Endokrine Therapie des metastasierten Mammakarzinoms

Beim HR(Hormonrezeptor)-positivem metastasierten Mammakarzinom (MBC) gilt die endokrine Therapie (ET) mit ihrem im Vergleich zur Chemotherapie günstigeren Nebenwirkungsprofil als Therapie der ersten Wahl, sofern die Tumorlast keinen unmittelbaren Einsatz eines Zytostatikums erfordert. Dabei können die einzelnen Medikamente als Monotherapie oder in Kombination mit zielgerichteten Substanzen eingesetzt werden. Vor allem kombinierte Therapieregimes sind Inhalt zahlreicher Studienkonzepte mit dem Ziel, die endokrine Säule der MBC-Therapie zu optimieren und die Behandlung mit einer beeinträchtigenden Chemotherapie hinauszuzögern. Seit kurzem stehen hier die Hemmung des PI3K/AKT/mTOR(„phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin“)-Signaltransduktionsweges sowie der CDK 4/6 („cyclin-dependent kinase 4/6“) besonders im Fokus.     

Endokrine Therapie des Mammakarzinoms

Endocrine therapy for hormone-receptor-positive breast cancer patients has changed in the last 10 years. Although tamoxifen is still of great importance, the third-generation aromatase inhibitors are asserting their value. Their preferred use as adjuvant therapy is still not clear (initial adjuvant treatment, switching, or prolonging the period of adjuvant therapy with aromatase inhibitors after 5 years of tamoxifen), but they are preferred for first-line treatment of advanced breast cancer. The antiestrogen fulvestrant has been established as second-line therapy, and new substance groups have been developed. The antigestagen lonaprisan is already being used in a phase II study.     

Therapie des metastasierten Mammakarzinoms

Zusammenfassung Die Heilungsrate beim metastasierten Mammakarzinom ist äußerst gering. Ziel der Behandlung im metastasierten Stadium ist die Symptomkontrolle bei Erreichen eines möglichst guten therapeutischen Index. Die Behandlung sollte entsprechend den publizierten Dosierungen erfolgen, zudem sollten valide Messparameter zur 2-monatlichen Wirksamkeitskontrolle vorhanden sein. Außerdem muss die Toxizität regelmäßig zyklusbezogen beurteilt werden. Für das Ansprechen bzw. Versagen einer Chemotherapie existieren bisher nur unspezifische klinische Prädiktoren wie frühe Progression nach adjuvanter Chemotherapie, reduzierter Allgemeinzustand oder Anzahl der Metastasenlokalisationen. Patientinnen mit einem negativen Steroidrezeptorstatus bzw. mit einem auf eine antiöstrogene Therapie refraktär gewordenen Tumor und langsamer Progression können in die für Monotherapien geeignete Gruppe eingeordnet werden. Patientinnen mit ausgedehnter metastatischer Erkrankung und gravierender Symptomatik oder drohendem Organversagen sollten mit einer Polychemotherapie behandelt werden. Mammakarzinome mit HER2-Überexpression können mit einer Kombination von monoklonalem humanisiertem Antikörper (Trastuzumab) und Zytostatika therapiert werden.     

State of the Art der endokrinen Therapie des metastasierten Mammakarzinoms

According to current knowledge metastatic breast cancer (MBC) is an incurable disease. Therefore, the focus of treatment is on improving quality of life and palliating symptoms besides prolonging survival. Endocrine therapy is the modality of choice for all ER- or PR-positive patients not requiring chemotherapy for rapidly progressive disease with massive symptoms. Aromatase inhibitors are the first choice in MBC for tamoxifen-naïve patients as well as for patients who have received adjuvant tamoxifen. Steroidal and nonsteroidal aromatase inhibitors can be used sequentially. The next step for the tamoxifen-naïve patient would be tamoxifen. Based on new data the antiestrogen fulvestrant is the next step in this algorithm, followed by the progestins. In the premenopausal situation a benefit from the combination of LHRH analogues and tamoxifen has been shown. Further therapy steps are extrapolated from the postmenopausal situation always in combination with ovarian suppression.     

Endokrine Therapie des Ovarialkarzinoms

Ovarian cancers express receptors for estrogens and gonadotropin-releasing hormone (GnRH) in 60% and 70% of cases, respectively. Therefore, they are candidates for endocrine treatment with tamoxifen, aromatase inhibitors (AI), and GNRH analogs. Tamoxifen and AI act by antagonizing tumoral estrogen receptors or by decreasing the estrogen plasma levels, respectively. GnRH analogs are very likely to act by binding to tumoral growth-promoting receptors for GnRH. Objective responses with endocrine treatment can be achieved in about 10% of the patients; disease stabilization occurs in 20% of cases. Major side effects have not been observed yet. All compounds have only been investigated in phase?II studies; however, it is unlikely that large phase?III studies will be performed for this indication. In heavily pretreated patients with advanced ovarian cancer-expressing receptors for estrogen or GnRH, endocrine treatment with tamoxifen, AI, and GnRH analogs is, therefore, a reasonable therapeutic strategy.     

