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Geburtshilfe Frauenheilkd 2002; 62(12): 1175-1182
DOI: 10.1055/s-2002-36365
Originalarbeit

Georg Thieme Verlag Stuttgart · New York

Verminderte Inzidenz von Brustkrebsmetastasen bei Patientinnen mit präoperativer Hormonersatztherapie (HRT)

Reduction of Metastases in Breast Cancer-Patients Treated with Preoperative Hormone Replacement Therapy (HRT): A Retrospective Analysis in 544 WomenF. Schütz 1 , I. J. Diel 1 , 2 , M. Püschel 1 , E. F. Solomayer 1 , T. von Holst 1 , P. Sinn 3 , U. Haus 4 , R. Kohnen 4 , G. Bastert 1
  • 1Universitätsfrauenklinik Heidelberg
  • 2CGG-Klinik Mannheim
  • 3Pathologische Universitätsklinik Heidelberg
  • 4Institute for Medical Research Management and Biometrics (IMEREM), Nürnberg
Further Information

Publication History

Eingang Manuskript: 18. Juni 2002 Eingang revidiertes Manuskript: 3. Oktober 2002

Akzeptiert: 8. Oktober 2002

Publication Date:
20 December 2002 (online)

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Zusammenfassung

Einführung

Die Substitution von Östrogenen und Gestagenen ist eine weit verbreitete Prophylaxe postmenopausaler Beschwerden wie Hitzewallungen, urogenitale Atrophie, Osteoporose und kardiovaskuläre Erkrankungen. Jedoch wurde in vielen Studien eine Langzeiteinnahme dieser Hormone mit einem erhöhten Risiko einer Brustkrebserkrankung verbunden, da die Mehrheit dieser Karzinome hormonabhängig wachsen. Auf der anderen Seite haben Brustkrebspatientinnen mit einer präoperativen HRT eine verminderte Mortalität und ein längeres Überleben gegenüber den nicht-substituierten.

Material und Methode

Wir haben bei 544 Patientinnen (zwischen 45 und 60 Jahren bei der Erstdiagnose) mit und ohne einer präoperativen HRT bezüglich des Risikos einer ossären Metastasierung untersucht. 154 Patientinnen waren prämenopausal (Mittel 48,0 ± 2,7 J.), 390 postmenopausal (54,5 ± 3,5 J.), 208 von letzteren waren hormonsubstituiert (Gruppe HRT+) und 182 nicht (Gruppe HRT-). Die (HRT+)-Patientinnen nahmen Östrogene über mindestens 12 Monate (Mittel 5,5 ± 4,0 J.) ein.

Ergebnisse

Obwohl die Tumorgröße der (HRT-)-Gruppe signifikant größer war als bei der (HRT+)-Gruppe (p = 0,024) und diese ein schlechteres Grading aufwiesen, konnte kein signifikanter Unterschied bezüglich des Nodalstatus, der S-Phase und der Hormonrezeptoren festgestellt werden. Die postoperative Therapie unterschied sich bei den postmenopausalen Patientinnen nicht signifikant. Bezüglich der Knochenmetastasen zeigte die Gruppe HRT- eine signifikant (p < 0,001) höhere Inzidenz gegenüber der Gruppe HRT+ (18 gegen 2 Patientinnen im Mittel nach 1,6 Jahren). Auch pulmonale (9 : 1) und hepatische Metastasen (13 : 5) waren häufiger bei nicht hormonsubstituierten Patientinnen anzutreffen.

Diskussion

In vivo und in klinischen Bisphosphonatstudien konnte gezeigt werden, dass ein gesunder Knochenstoffwechsel eine ossäre Metastasenbildung verhindern kann. Die Inzidenz von Knochen-, Leber- und Lungenmetastasen eines Mammakarzinoms kann durch eine präoperative HRT reduziert werden. Weitere, größere Studien sollten diesen Effekt aber noch genauer untersuchen.

Abstract

Introduction

Substitution of estrogenes and progestins is the most common therapy and prophylaxis for postmenopausal discomforts like hot flushes, osteoporosis, etc. However in the majority of studies long term HRT has been associated with an slightly increased risk of breast cancer. On the other hand patients with preoperative HRT have a lower mortality and a longer overall-survival.

Material and Methods

For further investigation we examined 544 patients between 45 and 60 years at time of first diagnosis of breast cancer with and without HRT with regard to the incidence of bone metastases. 154 patients were premenopausal (mean 48.0 ± 2.7 y), 390 were postmenopausal (54.5 ± 3.5 y), 208 of them received HRT (group HRT+) and 182 patients not (group HRT-). Patients of group HRT+ received estrogenes over a minimum of 12 months (mean 5.5 ± 4.0 y).

