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Cardiovascular events, early discontinuation of trastuzumab, and their impact on survival

Abstract

To evaluate how often trastuzumab therapy is ended early (i.e., early discontinuation) and how cardiovascular events and early discontinuation affect survival among older women with breast cancer. A population-based cohort of female Medicare beneficiaries with stage I–III breast cancer in 2005–2009 who received trastuzumab was assembled and followed through 2011. Completed trastuzumab treatment was defined as ≥11 months of continuous trastuzumab treatments with no delay between trastuzumab treatments >45 days. We identified trastuzumab-associated cardiovascular events as those occurring within 45 days before or after the last trastuzumab treatment. Using Cox proportional hazard models, we examined the association between early discontinuation of trastuzumab and cardiovascular events on all-cause mortality. Our cohort consisted of 585 women (mean age: 71.6 years). Approximately 41 % of women discontinued trastuzumab therapy early. Patients with early discontinuation of trastuzumab were more likely to have heart failure /cardiomyopathy, atrial fibrillation, and other cardiovascular events than women who completed trastuzumab. Cardiovascular events were strongly associated with an increased risk of all-cause mortality [adjusted hazard ratio (AHR) 3.54; 95 % confidence interval (CI) 1.87 to 6.68]. Women with early discontinuation of trastuzumab had a non-significant increase in risk of all-cause mortality (AHR: 1.74; 95 % CI 0.94 to 3.23), compared to women who completed trastuzumab. Early trastuzumab discontinuation was common among older patients, and often associated with adverse cardiovascular events. Development of cardiovascular events was associated with a higher mortality risk than early trastuzumab discontinuation, implying that reducing cardiovascular complications from trastuzumab therapy could likely have a substantive impact on overall survival in this population.

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References

  1. Slamon DJ, Godolphin W, Jones LA et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(4905):707–712

    Article  CAS  PubMed  Google Scholar 

  2. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182

    Article  CAS  PubMed  Google Scholar 

  3. Gschwind A, Fischer OM, Ullrich A (2004) The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat rev Cancer 4(5):361–370

    Article  CAS  PubMed  Google Scholar 

  4. Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792

    Article  CAS  PubMed  Google Scholar 

  5. Moja L, Tagliabue L, Balduzzi S et al (2012) Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev 4:CD006243

    PubMed  Google Scholar 

  6. Pivot X, Romieu G, Debled M et al (2013) 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 14(8):741–748

    Article  CAS  PubMed  Google Scholar 

  7. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ et al (2013) 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 382(9897):1021–1028

    Article  CAS  PubMed  Google Scholar 

  8. Telli ML, Hunt SA, Carlson RW, Guardino AE (2007) Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. J Clin Oncol 25(23):3525–3533

    Article  CAS  PubMed  Google Scholar 

  9. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659–1672

    Article  CAS  PubMed  Google Scholar 

  10. Romond EH, Perez EA, Bryant J et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353(16):1673–1684

    Article  CAS  PubMed  Google Scholar 

  11. Spielmann M, Roche H, Delozier T et al (2009) Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol 27(36):6129–6134

    Article  CAS  PubMed  Google Scholar 

  12. Murray LJ, Ramakrishnan S, O’Toole L, Manifold IH, Purohit OP, Coleman RE (2010) Adjuvant trastuzumab in routine clinical practice and the impact of cardiac monitoring guidelines on treatment delivery. Breast 19(5):339–344

    Article  CAS  PubMed  Google Scholar 

  13. Webster RM, Abraham J, Palaniappan N, Caley A, Jasani B, Barrett-Lee P (2012) Exploring the use and impact of adjuvant trastuzumab for HER2-positive breast cancer patients in a large UK cancer network. Do the results of international clinical trials translate into a similar benefit for patients in South East Wales? Br J Cancer 106(1):32–38

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Montserrat M, Leveque D, Barthelemy P, Bergerat JP (2012) Duration of adjuvant trastuzumab treatment in routine practice. Anticancer Res 32(10):4585–4588

    CAS  PubMed  Google Scholar 

  15. Piotrowski G, Gawor R, Stasiak A, Gawor Z, Potemski P, Banach M (2012) Cardiac complications associated with trastuzumab in the setting of adjuvant chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2—a prospective study. Arch Med Sci 8(2):227–235

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Tarantini L, Cioffi G, Gori S et al (2012) Trastuzumab adjuvant chemotherapy and cardiotoxicity in real-world women with breast cancer. J Card Fail 18(2):113–119

    Article  CAS  PubMed  Google Scholar 

  17. Fried G, Regev T, Moskovitz M (2013) Trastuzumab-related cardiac events in the treatment of early breast cancer. Breast Cancer Res Treat 142(1):1–7

    Article  CAS  PubMed  Google Scholar 

  18. Chen J, Long JB, Hurria A, Owusu C, Steingart RM, Gross CP (2012) Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Coll Cardiol 60(24):2504–2512

    Article  CAS  PubMed  Google Scholar 

  19. SEER-Medicare Linked Database http://healthservices.cancer.gov/seermedicare/overview/. Accessed 20 Sept 2010

  20. Carlson RW (2003) NCCN breast cancer clinical practice guidelines in oncology: an update. J Natl Compr Cancer Netw 1(Suppl 1):S61–S63

    Google Scholar 

  21. Park HS, Gross CP, Makarov DV, Yu JB (2012) Immortal time bias: a frequently unrecognized threat to validity in the evaluation of postoperative radiotherapy. Int J Radiat Oncol Biol Phys 83(5):1365–1373

