|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2008.21.4908 on August 3 2009 © 2009 American Society of Clinical Oncology.
Sowing the Soil for Cure? Results of the ABCSG-12 Trial Open a New Chapter in the Evolving Adjuvant Bisphosphonate Story in Early Breast CancerDepartment of Medical Oncology, Jules Bordet Institute, Brussels, Belgium
Department of Medicine, Centre Hospitalier Universitaire Brugmann; Université Libre de Bruxelles, Brussels, Belgium
Department of Medical Oncology, Jules Bordet Institute; Université Libre de Bruxelles, Brussels, Belgium
After their initial synthesis in 1865, bisphosphonates were largely used for industrial purposes to prevent calcium carbonate precipitation in the textile, agricultural, and oil sectors.1 More than 100 years later, bisphosphonates were shown to inhibit bone resorption in animal models.2 Since then, the role of bisphosphonates in the treatment of hypercalcemia, Paget's disease, and osteoporosis, as well as in the reduction of morbidity associated with bone metastases from breast,3–5 prostate,6 and plasma cell malignancies,7 has been established. The American Society of Clinical Oncology recommends "the extensive and early use of bisphosphonates" to prevent skeletal complications, such as pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia, in women with metastatic bone disease from breast cancer.8,9 A more recent international panel of experts concluded that bisphosphonates reduce the frequency and severity of skeletal complications in patients with bone metastases from a variety of different cancers.10 In the setting of cancer treatment–induced bone loss, the panel advised considering the use of bisphosphonates in patients presenting with risk factors for fractures but did not endorse the use of bisphosphonates in the adjuvant setting.
Clinical trials with bisphosphonates in patients with metastatic breast cancer have failed to demonstrate an overall survival (OS) benefit.3–5 However, bisphosphonates might have an impact on long-term survival if used in earlier stages of disease. The dissemination of breast cancer cells to bone marrow instigates a vicious self-sustaining cycle of destruction, whereby individual tumor cells release growth factors that stimulate stromal cells and osteoblasts to produce the receptor activator for nuclear factor Three clinical trials with the non–nitrogen-containing oral bisphosphonate clodronate in early breast cancer produced mixed results.13–15 A single-center German study involving 302 women with early breast cancer and detectable bone marrow metastases demonstrated a striking reduction in bone and visceral metastases and improvement in disease-free survival (DFS) and OS with two years of adjuvant clodronate therapy.13 With longer follow-up, the gain in OS persisted, although differences in DFS and bone metastasis–free and visceral metastasis–free survival were no longer apparent.16 A larger placebo-controlled multicenter study found that a similar schedule of oral clodronate for 2 years in conjunction with standard therapy for stage I to III breast cancer reduced the incidence of bone metastasis and improved OS with no observed difference in nonosseous metastasis.14,17 However, a small Finnish trial reported that three years of adjuvant clodronate did not improve overall survival and had no effect on bone recurrences and a negative impact on nonskeletal recurrences, particularly in women with estrogen receptor–negative disease.18,19 There are concerns that these results were skewed by imbalances between the clodronate and observation groups. On the basis of the data, which remained unconvincing when pooled in a meta-analysis, the US Food and Drug Administration announced that it would not consider approving clodronate in adjuvant breast cancer therapy until the results from the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-34 study—in which 3,323 women with stage I to II disease have been randomly selected to receive three years of clodronate or placebo—were available.20 There is reason to believe that newer generation bisphosphonates may deliver greater efficacy. Non–nitrogen-containing bisphosphonates, such as clodronate, can be metabolized to an adenosine triphosphate analog that is toxic for macrophages and osteoclasts. Nitrogen-containing bisphosphonates, including zoledronic acid and ibandronate, have a very different mechanism of action and are much more potent inhibitors of osteoclast-mediated bone resorption. They