Be sure to scroll all the way to the bottom of the page for some great web links.
Researchers Identify Genes Associated with Bone Metastasis
A new study from Dutch researchers finds gene profile of breast cancers likely to metastasize to bone.
Primary Source: “Genes Associated with Breast Cancer Metastatic to Bone.” Journal of Clinical Oncology, May 20, 2006; 24:2261-2267.
Expert Commentaries by
Clifford Hudis.MD
Chief, Breast Cancer Medicine Service
Memorial Sloan-Kettering Cancer
New York, NY
and
Gregory A. Clines, MD, PhD
Assistant Professor of Internal Medicine
University of Virginia
Charlottesville, VA
BREASTLINK ANALYSIS
By Mary Batten
This study is an important research effort toward developing a test that could predict which breast cancers are likely to metastasize to bone. Principal researcher Marcel Smid and his colleagues at Erasmus MC-Daniel den Hoed Cancer Center in Rotterdam, the Netherlands, identified a panel of genes distinctive of node-negative breast cancers that metastasized to bone (Ref. 1). Previously these researchers identified a 76-gene profile associated with patients at high risk for a distant recurrence (Ref. 2). The researchers suggest that the high-risk profile and the bone profile might be used in combination, first to identify patients at risk for distant recurrence and second to determine which of those patients would be eligible for bisphosphonate treatment to prevent bone metastasis. This research holds great promise but, as the authors acknowledge, a larger study is needed to confirm their findings before they can be incorporated in clinical practice.
BACKGROUND
Bone metastases develop in 60 to 80 percent of patients with metastatic breast cancer. Just why breast cancer so frequently metastasizes to bone is poorly understood. Various explanations have been proposed, including the possibility that the bone microenvironment somehow encourages circulating cancer cells to settle in bone and proliferate. Various growth factors have also been implicated (Refs. 3-6). However, the genes in breast cancer cells that promote metastasis to bone are largely unknown. In this study, the authors hypothesized that breast cancer metastasizing to bone would have a different genetic profile than breast cancer that metastasizes to other organs.
The Study
What Was Being Studied?
The genes involved in breast cancer that metastasizes to bone.
How Was Information Gathered?
The researchers used gene expression data from their previous study (Ref. 2) and analyzed 107 primary breast tumors in patients who were lymph node-negative at diagnosis and who had relapsed. Tumor samples were classified according to site of relapse. Sixty-nine samples were classified as bone and 38 samples as non-bone. With technology called microarray analysis, the researchers looked for a gene profile characteristic of bone metastasis but not of metastasis to other parts of the body.
Results
The researchers found that the gene expression profile from primary tumors that relapse to bone is significantly different from that of tumors relapsing to other parts of the body. A panel of 69 genes was characteristic of breast cancer that relapsed to bone. One gene in particular, known as TFF1, was highly expressed in samples from patients with bone metastasis. This finding was consistent with an earlier study of 610 breast tumors from both node-negative and node-positive patients by the senior researcher, Dr. John A. Foekens. That study also found higher expression of TFF1 in patients who relapsed to bone (Ref. 7).
The authors conclude: “Our study identifies a panel of genes relevant to bone metastasis in breast cancer. The subsequently developed classifier of tumors relapsing to bone could, after thorough confirmation on an extended number of independent samples, and in combination with our previously developed high-risk profile, provide a diagnostic tool for the recommendation of adjuvant bisphosphonate therapy in addition to endocrine therapy or chemotherapy” (Ref. 1).
Who Funded This Study?
The Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research.
EXPERT COMMENTS
Editor’s Note: We are fortunate to have two expert commentaries on this paper, one by oncologist Clifford Hudis, MD, of Memorial Sloan-Kettering Cancer Center; the other by researcher Gregory Clines, MD, PhD, of the University of Virginia.
By Clifford Hudis.MD
Chief, Breast Cancer Medicine Service
Memorial Sloan-Kettering Cancer Center
1275 York Avenue
New York, NY 20021
This is a well done study that tries to discover which genes play a role in the important process of bone metastasis. The gene profile identified by these authors holds promise but they are appropriately conservative in their conclusion when they say that this could provide a diagnostic tool if they are able to confirm it in a larger set of patients. An independent dataset that corroborates this would be important. More importantly, they make the leap to talking about bisphosphonates and they try to tie this to a clinical intervention, which would have to be tested. It’s not enough to know the set of genes, or any predictor for that matter, will tell you who’s going to have the problem. The next question is, does the treatment you’re talking about using work specifically in that population? So those are a couple more steps that will have to be taken before we know whether this particular gene profile will identify which breast cancers have a high risk of metastasizing to bone..
We’re always going to need more clinical trials but with respect to the intervention that the researchers mention, we don’t yet have approval of bisphosphonates to prevent metastasis in early stage breast cancer (in the United States. It is being used for this purpose in parts of Europe but the data are a little bit mixed right now. Of course, we use bisphosphonates extensively to prevent osteoporosis and there’s obviously overlap because many menopausal women have breast cancer and may end up on bisphosphonates anyway.
Breast cancer metastatic to bone is a very big issue for both clinical and translational investigators; and we don’t yet know the mechanism. These authors suggest that there must be something specific both about the breast cancer and the soil – the bone – that ties them together. Maybe there are some growth factors involved, maybe there’s a receptivity. One of the hopes with (this research group’s work is that they’ll identify the genes that actually play a role in this process and, therefore, figure out which of the genes really matter.
I think the next advances in this area will come from a lot of places, not just work like this but also from the therapeutic side. There are a lot of anti-bone metastasis disease drugs that have been developed and are in clinical trials right now.
