Zoledronat in der adjuvanten Therapie des rezeptornegativen Mammakarzinoms – Rationale und Erfahrungen mit Einzelfallentscheidungen

S. Paepke; J. U. Blohmer; M. Warm; R. Ohlinger; M. Kiechle

doi:10.1055/s-0030-1247430

Senologie - Zeitschrift für Mammadiagnostik und -therapie, Table of Contents

Senologie - Zeitschrift für Mammadiagnostik und -therapie 2010; 7(3): 213-217
DOI: 10.1055/s-0030-1247430

Wissenschaftliche Arbeit

Zoledronat in der adjuvanten Therapie des rezeptornegativen Mammakarzinoms – Rationale und Erfahrungen mit Einzelfallentscheidungen

Zoledronic Acid in Adjuvant Therapy of Receptor Negative Early Breast Cancer -- Rationale and First Experience in Individual Therapy StrategyS. Paepke¹ , J. U. Blohmer² , M. Warm³ , R. Ohlinger⁴ , M. Kiechle¹

¹Interdisziplinäres Brustzentrum der Technischen Universität München, Klinik für Frauenheilkunde und Geburtshilfe, Roman Herzog Comprehensive Cancer Center
²Brustzentrum City im St. Gertraudenkrankenhaus Berlin Wilmersdorf
³Brustzentrum der Universitätsfrauenklinik Köln
⁴Brustzentrum der Universitätsfrauenklinik Greifswald

Abstract

Zusammenfassung

Bereits frühe Untersuchungen zeigten einen Überlebensvorteil in Subgruppen durch die Bisphosphonat-Gabe bei metastasierten Patientinnen. Beim ossär metastasierten Mammakarzinom konnte durch die monatliche Zoledronat-Gabe eine Reduktion der Mortalität um 32 % erreicht werden [1]. Der vermutete Mechanismus besteht in der Veränderung des Mikromilieus von Tumorzellen, in apoptoseinduzierenden, antiangiogenetischen und antiadhäsiven Effekten [2] [3] [4] [5] [6] [7] . Hinzu kommt, dass Zoledronat die Interaktion zwischen Tumorzelle und Knochen bzw. Knochenmark stört. Der Knochenstoffwechsel wird herunterreguliert, damit verschlechtern sich die Wachstumsbedingungen in einem Prädilektionsort der Metastasierung. All diese Effekte scheinen zunächst vom Rezeptorstatus und der Differenzierung der zugrunde liegenden Mammakarzinomerkrankung unabhängig zu sein. Beim hormonrezeptorpositiven Mammakarzinom besteht in der adjuvanten Behandlung mit Zoledronat zunehmende Datensicherheit bezüglich der Progress- und Rezidivprophylaxe unabhängig vom Menopausestatus. Obwohl Zoledronat derzeit in der adjuvanten Versorgung des Mammakarzinoms außerhalb der Zulassung eingesetzt wird, scheint diese Therapie über Studien hinaus bereits im klinischen Alltag etabliert zu sein. In der besonderen therapeutischen Situation beim triple- oder hormonrezeptornegativen Mammakarzinom mit hohem Rezidivrisiko wird zunehmend im Rahmen von Studien aber auch in einzelnen Fällen ebenfalls Zoledronat eingesetzt.

Abstract

Previous studies have already shown a survival benefit in sub groups of metastatic breast cancer treated with bisphosphonates. Zoledronate given monthly to patients with metastatic disease to the bones showed a reduction in mortality of 32 % [1]. Conceivable mechanisms include changes in the microenvironment of tumor cells, induction of apoptotic pathways, reduction of angiogenesis and cell adhesion [2] [3] [4] [5] [6] [7] . Moreover, zoledronate interferes with the interaction between tumor cells and the bone marrow microenvironment. Bone metabolism is reduced, and proliferation requirements are disrupted in a major target location of metastatic disease. All these effects seem to be independent of the estrogen receptor status or grading of the primary breast tumor. There is accumulating evidence that adjuvant treatment with zoledronate improves progression and recurrent free survival in estrogen receptor positive breast cancer independent of the menopausal status. Although the use of zoledronic acid in the adjuvant setting is still off label, it has become a major corner stone in everyday clinical practice. Moreover, also in the special situation of triple negative or estrogen receptor negative breast cancer with a high risk of recurrence, zoledronate is increasingly used both within clinical trials and in individual cases.

