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Originally published as JCO Early Release 10.1200/JCO.2005.05.5319 on April 24 2006 © 2006 American Society of Clinical Oncology.
A "Bone" Fide Predictor of Metastasis? Predicting Breast Cancer Metastasis to BoneDepartments of Orthopedic Surgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD Bone is the most common site of breast cancer metastasis, with bone metastasis occurring in the majority of women with stage IV disease. These patients may experience marked morbidity with pain, decreased mobility, neurologic compromise, and/or pathologic fractures. Although the primary treatment for metastasis is systemic therapy directed at the underlying neoplasm, recent advances in therapy have led to the development of agents tailored to the treatment of bone metastasis including radiopharmaceuticals (eg, strontium-89 chloride) and bisphosphonates (eg, zoledronate or pamidronate). These agents localize predominantly to skeletal areas of high bone turnover like metastatic sites, thereby limiting systemic exposure, but their use is not without toxicity. The administration of bone-targeted radiopharmaceuticals has been associated with painful flare responses and myelosuppression,1,2 whereas bisphosphonates may lead to nephrotoxicity and osteonecrosis of the jaw.3-5 Ideally, oncologists would like to identify patients most likely to benefit from these therapies to avoid the consequences of over- and undertreatment. In addition, the possibility of prevention of bone metastases in early breast cancer patients is under investigation. This laudable goal presents two significant challenges; first is the paucity and inaccuracy of indicators of micrometastases, much less site-specific markers, and second is the demonstration that a specific intervention will reduce bone metastases. Perhaps the greatest obstacle to the successful identification of breast cancers with high metastatic potential is tumor heterogeneity. This is reflected in the myriad of possible clinical outcomes for patients initially diagnosed with tumors of seemingly similar stage and histopathology. One approach to this problem is to capitalize on the use of tools like microarray technology to find molecular signatures indicative of metastatic potential. In this issue, Smid et al6 have extended previously published work on a gene expression profile to predict distant metastasis in lymph node–negative breast cancer7 to report a putative molecular signature capable of predicting metastatic recurrence to bone. The investigators used conventional techniques to develop a 31-gene bone metastasis signature using a set of 107 patients with node-negative tumors who subsequently developed metastasis with or without bone involvement. This gene signature was developed using a training set (n = 72) and a test set (n = 35) of breast tumor specimens, stratified by site of relapse, estrogen receptor level, and metastasis-free interval. The 31-gene predictor was able to identify patients who ultimately developed bone metastasis with 100% sensitivity and 50% specificity. This is a modest improvement relative to estrogen receptor status (74% sensitivity and 63% specificity), which is currently the conventional clinical marker most closely associated with bone metastasis. This gene set would presumably be used to assess the potential for bone metastasis in patients already at high risk for metastatic relapse, as predicted by a poor prognosis gene signature.7,8 Gene expression signatures predicting breast cancer metastasis to other sites, such as the lung, are also being investigated.9,10 The combined application of these tests would theoretically allow organ-specific treatment options to be used to their full advantage, and patients unlikely to benefit from treatment could be spared unnecessary expense and exposure to toxic agents.
Another potential benefit of this data is the promotion of gene discovery efforts via elucidation of pathways driving metastasis to bone in human breast cancer. In a study by Kang et al,11 a 122-gene signature of bone metastasis was generated by comparing gene expression among sublines of the human breast cancer cell line, MDA-MB-231, that are highly metastatic to bone versus adrenal medulla in athymic nude mice. Four proteins from this experimentally derived bone metastasis signature (matrix metalloproteinase-1, interleukin-11, connective tissue–derived growth factor, and chemokine receptor CXCR4) were found to enhance bone metastasis on overexpression in the parental line, suggesting their functional importance in this process. In the current study,6 the authors found that genes encoding for trefoil factor-1 and -3 demonstrated the highest correlation with bone metastasis. Although the functional significance of these proteins in metastasis has not been demonstrated, trefoil peptides are known to possess promotogenic, proangiogenic, and antiapoptotic effects, making them interesting candidate metastasis genes.12-14 In addition, combining their 31-gene signature with the 122-gene bone signature described by Kang et al11 from the human breast cancer xenograft model, Smid et al6 found a common increase in the expression of genes involved in the fibroblast growth factor receptor-p42/44 mitogen-activated protein kinase pathway, suggesting its potential value as a therapeutic target. Lastly, a study by Woelfle et al15 reported a 73-gene signature capable of identifying lymph node–negative patients with or without bone marrow micrometastasis. Validation studies by tissue microarray showed that hypoxia-inducible factor-1
