Yes,

They have found certain combos are much more effective than others.

There is also the further promise of the anti-her2 drugs having a potential benefit for TNBC.

This has been in the hopper for some time- it really is a no brainer... Her2+ cells have an overgrowth of Epidermal Growth Factor Receptor cells and so do TN cells.

The end result of the reports may not have been "ABC does THIS or THAT"- but rather

"WE ARE GETTING THERE."

Back when I was first dx'd with TN the only news was that I was toast.

That was seven years ago. 

We have come a long way baby!

[2119] Targeting of breast cancer with non-oncology drugs possible novel therapeutic option for triple-negative breast cancer.

Liedtke C, Yan K, Wu Y, Hortobagyi GN, Symmans WF, Valero V, Goette M, Kiesel L, Pusztai L University Muenster, Muenster, Germany; The University of Texas M.D. Anderson Cancer Center, Houston, TX

Introduction: Triple-negative breast cancer (TNBC) is defined by lack of ER, and PR expression and normal HER2 expression. It is characterized by aggressive biological presentation and unfavorable outcome. It is associated with frequent lack of response to current chemotherapy agents. Recently, 392 drugged genes that serve as targets for 1557 both oncologic and non-oncologic drugs were identified from the pharmacologic database DrugBank (Lauss et al. Pharmacogenomics 2007). In this study, we compared expression levels of these known drug targets between TNBC and receptor-positive cancers. Methods: Gene expression profiles were obtained from fine needle biopsies of newly diagnosed early stage breast cancer before any therapy (n=133, MDACC dataset). Differential expression of these genes was validated in a second independent data set (n=286, Rotterdam dataset) and in a panel of cell lines (n=19). In order to assess the functional relevance of known drug targets overexpressed in TNBC we performed in vitro experiments. Cell lines were treated with various concentrations of selected drugs alone or in combination with paclitaxel. Results: We mapped 675 U133A probe sets representing 347 unique drug targets to the Affymetrix U133A Genechip. 44 drug targets were overexpressed in TNBC compared to non-TNBC in the MDACC dataset. Thirty-three of these (75%) were also overexpressed among TNBC compared to non-TNBC in the Rotterdam dataset. Glutathione-S-transferase pi (GSTpi, target of clomipramine) was the most highly and consistently overexpressed target in human TNBC and in estrogen- and HER2-receptor-negative breast cancer cell lines. The GSTpi overexpressing (and triple negative) human mammary cell line HBL-100 showed dose-dependent inhibition of growth after 144 hrs of incubation with clomipramine, whereas growth of the GSTpi-low expressing (non-triple negative) breast cancer cell lines MCF-7 and SKBR3 was not inhibited by this drug. Treatment with clomipramine did not alter sensitivity to paclitaxel in either cell line in vitro. Conclusion: Gene expression analysis indicates that targets for several known drugs are over expressed in TNBC relative to other types of breast cancers. We hypothesize that some of these drugs may influence the behavior of TNBC and may represent future therapeutic options. Further experiments are needed to fully explore the functional implications of these findings; however, our preliminary results suggest that inhibition of GSTpi with clomipramine leads to inhibition of cell growth of TNBC cell lines in vitro.

[2116] The mechanism of Astragalus membranaceus effects on the proliferation of human basal-like breast cancer cell line MDA-MB-468 from p53/MDM2 pathway.

