The Role of Previous Therapies and Sites of Metastasis as Influencing Factors on Discordance of ER, PR and HER2 Status Between Primary and Metastasized Breast Cancer.

BACKGROUND/AIM: The aim of the present study was to analyze metastasized breast cancer (BC) patients with regard to the discordance of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). We especially aimed to analyze the association between the change of tumor biology and previous treatment or metastatic sites. PATIENTS AND METHODS: Patients with metastasized BC who were treated at the Department of Gynecology/Breast Center of the University Hospital of Cologne were analyzed. RESULTS: Loss of HER2 occurred more frequently in lymph node metastases that were not in the axillary region (p=0.026). Letrozole showed a significant correlation with loss of ER and/or PR (p=0.041). Improved overall survival and post-metastasis survival were noticed with a gain of HER2 (p=0.044 and p=0.009, respectively) and concordant positive ER and PR status (p=0.002 and p=0.001, respectively). CONCLUSION: The discordance of receptors and the dependence of BC on therapies as well as metastatic sites stresses the necessity of early sample taking to offer patients suitable therapy options.

Profile and Outcome of Supraclavicular Metastases in Patients with Metastatic Breast Cancer: Discordance of Receptor Status Between Primary and Metastatic Site.

BACKGROUND: Breast cancer is a heterogenous and complex disease. A rare site of metastatic breast cancer disease is the neck. Data about supraclavicular metastases in patients with metastatic breast cancer are still lacking. Hence, our study aimed to analyze histological subtypes of supraclavicular metastases compared to the primary site. MATERIALS AND METHODS: This was a retrospective hospital-based cohort study of patients with breast cancer who developed supraclavicular metastases. Diagnosis of supraclavicular metastases was confirmed by biopsy or diagnostic lymph node extirpation. Histological subtypes were analyzed and Kaplan-Meier estimates were calculated for overall survival. RESULTS: A total of 20 patients were included in the analysis. The majority of the patients (12/20) had hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative supraclavicular metastases, disease in 3/20 patients was HR-positive/HER2-positive, HR-negative/HER2-positive in 1/20 patients and basal-like in 4/20 patients. Total discordance rates for estrogen receptor, progesterone receptor and HER2 between primary and metastatic tumors were 20.0%, 36.8% and 29.4%, respectively. The 5-year overall survival was 80%, whereas the 5-year survival after the onset of neck metastasis was 45%. CONCLUSION: As a rare site of metastatic breast cancer, supraclavicular metastases are associated with a worse median overall survival from their onset. The high rate of discordance of histological subtype stresses the necessity for biopsies in patients with supraclavicular metastasis.

Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity.

We initially performed a mutation screen of the coding region of the MC4R in 808 extremely obese children and adolescents and 327 underweight or normal-weight controls allowing for a case-control study. A total of 16 different missense, nonsense, and frameshift mutations were found in the obese study group; five of these have not been observed previously. In vitro assays revealed that nine [the haplotype (Y35X; D37V) was counted as one mutation] of the 16 mutations led to impaired cAMP responses, compared with wild-type receptor constructs. In contrast, only one novel missense mutation was detected in the controls, which did not alter receptor function. The association test based on functionally relevant mutations was positive (P = 0.006, Fisher's exact test, one-sided). We proceeded by screening a total of 1040 parents of 520 of the aforementioned obese young index patients to perform transmission disequilibrium tests. The 11 parental carriers of functionally relevant mutations transmitted the mutation in 81.8% (P = 0.033; exact one-sided McNemar test). These results support the hypothesis that these MC4R mutations represent major gene effects for obesity.

Glucose transporter 4 gene: association studies pertaining to alleles of two polymorphisms in extremely obese children and adolescents and in normal and underweight controls.

The human insulin-responsive glucose transporter 4 gene (GLUT4) has been related to non-insulin-dependent diabetes mellitus (NIDDM) in several studies. Obesity is commonly found in patients with NIDDM. Hence, genes involved in NIDDM might also be relevant for obesity. We have analyzed 212 extremely obese children and adolescents, 82 normal-weight students, and 94 underweight students for two single nucleotide polymorphisms (SNPs: promoter -30G/A; exon 4a: silent 2061T/C) in the vicinity of the GLUT4 by polymerase chain reaction with subsequent restriction fragment length polymorphism analyses (PCR-RFLP) or single-strand conformation polymorphism analyses (SSCP). Allele and genotype distributions were similar in all study groups (all p values > 0.05). Hence, we did not detect association of any of the analyzed SNP alleles in the GLUT4 to different weight extremes, so these seem not to be involved in weight regulation in our study groups.