Although these gene signature studies have uncovered a wealth of new genes with potential involvement in the process of metastasis to bone, it is a bit surprising that previously identified bone metastasis–promoting genes, such as parathyroid hormone–related protein,16 interleukin-8,17 and integrin In addition, current limitations in the use of microarray technology must also be considered if we are to successfully apply microarray data to generate bone metastasis predictors or to identify genes involved in bone metastasis. Microarray results are not yet highly reproducible between studies or across platforms. This is demonstrated by the comparison of two recent studies that attempted to generate a gene signature capable of predicting distant metastasis in lymph node–negative primary breast cancer.7,8 Although both studies included a similar number and type of patients, had comparable experimental designs, and used similar statistical methods of validation, the resulting 70- and 76-gene predictors overlapped by just three genes. This presents a considerable challenge for the clinical application of this approach in the near term. In addition, the bone metastasis gene signature reported here has relatively low specificity. This may reflect the capacity of microarray analysis to describe global mRNA expression information obtained from a tissue sample. Metastasis is a multistep process that likely requires the coordinated expression of many protein products. Thus, although a tumor may, in aggregate, express all the necessary genes for metastasis to bone, actual metastasis to bone may not occur unless these genes are coordinately expressed in an individual tumor cell. Finally, Smid et al6 proposed that a validated bone relapse classifier could serve as a tool to recommend adjuvant bisphosphonate therapy. Such a recommendation requires that the test be validated, easily performed, and readily interpreted. Furthermore, efficacy of the proposed adjuvant therapy should be demonstrated. The three reported randomized studies of adjuvant bisphosphonate have given mixed results, admittedly in populations that were not enriched for predisposition to bone metastasis.19-21 Results from the National Surgical Adjuvant Breast and Bowel Project B34 trial, a large randomized placebo-controlled trial of clodronate versus placebo in women with early-stage breast cancer who have received standard adjuvant systemic therapy, are eagerly awaited. Because primary breast tissue samples from women on this trial have been banked, this study could potentially provide a platform to test both the prognostic and predictive value of a bone metastasis panel. In conclusion, the development of gene signatures capable of identifying early-stage breast cancer patients at high risk for bone metastasis, as described in this issue,6 has the potential to significantly improve breast cancer management. The ability to treat patients in a more specific fashion may improve clinical outcome and prevent unnecessary treatment and expense. In addition, early identification of these patients could open the door for the development and application of novel therapeutics targeting early points in the metastatic cascade. Although this approach has enormous potential, its clinical application will require further developmental and validation studies, and the issues of reproducibility and cost effectiveness must be addressed. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions
ACKNOWLEDGMENTS Supported by Grant No. CA88843 by the National Institutes of Health (N.E.D.). REFERENCES 1. Lee CK, Aeppli DM, Unger J, et al: Strontium-89 chloride (Metastron) for palliative treatment of bony metastases: The University of Minnesota experience. Am J Clin Oncol 19:102-107, 1996[CrossRef][Medline] 2. Powsner RA, Zietman AL, Foss FM: Bone marrow suppression after strontium-89 therapy and local radiation therapy in patients with diffuse marrow involvement. Clin Nucl Med 22:147-150, 1997[CrossRef][Medline] 3. Banerjee D, Asif A, Striker L, et al: Short-term, high-dose pamidronate-induced acute tubular necrosis: The postulated mechanisms of bisphosphonate nephrotoxicity. Am J Kidney Dis 41:18, 2003[CrossRef][Medline] 4. Markowitz GS, Fine PL, Stack JI, et al: Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int 64:281-289, 2003[CrossRef][Medline] 5. Bamias A, Kastritis E, Bamia C, et al: Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: Incidence and risk factors. J Clin Oncol 23:8580-8587, 2005 6. Smid M, Wang Y, Klijn JGM, et al: Genes associated with breast cancer metastasizing to bone. J Clin Oncol 24:2261-2267, 2006 7. Wang Y, Klijn JG, Zhang Y, et al: Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365:671-679, 2005[Medline] 8. van't Veer LJ, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530-536, 2002[CrossRef][Medline] 9. Minn AJ, Gupta GP, Siegel PM, et al: Genes that mediate breast cancer metastasis to lung. Nature 436:518-524, 2005[CrossRef][Medline] 10. Montel V, Huang TY, Mose E, et al: Expression profiling of primary tumors and matched lymphatic and lung metastases in a xenogeneic breast cancer model. Am J Pathol 166:1565-1579, 2005 11. Kang Y, Siegel PM, Shu W, et al: A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3:537-549, 2003[CrossRef][Medline] 12. Prest SJ, May FE, Westley BR: The estrogen-regulated protein, TFF1, stimulates migration of human breast cancer cells. FASEB J 16:592-594, 2002 13. Rodrigues S, Van Aken E, Van Bocxlaer S, et al: Trefoil peptides as proangiogenic factors in vivo and in vitro: Implication of cyclooxygenase-2 and EGF receptor signaling. FASEB J 17:7-16, 2003 14. Kinoshita K, Taupin DR, Itoh H, et al: Distinct pathways of cell migration and antiapoptotic response to epithelial injury: Structure-function analysis of human intestinal trefoil factor. Mol Cell Biol 20:4680-4690, 2000 15. Woelfle U, Cloos J, Sauter G, et al: Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Res 63:5679-5684, 2003 16. Guise TA, Yin JJ, Taylor SD, et al: Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest 98:1544-1549, 1996[Medline] 17. Bendre MS, Gaddy-Kurten D, Mon-Foote T, et al: Expression of interleukin 8 and not parathyroid hormone-related protein by human breast cancer cells correlates with bone metastasis in vivo. Cancer Res 62:5571-5579, 2002 18. Pecheur I, Peyruchaud O, Serre CM, et al: Integrin alpha(v)beta3 expression confers on tumor cells a greater propensity to metastasize to bone. FASEB J 16:1266-1268, 2002 19. Saarto T, Vehmanen L, Virjunen P, et al: Ten-year followup of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. Acta Oncol 44:80-82, 2005[Medline] 20. Powles T, Paterson S, Kanis JA, et al: Randomized placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 20:3219-3224, 2002 21. Diel IJ, Solomayer ER, Costa SD, et al: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339:357-363, 1998
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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and cytokeratins 8, 18, and 19 were significantly correlated with the presence of tumor cells in the bone marrow. 