Schlüsselwörter

Triple negatives Mammakarzinom - Zoldronsäure - adjuvante Therapie - Falldiskussionen - Therapieempfehlung

Key words

Triple negative breast cancer - Zoldronat - adjuvant therapy - case discussion - therapy recommendation

Full Text

References

Literatur

1 Saad F. Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer. 2007; 110 1860-1867
2 Winter M C, Holen I, Coleman R E. Exploring the anti-tumour activity of bisphosphonates in early breast cancer. Cancer Treat Rev. 2008; 34 453-475
3 Santini D, Martini F, Fratto M E et al. In vivo effects of zoledronic acid on peripheral gammadelta T lymphocytes in early breast cancer patients. Cancer Immunol Immunother. 2009; 58 31-38
4 Wood J, Schnell C, Green J R. Zoledronic acid (Zometa), a potent inhibitor of bone resorption, inhibits proliferation and induces apoptosis in human endothelial cells in vitro and is anti-angiogenic in a murine growth factor implant model. In: ASCO Annual Meeting 2000, Program / Proceedings Abstracts, Vol. 19. Pp. Abstr. 2620
5 Santini D, Vincenzi B, Galluzzo S et al. Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res. 2007; 13 4482-4486
6 Senaratne S G, Pirianov G, Mansi J L et al. Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer. 2000; 82 1459-1468
7 Jagdev S P, Coleman R E, Shipman C M et al. The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer. 2001; 84 1126-1134
8 Costa L, Major P P. Effect of bisphosphonates on pain and quality of life in patients with bone metastases. Nat Clin Pract Oncol. 2009; 15 163-174
9 Diel I J, Solomayer E F, Costa S D et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med. 1998; 339 357-363
10 Diel I J, Jaschke A, Solomayer E F et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow -- a long-term follow-up. Ann Oncol. 2008; 19 2007-2011
11 Powles T, Paterson A, McCloskey E et al. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res. 2006; 8 R13
12 Saarto T, Blomqvist C, Virkkunen P et al. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol. 2001; 19 10-17
13 Gnant M, Mlineritsch B, Schippinger W et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009; 360 679-691
14 Coleman R, Bundred N, De Boer R et al. Impact of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST, ZO-FAST, and E-ZO-FAST. Poster presented at 32th SABCS, December 09–13, 2009; San Antonio, Texas USA; # 4082
15 Boissier S, Ferreras M, Peyruchaud O et al. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res. 2000; 60 2949-2954
16 Rachner T D, Singh S K, Schoppet M et al. Zoledronic acid induces apoptosis and changes the TRAIL / OPG ratio in breast cancer cells. Cancer Lett. 2010; 287 109-116
17 Hiraga T, Williams P J, Ueda A et al. Zoledronic acid inhibits visceral metastases in the 4T1 / luc mouse breast cancer model. Cancer Res. 2004; 10 4559-4567
18 Mystakidou K, Katsouda E, Parpa E et al. Randomized, open label, prospective study on the effect of zoledronic acid on the prevention of bone metastases in patients with recurrent solid tumors that did not present with bone metastases at baseline. Med Oncol. 2005; 22 195-201
19 Aft R, Naughton M, Trinkaus K et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol. 2010; 11 421-428
20 Lin Y, Park J W, Scott J et al. Zoledronic acid as adjuvant therapy for women with early stage breast cancer and disseminated tumor cells in bone marrow. J Clin Oncol. 2008; 26 559 [ASCO Annual Meeting Proceedings]; 26 (15S): 559
21 Rack B, Schindlbeck C, Strobl B et al. Efficacy of zoledronate in treating persisting isolated tumor cells in bone marrow in patients with breast cancer. A phase II pilot study. Dtsch Med Wochenschr. 2008; 133 285-289
22 Solomayer E, Gebauer G, Hirnle et al. Influence of zoledronic acid on disseminated tumor cells (DTC) in primary breast cancer patients. Cancer Research. 2009; 69 171
23 Rack B K, Schindlbeck C, Schneeweiss A et al. Persistance of circulating tumor cells (CTCs) in peripheral blood of breast cancer (BC) patients two years after primary diagnosis. J Clin Oncol. 2009; 27 (15 S) Abstr 554-Abstr554
24 Neville-Webbe H L, Rostami-Hodjegan A, Evans C A et al. Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostata cancer cells. Int J Cancer. 2005; 20: 113 364-371
25 Brubaker K D, Brown L G, Vessella R L et al. Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment. BMC Cancer. 2006; 6 15
26 Neville-Webbe H L, Evans C A, Coleman R E et al. Mechanisms of the synergistic interaction between the bisphosphonate zoledronic acid and the chemotherapy agent paclitaxel in breast cancer cells in vitro. Tumour Biol. 2006; 27 92-103
27 Ottewell P D, Woodward J K, Lefley D V et al. Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone. Mol Cancer Ther. 2009; 8 2821-2832
28 Coleman R E, Winter M C, Cameron D et al. The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer. 2010; 102 1099-1105
29 Empfehlungen der AGO, Stand 2010. http://www.agoonline.de/_download/unprotected/g_mamma_10_1_0_d_26_bisphosphonates.pdf
30 Rastogi P et al. Preoperative Chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project protocols B-18 and B-27. J Clin Oncol. 2008; 26 778-785

Dr. S. Paepke

Ltd. OA Senologie · IBZ der Technischen Universität · Roman Herzog Comprehensive Cancer Center

Ismaninger Str. 22

81675 München

Email: stefan.paepke@lrz.tum.de