Vol. 146 No. 5152 (2016)
Exploring prognostic factors for HER2-positive metastatic breast cancer: a retrospective cohort study in a major Swiss hospital
- Lilian Bringolf
- Bernhard Pestalozzi
- Daniel Fink
- Konstantin Dedes
BACKGROUND: Trastuzumab (Herceptin®, Roche) has significantly improved the prognosis of patients with HER2-positive metastatic breast cancer. Some patients remain in remission for many years. However, there are no prognostic markers associated with long-term survival. This study aimed to analyse treatment patterns of HER2-positive metastatic breast cancer at a single institution and explore prognostic factors for long-term survival after HER2-targeted treatment.
PATIENTS AND METHODS: This was a retrospective cohort study of all patients with HER2-positive metastatic breast cancer receiving first-line treatment with HER2-targeted therapy between 2004 and 2014 at the University Hospital of Zurich (n = 81). Overall survival (OS) and other time-to-event endpoints were determined with Kaplan-Meier curves and clinicopathological factors predicting long-term outcome were identified by use of the log-rank test.
RESULTS: The median OS for the cohort was 5.9 years (95% confidence interval [CI] 3.5–8.3). Twenty patients (28.6%) remained in complete remission after 1 year, 11 (15.7%) after 2 years and 4 (5.7%) beyond 5 years. The median progression-free survival was 13.6 months (95% CI 9.0–18.3). The objective response rate (ORR) was 60.5% with 16 (19.8%) complete responses and 33 (40.8%) partial responses. Six (7.4%) patients had brain metastases as first site of relapse and they had a median OS of 1.9 years (95% CI 1.7–2.2 years). Thirty-four of all 81 patients (42%) had developed brain metastases by the time of death or last follow-up. Median OS after diagnosis of brain metastases was 26 months (95% CI 19.9–32.0). Only primary brain metastases were found to be a prognostic marker associated with shorter overall survival. Hormone-receptor status and presence of visceral metastases at primary diagnosis were not associated with prognosis. Only four patients (4.9%) developed some degree of left ventricular dysfunction under treatment with trastuzumab.
CONCLUSIONS: HER2-targeted treatment has improved the overall survival of patients with HER2-postive metastatic breast cancer with median OS exceeding 5 years. There are, however, no predictive markers for a long-term survival. Only the absence of primary brain metastases seems to be an indicator of a good prognosis.
Clinical trial number: SNCTP000001431
- Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–92. doi:http://dx.doi.org/10.1056/NEJM200103153441101.
- Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al.; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659–72. doi:http://dx.doi.org/10.1056/NEJMoa052306.
- Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol. 2010;28(1):92–8. doi:http://dx.doi.org/10.1200/JCO.2008.19.9844.
- Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707–12. doi:http://dx.doi.org/10.1126/science.2470152.
- Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 1989;9(3):1165–72. doi:http://dx.doi.org/10.1128/MCB.9.3.1165.
- Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer. 2004;4(5):361–70. doi:http://dx.doi.org/10.1038/nrc1360.
- Balduzzi S, Mantarro S, Guarneri V, Tagliabue L, Pistotti V, Moja L, et al. Trastuzumab-containing regimens for metastatic breast cancer. Cochrane Database Syst Rev. 2014;6(6):CD006242. doi:http://dx.doi.org/10.1002/14651858.CD006242.pub2.
- Lobbezoo DJ, van Kampen RJ, Voogd AC, Dercksen MW, van den Berkmortel F, Smilde TJ, et al. Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2-positive subtype is associated with the most favorable outcome. Breast Cancer Res Treat. 2013;141(3):507–14. doi:http://dx.doi.org/10.1007/s10549-013-2711-y.
- Ihnenfeld Arciénega I, Imesch P, Fink D, Dedes KJ. Prolonged complete remission of metastatic HER2-positive breast cancer after continuous trastuzumab treatment: a case report and review of the literature. Target Oncol. 2015;10(2):297–301. doi:http://dx.doi.org/10.1007/s11523-014-0350-9.
- Giordano SH, Temin S, Kirshner JJ, Chandarlapaty S, Crews JR, Davidson NE, et al.; American Society of Clinical Oncology. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32(19):2078–99. doi:http://dx.doi.org/10.1200/JCO.2013.54.0948.
- Beda M, Basso U, Ghiotto C, Monfardini S; M. B. When should trastuzumab be stopped after achieving complete response in HER2-positive metastatic breast cancer patients? Tumori. 2007;93(5):491–2.
- Syrios J, Dokou A, Tsavaris N. Sustained complete remission of human epidermal growth factor receptor 2-positive metastatic breast cancer in the liver during long-term trastuzumab (Herceptin) maintenance therapy in a woman: a case report. J Med Case Reports. 2010;4(1):401. doi:http://dx.doi.org/10.1186/1752-1947-4-401.
- Murthy P, Kidwell KM, Schott AF, Merajver SD, Griggs JJ, Smerage JD, et al. Clinical predictors of long-term survival in HER2-positive metastatic breast cancer. Breast Cancer Res Treat. 2016;155(3):589–95. doi:http://dx.doi.org/10.1007/s10549-016-3705-3.
