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Risk factors for skeletal-related events in patients with bone metastasis from breast cancer undergoing treatment with zoledronate

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Abstract

Background

Skeletal-related events (SREs) are significant contributors to the morbidity and mortality in patients with bone metastasis from breast cancer. Thus, bone-modifying agents (BMAs) are recommended in this population. However, the baseline risk factors of SREs in patients with bone metastasis from breast cancer receiving BMAs are not well understood.

Methods

We analyzed the patient-level data from a controlled arm of a clinical trial comparing denosumab with zoledronate in patients with bone metastases from breast cancer (ClinicalTrial.gov ID: NCT00321464) available at Project Data Sphere, a broad-access research platform that collects and curates patient-level data from completed, phase III cancer trials. The primary endpoint was the first SRE after the inclusion to the trial. The time to the first on study SRE was analyzed using Cox proportional hazards model based on patients’ baseline characteristics including age, race, ECOG performance status (PS), histology and immunohistochemistry of breast cancer, and urine and serum laboratory data.

Results

Among 756 patients in the zoledronate arm of the trial, we excluded 64 patients with a documented history of osteopenia or osteoporosis. The median age of the patients was 56 years old, the median follow-up was 553 days, and 249 patients (36%) had SREs. The univariate analysis showed that black or African American heritage, ECOG PS > 0, human epidermal growth factor receptor 2 (HER2) positivity, high urine N-telopeptide cross-links / creatinine ratio (NTx/Cre), and elevated serum alkaline phosphatase (ALP) are significant baseline risk factors for SREs. Patients with the characteristics of ECOG PS > 0, HER2 positivity, and elevated ALP also showed a significantly higher hazard ratio of SREs in multivariate analysis.

Conclusions

We determined risk factors for SREs in patients with bone metastasis from breast cancer.

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Abbreviations

ALP:

Alkaline phosphatase

BALP:

Bone specific alkaline phosphatase

BMA:

Bone-modifying agent

BMD:

Bone mineral density

CI:

Confidence interval

HR:

Hazard ratio

NTx/Cre:

N-telopeptide cross-links / creatinine ratio

PF:

Pathologic fracture

PS:

Performance status

RTB:

Radiation therapy to bone

SCC:

Spinal cord compression

SRE:

Skeletal-related event

STB:

Surgical therapy to bone

References

  1. American Cancer Society. Breast Cancer Facts & Figures 2017–2018. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-2018.pdf. Accessed January 27, 2020.

  2. Kuchuk I, Hutton B, Moretto P, Ng T, Addison CL, Clemons M (2013) Incidence, consequences and treatment of bone metastases in breast cancer patients—experience from a single cancer centre. J Bone Oncol 2(4):137–144. https://doi.org/10.1016/j.jbo.2013.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Harries M, Taylor A, Holmberg L et al (2014) Incidence of bone metastases and survival after a diagnosis of bone metastases in breast cancer patients. Cancer Epidemiol 38(4):427–434. https://doi.org/10.1016/j.canep.2014.05.005

    Article  CAS  PubMed  Google Scholar 

  4. Yang M, Liu C, Yu X (2019) Skeletal-related adverse events during bone metastasis of breast cancer: current status. Discov Med. 27(149):211–220

    PubMed  Google Scholar 

  5. Sathiakumar N, Delzell E, Morrisey MA et al (2012) Mortality following bone metastasis and skeletal-related events among women with breast cancer: A population-based analysis of US Medicare beneficiaries, 1999–2006. Breast Cancer Res Treat. 131(1):231–238. https://doi.org/10.1007/s10549-011-1721-x

    Article  CAS  PubMed  Google Scholar 

  6. O’Carrigan B, Wong MHF, Willson ML, Stockler MR, Pavlakis N, Goodwin A (2017) Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD003474.pub4

    Article  PubMed  PubMed Central  Google Scholar 

  7. Van Poznak C, Somerfield MR, Barlow WE et al (2017) Role of bone-modifying agents in metastatic breast cancer: An American Society of Clinical oncology-cancer Care Ontario focused guideline update. J Clin Oncol 35(35):3978–3986. https://doi.org/10.1200/JCO.2017.75.4614

    Article  CAS  PubMed  Google Scholar 

  8. Dibekoglu C, Turanli S, Karaman N, Caglar Ozcelik K, Erdogan O (2015) Bone fracture in breast cancer patients with isolated bone metastasis. Chir 110(1):43–48

    CAS  Google Scholar 

  9. Yamashiro H, Takada M, Nakatani E et al (2014) Prevalence and risk factors of bone metastasis and skeletal related events in patients with primary breast cancer in Japan. Int J Clin Oncol 19(5):852–862. https://doi.org/10.1007/s10147-013-0643-5

    Article  PubMed  Google Scholar 

  10. Aft R, Chavez-MacGregor M, Trinkaus K, Naughton M, Weilbaeche rK. Effect of zoledronic acid on bone loss in women undergoing chemotherapy for breast cancer. https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01457365/full.

