 SNPs, density, and breast cancer-specific survival were analyzed using logistic/Cox regression, adjusted for factors affecting density and survival. Variants significantly associated with either density or survival were validated in a large independent breast cancer cohort (LIBRO-1). Results Minor homozygotes of SNPs rs9383589, CCDC170 and rs6557161, ESR1 were associated with high breast density (adjusted odds ratio [AOR] 8.97, 95% confidence interval [CI] 1.35–59.57; AOR 2.08, 95% CI 1.19–3.65, respectively) and poorer breast cancer survival (adjusted hazard ratio [HRadj] 6.46, 95% CI 1.95–21.39; HRadj 2.30, 95% CI 1.33–3.96, respectively) compared to major homozygotes. For SNP rs3757318, ESR1, minor homozygotes (HRadj 7.46, 95% CI 2.28–24.45) were associated with poorer survival. We confirmed that rs6557161, ESR1 was significantly associated with both density and survival in the LIBRO-1 study. Conclusion These findings support a shared genetic basis for density and breast cancer survival. The SNP significantly associated with both density and survival in both cohorts may be of interest in future research investigating polygenic risk scores for breast cancer risk and screening stratification purposes.

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Prognostic value of the genomic grade index (GGi) as compared to centrally measured Ki-67 IHC and mitotic index in early breast cancer patients

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.11094 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 11094-11094

Author(s):

F. Bertucci ◽

J. M. Le Doussal ◽

D. Birnbaum ◽

R. Tagett ◽

A. Martinec ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Mitotic Index ◽

Prognostic Value ◽

Cox Regression ◽

Histological Grade ◽

Breast Cancer Patients ◽

Ki 67 ◽

Genomic Grade Index ◽

Grade Index

11094 Background: Genomic grading has been proposed to improve tumor grading. The genomic grade index (GGi) is a 97-gene continuous measure which resolves 80% of histological grade 2 (HG 2) tumors into HG 1 and HG 3 risk categories. GGi has higher prognostic value than HG in patients treated with and without systemic adjuvant endocrine and chemotherapy. A key issue is whether the GGi adds prognostic information to centrally-determined mitotic index and Ki-67 IHC. Methods: The control arm of the PACS 01 trial included 996 women with node-positive (N+) early breast cancer treated with six cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) and tamoxifen as required. 128 genomic profiles could be obtained from available frozen tumor samples using Affymetrix U133 Plus 2.0 gene chips through the “Carte d'Identite des Tumeurs” program of the French Ligue Nationale contre le Cancer. The Genomic Grade index (GGi) was computed using Ipsogen MapQuant Dx(R). Central Elston-Ellis grade, mitotic index (mitosis / mm2), and Ki-67 IHC (% positive cells) were available for 125 patients. The GGi and histological parameters were correlated to the 5-year metastasis status (MFS-5) by ROC analysis and to the metastasis hazard (follow-up of 6.2 ± years) by Cox regression. Results: In ER+ patients (n=93), the GGi was the only significant correlate to metastasis hazard in multivariate Cox regression with histological parameters (HR = 3.5 [1.7–7.5], p<0.001). It was the best predictor of MFS-5 (ROC AUC = 0.83, p=1E-6) when compared to histological parameters (ROC AUC = 0.71, 0.72 and 0.66 resp. p=0.003 to 0.03). In HG 2 subgroup (n=43), the GGi was the only significant predictor of MFS-5 (ROC AUC = 0.81, p=0.016). Conclusions: In our sample of N+ ER+ breast cancer patients, the GGi improved prognostication compared to centrally-measured mitotic index and Ki-67 IHC used alone and in combination. Moreover, the GGi was the only prognostic factor in histological grade 2 patients. [Table: see text]

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The Low Expression of MEOX2 is Associated With Poorer Survival in Breast Cancer

10.21203/rs.3.rs-1128452/v1 ◽

2021 ◽

Author(s):

Huxia Wang ◽

Yanan Tang ◽

Meixia Wang ◽

Caixia Ding ◽

Xiaomin Yang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Cancer Progression ◽