inhibit the mevalonate pathway that leads to the prenylation of key intracellular signaling proteins.21 Many of these proteins are guanosine triphosphate–binding peptides essential for signal transduction, including Rho and Ras, that regulate key osteoclast functions, including attachment and survival. Inhibition of prenylation alters cell membrane integrity and induces osteoclast apoptosis. Nitrogen-containing bisphosphonates have also been shown to directly induce tumor cell apoptosis, inhibit angiogenesis, and prevent tumor cell adhesion to bone and invasion of stroma, and in preclinical models, they have displayed antitumor synergy in combination with chemotherapy, endocrine therapy, and radiotherapy in a manner more potent than that of clodronate.22,23 There is also reason to believe that nitrogen-containing bisphosphonates may exert their antitumor effects outside of the bone milieu. In a murine model with breast cancer cells implanted into the mammary fat pad, zoledronic acid suppressed bone, liver, and lung metastases, prolonging the OS of treated mice.24 The combination of zoledronic acid and doxorubicin produced synergistic antitumor activity in a primary breast cancer murine model without any microscopic evidence of extra-skeletal disease.25 These findings are additionally supported by preliminary data from the AZURE (Adjuvant Zoledronic Acid Reduce Recurrence) trial demonstrating that the addition of zoledronic acid to neoadjuvant chemotherapy resulted in smaller residual tumor size and a higher proportion of patients achieving pathologic complete response when compared with chemotherapy alone.26 To our knowledge, the Austrian Breast and Colorectal Cancer Study Group ABCSG-12 trial reported by Gnant et al27 was the first study to suggest that the addition of a nitrogen-containing bisphosphonate improves long-term outcome in early-stage breast cancer. Building on the results of the prior ABCSG-5 trial from the same group,28 this study used a 2 x 2 factorial design to randomly assign 1,803 premenopausal women with stage I to II breast cancer to receive 3 years of monthly goserelin, a gonadotropin-releasing hormone agonist, in combination with either tamoxifen or anastrozole. In the second randomization, patients received either zoledronic acid every 6 months for 3 years or no additional therapy. Previously, Gnant et al29 had demonstrated that zoledronic acid could prevent bone loss during the 3 years of adjuvant therapy in both the anastrozole and tamoxifen groups. Two years after the completion of endocrine treatment, there was partial recovery of bone loss in patients who did not receive zoledronic acid. In contrast, patients treated with zoledronic acid had an increased bone mineral density at 5 years from baseline (+4.0%; P = .02).30 With a median follow-up of 48 months, 4-year DFS and 4-year OS for this entire cohort were 92% and 98%, respectively, even though 30% of women enrolled had node-positive disease, and adjuvant chemotherapy was not administered. The comparison between tamoxifen and anastrozole failed to show any difference in DFS or OS; however, the trial was underpowered to detect the size of effect reported in the postmenopausal aromatase inhibitor studies.31–33 The addition of zoledronic acid resulted in a statistically significant 36% reduction in risk of a DFS event (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P = .01), with a trend toward improvement in OS (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P = .11). Although only 137 DFS events had occurred at the time of reporting, zoledronic acid seemed to reduce all categories of breast cancer–related DFS events (eg, distant osseous and nonosseous recurrences, locoregional recurrences, and contralateral primary breast cancers) with minimal observed toxicity. These intriguing results raise as many open questions as they address. Namely, given the pluripotent preclinical effects of bisphosphonates, what is the underlying mechanism of action driving the observed differences in DFS? Or, to borrow from Paget's seminal theory of cancer metastasis,34 do bisphosphonates target the seed, soil, or both? With regard to the soil, endocrine treatment alone resulted in a dramatic 14.4% reduction in overall bone mineral density at 36 months in the ABCSG-12 trial, an effect that was blunted by the addition of zoledronic acid.29 Combined use of an aromatase inhibitor with ovarian suppression for premenopausal women with early breast cancer is the most