  11. Trinkaus M, Simmons C, Myers J, Dranatisaris G, Clemons M (2010) Skeletal-related events (SREs) in breast cancer patients with bone metastases treated in the nontrial setting. Support Care Cancer 18(2):197–203. https://doi.org/10.1007/s00520-009-0645-z

    Article  PubMed  Google Scholar 

  12. Domchek SM, Younger J, Finkelstein DM, Seiden MV (2000) Predictors of skeletal complications patients with breast carcinoma. Cancer 89(2):363–368. https://doi.org/10.1002/1097-0142(20000715)89:2<363:AID-CNCR22>3.0.CO;2-3

    Article  CAS  PubMed  Google Scholar 

  13. Stopeck AT, Lipton A, Body JJ et al (2010) Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: A randomized, double-blind study. J Clin Oncol 28(35):5132–5139. https://doi.org/10.1200/JCO.2010.29.7101

    Article  CAS  PubMed  Google Scholar 

  14. Zheng Z, Chen L, Lee J-H, Royce M, Schroeder T, Lee DY (2018) Racial/ethnic disparities in skeletal-related events among women treated with bisphosphonate therapy for bone metastasis secondary to breast cancer. J Clin Oncol. 36(15):e13092–e13092. https://doi.org/10.1200/jco.2018.36.15_suppl.e13092

    Article  Google Scholar 

  15. Jayasekera J, Onukwugha E, Bikov K, Hussain A (2015) Racial variation in the clinical and economic burden of skeletal-related events among elderly men with stage IV metastatic prostate cancer. Expert Rev Pharmacoeconomics Outcomes Res 15(3):471–485. https://doi.org/10.1586/14737167.2015.1024662

    Article  Google Scholar 

  16. Cauley JA, Lui LY, Ensrud KE et al (2005) Bone mineral density and the risk of incident non-spinal fractures in black and white women. J Am Med Assoc 293(17):2102–2108. https://doi.org/10.1001/jama.293.17.2102

    Article  CAS  Google Scholar 

  17. Rose DP, Gracheck PJ, Davis LV (2015) The interactions of obesity, inflammation and insulin resistance in breast cancer. Cancers (Basel) 7(4):2134–2168. https://doi.org/10.3390/cancers7040883

    Article  CAS  Google Scholar 

  18. da Silva GT, Bergmann A, Thuler LCS (2016) Skeletal related events in patients with bone metastasis arising from non-small cell lung cancer. Support Care Cancer 24(2):731–736. https://doi.org/10.1007/s00520-015-2835-1

    Article  PubMed  Google Scholar 

  19. Sun JM, Ahn JS, Lee S et al (2011) Predictors of skeletal-related events in non-small cell lung cancer patients with bone metastases. Lung Cancer 71(1):89–93. https://doi.org/10.1016/j.lungcan.2010.04.003

    Article  PubMed  Google Scholar 

  20. Owari T, Miyake M, Nakai Y et al (2018) Clinical Features and Risk Factors of Skeletal-Related Events in Genitourinary Cancer Patients with Bone Metastasis: A Retrospective Analysis of Prostate Cancer, Renal Cell Carcinoma, and Urothelial Carcinoma. Oncology 95(3):170–178. https://doi.org/10.1159/000489218

    Article  PubMed  Google Scholar 

  21. Savci-Heijink CD, Halfwerk H, Hooijer GKJ, Horlings HM, Wesseling J, van de Vijver MJ (2015) Retrospective analysis of metastatic behaviour of breast cancer subtypes. Breast Cancer Res Treat 150(3):547–557. https://doi.org/10.1007/s10549-015-3352-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yanae M, Fujimoto S, Tane K et al (2017) Increased risk of SSEs in bone-only metastatic breast cancer patients treated with zoledronic acid. J Bone Oncol 8:18–22. https://doi.org/10.1016/j.jbo.2017.08.004

    Article  PubMed  PubMed Central  Google Scholar 

  23. Day KC, Hiles GL, Kozminsky M et al (2017) HER2 and EGFR overexpression support metastatic progression of prostate cancer to bone. Cancer Res 77(1):74–85. https://doi.org/10.1158/0008-5472.CAN-16-1656

    Article  CAS  PubMed  Google Scholar 

  24. Izumi K, Mizokami A, Itai S et al (2012) Increases in bone turnover marker levels at an early phase after starting zoledronic acid predicts skeletal-related events in patients with prostate cancer with bone metastasis. BJU Int 109(3):394–400. https://doi.org/10.1111/j.1464-410X.2011.10192.x

    Article  CAS  PubMed  Google Scholar 

  25. Saraç F, Saygılı F (2007) Causes of high bone alkaline phosphatase. Biotechnol Biotechnol Equip 21(2):194–197. https://doi.org/10.1080/13102818.2007.10817444

    Article  Google Scholar 

  26. Nozawa M, Hara I, Matsuyama H et al (2015) Significance of baseline bone markers on disease progression and survival in hormone-sensitive prostate cancer with bone metastasis. World J Urol 33(9):1263–1268. https://doi.org/10.1007/s00345-014-1431-1

    Article  CAS  PubMed  Google Scholar 

  27. McGrath LJ, Overman RA, Reams D et al (2018) Use of bone-modifying agents among breast cancer patients with bone metastasis: Evidence from oncology practices in the us. Clin Epidemiol 10:1349–1358. https://doi.org/10.2147/CLEP.S175063

    Article  PubMed  PubMed Central  Google Scholar 

  28. USCS Data Visualizations - CDC. https://gis.cdc.gov/Cancer/USCS/DataViz.html. Accessed May 19, 2020.

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Acknowledgements

This publication is based on research using information obtained from www.projectdatasphere.org, which is maintained by Project Data Sphere. Neither Project Data Sphere nor the owner(s) of any information from the web site has contributed to, approved or is in any way responsible for the contents of this publication.

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Authors and Affiliations

  1. Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, New York, NY, USA

    Hirotaka Miyashita & Christina Cruz

  2. Mount Sinai Beth Israel Comprehensive Cancer Center, New York, NY, USA

    Stephen Malamud

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  1. Hirotaka Miyashita
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Correspondence to Hirotaka Miyashita.

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Miyashita, H., Cruz, C. & Malamud, S. Risk factors for skeletal-related events in patients with bone metastasis from breast cancer undergoing treatment with zoledronate. Breast Cancer Res Treat 182, 381–388 (2020). https://doi.org/10.1007/s10549-020-05712-4

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