Cox Regression ◽

Histological Grade ◽

The Cancer Genome Atlas ◽

Breast Cancer Patients ◽

Normal Tissues ◽

Cancer Genome Atlas ◽

And Function

Abstract The regulation of vertebrate limb myogenesis gene, Mesenchyme Homeobox 2 (MEOX2), has been reported to be associated with most cancer progression closely. However, its role and function in breast cancer are unidentified. Here, we aim to investigate the association of MEOX2 expression with clinicopathological features and the survival probability of breast cancer. The MEOX2 expression in breast cancer was first analyzed from The Cancer Genome Atlas (TCGA) database. Then, the association of MEOX2 with patients’ clinicopathological variables and prognostic probability were detected by bioinformatics analysis. Moreover, a high-throughput tissue microarray containing 135 cases of breast cancer was used to further clarify the expression of MEOX2 in breast cancer patients. The expression of MEOX2 is inhibited in breast cancer than in normal tissues, and the lower MEOX2 expression indicates the poorer prognosis of breast cancer patients. In addition, the histological grade of MEOX2 expression is negatively correlated with the Ki67 level. Multivariate COX regression also verified that MEOX2 was an independent prognostic factor in breast cancer patients. Based on our results, we can conclude that lower MEOX2 expression was related to tumor proliferation and could be a new diagnostic and prognostic biomarker of breast cancer.

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The Value of Ultrasound Diagnosed Axillary Lymph Node in Avoiding Axillary Surgery in Early Breast Cancer Patients

10.21203/rs.3.rs-81453/v1 ◽

2020 ◽

Author(s):

Na Liu ◽

Liu Yang ◽

Xinle Wang ◽

Meiqi Wang ◽

Ruoyang Li ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Cancer Patients ◽

Axillary Lymph Node ◽

Histological Grade ◽

False Negative ◽

Axillary Lymph ◽

Breast Cancer Patients ◽

Ki 67 ◽

Axillary Surgery

Abstract Background: Axillary lymph node dissection can be avoided in early stage breast cancer patients with negative sentinel lymph node biopsy. However, the possibility of avoiding axillary surgery in patients without axillary lymph node metastasis (ALNM) by preoperative imaging is still under exploration. Thus, the objectives of this study were to investigate the high-risk factors of false negative of ALNM diagnosed by preoperative ultrasound (US) and to find out who could be avoided axillary surgery in the US negative ALNM patients.Methods: This study retrospectively analyzed 3,361 patients with primary early breast cancer diagnosed in the Breast Center of the Fourth Hospital of Hebei Medical University from January 2010 to December 2012. All patients had undergone routine preoperative US and then axillary lymph node dissected. This study investigated the clinicopathological features of axillary lymph node (ALN) negative patients diagnosed by preoperative US and its correlation with prognosis. The follow-up data for disease-free survival (DFS) and overall survival (OS) were obtained from 2,357 patients. Results: The sensitivity, specificity and accuracy of axillary US in this cohort were 66.24%, 76.62% and 73.87%. The proportion of patients in the false negative group was higher than that in true negative in the group of age < 50 years old (P = 0.002), tumor size > 2cm (P = 0.008), estrogen receptor (ER) positive (P = 0.005), progesterone receptor (PR) high expression (P = 0.007), nuclear-associated antigen Ki-67 (Ki-67) >20% (P = 0.030), visible vascular tumor thrombus (P < 0.001) and histological grade>2 (P < 0.001). Prognostic analysis of false negative and true negative ultrasonographic diagnosis of ALN metastasis: when ALNM was not found by preoperative ultrasound, there was no significant difference in patients with ALNM≤3 compared with patients without lymph node metastasis in patients of age ≥ 50 years old, tumor size ≤ 2cm, Ki-67 ≤ 20%, or histological grade ≤ 2. Conclusion: The surgery of ALN may be avoided for the preoperative US diagnosed ALNs negative in early breast cancer patients who had advanced age, small tumor size, low expression of Ki-67 and low histological grade.

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Clinical significance of crown-like structures to trastuzumab response in patients with primary invasive HER2+ breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e12533 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e12533-e12533

Author(s):

Constantinos Savva ◽

Charles N Birts ◽

Stéphanie A Laversin ◽

Alicia Lefas ◽

Jamie Krishnan ◽

...