potent inducer of treatment-related bone loss.35 Elevated baseline markers of bone turnover may predict shorter bone metastasis–free survival.36 At the end of 3 years of endocrine therapy in the ABCSG-12 trial, in women who did not receive zoledronic acid, bone loss was significantly greater at the lumbar spine in the anastrozole plus goserelin group than it was in the tamoxifen plus goserelin group (–17.4% and –11.6%, respectively). Although not prospectively defined, subgroup analysis suggested that the observed benefit from the addition of zoledronic acid may have been driven by the anastrozole cohort, lending support to the idea that bisphosphonates may eliminate the fertile breeding ground induced by this form of cancer therapy. Another possible explanation is that the baseline condition of the bone matrix, rather than the rate of bone loss, determines whether circulating metastatic breast cancer cells are able to proliferate in the bone microenvironment. Unfortunately, baseline bone densitometry measurements were only performed in a subgroup of 400 women enrolled onto the ABCSG-12 study. Additional studies are required to address this important question. Does the creation of a hostile soil for circulating breast cancer cells account for the reduction in all categories of DFS events observed with the addition of zoledronic acid in the ABCSG-12 trial?27 In preclinical studies, the antitumor activity of zoledronic acid was dose and schedule dependent.37 The administration of zoledronic acid in the ABCSG-12 trial (4 mg every 6 months for 3 years) may not have been intensive enough to invoke direct antitumor effects outside of the bone milieu as an explanation for the observed differences in clinical outcome. Approximately 70% of patients with metastatic breast cancer develop bone metastases during the course of their illness. As Paget34 observed in his seminal studies of autopsy specimens, there are clear differences in tropism to distant metastatic sites according to the tissue of cancer origin. Even within the spectrum of primary breast cancers, the luminal (or estrogen receptor expressing) subtypes demonstrate a greater frequency of bone and pleural metastases, whereas the basal and human epidermal growth factor receptor 2 subtypes are more likely to relapse in brain, liver, and lung.38 Enrollment onto the ABCSG-12 trial was limited to premenopausal women with endocrine-sensitive disease, indicating that type of "seed" may be critical in selecting patients appropriate for a bone-directed metastasis eradication strategy. Soon to be reported studies with broader inclusion criteria, such as the NSABP B-34 and AZURE BIG (Breast International Group) 1-04 trials, should help clarify this issue. It may be possible to refine the prediction of patients with early disease at risk of subsequent bone metastasis using gene expression profiling.39 Early studies have suggested that genes linked to cellular adhesion and the fibroblast growth factor–mitogen-activated protein kinase pathway may be particularly important in the process of breast cancer metastasis to bone.39,40 If one presupposes that the effect of bisphosphonates is to create an unfavorable "soil" for a predisposed "seed," it is difficult to account for the reduction in nonosseous and locoregional recurrences seen in the ABCSG-12 trial.27 Although additional follow-up is needed to confirm these intriguing observations, the finding that a bone-directed therapy may reduce nonosseous and locoregional recurrences challenges our existing paradigm, in which systematic spread to distant sites is believed to be a late event in cancer progression. Elegant preclinical experiments with mouse models have suggested that cancer cells may disseminate early from premalignant lesions, and these early disseminated tumor cells are able to grow into detectable metastases before the transition to frankly invasive disease at the primary site occurs.41 Might bisphosphonates prevent the establishment of subsequent nonskeletal metastases and locoregional recurrences by eradicating dormant disseminated tumor cells in the bone microenvironment? Early clinical studies indicate that adjuvant zoledronic acid therapy may increase the rate of clearance of bone marrow disseminated tumor cells.42–44 This raises the tantalizing possibility that the early elimination of such minimal residual disease may have been a harbinger of the skeletal, nonskeletal, and locoregional recurrences observed in the ABCSG-12 trial.