Ye MN, Chen HF, Deng Y Longhua Hospital, Shanghai, Shanghai, China

Background: Based on the expression of ER,PR and Her2, breast cancer is classified into several subtypes. Thereinto, basal-like type (triple-negative phenotype) is associated with poor prognosis. Patients with this type are unlikely to benefit from currently available targeted therapy. And some researches revealed traditional Chinese medicine could play an important role in breast cancer treatment. p53 mutations can be found in most of basal-like breast cancer patients and this types cell lines. In our study, we mainly focused on the mechanism of Astragalus membranaceus effect on the proliferation of MDA-MB-468 cell from p53/MDM2 pathway.
Material and Methods: The MDA-MB-468 cells were intervened by Astragalus membranaceus Injection (AMI) which contains 1g/ml crude drugs. The effect of AMI on the proliferation of the MDA-MB-468 cells was detected by MTT assay and its time-effect relationship was observed by cell counting kit-8 (CCK-8) assay. At two days after AMI intervention, the mRNA expression of some indicators were assessed by Real-time Quantitative PCR, including p53, MDM2, EGFR, PIP, PI3K, Akt1, Akt2 and PTEN. The anti-proliferation effect of AMI on the cells proliferation was detected by MTT assay after PTEN gene was knocked down by the small interfering RNA (SiRNA), and the protein expressions of EGFR, p-Akt, MDM2 and p53 were obtained by in-cell western assay.
Results: According to MTT assay, AMI could obviously inhibit the proliferation of the MDA-MB-468 cells (p<0.05) and the effect was stronger when combined with Tarceva (p<0.01); When the PTEN gene was knocked down, AMI only combined with Tarceva could inhibit the cells proliferation (p<0.005). CCK-8 assay showed that the anti-proliferation effect of AMI was positively correlated with the intervention duration. Real-time Quantitative PCR revealed that AMI could up-regulate the PTEN gene expression (p<0.001) and down-regulate the p53 (p<0.01), MDM2 (p<0.01), Akt2 (p<0.001) and PIP (p<0.001) gene expressions. In-cell western assay indicated that p53 protein was down-regulated at 15min(p<0.05) and 1h(p<0.001), and p-Akt protein expression showed significant down-regulation at 15min(p<0.01), 30min(p<0.001) and 2d(p<0.001) after AMI intervene; when AMI combined with Tarceva, the duration of the down-regulation effect to p53 and p-Akt were all prolonged, and EGFR and MDM2 expressions were down-regulated(p<0.05, p<0.005). After PTEN SiRNA intervene, AMI down-regulate p53 (p<0.001), p-Akt (p<0.005) and EGFR (p<0.05) protein expressions; and its down-regulation effect to p-Akt reduced, but increased to p53, and EGFR.
Discussion: AMI can significantly inhibit the proliferation of MDA-MB-468 cells and present a time-dependent manner. The effect became stronger after combined with Tarceva. The main mechanism of its anti-proliferation effect may be to activate the positive feedback loop of the p53/ MDM2 pathway. It negatively regulates the PI3K by up-regulating the PTEN gene expression to promote the phosphorylation at D3 point of PIP3, so Akts phosphorylation level is down-regulated and the cells proliferation was inhibited.
 

DNA Repair Company Announces New Clinical Findings Which May Help to Guide Breast Cancer Treatment

BOSTON--(BUSINESS WIRE)--The DNA Repair Company (DNAR), an early-stage company focused on personalized approaches to cancer treatment, announced today that it has identified a promising set of protein biomarkers that may aid in the treatment of a particularly aggressive form of breast cancer. These findings were presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

The DNAR study was conducted in collaboration with investigators from the Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center, both in Boston. The lead author of the study, Brian Alexander, MD, physician resident at the Harvard Radiation Oncology Program and currently a White House Fellow, was selected as a recipient of the prestigious AstraZeneca Clinical Scholars Award in recognition of the merits of the study.

The study was conducted using clinical data with so-called “triple-negative” breast cancer, a form of the disease that is not responsive to therapies targeting estrogen receptors, progesterone receptors, or the HER2 receptor. The prognosis for triple-negative breast cancer is poor, due in part to the more limited set of treatment options available.

Clinical biopsies from 143 patients were examined to determine whether the modulation of various DNA repair proteins might have an impact on disease progression. DNA repair pathways correct DNA that has been damaged by many common forms of cancer treatment (e.g. chemotherapy and radiation) and play a central role in making tumors resistant to therapy.

With clinical samples from half of the patients, the investigators discovered a statistically significant correlation between the presence of four DNA repair proteins and recurrence-free survival. Investigators were then able to validate the correlation with progression-free survival seen in this cohort by testing the four proteins in the second group of patients. The marker panel distinguished a high risk group of patients with a medium time to recurrence of 14 months from low risk patients with median time to recurrence of >10 years. Even though a number of DNA repair markers produced statistically significant results individually, results observed with the four DNA repair marker panel were superior to those seen with a number of single markers.

These findings are significant, because they suggest that monitoring DNA repair protein profiles in patients with triple-negative breast cancer will contribute important insights as prognostic or predictive tools. In addition, DNA repair pathways may provide a promising target for developing novel therapies for the disease.

“These findings provide intriguing evidence that the activity of certain DNA repair pathways play an important role in determining how patients with triple-negative breast cancer will respond to therapy, and further validation will help focus drug development on approaches most likely to succeed,” said lead investigator Judy E. Garber, MD, MPH, Director of the Cancer Risk and Prevention Program at Dana-Farber and Associate Professor of Medicine, Harvard Medical School. “The frequently poor prognosis for patients with this form of breast cancer lends increased urgency to understanding the molecular basis of the disease, and its implications for treatment and new drug development.”

About DNAR

DNAR is leveraging its deep knowledge of the role that DNA repair pathways play in cancer to create new tools that give physicians unprecedented data-driven insights into which course of treatment will work most effectively for an individual patient. DNAR aims to improve patient care by improving physicians’ ability to prescribe the most effective treatments the first time from the host of therapeutic options available. DNAR is advancing a major goal of personalized medicine – to identify the right therapy for the right patient, and to reduce the need for “trial and error” medicine.