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Cancer Patients ◽

Metastatic Disease ◽

Cox Regression ◽

Prognostic Significance ◽

Metabolic Reprogramming ◽

Breast Cancer Patients ◽

Adjuvant Trastuzumab ◽

Her2 Breast Cancer

e12533 Background: Obesity is associated with breast cancer development and worse survival. Obesity can initiate, promote, and maintain systemic inflammation via metabolic reprogramming of macrophages that encircle adipocytes, termed crown-like structures (CLS). In breast cancer patients, CLS are present in 36-50% of patients and have been associated with anthropometric parameters. Here we focus on HER2+ breast cancer. The role of adiposity in HER2+ breast cancer is conflicting which may be attributed to the tumour heterogeneity. Adiposity has also been shown to affect the local immune environment of solid tumours. However, the prognostic significance of CLS in HER2+ breast cancer is still unknown. Methods: We investigated the prognostic significance of CLS in a cohort of 219 patients with primary HER2+ breast cancer who were diagnosed between 1982 to 2012 in Southampton General Hospital. This cohort includes 76 HER2+ trastuzumab naïve patients and 143 HER2+ patients treated with adjuvant trastuzumab. We stained FFPE tumour samples for the expression of CD68, CD16 and CD32B on CLS and correlated these to clinical outcomes. CLS were defined as CLS within distant adipose tissue, CLS within the adipose-tumour border (B-CLS) and intratumoural CLS. CLS were quantified manually in full face sections by two independent scorers and descriptive and Cox regression analysis was carried out. Results: A total of 201 tumours were suitable for CLS analyses. The median follow-up was 34.74 months (range, 0.43-299.08). In the trastuzumab naive cohort, B-CLS≤1 and B-CLS > 1 were present in 37 (52.11%) and 34 (47.89%), respectively. In the trastuzumab treated cohort, B-CLS≤1 were identified in 69 (53.08%) and B-CLS > 1 were found in 61 (46.92%) of the tumours. CLS were more commonly found in the adipose-tumour border (60.89%) rather than in the distant adipose tissue (36.14%) or intratumorally (14.36%). The presence of any CLS was significantly associated with BMI≥25 kg/m2 (p = 0.018). There was strong evidence of association between CD68+CD32B+ B-CLS and BMI≥25 kg/m2 (p = 0.007). Co-expression of CD16 and CD32B by B-CLS was more frequent in patients with BMI≥25 kg/m2 (p = 0.036). Survival analysis showed shorter time to metastatic disease in patients with CD68+ B-CLS > 1 (p = 0.011) in the trastuzumab treated cohort. Subgroup analysis revealed that in the BMI≥25 kg/m2 group, patients with CD68+ B-CLS > 1 had shorter time to metastatic disease compared to patients with B-CLS≤1 (p = 0.004). Multivariate cox regression showed that B-CLS > 1 is an independent prognostic factor for shorter time to metastatic disease in patients with primary HER2+ breast cancer that received adjuvant trastuzumab (HR 6.81, 95%CI (1.38-33.54), p = 0.018). Conclusions: B-CLS can be potentially used as a predictive biomarker to optimize the stratification and personalisation of treatment in HER2-overexpressed breast cancer patients.

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Immune-related gene based prognostic signature for the risk stratification analysis of breast cancer

Current Bioinformatics ◽

10.2174/1574893616666211005110732 ◽

2021 ◽

Vol 16 ◽

Author(s):

Dongqing Su ◽

Qianzi Lu ◽

Yi Pan ◽

Yao Yu ◽

Shiyuan Wang ◽

...

Keyword(s):

Breast Cancer ◽

Regression Analysis ◽

Cancer Patients ◽

Risk Score ◽

Cox Regression ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Breast Cancer Patients ◽

Cox Regression Analysis ◽

Score Model

Background: Breast cancer has plagued women for many years and caused many deaths around the world. Method: In this study, based on the weighted correlation network analysis, univariate Cox regression analysis and least absolute shrinkage and selection operator, 12 immune-related genes were selected to construct the risk score for breast cancer patients. The multivariable Cox regression analysis, gene set enrichment analysis and nomogram were also conducted in this study. Results: Good results were obtained in the survival analysis, enrichment analysis, multivariable Cox regression analysis and immune-related feature analysis. When the risk score model was applied in 22 breast cancer cohorts, the univariate Cox regression analysis demonstrated that the risk score model was significantly associated with overall survival in most of the breast cancer cohorts. Conclusion: Based on these results, we could conclude that the proposed risk score model may be a promising method, and may improve the treatment stratification of breast cancer patients in the future work.

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