Results

Although tumor size and grading of group HRT- were significantly higher than in group HRT+ (p = 0.024), nodal status, S-phase fraction, and hormone-receptor status showed no significant differences. Adjuvant treatment in the postmenopausal groups were also not significantly different. In regard to the incidence of metastases patients without HRT have significantly (p < 0.001) more bone metastases (18 patients of group HRT- versus 2 patients of group HRT+). Also pulmonal (9 : 1) and liver (13 : 5) metastases were significantly more frequent in patients without a preoperative HRT.

Discussion

It was shown in vivo and in clinical bisphosphonate trials that a normalization of bone metabolism is able to reduce subsequent bone metastases efficiently. We may assume that the incidence of bone metastases can be reduced by normalizing bone metabolism (soil) and lowering conditions of tumor cell seeding by HRT.

Literatur

  • 1 Flesch-Janys D, Köchel A, Koch P, Berger J, Braendle W. Prävalenz postmenopausaler Hormonsubstitution in Hamburg am Beispiel der Verordnungsdaten der AOK 1998 und TK 1999.  Geburtsh Frauenheilk. 2001;  61 996
    PubMedSearch in Google Scholar
  • 2 Watts N B. Postmenopausal osteoporosis.  Obstr Gyn Survey. 1999;  54 532-538
    PubMedSearch in Google Scholar
  • 3 Christiansen C, Christensen M S, McNair P, Hagen C, Stocklund K E. Prevention of early postmenopausal bone loss: controlled 2-year study in 315 normal females.  Transbol I Europ J Clin Invest. 1980;  10 273-279
    PubMedSearch in Google Scholar
  • 4 Delmas P D. Markers of bone turnover for monitoring treatment of osteoporosis with antiresorptive drugs.  Osteoporos Int. 2000;  11 177-187
    PubMedSearch in Google Scholar
  • 5 Barrett-Connor E, Stuenkel C A. Hormone replacement therapy (HRT) - risks and benefits.  Int J Epidemiol. 2001;  30 423-426
    CrossrefPubMedSearch in Google Scholar
  • 6 Hulley S, Grady D, Bush T. et al . Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group.  JAMA. 1998;  280 605-613
    CrossrefPubMedSearch in Google Scholar
  • 7 PEPI-Trial Writing Group . Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The postmenopausal estrogen/progestin interventions (PEPI) Trial.  JAMA. 1995;  273 199-208
    CrossrefPubMedSearch in Google Scholar
  • 8 Lenfant C. Statement on preliminary trends in the Women's Health Initiative. NHLBI Communications Office. 2001; http://www.nhlbi.nih.gov/whi/index.html. 
  • 9 Mulnard R A, Cotman C W, Kawas C, van Dyck C H, Sano M, Doody R. for the Alzheimer's disease cooperative study . Estrogen replacement therapy for treatment of mild to moderate.  JAMA. 2000;  283 1007-1015
    CrossrefPubMedSearch in Google Scholar
  • 10 Grodstein F, Newcomb P A, Stampfer M J. Postmenopausal hormone replacement therapy and the risk of colorectal cancer: a review and metaanalysis.  Am J Med. 1999;  106 574-582
    PubMedSearch in Google Scholar
  • 11 Grodstein F, Stampfer M J, Colditz G AA, Willett W C, Manson J E, Joffe M, Rosner B, Fuchs C, Hankinson S E, Hunter D J, Hennekens C H, Speizer F E. Postmenopausal hormone therapy and mortality.  N Engl J Med. 1997;  336 1769-1775
    CrossrefPubMedSearch in Google Scholar
  • 12 Lethaby A, Farquhar C, Sarkis A, Roberts H, Jepson R, Barlow D. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Oxford; The Cochrane Library 2000 Issue 4
    Search in Google Scholar
  • 13 Beckmann M W, Jap D, Kuschel B, Dall P, Lux M P, Hanstein B, Bender H G. Ovarielle Steroidhormone und Anti-Östrogene: Risiken zu und Prävention in der Karzinogenese der Mamma und des Endometriums in der Postmenopause.  Geburtsh Frauenheilk. 2000;  60 77-84
    PubMedSearch in Google Scholar
  • 14 Hale G E, Hughes C L, Cline J M. Endometrial cancer: hormonal factors, the perimenopausal “window of risk”, and isoflavones.  J Clin Endocrin Metabol. 2002;  87 3-15
    PubMedSearch in Google Scholar
  • 15 Speroff L. Postmenopausal hormone therapy into the 21st century.  Maturitas. 1997;  S3-S10