Of the six acquired capabilities of cancer cells proposed by Hanahan et al45 as the "hallmarks of cancer," tissue invasion and metastasis are the most poorly understood. It is now possible to detect and molecularly characterize subpopulations of rare circulating tumor cells in patients without clinically apparent metastatic disease.46 The ABCSG-12 trial illustrates how much remains to be understood about the process of cancer metastasis. There is a wide array of emerging therapies directed against the bone microenvironment, such as inhibitors of the receptor activator for nuclear factor While waiting for this new and exciting knowledge to emerge, should clinicians routinely incorporate bisphosphonates into adjuvant therapy? A single randomized trial contingent on 137 DFS events is insufficient to change the current standard of care. The open-label design of the ABCSG-12 trial may have introduced bias favoring the earlier detection of bone metastases in the standard therapy arm, and longer follow-up is required to establish the stability of these early efficacy results. Moreover, concerns that the effect of zoledronic acid treatment may have been driven by the experimental anastrozole and goserelin arm—and concerns about the administration of endocrine therapy for only the nonstandard duration of 3 years—in this study suggest that it is too early to treat all patients with early-stage breast cancer with adjuvant bisphosphonate therapy. Reserving final judgment until the results of the NSABP B-34 and AZURE trials are available is prudent, although the delay in presentation of the efficacy analyses raises concern that the event rates may be lower than anticipated, or there may not be significant differences in outcome with the addition of a bisphosphonate. Nevertheless, on the basis of the striking treatment effect and minimal toxicity observed in the ABCSG-12 trial,27 it is certainly reasonable to discuss the benefits of early rather than late administration of zoledronic acid every 6 months in premenopausal women receiving adjuvant ovarian suppression to prevent treatment-related bone loss and subsequent fractures and possibly reduce the risk of breast cancer relapse.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Martine J. Piccart-Gebhart, AstraZeneca, Novartis Expert Testimony: None Other Remuneration: None
Conception and design: Philippe L. Bedard, Jean-Jacques Body, Martine J. Piccart-Gebhart Administrative support: Martine J. Piccart-Gebhart Manuscript writing: Philippe L. Bedard, Jean-Jacques Body, Martine J. Piccart-Gebhart Final approval of manuscript: Philippe L. Bedard, Jean-Jacques Body, Martine J. Piccart-Gebhart
1. Fleisch H: Development of bisphosphonates. Breast Cancer Res 4:30–34, 2002.[Medline] 2. Fleisch H, Russell RGG, Bisaz S, et al: The influence of pyrophosphate analogues (diphosphonates) on the precipitation and dissolution of calcium phosphate in vitro and in vivo. Calcif Tissue Res 2:10–10a, 1968 (suppl.[CrossRef] 3. Paterson AH, Powles TJ, Kanis JA, et al: Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 11:59–65, 1993.[Abstract] 4. Hortobagyi GN, Theriault RL, Porter L, et al: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases: Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 335:1785–1791, 1996. 5. Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomized, placebo-controlled trial—Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 17:846–854, 1999. 6. Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458–1468, 2002. 7. Berenson JR, Lichtenstein A, Porter L, et al: Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma: Myeloma Aredia Study Group. N Engl J Med 334:488–493, 1996. 8. Hillner BE, Ingle JN, Berenson JR, et al: American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer: American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol 18:1378–1391, 2000. 9. Hillner BE, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042–4057, 2003. 10. Aapro M, Abrahamsson PA, Body JJ, et al: Guidance on the use of bisphosphonates in solid tumours: Recommendations of an international expert panel. Ann Oncol 19:420–432, 2008. 11. Guise TA, Mundy GR: Cancer and bone. Endocr Rev 19:18–54, 1998. 12. Roodman GD: Mechanisms of bone metastasis. N Engl J Med 350:1655–1664, 2004. 13. Diel IJ, Solomayer EF, Costa SD, et al: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339:357–363, 1998. 14. 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. 15. Saarto T, Blomqvist C, Virkkunen P, et al: Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 19:10–17, 2001. 16. Jaschke A, Bastert G, Solomayer EF, et al: Adjuvant clodronate treatment improves the overall survival of primary breast cancer patients with micrometastases to bone marrow: A longtime follow-up. J Clin Oncol 22:9s; 2004 (suppl) abstr 529. 17. Powles T, Paterson A, McCloskey E, et al: Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 8:R13; 2006.