Abstract
Breast cancer is a leading cause of cancer death in women. Despite the success of drugs such as tamoxifen in tackling this disease, many patients are unresponsive or quickly become resistant to drug treatment. An attempt at solving this “significant clinical problem” is underway at Cardiff University, UK, where research is focused on preventing, or potentially even reversing, this process of drug resistance.
‘…research is focused on preventing, or potentially even reversing, this process of drug resistance.’
Tamoxifen, taken in pill form, is widely used in the treatment of hormone-sensitive breast cancer and is one of the main drugs used for this purpose. It is prescribed to patients for approximately 5 years in order to help prevent reoccurrence of the cancer and also to prevent cancer developing in the other breast. In addition, tamoxifen may be prescribed to women at high risk of breast cancer; some research suggests that it may reduce the risk of developing a hormone-dependent breast cancer by up to a third. Tamoxifen functions by competitively binding to estrogen receptors and blocking its activity as, in the majority of breast cancers, estrogen stimulates proliferation of breast cancer cells.
Researchers from the Welsh School of Pharmacy's Tenovus Centre for Cancer Research have found that by inhibiting the activity of a protein in the cancer, it may be possible to combat tamoxifen resistance. The researchers noted that when breast cancer cells grown in vitro developed tamoxifen resistance, a high increase in Src protein activity was observed. Preventing activity of Src may allow prevention or reversal of tamoxifen resistance.
“Src (is) more active in tamoxifen-resistant than tamoxifen-sensitive breast cancer cells.”
Lead researcher, Stephen Hiscox of the Welsh School of Pharmacy commented, “We have previously shown that when breast cancer cells become resistant to medicines such as tamoxifen in the laboratory, they become more aggressive with an invasive behaviour. These are characteristics that can be promoted by Src, a protein which we have recently shown to be more active in tamoxifen-resistant than tamoxifen-sensitive breast cancer cells.”
‘…cotreatment of cells with tamoxifen and AZD0530 was able to prevent drug resistance occurring initially.’
Researchers from The Tenovus Centre for Cancer Research collaborated with AstaZeneca and discovered that treatment with a specific inhibitor of Src activity, AZD0530, was able to reduce the aggressive behaviour of the cells as well as reversing the process of resistance in tamoxifen-resistant cells. Furthermore, it was found that the cotreatment of cells with tamoxifen and AZD0530 was able to prevent drug resistance occurring initially.
AZD0530 is currently in the early stage of clinical trials and it is thought that utilization of this inhibitor may provide a significant benefit to women for whom tamoxifen had been rendered of little use. However, it will first be necessary for the laboratory results of this study to be reproduced in the clinic.
‘…utilization of (AZD0530) may provide a significant benefit to women for whom tamoxifen had been rendered of little use.’
Robert Nicholson, Director of the Tenovus Centre for Cancer Research, believes that these findings represent a milestone in their research, “Whilst little is known about the mechanisms used by breast cancers to become resistant to common therapies such as tamoxifen, it remains a significant clinical problem. Therefore the ability to restore sensitivity to therapy, or to even prevent resistance arising in the first place, could be of huge benefit to a large number of breast cancer patients.”
“…the ability to restore sensitivity to therapy, or to even prevent resistance arising in the first place, could be of huge benefit to a large number of breast cancer patients.”
Source: Cardiff University Press Release.
in brief…
Bundred NJ, Campbell ID, Davidson N et al.: Cancer (2008) (Epub ahead of print).
A new study has highlighted the potential for zoledronic acid to be used as bone protection therapy for postmenopausal women with estrogen receptor-positive early breast cancer receiving letrozole. A total of 1065 patients receiving adjuvant letrozole were randomly assigned to zoledronic acid with either immediate- or delayed-start. Zoledronic acid was administered to the latter group if lumbar spine or total hip T-score decreased below −2.0 or when a nontraumatic fracture occurred. Results of the study showed an increase in lumbar spine bone mineral density (BMD) after 12 months in the immediate-start cohort whereas the delayed-start group demonstrated a decline in lumbar BMD at 12 months. The differences in lumbar spine BMD and total hip BMD across the two groups were 5.7 and 3.6%, respectively. Researchers concluded that, in the case of postmenopausal women receiving adjuvant letrozole, immediate zoledronic acid prevented bone loss.