Endokrine Therapie des Endometriumkarzinoms

Endometrial cancer originates from the endometrium which is hormone dependent. In addition, many endometrial cancers express receptors for progestagens and/or estrogens, therefore, endocrine therapy for this malignancy has been studied for many decades. High dose progestagens are the backbone of fertility sparing conservative treatment of atypical endometrial hyperplasia and of very early stages of well differentiated endometrial cancers in women wishing to preserve child bearing capability. In many studies it has been shown that adjuvant therapy with high dose progestagens after primary surgical treatment is of no benefit. In the palliative situation, when recurrent tumor and/or metastases are no longer amenable to surgery and/or radiotherapy, patients with grade 1 or 2 tumors or with expression of progesterone and/or estrogen receptors should be treated with high dose progestagens if tumor manifestations are not life-threatening. If tumors first respond to this endocrine therapy and then become resistant, a second endocrine therapy using either tamoxifen or fulvestrant (off-label use!) can be considered.     

Stadienadaptierte Therapie des Mammakarzinoms

In Germany more than 50,000 women are newly diagnosed with breast cancer each year of whom 19,000 die. The mortality is decreasing probably because of better and more consequent adjuvant and metastatic treatment rather than increasing incidence. The following article demonstrates that not only the stage of breast cancer but also prognostic and predictive factors, like hormone (estrogen, progesterone) receptor status and the her-2/ neu status, are of the utmost importance when deciding on the adjuvant and metastatic treatment. Neoadjuvant treatment should be considered if all information is available at the time of diagnosis before surgery and the decision on the adjuvant treatment can be made at that time point. Local therapy, such as surgery and radiation are absolutely necessary in the treatment of primary breast cancer. In advanced and metastatic breast cancer the pre-treatment and palliative targets are the main factors which have to be considered.     

Zielgerichtete Therapie des Mammakarzinoms

Targeted therapy based on the understanding of the molecular principles of malignant transformation and tumour heterogeneity has resulted in substantial progress in breast cancer therapy. The success of targeted therapy depends on the selection of patients. At present the hormone receptor and HER2-status are the generally accepted predictive markers of response to endocrine and anti-HER2 therapy, respectively. It is the role of pathology to assure standardization and quality control of the determination. However, simply knowing that the target exists is not optimal to tailor adjuvant therapy. Currently, newer technologies are aimed at identifying molecular signatures that characterize breast cancer patients who are most likely to respond to specific targeted therapies. So far, the available gene expression assays (RT-PCR or microarray-based) are not sufficiently validated to recommend routine use. The promotion of development and consolidation of tissue-based predictive assays is one of the primary future tasks of pathology.     

Adjuvante endokrine Therapie des Mammakarzinoms

Zusammenfassung Die endokrine Therapie ist einer der Hauptpfeiler in der adjuvanten Situation des primären rezeptorpositiven Mammakarzinoms. In der postmenopausalen Adjuvans ist Tamoxifen in zahlreichen Studien mit hohen Patientenzahlen über Jahre untersucht worden. Es ist bisher Goldstandard. Die in den letzten Jahren veröffentlichten Studienergebnisse mit Aromatasehemmern der 3. Generation in der adjuvanten Therapie haben jedoch dazu geführt, dass ein Umdenken der bisherigen Therapie mit Tamoxifen stattfinden könnte. Insbesondere die letzten veröffentlichten Ergebnisse der International Exemestane Study Group und der ATAC-Trialist Group sprechen für einen Vorteil in der sequenziellen Behandlung und in der 5-Jahres-Therapie von Beginn an mit Aromatasehemmern. Es zeigen sich Hinweise auf eine Verlängerung des krankheitsfreien Intervalls, eine Reduktion der kontralateralen Rezidive und eine Verbesserung hinsichtlich des Zeitraums des Auftretens distanter Metastasierung. Die Nachbeobachtungszeit der Studien muss abgewartet werden, bis man endgültige Aussagen über Nebenwirkungsprofile treffen kann. Die aktuellen Studienergebnisse und Konsensuserklärungen werden zusammengefasst und die daraus resultierenden Konsequenzen für die adjuvante Therapie in der derzeitigen Situation dargelegt.     

Update operative Therapie des Mammakarzinoms

Operative therapy of breast cancer has undergone decisive further development especially in the reduction of local radicality. Multistage therapy concepts mean that operations must not necessarily be carried out at the initiation of therapy. Radical mastectomy according to Halsted was the operative standard for breast cancer for a long time but nowadays, up to 70–80?% of patients receive breast-conserving surgery. Although this therapy has been preferred for decades, there is no final consensus on adequate resection margins. The strategy of axillary lymph node resection has also changed. Only a few years ago a complete axillary dissection was basically deemed necessary but nowadays, the available data on breast-conserving therapy do not recommend this, even in the case of positive sentinel node status. Neoadjuvant therapy concepts allow when necessary a further increase in breast-conservation. In other cases all reconstructive possibilities should be checked if mastectomy is indicated.     