[CrossRef][Medline] 18. Saarto T, Vehmanen L, Elomaa I, et al: The effect of clodronate and antioestrogens on bone loss associated with oestrogen withdrawal in postmenopausal women with breast cancer. Br J Cancer 84:1047–1051, 2001.[CrossRef][Medline] 19. Saarto T, Vehmanen L, Virkkunen P, et al: Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. Acta Oncol 43:650–656, 2004.[CrossRef][Medline] 20. Bayer HealthCare Pharmaceuticals. Further trial data awaited for Bonefos® (NDA) in the U.S. http://www.viva.vita.bayerhealthcare.com/index.php?id=386&tx_ttnews%5Btt_news%5D=11177&tx_ttnews%5BbackPid%5D=386&cHash=b03e7f4a65. 21. Luckman SP, Hughes DE, Coxon FP, et al: Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 13:581–589, 1998.[CrossRef][Medline] 22. Paterson AH: The role of bisphosphonates in early breast cancer. Oncologist 11:13–19, 2006 (suppl 1. 23. Winter MC, Holen I, Coleman RE: Exploring the anti-tumour activity of bisphosphonates in early breast cancer. Cancer Treat Rev 34:453–475, 2008.[CrossRef][Medline] 24. Hiraga T, Williams PJ, Mundy GR, et al: The bisphosphonate ibandronate promotes apoptosis in MDA-MB-231 human breast cancer cells in bone metastases. Cancer Res 61:4418–4424, 2001. 25. Ottewell PD, Monkkonen H, Jones M, et al: Antitumor effects of doxorubicin followed by zoledronic acid in a mouse model of breast cancer. J Natl Cancer Inst 100:1167–1178, 2008. 26. Winter MC, Thorpe HC, Burkinshaw R, et al: The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response: Exploratory evidence for direct anti-tumor activity in breast cancer. Cancer Res 69:5101; 2009.[CrossRef] 27. Gnant M, Mlineritsch B, Schippinger W, et al: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360:679–691, 2009. 28. Jakesz R, Hausmaninger H, Kubista E, et al: Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: Evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer—Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 20:4621–4627, 2002. 29. Gnant MF, Mlineritsch B, Luschin-Ebengreuth G, et al: Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: A report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 25:820–828, 2007. 30. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al: Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol 9:840–849, 2008.[CrossRef][Medline] 31. Baum M, Budzar AU, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131–2139, 2002.[CrossRef][Medline] 32. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092, 2004. 33. Thürlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747–2757, 2005. 34. Paget S: The distribution of secondary growths in cancer of the breast. Lancet 133:571–573, 1889.[CrossRef] 35. Coleman RE, Body JJ, Gralow JR, et al: Bone loss in patients with breast cancer receiving aromatase inhibitors and associated treatment strategies. Cancer Treat Rev 34:S31–S42, 2008.[CrossRef][Medline] 36. Lipton A, Chapman JW, Demers L, et al: Use of elevated bone turnover to predict bone metastasis. J Clin Oncol 26:28s; 2008 (suppl) abstr 591. 37. Green JR: Bisphosphonates: Preclinical review. Oncologist 9:3–13, 2004 (suppl 4. 38. Smid M, Wang Y, Zhang Y, et al: Subtypes of breast cancer show preferential site of relapse. Cancer Res 68:3108–3114, 2008. 39. Smid M, Wang Y, Klijn JG, et al: Genes associated with breast cancer metastatic to bone. J Clin Oncol 24:2261–2267, 2006. 40. 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] 41. Hüsemann Y, Geigl JB, Schubert F, et al: Systemic spread is an early step in breast cancer. Cancer Cell 13:58–68, 2008.[CrossRef][Medline] 42. Lin A, Park J, Melisko M, et al. Zoledronic acid (ZA) as adjuvant therapy for women with early stage breast cancer and disseminated tumor cells (DTC) in bone marrow (BM) 6th European Breast Cancer Conference, Berlin, Germany, April 15-19, 2008, abstr 242. 43. Rack BK, Jueckstock J, Genss EM, et al: Effect of zoledronate on persisting isolated tumor cells in the bone marrow of patients without recurrence of early breast cancer. Breast Cancer Res Treat 106:S40; 2007 (suppl 1) abstr 511. 44. Solomayer E, Gebauer G, Hirnle P, et al: Influence of zoledronic acid on disseminated tumor cells (DTC) in primary breast cancer patients. Cancer Res 69:2048; 2009.[CrossRef] 45. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100:57–70, 2000.[CrossRef][Medline] 46. Nagrath S, Sequist LV, Maheswaran S, et al: Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450:1235–1239, 2007.[CrossRef][Medline]
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
INTRODUCTION
AUTHORS' DISCLOSURES OF...
B ligand (RANKL), leading to the activation of osteoclasts. These activated osteoclasts resorb bone matrix–liberating potent growth factors that promote tumor cell colonization, inhibit apoptosis, and drive proliferation.
vβ3 integrins, which will form the foundation of future clinical trials in early-stage breast cancer. To capitalize on the promise of the ABCSG-12 trial, such studies must integrate new technologies to accelerate biomarker development and expand our understanding of the biology of cancer metastasis. 