Wheeler CM, Bautista OM, Tomassini JE et al.: Vaccine. 26, 686–696 (2008).
A recent study of 1877 women, aged 16–23 years, investigated the safety and immunogenicity of coadministered quadrivalent human papillomarvirus (HPV) −6/11/16/18 L1 VLP and hepatitis B (HBV) vaccines in women. Participants were randomly assigned to receive either HPV and HBV vaccines combined, HPV vaccine plus placebo, HBV vaccine plus placebo or a double placebo. The results demonstrated that coadministration of HPV and HPV vaccines resulted in robust anti HPV-6, −11, −16 and −18 geometric mean titers (GMTs) and 99% seroconversion rates at month 7. These results were noninferior to those of HBV vaccine alone. In addition, high anti-HB GMTs were observed at month 7 following simultaneous vaccination. The level of GMTs following coadministered vaccine was found to be lower at month 7 than following HBV vaccine alone. However, more than 96% of participants achieved an anti-HBs seroprotection level of more or equal to 10 mlU/ml, a level that was noninferior to that caused by HBV vaccine alone. The researchers conclude that the coadministered vaccines were well-tolerated and do not have a negative impact on the efficacy of either vaccine. Moreover, they suggest that the option for coadministered vaccine may improve protection levels against HPV and HBV.
Basal cell-like breast cancer may be an independent risk factor for distant metastases in African–American women
A recent study has suggested that African–American women with basal cell-like breast cancer are almost six-times more likely to develop distant metastases than peers suffering from luminal A-type breast cancer.
Basal-type breast cancer constitutes 39% of breast cancers amongst premenopausal African–American women, whereas this subtype represents only 16% of breast cancers in Caucasian women. The researchers suggest that the higher level of basal-type breast cancer may account for the poor prognosis often observed in African–Americans.
Based on distinct clinical and pathological features, as well as response to chemotherapy, four subtypes of breast cancer have been classified: luminal A, luminal B, basal cell-like, and Her-2/neu. For this study, a retrospective analysis of 372 African–American women who were diagnosed and treated for breast cancer between the years 1998 to 2005 was conducted, and women were classified into the aforementioned subtypes. 55.4% were classified as luminal A; 21.2% as basal cell-like; 11.8% as luminal B; and 11.6% as Her-2/neu.
The results of the study demonstrated that premenopausal women were 8.8-times more likely to develop locoregional recurrence and 1.8-times more likely to develop distant metastates, compared with postmenopausal women. Women with basal cell-like breast cancer were not at an increased risk of developing locoregional recurrence, compared with women who suffered from the luminal A subtype. However, those with basal cell-type were shown to be 5.8-times more likely to develop distant metastases. In addition, the study highlighted the large number of women with basal cell-like breast cancer who were treated with adjuvant chemotherapy. At 55%, this was the highest percentage of all the subtypes, despite recent findings that basal-cell like tumors are particularly sensitive to chemotherapy.
The researchers conclude that their findings must be followed up by additional prospective studies in order to “individualize adjuvant therapy and to evaluate alternative forms of systemic treatment in African–American women.”
Source: Ihemelandu CU, Naab TJ, Mezghebe HM et al.: Basal cell-like (triple-negative) breast cancer, a predictor of distant metastasis in African American women. Am J. Surg. 195, 153–158 (2008).
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Researchers call for lung cancer screening amongst breast cancer survivors
New research suggests that breast cancer survivors who receive radiotherapy and have a history of smoking should receive screening for lung cancer.
The study demonstrated that patients in receipt of postmastectomy radiotherapy (PMRT) who also smoke, have an increased risk of ipsilateral lung cancer compared with those who do not receive PMRT or smoke. Data used for the study was obtained from women enrolled in the Connecticut Tumor Registry, diagnosed with breast cancer between 1965 and 1989. The records were compared for pathology, breast cancer therapy and smoking history.