By Gregory A. Clines, MD, PhD
Assistant Professor of Internal Medicine
University of Virginia
Charlottesville, VA
e-mail:
gc4z@virginia.edu
These researchers did a good job with the resources they had. They studied primary breast tumors from patients who already had metastases and determined what gene signatures were different about those primary breast tumors that made them go either to bone or not to bone.
This research is a beginning toward developing a way to identify which breast cancers have a high risk of spreading to bone. However, translating this study to a patient who has just been diagnosed with breast cancer and predicting her chance of developing metastasis to bone may be a bit of a leap because the patients selected for microarray analysis in this study already had metastases. It would be interesting to use their gene signature and go back and look at newly diagnosed patients to see what happens over the long term.
There are a number of mechanisms involved in bone metastasis, which is a very complex process. For a tumor cell to go from the primary site to a distant site is a multi-step process. First, the tumor cell has to escape from its primary environment; it has to invade and travel in the vascular system either through the lymph system or through the blood, and then it has to attach to a distant site . It has to home to a certain tissue. Then it must invade or extravasate from the vessels in a distant site and be able to grow there. If there is a disruption in any one of those processes, metastasis won’t occur. When you look at bone metastasis or any metastasis at all, what you’re studying is two different cell types. You’re looking at the interaction between the cancer cell and the target organ. It becomes very complicated when you’re looking at interactions between the cancer cells and bone cells. In our lab, we’re investigating bone cells in animal models. Dr. Theresa Guise here at the University of Virginia has been on the forefront of this work and she has published a number of papers that have examined the interaction between breast cancer cells and osteoclasts. She has identified a number of factors. We already know the importance of TGF beta and parathyroid hormone-related protein. We know that those two proteins are necessary for breast cancer to be able to grow in bone and cause metastasis in animal models.
Certain types of tumors preferentially go to bone, where they form osteolytic lesions. Breast cancer is one example. Prostate cancer also has a predilection to metastasize to bone where they can form osteoblastic lesions. Most patients who have advanced–stage prostate cancer will have bone metastasis.
There are some good human clinical data showing that bisphosphonates reduce skeletal-related events in patients who have established bone metastasis. This has been shown with breast cancer mostly but there are some good studies with prostate cancer and other solid tumors such as renal cell carcinoma and lung cancer. So far, there’s no clinical evidence in humans that bisphosphonates prevent the development of bone metastasis. However, in our animal models, we are seeing a treatment effect with bisphosphonates.. In an animal model of prostate cancer, bisphosphonates reduce the size of bone metastasis. Other groups have done similar studies using breast cancer. Recently Dr. Guise presented data showing that Zometa, which is probably the most widely used bisphosphonate with patients with bone metastasis, reduced the size of prostate cancer bone metastasis in an animal model.
Research is progressing. There’s still much we don’t know because the development of bone metastasis is a multistep process. It’s probably multiple genes involving multiple signaling pathways in the breast cancer cells that lead to bone metastasis. At least with this paper, the investigators looked for gene signatures that predict prognosis in some of these patients. I think that the next step for this group will be to determine whether certain gene signatures can predict which primary breast tumors in the early stages will metastasize to bone..
References
Bibliography
1. Smid M, Wang Y, Klijn JGM, et al. “Genes Associated with Breast Cancer Metastatic to Bone.” Journal of Clinical Oncology, May 20, 2006; 24:2261-2267.
2. Wang Y, Klijn JG, Zhang Y, et al. “Gene-Expression Profiles to Predict Distant Metastasis of Lymph-Node-Negative Primary Breast Cancer.” Lancet 2005; 365:671-679.
3. James JJ, Evans AJ, Pinder SE, et al. “Bone Metastases from Breast Carcinoma: Histopathological-Radiological Correlations and Prognostic Features.” British Journal of Cancer 2003; 89:660-665.
4. Coleman RE. “Skeletal Complications of Malignancy.” Cancer 1997; 80:1588-1594.
5. Koenders PG, Beex LV, Langens R, et al. “Steroid Hormone Receptor Activity of Primary Human Breast Cancer and Pattern of First Metastasis: The Breast Cancer Study Group.” Breast Cancer Research & Treatment 1991; 18:27-32.
6. Roodman GD. “Mechanisms of Bone Metastasis.” New England Journal of Medicine 2004; 350:1655-1664.
7. Foekens JA, van Putten WL, Portengen H, et al. “Prognostic Value of PS2 and Cathepsin D in 710 Human Primary Breast Tumors: Multivariate Analysis.” Journal of Clinical Oncology 1993; 11:899-908.
Internet Sources
When Breast Cancer Spreads
Howard Hughes Medical Institute, Dec. 2003
http://hhmi.org/bulletin/dec2003/bre...stcancer2.html
Gene-Expression Profile Testing
National Breast Cancer Coalition, April 2005
http://www.natlbcc.org/bin/index.asp...epid=9&btnid=2
What is Bone Metastasis?
American Cancer Society
http://www.cancer.org/docroot/CRI/co...astasis_66.asp
Bone Cancer FAQ
http://spade39.ncl.ac.uk/ccw/faq/
Management of Bone Metastases in Advanced Breast Cancer
Moffitt Cancer Center
https://www.moffitt.usf.edu/pubs/ccj/v6s2/article6.htm
Distinctive Genetic Program Guides Breast Cancer’s Deadly Spread
Science Blog from Howard Hughes Medical Institute, June 2003
http://www.scienceblog.com/community.../20033021.html
Linear Mode
