BreastScreen Australia evaluation : a review of methodological options for evaluating the effect of BreastScreen Australia on breast cancer mortality

This report provides evidence-based recommendations for appropriate and cost-effective methods that could be used to evaluate the impact of the national BreastScreen Australia population-based mammographic screening program on mortality from female breast cancer. The report represents a significant collaboration between the Australian Government, the National Breast Cancer Centre as well as Australian and international experts in mammography research and evaluation, epidemiology and health services research.

The recommendations are based on a review of national and international evidence on approaches used to assess the impact of mammography screening programs on breast cancer mortality in other settings. The review has used a systematic approach to assessing the strategic and methodological approaches taken in each of the studies identified and their potential limitations.

The national evaluation of the BreastScreen Australia Program aims to assess the appropriateness, efficiency and effectiveness of the BreastScreen Program. The completion of this report marks an important first step in that process. In addition, the review and recommendations in this report may have broader application at an international level.

Adjuvant therapy, not mammographic screening, accounts for most of the observed breast cancer specific mortality reductions in Australian women since the national screening program began in 1991

There has been a 28% reduction in age-standardised breast cancer mortality in Australia since 1991 when the free national mammographic program (BreastScreen) began. Therefore, a comparative study between BreastScreen participation and breast cancer age specific mortality trends in Australia was undertaken for two time periods between 1991 and 2007, where women aged 50–59 and 60–69 years, who were invited to screen, were compared to women aged 40–49 and 70–79 years who were not invited, but who did have access to the program. There were mortality reductions in all four age groups between 1991–1992 and 2007, resulting in 5,849 (95% CI 4,979 to 6,718) fewer women dying of breast cancer than would have otherwise been the case. Women aged 40–49 years, who had the lowest BreastScreen participation (approximately 20%), had the largest mortality reduction: 44% (95% CI 34.8–51.2). Women aged 60–69 years, who had the highest BreastScreen participation (approximately 60%), had the smallest mortality reduction: 19% (95% CI 10.5–26.9). As BreastScreen participation by invited women aged 50–69 years only reached a maximum of about 55–60% in 1998–1999, a decline in mortality in Australian women cannot be attributed to BreastScreen prior to this time. Thus, almost 60% of the Australian decline in breast cancer mortality since 1991 cannot be attributed to BreastScreen. Therefore, mammographic screening cannot account for most of the reductions in breast cancer mortality that have occurred in Australian women since 1991 and may have contributed to over-diagnosis. Most, if not all, of the reductions can be attributed to the adjuvant hormonal and chemotherapy, which Australian women have increasingly received since 1986.

Primary systemic therapy in HER2-amplified breast cancer : a clinical review

Primary systemic therapy (PST) in early breast cancer is utilized in locally advanced breast tumors and when breast-conserving surgery is desirable. In addition, the PST setting provides an opportunity to monitor response including histopathological and biomarker examination of the tumor and host tissues before and after systemic therapy. Trastuzumab is a monoclonal antibody targeting the hEGF receptor that is overexpressed in 15–20% of breast tumors. Trastuzumab is effective in prolonging survival when used to treat women with hEGF receptor overexpressed tumors, both in adjuvant and metastatic disease settings. Trastuzumab has also shown promising activity in PST/neoadjuvant studies by achieving high rates of complete pathologic response. This is a review of clinical studies that incorporated trastuzumab in PST and/or neoadjuvant chemotherapy, including the results of recently reported studies using trastuzumab in combination with other novel therapies such as lapatinib or pertuzumab.

Alternative targeted therapy for early HER2 positive breast cancer

Her2 (erbB2) receptor is overexpressed in around twenty percent of early breast cancer and historically conferred a poorer prognosis (1). Targeted anti-Her2 therapy has significantly improved outcomes for these women.