Osteoporoserisiko nach adjuvanter Therapie des Mammakarzinoms

Breast cancer and osteoporosis are two of the most frequent diseases in Germany, affecting about 5–6 Million postmenopausal women. Estrogen may be the link between bone and the risk of breast cancer because of its potent effects on the mitotic activity of breast epithelium and on bone turnover. Depending on baseline BMD, the adjuvant therapy of premenopausal breast cancer patients can lead to a substantially increased risk of osteoporotic fracture. In postmenopausal women, the influence of chemotherapy on BMD is less pronounced. Endocrine therapy of hormone sensitive breast cancer using tamoxifene has been shown to have a protective effect on BMD. Third generation aromatase inhibitors, two non-steroid and one steroid, have recently been introduced into clinical practice. Recently, the results of the ATAC trial have demonstrated a significant increase in fracture risk for a non-steroidal preparation. The preclinical and recent clinical results of the steroid aromatase inhibitor on bone turnover show an opposite effect. Consequently, adjuvant therapy of pre- and postmenopausal women with breast cancer can lead to a significant decrease in BMD and an increased risk of osteoporotic fracture.     

Innovationen in der Therapie des Mammakarzinoms

At the 34th San Antonio Breast Cancer Symposium (December 2011) new data on the therapy of metastatic breast cancer were presented, including results which indicated a superiority of dual HER2 targeted therapy with trastuzumab and pertuzumab and the results on treatment with mTOR inhibitor everolimus and exemestan. The evidence for the use of bisphosphonates in adjuvant therapy is more heterogeneous than ever. In addition to presentation of the option to waiver an axilla dissection in certain tumor patient constellations the focus was on systemic and surgical therapy of primary breast cancer.     

4-Hydroxyandrostendion (4-OHA): ein neuer Aromatasehemmer zur Therapie des postmenopausalen,metastasierten Mammakarzinoms

Zusammenfassung 4-OHA ist ein klinisch wirksamer Aromatasehemmer, aufgrund der hohen Selektivit?t ist keine Kortikoidsubstitution erforderlich. Die Behandlung mit 4-OHA stellt bei gegenüber dem Aminoglutethmid vergleichbar therapeutischer Wirksamkeit aufgrund der deutlich geringeren Nebenwirkungen und der guten Therapieakzeptanz eine wesentliche Bereicherung der additiven Therapiema?nahmen dar.     

Sentinel-Lymphknoten-Biopsie in der Therapie des Mammakarzinoms

Axillary nodal status is one of the most important prognostic factors in primary breast cancer. The systematic axillary dissection produces a significant postoperative morbidity. For a selected group of patients the sentinel-lymph-node-biopsy is a safe and less invasive alternative. For Germany a consensus paper on this issue has recently been published. With a careful selection of patients, the use of sufficient tools for quality management and a standardized interdisciplinary cooperation of surgeons experienced in the method with colleagues from the nuclear medicine and pathology the sentinel-lymph-node-biopsy can be performed as an alternative to the complete axillary dissection level I and II in the clinical routine.     

Aromatasehemmer in der endokrinen Therapie des Mammakarzinoms

Aromatase inhibitors have replaced tamoxifen as first choice in postmenopausal women with steroid receptor-positive disease. A series of prospective randomized trials demonstrated that anastrozole, letrozole, and exemestane are superior to tamoxifen in terms of therapy response, progression-free survival, and overall survival. Recent large clinical trials have examined these therapeutic agents in the adjuvant setting. The ATAC trial demonstrated that anastrozole significantly reduces both the rates of local and distant recurrences among women with steroid receptor-positive disease in comparison to tamoxifen. Two other large clinical trials examined the sequential use of tamoxifen and letrozole and exemestane. After a median follow-up of 2.4 years, letrozole proved superior in terms of recurrences. Also, exemestane after tamoxifen leads to a significant reduction of recurrences and contralateral breast cancers. There was no difference in overall survival in both studies.     

Aromatasehemmer in der adjuvanten Therapie des Mammakarzinoms

Aromatase inhibitors are widely accepted for the endocrine therapy of breast carcinoma. By blocking the aromatase enzyme, aromatase inhibitors reduce the synthesis of estrogen and decrease the estrogen levels that account for the proliferation of hormone-sensitive breast cancer. There is a new generation of steroid (Exemestan) and nonsteroid (Anastrozol, Letrozol) aromatase inhibitors that show strong antitumor activity with an acceptable spectrum of side effects. This new generation of aromatase inhibitors is widely accepted as first- and second-line treatment options for advanced breast cancer. Although the antiestrogen tamoxifen remains the gold standard for the adjuvant treatment of hormone-responsive breast cancer, new studies predict a likely switch towards aromatase inhibitors in the near future. However, further studies and longer follow-up times of recent studies are needed. This article describes the relevance of aromatase inhibitors for the adjuvant therapy of breast cancer.