    PubMedSearch in Google Scholar
  • 16 Clinical synthesis panel on HRT.  Lancet. 1999;  354 152-155
    CrossrefPubMedSearch in Google Scholar
  • 17 Negri E, Tzonou A, Beral V, Lagiou P, Trichopoulos D, Parazzini F, Franceschi S, Booth M, La Vecchia C. Hormonal therapy for menopause and ovarian cancer in a collaborative re-analysis of European studies.  Int J Cancer. 1999;  80 848-851
    CrossrefPubMedSearch in Google Scholar
  • 18 Verheul H AM, Coelingh-Bennink H JT, Kenemans P, Atsma W J, Burger C W, Eden J A, Hammar M, Marsden J, Purdie D W. Effects of estrogens and hormone replacement therapy on breast cancer risk and on efficacy of breast cancer therapies.  Maturitas. 2000;  36 1-17
    CrossrefPubMedSearch in Google Scholar
  • 19 Clemons M, Goss P. Mechanisms of disease: estrogen and the risk of breast cancer.  N Engl J Med. 2001;  344 276-285
    CrossrefPubMedSearch in Google Scholar
  • 20 Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Estrogen-progestin replacement and risk of breast cancer.  JAMA. 2000;  284 691-694
    CrossrefPubMedSearch in Google Scholar
  • 21 Santen R J, Pinkerton J, McCartney C, Petroni G R. Risk of breast cancer with progestins in combination with estrogen as hormone replacement therapy.  J Clin Endocrinol Metab. 2001;  86 16-23
    CrossrefPubMedSearch in Google Scholar
  • 22 Hofseth L J, Raafat A M, Osuch J R, Pathak D R, Slomski C A, Haslam S Z. Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast.  J Clin Endocrin Metab. 1999;  84 4559-4565
    CrossrefPubMedSearch in Google Scholar
  • 23 Beral V, Bull D, Doll R, Key T, Peto R, Reeves G. Collaborative Group on Hormonal Factors in Breast Cancer . Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer.  Lancet. 1997;  350 1047-1059
    CrossrefPubMedSearch in Google Scholar
  • 24 Bush T L. Hormone replacement therapy and breast cancer: a qualitative review.  Obstet Gynecol. 2001;  98 498-508
    CrossrefPubMedSearch in Google Scholar
  • 25 Schairer C, Gail M, Byrne C, Rosenberg P S, Sturgeon S R, Brinton L A, Hoover R N. Estrogen replacement therapy and breast cancer survival in a large screening study.  J Nat Canc Inst. 1999;  91 264-270
    PubMedSearch in Google Scholar
  • 26 Hunt K, Vessey M, McPherson K. Mortality in a cohort of long-term users of HRT: an updated analysis.  Br J Obstet Gynaecol. 1990;  97 1080-1086
    PubMedSearch in Google Scholar
  • 27 Persson I, Yuen J, Bergkvist L, Schairer C. Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy - long-term follow-up of a Swedish cohort.  Int J Canc. 1996;  67 327-332
    CrossrefPubMedSearch in Google Scholar
  • 28 Jernström H, Frenander J, Fernö M, Olsson H. Hormone replacement therapy before breast cancer diagnosis significantly reduces the overall death rate compared with never-use among 984 breast cancer patients.  Brit J Canc. 1999;  80 1453-1458
    PubMedSearch in Google Scholar
  • 29 Nanda K, Bastian L A, Schulz K. Hormone replacement therapy and the risk of death from breast cancer: a systematic review.  Am J Obstet Gynecol. 2002;  186 325-334
    CrossrefPubMedSearch in Google Scholar
  • 30 Strickland D M, Gambrell R D, Butzin C A, Strickland K. The relationship between breast cancer survival and prior postmenopausal estrogen use.  Obstet Gynecol. 1992;  80 400-404
    PubMedSearch in Google Scholar
  • 31 Magnusson C, Holmberg L, Norden T, Lindgren A, Persson I. Prognostic characteristics in breast cancer after hormone replacement therapy.  Brest Canc Res Treat. 1996;  38 325-334
    PubMedSearch in Google Scholar
  • 32 Fowble B, Hanlon A, Freedman G, Patchefsky A, Kessler H, Nicolaou N, Hoffman J, Sigurdson E, Boraas M, Goldstein L. Postmenopausal hormone replacement therapy: effect on dagnosis and outcome in early stage invasive breast cancer treated with conservative surgery and radiation.  J Clin Oncol. 1999;  17 1680-1688
    PubMedSearch in Google Scholar
