Brain metastases from breast cancer: prognostic significance of HER-2 overexpression, effect of trastuzumab and cause of death

Romuald Le Scodan, Ludivine Jouanneau, Christophe Massard, Maya Gutierrez, Youlia Kirova, Pascal Cherel, Julie Gachet, Alain Labib, Emmanuelle Mouret-Fourme, Romuald Le Scodan, Ludivine Jouanneau, Christophe Massard, Maya Gutierrez, Youlia Kirova, Pascal Cherel, Julie Gachet, Alain Labib, Emmanuelle Mouret-Fourme

Abstract

Background: To access the prognostic significance of HER-2 overexpression, the effect of trastuzumab and the cause of death in patients with brain metastases (BM) from breast cancer (BC).

Methods: We analyzed the outcome of 130 patients with BM from BC who received whole-brain radiotherapy (WBRT) (without surgery or radiosurgery) between January 1998 and April 2006. Demographic data, tumor characteristics, and treatments were prospectively recorded. The impact of HER-2 overexpression and trastuzumab-based therapy on overall survival (OS) and the cause of death were evaluated.

Results: The median follow-up for the whole population was 6.25 months (mean: 9.15; range: 0.23-53). The median survival time and 1-year survival rates after BM diagnosis were 7.43 months and 35.8% (95% CI: 28-45.7) respectively. The median survival time for HER-2 negative patients (n = 78), HER-2 positive patients not treated with trastuzumab (n = 20) and HER-2 positive patients treated with trastuzumab (n = 32) were 5.9 months, 5.6 months and 19.53 months, respectively. The 1-year survival rates were 26.1%, 29.2% and 62.6% respectively, (p < 0.004). Among the 18 HER-2 positive patients treated with trastuzumab who died, 11 (61%) apparently succumbed from CNS progression, in the face of stable or responsive non-CNS disease. Trastuzumab-based therapy was associated with a 51% reduction in the risk of death (multiadjusted hazard ratio: 0.49; 95% CI, 0.29-0.83).

Conclusions: In our experience, trastuzumab-based therapy for HER-overexpressing tumors was associated with improved survival in BM BC patients. This subgroup of patients may benefit from innovative approaches, in order to obtain better intra cerebral control.

Figures

Figure 1
Figure 1
Survival curves according to HER-2 status and delivery of trastuzumab-based therapy.

