ESTROGEN RECEPTOR KAO MEHANIZAM REZISTENCIJE NA TRASTUZUMAB
Sažetak
HER2 pozitivi hormonosenzitivni (HER2+/HR+) karcinomi se od nedavno izdvajaju kao poseban entitet. Postoji pretpostavka da povišena ekspresija i/ili aktivnost estrogen receptora (ER) može predstavljati mehanizam izbegavanja ili alternativni put koji dovodi do rezistencije na anti HER2 terapiju.
Ispitati ishod bolesti kao stopu kliničke koristi (CCR-Clinical benefit rate), vreme do progresije bolesti (PFS) i ukupno preživljavanje (OS) kako u celoj grupi pacijenata sa HER2 pozitivnim metastatskim karcinomom dojke lečenih sistemskom primenom trastuzumaba uz hemioterapiju tako i izmedju pacijenata sa različitim statusom hormonskih receptora HR+/HER2+ (ER+ i/ili PR+/HER2+) u odnosu na HR-/HER2+ (ER-/PR-/HER2+).
Studijom je obuhvaćen 121 pacijent sa patohistološki verifikovanim HER2+ metastatskim karcinomom dojke koji su lečeni tokom 2017. godine primenom trastuzumaba sa hemioterapijom i praćeni sve do juna 2020.g
Prosečna starost bolesnica bila je 55,45±9,83 godine. HR pozitivno je bilo 53.7% pacijentkinja, a HR- 46.3% pacijenktinja.Vreme do progresije bolesti se statistički značajno razlikuje u odnosu na status HR. Pacijenti sa HR- imaju duži PFS u odnosu na pacijente sa HR+ (15 meseci vs 8 meseci). Pacijenti sa HR- tumorima imaju za 62% niži rizik od progresije bolesti u odnosu na HR+ tumore (HR 0.382; 95%CI 0.261-0.558, p<0.001). Ukupno preživaljavanje se statistički značajno razlikuje u odnosu na status HR (p=0,034). Pacijenti sa HR- imaju duže preživaljavanje u odnosu na pacijente sa HR+ (43 meseci vs 35 meseci). Hormononesenzitivni imaju za 43% manji rizik od smrti u odnosu na hormonosenzitivne tumore (HR 0.576;95%CI 0.342-0.972, p=0.039).
S obzirom da HR+/HER2 – tumori imaju lošiji ishod lečenja trastuzumabom buduća klinička ispitivanja bi trebalo da budu usmerena nakombinaciju hormonoterapije i anti HER2 terapije kod ovog podtipa karcinoma.
Reference
Arpino G, Gutierrez C, Weiss H, Rimawi M, Massarweh S, Bharwani L, et al. Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst 2007;99(9):694-705. [CrossRef][PubMed]
Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012;379:633-40. [CrossRef][PubMed]
Baselga J. Herceptin alone or in combination with chemotherapy in the treatment of HER2-positive metastatic breast cancer: Pivotal trials. Oncology 2001;61:14-21. [CrossRef][PubMed]
Bonotto M, Gerratana L, Poletto E, Driol P, Giangreco M, Russo S, et al. Measures of Outcome in Metastatic Breast Cancer: Insights From a Real-World Scenario. The Oncologist 2014;19:608-15. [CrossRef][PubMed]
Brufsky A, Lembersky B, Schiffman K, Lieberman G, Paton V. Hormone Receptor Status Does Not Affect the Clinical Benefit of Trastuzumab Therapy for Patients with Metastatic Breast Cancer. Clin Breast Cancer 2005;6(3):247-52. [CrossRef][PubMed]
Chung A, Cui X, William Audeh, Giuliano A. Current status of anti-her2 therapies: predicting and over-coming herceptin resistance. Clin Breast Cancer 2013; 13(4):223-32. [CrossRef][PubMed]
Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, et al. Multinational study of the efficacy and safety of humanized anti-HER2 mono-clonal antibody in women who have HER2-overex-pressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999;17:2639-48. [CrossRef][PubMed]
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R. et al. New response evaluation criteria in solid tumours:Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. [CrossRef][PubMed]
Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multi-centre, open-label, phase 2 trial. Lancet Oncol 2012; 13:25-32. [CrossRef][PubMed]
Giuliano M, Hu H, Wang YC Fu X, Nardone A, Herrera S, et al. Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with anti-HER2 therapy. Clin Cancer Res 2015;21:3995-4003. [CrossRef][PubMed]
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61:69-90. [CrossRef][PubMed]
Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, et al. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res 2009;69:6871-8. [CrossRef][PubMed]
Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, et al. Randomized Phase II Trial of the Efficacy and Safety of Trastuzumab Combined With Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer Administered As First-Line Treatment: The M77001 Study Group. J Clin Oncology 2005;23(19): 4265-74. [CrossRef][PubMed]
Montemurro F, Di Cosimo S, Arpino G. Human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive breast cancer: new insights into molecular interactions and clinical impli-cations. Ann of Oncol 2013;24:2715-24. [CrossRef][PubMed]
Montemurro F, Rossi V, Rocca MC, Martinello R, Verri E, Redana S, et al. Hormone-Receptor Expression and Activity of Trastuzumab With Chemotherapy in HER2-Positive Advanced Breast Cancer Patients. Cancer 2012;118(1):17-26. [CrossRef][PubMed]
Munzone E, Curigliano G, Rocca A, Bonizzi G, Renne G, Goldhirsch A, et al. Reverting estrogen-receptor-negative phenotype in HER-2 overexpressing advan-ced breast cancer patients exposed to trastuzumab plus chemotherapy. Breast Cancer Res 2006;8:R4. [CrossRef][PubMed]
Nahta R, O’Regan RM. Therapeutic implications of estrogen receptor signaling in HER2-positive breast cancers. Breast Cancer Res Treat 2012;135:39-48. [CrossRef][PubMed]
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.Toxicity and response criteria of the eastern cooperative oncology group. Am J Clin Oncol 1982;5:649-55. [CrossRef][PubMed]
Rexer BN, Arteaga CL. Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit Rev Oncog 2012;17:1-16. [CrossRef][PubMed]
Rimawi MF, Wiechmann LS, Wang YC, Huang C, Migliaccio I, Wu MF, et al. Reduced dose and inter-mittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway in HER-2/neu overexpressing breast tumor xenografts. Clin Cancer Res 2011;17(6):1351-61. [CrossRef][PubMed]
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-82. [CrossRef][PubMed]
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;344:783-92. [CrossRef][PubMed]
Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, doubleblind, placebo-controlled, phase 3 study. Lancet Oncol 2013;14:461-71. [CrossRef][PubMed]
Tandon AK, Clark GM, Chamness GC, Ullrich A, McGuire WL. HER-2/neu oncogene protein and prog-nosis in breast cancer. J Clin Oncol 1989;7:1120-8. [CrossRef][PubMed]
Tripathy D, Kaufman PA, Brufsky AM, Mayer M, Yood MU, Yoo B, et al. First-line treatment patterns and clinical outcomes in patients with HER2-positive and hormone receptor-positive metastatic breast cancer from registHER. Oncologist 2013;18:501-10. [CrossRef][PubMed]
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;20:719-26. [CrossRef][PubMed]
Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, Fu X, et al. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers - role of estrogen receptor and HER2 reactiva-tion. Breast Cancer Res 2011;13(6):R121. [CrossRef][PubMed]
Xia W, Bacus S, Hegde P, Husain I, Strum J, Liu L, et al. A model of acquired autoresistance to a potent erbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci USA 2006;103:7795-800. [CrossRef][PubMed]