  • 33 Steinberg K K, Smith S J, Thacker S B, Stroup D F. Breast cancer risk and duration of estrogen use: the role of study design in meta-analysis.  Epidemiol. 1994;  5 415-421
    PubMedSearch in Google Scholar
  • 34 Li C I, Weiss N S, Stanford J L, Daling J R. Hormone replacement therapy in relation to risk of lobular and ductal breast carcinoma in middle-aged women.  Cancer. 2000;  88 2570-2577
    CrossrefPubMedSearch in Google Scholar
  • 35 Hunter D, Willet W. Diet, body size, and breast cancer.  Epidemiol Rev. 1993;  15 110-132
    PubMedSearch in Google Scholar
  • 36 Ursin G, Tseng C C, Paganini-Hill A, Enger S, Wan P C, Pike M C, Ross R K. Does menopausal hormone replacement therapy interact with known factors to increase risk of breast cancer?.  J Clin Oncol. 2002;  20 699-706
    CrossrefPubMedSearch in Google Scholar
  • 37 Ross R K, Paganini-Hill A, Wan P C, Pike M C. Effect of HRT on breast cancer risk: estrogen vs. estrogen plus progestin.  J Nat Canc Inst. 2000;  92 328-332
    PubMedSearch in Google Scholar
  • 38 Holli K, Isola J, Cuzick J. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy.  J Clin Oncol. 1998;  16 3115-3120
    PubMedSearch in Google Scholar
  • 39 Gapstur S M, Morrow M, Sellers T A. Hormone replacement therapy and risk of breast cancer with a favorable histology: results of the Iowa Women's Health Study.  Obstet Gynec Survey. 1999;  2091-2097
    PubMedSearch in Google Scholar
  • 40 Bonnier P, Bessenay F, Sasco A J, Beedassy B, Lejeune C, Romain S, Charpin C, Piana L, Martin P M. Impact of menopausal hormone-replacement therapy on clinical and laboratory characteristics of breast cancer.  Int J Canc. 1998;  79 278-282
    PubMedSearch in Google Scholar
  • 41 Bonnier P, Sakr R, Bessenay F, Lejeune C, Charpin C, Martin P M, Piana L. Effects of hormone replacement therapy for menopause on prognostic factors of breast cancer.  Gynecol Obstet Fertil. 2000;  28 745-753
    PubMedSearch in Google Scholar
  • 42 Aalen O O. Effects of frailty in survival analysis.  Stat Methods Med Res. 1994;  3 227-243
    PubMedSearch in Google Scholar
  • 43 Persson I, Bergkvist C, Lindgren C, Yuen J. HRT and major risk factors reproductive cancers, osteoporosis and chronic heart disease: evidence of confounding by exposure characteristics.  J Clin Epidemiol. 1997;  50 611-618
    CrossrefPubMedSearch in Google Scholar
  • 44 Schairer C, Byrne C, Keyl P M, Brinton L A, Sturgeon R, Hoover R N. Menopausal estrogen and estrogen-progestin therapy and risk of breast cancer (USA).  Cancer Cases Control. 1994;  5 491-500
    PubMedSearch in Google Scholar
  • 45 Squitieri R, Tartter P I, Ahmed S, Brower S T, Theise N D. Carcinoma of the breast in postmenopausal hormone user and nonuser control groups.  J Am Coll Surg. 1994;  178 167-170
    PubMedSearch in Google Scholar
  • 46 Bonnier P, Romain S, Giacalone P L, Laffargue F, Martin P M, Piana L. Clinical and biologic prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy.  Obstet Gynecol. 1995;  85 11-17
    CrossrefPubMedSearch in Google Scholar
  • 47 Harding C, Knox W F, Faragher E B, Baildam A, Bundred N J. Hormone replacement therapy and tumour grade in breast cancer: prospective study in screening unit.  BMJ. 1996;  312 1646-1647
    PubMedSearch in Google Scholar
  • 48 Stallard S, Litherland J C, Cordiner C M, Dobson H M, George W D, Mallon E A, Hole D. Effect of hormone replacement therapy on the pathological stage of breast cancer: population based, cross sectional study.  Brit Med J. 2000;  320 348-349
    PubMedSearch in Google Scholar
  • 49 Jones C, Ingram D, Mattes E, Hahnel R. The effect of hormone replacement therapy on prognostic indices in women with breast cancer.  Med J Aust. 1994;  161 106-110
    PubMedSearch in Google Scholar
  • 50 Lower E E, Blau R, Gazder P, Stahl D L. The effect of estrogen usage on the subsequent hormone receptor status of primary breast cancer.  Breast Canc Res Treat. 2000;  58 205-211
    PubMedSearch in Google Scholar