Synthesis and biological evaluation of novel folic acid receptor-targeted, β-cyclodextrin-based drug complexes for cancer treatment

Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD)-based nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive [FR(+)] cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS), high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and circular dichroism. Drug complexes of adamatane (Ada) and cytotoxic doxorubicin (Dox) with FACD were readily obtained by mixed solvent precipitation. The average size of FACD-Ada-Dox was 1.5-2.5 nm. The host-guest association constant Ka was 1,639 M-1 as determined by induced circular dichroism and the hydrophilicity of the FACDs was greatly enhanced compared to unmodified CD. Cellular uptake and FR binding competitive experiments demonstrated an efficient and preferentially targeted delivery of Dox into FR-positive tumor cells and a sustained drug release profile was seen in vitro. The delivery of Dox into FR(+) cancer cells via endocytosis was observed by confocal microscopy and drug uptake of the targeted nanoparticles was 8-fold greater than that of non-targeted drug complexes. Our docking results suggest that FA, FACD and FACD-Ada-Dox could bind human hedgehog interacting protein that contains a FR domain. Mouse cardiomyocytes as well as fibroblast treated with FACD-Ada-Dox had significantly lower levels of reactive oxygen species, with increased content of glutathione and glutathione peroxidase activity, indicating a reduced potential for Dox-induced cardiotoxicity. These results indicate that the targeted drug complex possesses high drug association and sustained drug release properties with good biocompatibility and physiological stability. The novel FA-conjugated β-CD based drug complex might be promising as an anti-tumor treatment for FR(+) cancer.

Correlation between extent of osteolytic damage and metastatic burden of human breast cancer metastasis in nude mice: Real-time PCR quantitation

Orthotopic or intracardiac injection of human breast cancer cell lines into immunocompromised mice allows study of the molecular basis of breast cancer metastasis. We have established a quantitative real-time PCR approach to analyze metastatic spread of human breast cancer cells inoculated into nude mice via these routes. We employed MDA-MB-231 human breast cancer cells genetically tagged with a bacterial β-galactosidase (Lac-Z) retroviral vector, enabling their detection by TaqMan® real-time PCR. PCR detection was linear, specific, more sensitive than conventional PCR, and could be used to directly quantitate metastatic burden in bone and soft organs. Attesting to the sensitivity and specificity of the PCR detection strategy, as few as several hundred metastatic MDA-MB-231 cells were detectable in 100 μm segments of paraffin-embedded lung tissue, and only in samples adjacent to sections that scored positive by histological detection. Moreover, the measured real-time PCR metastatic burden in the bone environment (mouse hind-limbs, n=48) displayed a high correlation to the degree of osteolytic damage observed by high resolution X-ray analysis (r 2=0.972). Such a direct linear relationship to tumor burden and bone damage substantiates the so-called `vicious cycle' hypothesis in which metastatic tumor cells promote the release of factors from the bone which continue to stimulate the tumor cells. The technique provides a useful tool for molecular and cellular analysis of human breast cancer metastasis to bone and soft organs, can easily be extended to other cell/marker/organ systems, and should also find application in preclinical assessment of anti-metastatic modalities.

Breast cancer prognosis risk estimation using integrated gene expression and clinical data

Novel prognostic markers are needed so newly diagnosed breast cancer patients do not undergo any unnecessary therapy. Various microarray gene expression datasets based studies have generated gene signatures to predict the prognosis outcomes, while ignoring the large amount of information contained in established clinical markers. Nevertheless, small sample sizes in individual microarray datasets remain a bottleneck in generating robust gene signatures that show limited predictive power. The aim of this study is to achieve high classification accuracy for the good prognosis group and then achieve high classification accuracy for the poor prognosis group.

RRHGE: a novel approach to classify the estrogen receptor based breast cancer subtypes

Breast cancer is the most common type of cancer among females with a high mortality rate. It is essential to classify the estrogen receptor based breast cancer subtypes into correct subclasses, so that the right treatments can be applied to lower the mortality rate. Using gene signatures derived from gene interaction networks to classify breast cancers has proven to be more reproducible and can achieve higher classification performance. However, the interactions in the gene interaction network usually contain many false-positive interactions that do not have any biological meanings. Therefore, it is a challenge to incorporate the reliability assessment of interactions when deriving gene signatures from gene interaction networks. How to effectively extract gene signatures from available resources is critical to the success of cancer classification.

A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes

'Taste' changes are commonly reported during chemotherapy. It is unclear to what extent this relates to actual changes in taste function or to changes in appetite and food liking and how these changes affect dietary intake and nutritional status.