References

    1. Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol. 2004;22:3608–17. doi: 10.1200/JCO.2004.01.175.
    1. Bendell JC, Domchek SM, Burstein HJ. et al.Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 2003;97:2972–7. doi: 10.1002/cncr.11436.
    1. Burstein HJ, Lieberman G, Slamon DJ, Winer EP, Klein P. Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy. Ann Oncol. 2005;16:1772–7. doi: 10.1093/annonc/mdi371.
    1. Clayton AJ, Danson S, Jolly S. et al.Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer. 2004;91:639–43.
    1. Gabos Z, Sinha R, Hanson J. et al.Prognostic Significance of Human Epidermal Growth Factor Receptor Positivity for the Development of Brain Metastasis After Newly Diagnosed Breast Cancer. J Clin Oncol. 2006;24:5658–63. doi: 10.1200/JCO.2006.07.0250.
    1. Lower EE, Glass E, Blau R, Harman S. HER-2/neu expression in primary and metastatic breast cancer. Breast Cancer Res Treat. 2009;113:301–6. doi: 10.1007/s10549-008-9931-6.
    1. Miller KD, Weathers T, Haney LG. et al.Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival. Ann Oncol. 2003;14:1072–7. doi: 10.1093/annonc/mdg300.
    1. Shmueli E, Wigler N, Inbar M. Central nervous system progression among patients with metastatic breast cancer responding to trastuzumab treatment. Eur J Cancer. 2004;40:379–82. doi: 10.1016/j.ejca.2003.09.018.
    1. Slimane K, Andre F, Delaloge S. et al.Risk factors for brain relapse in patients with metastatic breast cancer. Ann Oncol. 2004;15:1640–4. doi: 10.1093/annonc/mdh432.
    1. Fokstuen T, Wilking N, Rutqvist LE. et al.Radiation therapy in the management of brain metastases from breast cancer. Breast Cancer Res Treat. 2000;62:211–6. doi: 10.1023/A:1006486423827.
    1. Khuntia D, Brown P, Li J, Mehta MP. Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol. 2006;24:1295–304. doi: 10.1200/JCO.2005.04.6185.
    1. Lentzsch S, Reichardt P, Weber F, Budach V, Dorken B. Brain metastases in breast cancer: prognostic factors and management. Eur J Cancer. 1999;35:580–5. doi: 10.1016/S0959-8049(98)00421-3.
    1. Gaspar L, Scott C, Rotman M. et al.Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37:745–51. doi: 10.1016/S0360-3016(96)00619-0.
    1. Le Scodan R, Massard C, Mouret-Fourme E. et al.Brain metastases from breast carcinoma: validation of the radiation therapy oncology group recursive partitioning analysis classification and proposition of a new prognostic score. Int J Radiat Oncol Biol Phys. 2007;69:839–45. doi: 10.1016/j.ijrobp.2007.04.024.
    1. Lagerwaard FJ, Levendag PC, Nowak PJ. et al.Identification of prognostic factors in patients with brain metastases: a review of 1292 patients. Int J Radiat Oncol Biol Phys. 1999;43:795–803. doi: 10.1016/S0360-3016(98)00442-8.
    1. Lorenzoni J, Devriendt D, Massager N. et al.Radiosurgery for treatment of brain metastases: estimation of patient eligibility using three stratification systems. Int J Radiat Oncol Biol Phys. 2004;60:218–24. doi: 10.1016/j.ijrobp.2004.02.017.
    1. Rades D, Dunst J, Schild SE. A new scoring system to predicting the survival of patients treated with whole-brain radiotherapy for brain metastases. Strahlenther Onkol. 2008;184:251–5. doi: 10.1007/s00066-008-1831-5.
    1. Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys. 2008;70:510–4. doi: 10.1016/j.ijrobp.2007.06.074.
    1. Weltman E, Salvajoli JV, Brandt RA. et al.Radiosurgery for brain metastases: a score index for predicting prognosis. Int J Radiat Oncol Biol Phys. 2000;46:1155–61. doi: 10.1016/S0360-3016(99)00549-0.
    1. Bartsch R, Rottenfusser A, Wenzel C. et al.Trastuzumab prolongs overall survival in patients with brain metastases from Her2 positive breast cancer. J Neurooncol. 2007;85:311–7. doi: 10.1007/s11060-007-9420-5.
    1. Dawood S, Broglio K, Esteva FJ. et al.Defining prognosis for women with breast cancer and CNS metastases by HER2 status. Ann Oncol. 2008;19:1242–8. doi: 10.1093/annonc/mdn036.
    1. Eichler AF, Kuter I, Ryan P. et al.Survival in patients with brain metastases from breast cancer: the importance of HER-2 status. Cancer. 2008;112:2359–67. doi: 10.1002/cncr.23468.
    1. Kirsch DG, Ledezma CJ, Mathews CS. et al.Survival after brain metastases from breast cancer in the trastuzumab era. J Clin Oncol. 2005;23:2114–6. doi: 10.1200/JCO.2005.05.249.
    1. Melisko ME, Glantz M, Rugo HS. New challenges and opportunities in the management of brain metastases in patients with ErbB2-positive metastatic breast cancer. Nat Clin Pract Oncol. 2009;6:25–33. doi: 10.1038/ncponc1243.
    1. Park BB, Uhm JE, Cho EY. et al.Prognostic factor analysis in patients with brain metastases from breast cancer: how can we improve the treatment outcomes? Cancer Chemother Pharmacol. 2009;63:627–33. doi: 10.1007/s00280-008-0779-6.
    1. Nam BH, Kim SY, Han HS. et al.Breast cancer subtypes and survival in patients with brain metastases. Breast Cancer Res. 2008;10:R20. doi: 10.1186/bcr1870.
    1. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81. doi: 10.2307/2281868.
    1. Chang J, Clark GM, Allred DC. et al.Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor. Cancer. 2003;97:545–53. doi: 10.1002/cncr.11083.
    1. Engel J, Eckel R, Aydemir U. et al.Determinants and prognoses of locoregional and distant progression in breast cancer. Int J Radiat Oncol Biol Phys. 2003;55:1186–95. doi: 10.1016/S0360-3016(02)04476-0.
    1. Barnholtz-Sloan JS, Sloan AE, Davis FG. et al.Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol. 2004;22(14):2865–72. doi: 10.1200/JCO.2004.12.149.
    1. Gonzalez-Angulo AM, Cristofanilli M, Strom EA. et al.Central nervous system metastases in patients with high-risk breast carcinoma after multimodality treatment. Cancer. 2004;101(8):1760–6. doi: 10.1002/cncr.20530.
    1. Pestalozzi BC, Zahrieh D, Price KN. et al.Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG) Ann Oncol. 2006;17(6):935–44. doi: 10.1093/annonc/mdl064. Epub 2006 Apr 7.
    1. Church DN, Modgil R, Guglani S. et al.Extended survival in women with brain metastases from HER2 overexpressing breast cancer. Am J Clin Oncol. 2008;31(3):250–4. doi: 10.1097/COC.0b013e31815a43c4.
    1. Bendell JC, Domchek SM, Burstein HJ. et al.Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 2003;97:2972–7. doi: 10.1002/cncr.11436.
    1. Park YH, Park MJ, Ji SH. et al.Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients. Br J Cancer. 2009;100:894–900. doi: 10.1038/sj.bjc.6604941.
    1. Stemmler H-J, Schmitt M, Willems A. et al.Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs. 2007;18:23–28. doi: 10.1097/.
    1. Liang K, Lu Y, Jin W. et al.Sensitization of breast cancer cells to radiation by trastuzumab. Mol Cancer Ther. 2003;2:1113–20.
    1. Chargari C, Idrissi HR, Pierga JY, Preliminary Results of Whole Brain Radiotherapy with Concurrent Trastuzumab for Treatment of Brain Metastases in Breast Cancer Patients. Int J Radiat Oncol Biol Phys. 2010. in press .
    1. Pieńkowski T, Zielinski CC. Trastuzumab treatment in patients with breast cancer and metastatic CNS disease. Ann Oncol. 2010;21(5):917–24. doi: 10.1093/annonc/mdp353. Epub 2009 Aug 28.
    1. Lin NU, Diéras V, Paul D. et al.Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009;15:1452–9. doi: 10.1158/1078-0432.CCR-08-1080.
    1. Cassier PA, Ray-Coquard I, Sunyach MP. et al.A phase 2 trial of whole-brain radiotherapy combined with intravenous chemotherapy in patients with brain metastases from breast cancer. Cancer. 2008;113(9):2532–8. doi: 10.1002/cncr.23858.
    1. Li J, Bentzen SM, Renschler M. et al.Regression after wholebrain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol. 2007;25:1260–1266. doi: 10.1200/JCO.2006.09.2536.
    1. DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology. 1989;39:789–96.

Source: PubMed

Подписаться