- Tisman G. Inhibition of HER2/estrogen receptor cross-talk, probable relation to prolonged remission of stage IV breast cancer: a case report. Tumori. 2009;95(6):804–7.
- Lin NU, Winer EP. Brain metastases: the HER2 paradigm. Clin Cancer Res. 2007;13(6):1648–55. doi:http://dx.doi.org/10.1158/1078-0432.CCR-06-2478.
- Gullo G, Zuradelli M, Sclafani F, Santoro A, Crown J. Durable complete response following chemotherapy and trastuzumab for metastatic HER2-positive breast cancer. Ann Oncol. 2012;23(8):2204–5. doi:http://dx.doi.org/10.1093/annonc/mds221.
- Huober J, Fasching PA, Barsoum M, Petruzelka L, Wallwiener D, Thomssen C, et al. Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer – results of the eLEcTRA trial. Breast. 2012;21(1):27–33. doi:http://dx.doi.org/10.1016/j.breast.2011.07.006.
- Olson EM, Najita JS, Sohl J, Arnaout A, Burstein HJ, Winer EP, et al. Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast. 2013;22(4):525–31. doi:http://dx.doi.org/10.1016/j.breast.2012.12.006.
- Huober J, Baumann M, Rochlitz C, Aebi S, Güth U, von Moos R, et al. Trastuzumab treatment beyond progression in advanced breast cancer: patterns of care in six Swiss breast cancer centers. Oncology. 2011;81(3-4):160–6. doi:http://dx.doi.org/10.1159/000333396.
- Jackisch C, Schoenegg W, Reichert D, Welslau M, Selbach J, Harich HD, et al. Trastuzumab in advanced breast cancer--a decade of experience in Germany. BMC Cancer. 2014;14(1):924. doi:http://dx.doi.org/10.1186/1471-2407-14-924.
- Yeo B, Kotsori K, Mohammed K, Walsh G, Smith IE. Long-term outcome of HER2 positive metastatic breast cancer patients treated with first-line trastuzumab. Breast. 2015;24(6):751–7. doi:http://dx.doi.org/10.1016/j.breast.2015.09.008.
- Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, et al.; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109–19. doi:http://dx.doi.org/10.1056/NEJMoa1113216.
- Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al.; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724–34. doi:http://dx.doi.org/10.1056/NEJMoa1413513.
- Pestalozzi BC, Zahrieh D, Price KN, Holmberg SB, Lindtner J, Collins J, et al.; International Breast Cancer Study Group (IBCSG). 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:http://dx.doi.org/10.1093/annonc/mdl064.
- Pestalozzi BC, Brignoli S. Trastuzumab in CSF. J Clin Oncol. 2000;18(11):2349–51. doi:http//dx.doi/10.1200/jco.2000.18.11.2349.
- Stemmler HJ, Kahlert S, Siekiera W, Untch M, Heinrich B, Heinemann V. Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer. Breast. 2006;15(2):219–25. doi:http://dx.doi.org/10.1016/j.breast.2005.04.017.
- Dijkers EC, Oude Munnink TH, Kosterink JG, Brouwers AH, Jager PL, de Jong JR, et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther. 2010;87(5):586–92. doi:http://dx.doi.org/10.1038/clpt.2010.12.
- Gril B, Palmieri D, Bronder JL, Herring JM, Vega-Valle E, Feigenbaum L, et al. Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J Natl Cancer Inst. 2008;100(15):1092–103. doi:http://dx.doi.org/10.1093/jnci/djn216.
- Kaplan MA, Isikdogan A, Koca D, Kucukoner M, Gumusay O, Yildiz R, et al. Clinical outcomes in patients who received lapatinib plus capecitabine combination therapy for HER2-positive breast cancer with brain metastasis and a comparison of survival with those who received trastuzumab-based therapy: a study by the Anatolian Society of Medical Oncology. Breast Cancer. 2014;21(6):677–83. doi:http://dx.doi.org/10.1007/s12282-013-0441-y.
- Witzel I, Müller V, Abenhardt W, Kaufmann M, Schoenegg W, Schneeweis A, et al. Long-term tumor remission under trastuzumab treatment for HER2 positive metastatic breast cancer – results from the HER-OS patient registry. BMC Cancer. 2014;14(1):806. doi:http://dx.doi.org/10.1186/1471-2407-14-806.
- Montemurro F, Prat A, Rossi V, Valabrega G, Sperinde J, Peraldo-Neia C, et al. Potential biomarkers of long-term benefit from single-agent trastuzumab or lapatinib in HER2-positive metastatic breast cancer. Mol Oncol. 2014;8(1):20–6. doi:http://dx.doi.org/10.1016/j.molonc.2013.08.013.
- Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20(3):719–26. doi:http://dx.doi.org/10.1200/JCO.20.3.719.
- Baumann C, Castiglione-Gertsch M. Trastuzumab. Schweiz Med Forum. 2007;7:879–83.
- Brufsky AM, Mayer M, Rugo HS, Kaufman PA, Tan-Chiu E, Tripathy D, et al. Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from registHER. Clin Cancer Res. 2011;17(14):4834–43. doi:http://dx.doi.org/10.1158/1078-0432.CCR-10-2962.