  • 51 Cobleigh M A, Norlock F E, Oleske D M, Starr A. Hormone replacement therapy and high S phase in breast cancer.  JAMA. 1999;  281 1528-1530
    CrossrefPubMedSearch in Google Scholar
  • 52 Pfeilschifter J, Diel I J. Osteoporosis due to cancer treatment: pathogenesis and management.  J Clin Oncol. 2000;  18 1570-1593
    PubMedSearch in Google Scholar
  • 53 Manson A E, Martin K A. Postmenopausal hormone replacement therapy.  N Engl J Med. 2001;  345 34-40
    CrossrefPubMedSearch in Google Scholar
  • 54 committee opinion A COG. Hormone replacement therapy in women with previously treated breast cancer.  Int J Gyn Obstet. 2000;  69 67-71
    PubMedSearch in Google Scholar
  • 55 Dupont W D, Page D L, Parl F F, Plummer W D, Schuyler P A, Kasami M, Jensen R A. Estrogen replacement therapy in women with a history of proliferative breast cancer.  Cancer. 1999;  85 1277-1283
    CrossrefPubMedSearch in Google Scholar
  • 56 Suriano K A, Mchale M, McLaren C E, Li K T, Re A, Disaia P J. Estrogen replacement therapy in endometrial cancer patients: a matched control study.  Obstet Gynaecol. 2001;  97 555-560
    CrossrefPubMedSearch in Google Scholar
  • 57 Vassilopoulou-Sellin R, Asmar L, Hortobagyi G N, Klein M J, McNeese M, Singletary S E, Theriault R L. Estrogen replacement therapy after localized breast cancer: clinical outcome of 319 women followed prospectively.  J Clin Oncol. 1999;  17 1482-1487
    PubMedSearch in Google Scholar
  • 58 O'Meara E S, Rossing M A, Daling J R, Elmore J G, Barlow W E, Weiss N S. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality.  J Natl Cancer Inst. 2001;  93 754-762
    CrossrefPubMedSearch in Google Scholar
  • 59 Diel I J, Kaufmann M, Costa S D, Holle R, von Minkwitz G, Solomayer E F, Bastert G. Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison to nodal status.  J Natl Cancer Inst. 1996;  88 1652-1658
    CrossrefPubMedSearch in Google Scholar
  • 60 Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich C R, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, Riethmuller G, Schlimok G. Cytokeratin positive bone marrow micrometastasis and survival of breast cancer patients with stage I and III disease.  N Engl J Med. 2000;  342 525-533
    CrossrefPubMedSearch in Google Scholar
  • 61 Braun S, Kentenich C, Janni W, Hepp F, de Waal J, Willgeroth F, Sommer H, Pantel K. Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high risk breast cancer patients.  J Clin Oncol. 2000;  18 80-86
    PubMedSearch in Google Scholar
  • 62 Fischer B, Wolmark N, Redmont C. et al . Findings from NSABP-protocol No. B-04: Comparison of radical mastectomy with alternative treatments - the clinical or biologic significance of medial central breast cancer.  Cancer. 1981;  48 1863-1872
    PubMedSearch in Google Scholar
  • 63 Kanis J A, McCloskey E V, Powles T, Paterson A HG, Ashley S, Spector T. A high incidence of vertebral fracture in women with breast cancer.  J Canc. 1999;  79 1179-1181
    PubMedSearch in Google Scholar
  • 64 Diel I J. Antitumor effects of bisphosphonates.  Drugs. 2000;  59 391-399
    PubMedSearch in Google Scholar
  • 65 Diel I J, Solomayer E F, Costa S D, Gollan C, Goerner R, Wallwiener D, Kauffmann M, Bastert G. Reduction in new metastases in breast cancer with adjuvant clodronate treatment.  N Engl J Med. 1998;  339 357-363
    CrossrefPubMedSearch in Google Scholar
  • 66 Abdaimi K, Dion N, Papavasiliou V, Cardinal P E, Binderup L, Goltzmann D, Ste-Marie L G, Kremer R. The vitamin D analogue EB 1089 prevents skeletal metastasis and prolongs survival time in nude mice transplanted with human breast cancer cells.  Cancer Research. 2000;  60 4412-4418
    PubMedSearch in Google Scholar
  • 67 Marcus R. New perspectives on the skeletal role of estrogen.  J Clin Endocrin Metab. 1998;  83 2236-2238
    PubMedSearch in Google Scholar

Dr. med. Florian Schütz

Universitätsfrauenklinik Heidelberg

Voss-Straße 9

69115 Heidelberg

Email: florian_schuetz@med.uni-heidelberg.de