In women who did not receive PMRT, those who had smoked had a 5.9-fold increased risk of lung cancer, compared with nonsmokers. Patients who smoked and had undergone PMRT were at a 1.8-fold increased risk, compared with nonsmokers who did not receive PMRT. Smoking and PMRT were associated with an increased risk of all histologic types of lung cancer; the adjusted ORs for the joint effects of smoking and PMRT were 10.5 and 37.6% for the contralateral and ipsilateral lung, respectively.
“Given those findings, breast cancer survivors who are or have been smokers and have received radiotherapy may be appropriate candidates for lung cancer screening with spiral commuted tomography,” the researchers commented.
PMRT has been found to reduce the risk for local recurrence as well as offering an improved survival rate for patients with certain high-risk cancers. However, second primary cancers are a potential repercussion of the treatment. Neuget et al. suggest that smoking history should be taken into account when discussing treatment options with patients with newly diagnosed breast cancer. They conclude, “Research is needed to determine whether or not smoking cessation after radiotherapy may reduce its late effects.”
Source: Kaufman EL, Jacobson JS, Hershman DL, Desai M, Neugut AI: Effect of breast cancer radiotherapy and cigarette smoking on risk of second primary lung cancer. J. Clin. Oncol. 26, 392–398 (2008).
Women's Genome Health Study to complete in 2008
The Women's Genome Health Study (WGHS) carried out by Amgen researchers, is aimed at investigating underlying genetic variations in women that may predispose them to diseases such as heart disease, stroke, breast cancer, diabetes and osteoporosis. A total of 28,000 women have been followed for over 10 years.
Joe Miletich, Amgen's senior vice president, Research & Development, noted that “because the Women's Genome Health Study is unique in its size and the length of time participants have been followed, it will allow scientists to focus on the genetic risk factors for diseases with extraordinary statistical power.” Progress of the study is measued by the number of single nucleotide polymorphisms (SNPs) that are processed; it is estimated that the rate of the study will proceed at “just shy of 900 SNPs a month for the WGHS. This equates to more than 2000 individuals genotyped a month.” This rate is much faster than was anticipated at the onset of the study and as such has allowed Amgen researchers to undertake further research programs such as “finding genetic predictors of treatment response among clinical trial participants enrolled in studies of Amgen therapeutic candidates.”
Discussing the potential of the research, Miletich commented, “We expect this study to have a significant impact for years to come on healthcare research, including understanding diseases, discovering new targets for therapeutic intervention, and developing new medicines”.
It is expected that screening will be completed by the third quarter of 2008.
Source: Amgen press release.
Study warns of potential for drug resistance in cancer therapy
A recent study has highlighted a method by which BRCA2-deficient cells may be able to acquire resistance to poly(ADP-ribose) polymerase (PARP) inhibitors, a new therapeutic approach that has been shown to be effective against BRCA2 tumors in early clinical trials.
It is hoped that this research may help identify patients for whom treatment will be most effective, leading to a more individualized approach. Herbie Newell, Cancer Research UK's executive director of translational research, remarked, “This research deepens our understanding of why some breast cancer patients with a faulty BRCA2 gene may stop responding to treatment. This type of research is becoming increasingly important as we seek to tailor cancer therapies to individual patients.”
The study found that intragenic deletion of the protein-truncating c.6174delT frameshift mutation and restoration of the open reading frame allowed expression of new BRCA2 isoforms with resistance to PARP inhibitors. The researchers believe that these findings have important implications in improving current understanding of drug resistance, as well as in defining functionally important domains within BRCA2. lan Ashworth, director of the Breakthrough Breast Cancer Research Centre, commented, “Drug resistance is a problem common to all types of cancer, yet this important process is poorly understood. Our work has shown how this occurs in some women with cancer. In the future we hope to be able to use this information to predict whether cancer patients will benefit from particular treatments.”
Source: Edwards SL, Brough R, Lord CJ: Resistance to therapy caused by intragenic deletion in BRCA2. Nature (2008) (Epub ahead of print).