Abstract Background Hormone Receptor (HR)‐discordance between primary breast cancer and metastasis is a known biological phenomenon. Discordance studies usually comprise a heterogeneous group of HR‐positive and negative patients and allow for the comparison of changes in HR‐status from the primary to the recurrent disease. However, in a clinical setting, the rate of estrogen receptor‐conversion following endocrine therapy with agents such as Tamoxifen (TAM) in estrogen receptor‐positive cancers is of primary interest as opposed to total receptor discordance. Aim To investigate the rate of estrogen receptor‐conversion associated with tumor progression in estrogen receptor‐positive breast cancer patients following adjuvant TAM administration and to compare the results with the meta‐analysis data of HR‐discordance studies. Methods and Results A retrospective double‐center review of biomarkers in 67 estrogen receptor‐positive breast cancer patients who underwent TAM treatment in the adjuvant setting. The estrogen and progesterone receptor‐status were compared at the time of diagnosis and following relapse and the Disease‐free Survival, mean duration of TAM treatment as well as the operative, radiation, and cytotoxic therapies registered before TAM treatment, were recorded. Initially, all patients were estrogen receptor‐positive. The average age at the time of diagnosis was 52.8 ± 12.4 years. After recurrence, only 47 patients (70.1%) were still estrogen receptor‐positive with a highly significant loss of estrogen receptor‐expression in 29.9% of cases. The mean duration of TAM treatment was 40.7 ± 19.9 months. 45 patients (i.e., 67.2%) progressed during the TAM treatment and the remaining 22 patients (32.8%) developed relapse after the TAM treatment had finished. Initially, there were 82.1% progesterone receptor‐positive and 17.9% progesterone receptor‐negative, but after relapse the progesterone receptor‐positive cases diminished significantly to 53.7%, showing a progesterone receptor‐loss of 28.4%. Conclusion The rate of estrogen receptor‐loss associated with tumor progression following TAM treatment is approximately 30%, which is of clinical relevance in order to evaluate further endocrine efficacy in these patients. This rate of receptor conversion is roughly 6‐13% higher compared to the recently published meta‐analysis data of discordance studies. This discrepancy could possibly be due to anti‐hormonal therapy with TAM accentuating receptor conversion.
This book contains the results of the Open Notebook Science Solubility Challenge. All experimental measurements are provided with a link to either the laboratory notebook page where the experiment was carried out or to a literature reference. The Challenge was sponsored by Submeta, Nature and Sigma-Aldrich.
Gene transfer presents a potentially useful approach for the treatment of diseases refractory to conventional therapies. Various preclinical and clinical strategies have been explored for treatment of gynecological diseases. Given the direst need for novel treatments, much of the work has been performed with gynecological cancers and ovarian cancer in particular. Although the safety of many approaches has been demonstrated in early phase clinical trials, efficacy has been mostly limited so far. Major challenges include improving gene transfer vectors for enhanced and selective delivery and achieving effective penetration and spread within advanced and complex tumor masses. This review will focus on current and developmental gene transfer applications for gynecological diseases.
Breast cancer is a leading cause of death in the United States. Despite some advances in treatment of primary breast cancer, patients with metastatic disease still have no chance of cure and conventional treatment modalities remain palliative. Therefore, the identification of new agents with better antitumor activity merits a high priority in the treatment of advanced or metastatic breast cancer. In this regard, gene therapy with adenoviral (Ad) vectors is a promising new approach for different tumor types. A critical factor determining the utility of Ad vectors for cancer gene therapy is the selectivity of their transgene expression in cancer cells. Strategies to restrict adenoviral-mediated transgene expression are important to avoid side effects due to gene transfer into healthy cells, especially the liver. However, currently available TSPs used in the context of Ad-based breast cancer targeting, are generally not tumor-specific but tissue specific. In this context, Heparanase (HPR), a heparan sulfate-specific endo-β-D-glucuronidase, is highly overexpressed in human cancers including breast cancer and has been shown to play an important role in tumor metastasis. In contrast, HPR expression is low or undetectable in differentiated, healthy tissue. To evaluate the utility of HPR as a TSP for breast cancer gene therapy, RT-PCR was performed to evaluate the expression of the HPR gene in various established breast cancer cell lines, primary human breast cancer tissue samples and normal breast cell lines. We constructed an Ad vector, AdHPR.luc, encoding luciferase under the control of the HPR promoter to determine relative activity in a variety of breast cancer, normal human breast cell lines and purified breast cancer tissue samples. An Ad vector containing the ubiquitously expressed CMV promoter (AdCMV.luc) was used as control. Biodistribution and liver tropism was evaluated after i.v. virus injection into a mouse model. Quantitative RT-PCR reveals a 4.5 – 44.6 fold, (p<0.05) increased expression of the HPR gene in several breast cancer cell lines compared to a normal breast control cell line. In primary breast cancer patient samples the average HPR mRNA copy number was significantly increased (90 fold, p<0.05). When compared to the ubiquitous CMV promoter, the HPR promoter showed a high level of activity in four breast cancer cell lines (5.5% – 12.7% compared to CMV) and primary breast cancer patient samples (8.8%– 14.4%), whereas activity in normal breast cells (1% compared to CMV) was low. The mouse liver toxicity and biodistribution profile of AdHPR.luc is significantly (2.3 fold, p<0.05) repressed compared to AdCMV.luc. In conclusion, we have identified the HPR promoter as a candidate for transcriptional targeting of breast cancer. In an Ad backbone, this promoter appears to be highly active in human breast cancer cells. These findings place the HPR pathway as a target for the development of breast cancer directed gene therapy strategies.
