The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with risk of ovarian cancer. Here we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 Odds Ratio (OR)=1.10, 95% Confidence Interval (CI) 1.05 – 1.15, p=3.49 × 10-5] and triple negative (TN) (ER, PR and HER2 negative) breast cancer [rs8170 OR=1.22, 95% CI 1.13 – 1.31, p=2.22 × 10-7]. However, rs8170 was no longer associated with ER-negative breast cancer risk when TN cases were excluded [OR=0.98, 95% CI 0.89 – 1.07, p=0.62]. In addition, a combined analysis of TN cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC) (n=3,566) identified a genome-wide significant association between rs8170 and TN breast cancer risk [OR=1.25, 95% CI 1.18 – 1.33, p=3.31 × 10-13]. Thus, 19p13.1 is the first triple negative-specific breast cancer risk locus and the first locus specific to a histological subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple negative tumors and other subtypes likely arise through distinct etiologic pathways.

Background

In vitro and in vivo analyses have shown differences in chemosensitivity between breast cancers associated with BRCA1/2 mutations compared to sporadic variants. In the preoperative setting, the tumor response can be directly measured. Therefore, preoperative systemic treatment (PST) offers the opportunity to assess the chemosensitivity in vivo. However, there have been neither clear guidelines for mutation carriers in terms of choice of chemotherapy regimen nor recommendations how to proceed in case of an inadequate response to PST.

Case Report

Herein, we present the history of a 39-year-old woman with bilateral breast cancer who was tested positive for germ-line BRCA1 mutation while under PST. We performed a comprehensive literature review covering the MEDLINE database from 1992 to 2010 on published data regarding PST options for BRCA mutation carriers.

Conclusions

If results of genetic testing are obtained during PST, individual therapy adaptations can be discussed with respect to mainly retrospective data of response to specific drugs. However, larger studies with longer follow-up are eagerly needed to draw firm conclusions before any specific treatment recommendations can be given for BRCA mutation carriers. PST is an ideal setting to evaluate such treatment options and to describe predictive markers that can help define subgroups that benefit most.

Background

Varicose veins affect up to 40% of men and up to 51% of women. The pathophysiology of primary varicosis is poorly understood. Theories ranging from incompetence of the venous valves to structural changes in the vein wall have been proposed.

Methodology/Principal Findings

We analyzed the functional state of the intramural smooth muscle cells (n = 14 pairs matched for age and gender) and the expression of relaxin-2 and its receptors RXFP1 and RXFP2 in samples of varicose and healthy great saphenous veins (GSV) (n = 21 healthy GSV; n = 46 varicose GSV). Relaxin-2 and RXFP1 contents were determined in tissue samples (n = 9 samples per group). Pharmacological analyses were performed in a perfusion chamber. Morphometric determination of the nuclear size of the smooth muscle compartment yielded no significant difference in varicose GSV in comparison with the healthy controls. Relaxin-2 and its receptors were expressed in the muscular layer, endothelial cells and in blood vessels contained in the vein wall. Immunohistochemical expression of relaxin-2, RXFP1 and RXFP2 was significantly decreased in varicose GSV. Relaxin-2 and RXFP1 measured by ELISA and Western Blot were decreased in varicose GSV (relaxin-2 ELISA healthy vs. varicose GSV: 12.49±0.66 pg/mg versus 9.12±3.39 pg/mg of total protein; p = 0.01; Student's T-test). Contractions of vein samples induced by cholinergic or adrenergic stimulation were antagonized by relaxin-2.

Conclusions/Significance

We report that relaxin-2 and its receptors RXFP1 and RXFP2 are expressed in GSV and that their expression is significantly decreased in varicose GSV. Further, we were able to demonstrate a functional pharmacological relaxin-2 system in varicose GSV. Our results suggest a novel role for relaxin-2 in the pathogenesis of primary varicosis, rendering relaxin-2 a novel possible pharmacological agent for the treatment of this widely prevailing venous disease.

Background

Oral (p.o.) chemotherapy treatments gained increasing importance in the palliative treatment of metastatic breast cancer (MBC). Aim of this survey was to evaluate the acceptance of p.o. treatment and patients' individual attitudes towards it.

Methods

A specific 14 item-questionnaire was designed. Patients suffering from breast cancer receiving a newly launched p.o. or i.v. chemotherapy treatment were prospectively evaluated during 4 months of time. 224 questionnaires using descriptive statistics, chi-square test, Spearman correlation were evaluated.

Results

Patients' median age was 54 years, 164 received i.v., 60 p.o therapy. 89% with p.o. and 67% with i.v. regimens would choose p.o. over i.v. therapy, if equal efficacy is guaranteed. Significant differences were especially found in terms of personal benefit (55% i.v., 92% p.o.), reduced feeling of being ill due to p.o. treatment (26% i.v., 65% p.o.), better coping with disease due to p.o. therapy (36% i.v., 68% p.o.). Side effects were significantly less often reported under p.o. treatment (19% p.o. vs. 53% i.v.)

Conclusion

P.o. chemotherapy shows a high acceptance in MBC patients under palliative therapy. Compliance can be achieved in particular through a differentiated indication, patient education and competent support along a p.o. treatment.

Summary

Prodrugs can have the advantage over parent drugs in increased activation and cellular uptake. The multidrug ETC-L-FdUrd and the duplex drug ETC-FdUrd are composed of two different monophosphate-nucleosides, 5-fluoro-2′deoxyuridine (FdUrd) and ethynylcytidine (ETC), coupled via a glycerolipid or phosphodiester, respectively. The aim of the study was to determine cytotoxicity levels and mode of drug cleavage. Moreover, we determined whether a liposomal formulation of ETC-L-FdUrd would improve cytotoxic activity and/or cleavage. Drug effects/cleavage were studied with standard radioactivity assays, HPLC and LC-MS/MS in FM3A/0 mammary cancer cells and their FdUrd resistant variants FM3A/TK−. ETC-FdUrd was active (IC50 of 2.2 and 79 nM) in FM3A/0 and TK− cells, respectively. ETC-L-FdUrd was less active (IC50: 7 nM in FM3A/0 vs 4500 nM in FM3A/TK−). Although the liposomal formulation was less active than ETC-L-FdUrd in FM3A/0 cells (IC50:19.3 nM), resistance due to thymidine kinase (TK) deficiency was greatly reduced. The prodrugs inhibited thymidylate synthase (TS) in FM3A/0 cells (80–90%), but to a lower extent in FM3A/TK− (10–50%). FdUMP was hardly detected in FM3A/TK− cells. Inhibition of the transporters and nucleotidases/phosphatases resulted in a reduction of cytotoxicity of ETC-FdUrd, indicating that this drug was cleaved outside the cells to the monophosphates, which was verified by the presence of FdUrd and ETC in the medium. ETC-L-FdUrd and the liposomal formulation were neither affected by transporter nor nucleotidase/phosphatase inhibition, indicating circumvention of active transporters. In vivo, ETC-FdUrd and ETC-L-FdURd were orally active. ETC nucleotides accumulated in both tumor and liver tissues. These formulations seem to be effective when a lipophilic linker is used combined with a liposomal formulation.