    Article  PubMed  Google Scholar 

  22. Suissa S (2008) Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 167(4):492–499

    Article  PubMed  Google Scholar 

  23. Elixhauser A, Steiner C, Harris DR, Coffey RM (1998) Comorbidity measures for use with administrative data. Med Care 36(1):8–27

    Article  CAS  PubMed  Google Scholar 

  24. Quan H, Sundararajan V, Halfon P et al (2005) Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care 43(11):1130–1139

    Article  PubMed  Google Scholar 

  25. Romond EH, Jeong JH, Rastogi P et al (2012) Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 30(31):3792–3799

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Suter TM, Procter M, van Veldhuisen DJ et al (2007) Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol 25(25):3859–3865

    Article  CAS  PubMed  Google Scholar 

  27. Ezaz G, Long JB, Gross GP et al (2014) Risk prediction model for heart failure and cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Heart Assoc 3:e000472

    Article  PubMed Central  PubMed  Google Scholar 

  28. Cardinale D, Colombo A, Sandri MT et al (2006) Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 114(23):2474–2481

    Article  CAS  PubMed  Google Scholar 

  29. Oliva S, Cioffi G, Frattini S et al (2012) Administration of angiotensin-converting enzyme inhibitors and beta-blockers during adjuvant trastuzumab chemotherapy for nonmetastatic breast cancer: marker of risk or cardioprotection in the real world? Oncologist 17(7):917–924

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Curigliano G, Cardinale D, Suter T et al (2012) Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann of oncol 23(Suppl 7):155–166

    Article  Google Scholar 

  31. Tsai HT, Isaacs C, Fu AZ et al (2014) Risk of cardiovascular adverse events from trastuzumab (Herceptin) in elderly persons with breast cancer: a population-based study. Breast Cancer Res Treat 144(1):163–170

    Article  CAS  PubMed  Google Scholar 

  32. Brunello A, Monfardini S, Crivellari D, et al. (2008) Multicenter analysis of activity and safety of trastuzumab plus chemotherapy in advanced breast cancer in elderly women (>70 years). J Clin Oncol 26 (Abstr 1096). http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=33834. Accessed 7 April 2011

  33. Lamont EB, Lan L (2014) Sensitivity of medicare claims data for measuring use of standard multiagent chemotherapy regimens. Med Care 52(3):e15–e20

    Article  PubMed  Google Scholar 

  34. Freedman RA, Vaz-Luis I, Barry WT, Lii H, Lin NU, Winer EP, Keating NL (2014) Patterns of chemotherapy, toxicity, and short-term outcomes for older women receiving adjuvant trastuzumab-based therapy. Breast Cancer Res Treat 145(2):491–501

    Article  CAS  PubMed  Google Scholar 

  35. Birman-Deych E, Waterman AD, Yan Y, Nilasena DS, Radford MJ, Gage BF (2005) Accuracy of ICD-9-CM codes for identifying cardiovascular and stroke risk factors. Med Care 43(5):480–485

    Article  PubMed  Google Scholar 

  36. Lee DS, Donovan L, Austin PC et al (2005) Comparison of coding of heart failure and comorbidities in administrative and clinical data for use in outcomes research. Med Care 43(2):182–188

    Article  PubMed  Google Scholar 

  37. Surveillance, Epidemiology, and End Results Program—Turning Cancer Data Into Discovery. http://seer.cancer.gov/seerstat/databases/ssf/her2-derived.html. Assessed 17 Nov 2013

  38. Maggiore RJ, Gross CP, Hurria A (2010) Polypharmacy in older adults with cancer. Oncologist 15(5):507–522

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Ramjaun A, Nassif MO, Krotneva S et al (2013) Improved targeting of cancer care for older patients: a systematic review of the utility of comprehensive geriatric assessment. J Geriatr Oncol 4(3):271–281

    Article  PubMed  Google Scholar 

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Acknowledgments

The collection of the California cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract N01-PC-35136 awarded to the Northern California Cancer Center, contract N01-PC-35139 awarded to the University of Southern California, and contract N02-PC-15105 awarded to the Public Health Institute; and the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under agreement #U55/CCR921930-02 awarded to the Public Health Institute. The authors of this report are responsible for its content. The ideas and opinions expressed herein are those of the author(s) and endorsement by the State of California, Department of Public Health the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors is not intended nor should be inferred. The authors acknowledge the efforts of the Applied Research Program, NCI; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database. The interpretation and reporting of the SEER-Medicare data are the sole responsibility of the authors. This work was funded by an American Heart Association Grant-in-Aid Award (12GRNT9580005 to J Chen).

Conflict of interest

Dr. Gross receives support from Medtronic, Inc., Johnson & Johnson, and 21st Century Oncology. Dr. Gross is also a member of a scientific advisory board for FAIR Health, Inc. These supports were not used for any portion of the current manuscript. Dr. Hurria has received research support from Celgene Corporation and GlaxoSmithKline, and consulting fees from Seattle Genetics and GTx, Inc., for work performed outside the scope of this study. None of the other coauthors have conflicts to report.

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Correspondence to Shi-Yi Wang.

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Wang, SY., Long, J.B., Hurria, A. et al. Cardiovascular events, early discontinuation of trastuzumab, and their impact on survival. Breast Cancer Res Treat 146, 411–419 (2014). https://doi.org/10.1007/s10549-014-3029-0

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