DÄ internationalArchive6/2010Recurrent Breast Cancer

Review article

Recurrent Breast Cancer

Treatment Strategies for Maintaining and Prolonging Good Quality of Life

Dtsch Arztebl Int 2010; 107(6): 85-91. DOI: 10.3238/arztebl.2010.0085

Gerber, B; Freund, M; Reimer, T

Background: Recurrent breast cancer remains a challenge for interdisciplinary treatment even though new therapeutic options are available.
Methods: The PubMed database was selectively searched for articles that appeared from 1999 to 2009 and contained the key words „breast cancer,“ „recurrence,“ „metastatic,“ „advanced,“ and „treatment“. Fur-ther sources consulted for this review included the German S3 guide-line, the treatment recommendations of the German AGO-Mamma group, the NCCN guidelines, and the Cochrane database.
Results: Locoregional recurrences are treated with curative intent. Metastatic breast cancer must be treated on an individualized basis: The treatment should be continued as long as its benefits for the individual patient outweigh its adverse side effects. Endocrine treatment is indicated for all patients whose tumors are hormone-receptor positive or of unknown receptor status and who have enough time for a response to be seen. Chemotherapy should be given if the tumor is hormone-receptor negative, if a rapid response is urgently needed, or if endocrine treatment has failed to produce a response. Combination chemotherapy improves response rates and prolongs progression-free survival, yet it does not prolong overall survival in comparison to monochemotherapy. In HER2-positive patients, first-line treatment with trastuzumab and monochemotherapy prolongs overall survival. Other treatment options include angiogenesis inhibitors, various tyrosine kinases inhibitors, radiotherapy, bisphosphonates, surgical or other ablative treatment of metastases, or a combination of these approaches, applied either simultaneously or consecutively.
Conclusions: While locoregional recurrences of breast cancer should be treated with curative intent, breast cancer with distant metastases is currently not curable. It is treated with the intention of restoring and maintaining good quality of life and relieving symptoms due to the metastases, rather than prolonging survival.
LNSLNS At present around 40% of all patients with breast cancer suffer a recurrence; most of them die from it (1, e1e3). Breast cancer thus remains the most common cause of cancer-related death in women. The risk of recurrence is highest in the first 2–3 years and then decreases continuously, although it never reaches zero (e4). Ten percent to 20% of all recurrences are isolated locoregional recurrences, while 60% to 70% are distant metastases in one “anatomical structure,” or else in multiple locations (2, e4). The incidence and location of recurrences depend on the initial tumor stage, previous therapy, tumor biology, and the sensitivity of the diagnosis (Table gif ppt) (1, 3, 4, e5, e6) (Cheang et al.: Breast cancer molecular subtypes and locoregional recurrence. J Clin Oncol [Proceedings of ASCO] 26, [May 20 Suppl; Abstr 510] 2008). This article will give a systematic overview of treatment for recurrent breast cancer.

Materials and methods
A selective literature search was carried out in the PubMed database using the search terms “breast cancer” and “recurrence,” “metastatic,” “advanced,” and “treatment” for the period from 1999 to January 2009. Contributions to international congresses on breast cancer in 2008 (ASCO, American Society of Clinical Oncology; SABCS, San Antonio Breast Cancer Symposium; ECCO, European Cancer Organisation; EBCC, European Breast Cancer Conference) were also included. The current German S3 Guidelines (5), the treatment recommendations of AGO-Mamma (the Breast Group of the German Gynecological Oncology Working Group, the Arbeitsgemeinschaft Gynäkologische Onkologie, Organgruppe Mamma) (6) and the American NCCN (National Comprehensive Cancer Network) Guidelines (7) together with the Cochrane Database (8) were also included. The statements were evaluated—if this had not already been done in the guidelines themselves—according to the Oxford -criteria (evidence level, EL) (e7) and the AGO recommendation grades (Box 1 gif ppt).

General recommendations
Since hormone-receptor expression and HER2 expression can change in the course of metastasization, determination of receptor status should always be carried out when recurrence occurs, if reasonably -possible (EL 1/A AGO-GR++) (e8). In order to detect any further metastases, a re-staging procedure is -recommended (chest radiography, bone scintigraphy and liver ultrasonography) (EL 5/D AGO-GR++), -although this has not be shown to carry any survival advantage for the patient.

Locoregional recurrence
Local disease recurrence (Box 2 gif ppt) is generally treated curatively (9). In some cases it can be difficult to distinguish between a locoregional recurrence and an ipsilateral second tumor. Features suggesting a second tumor—which like primary breast cancer should be treated curatively—are:

• A long interval of time since the first tumor
• A different location in the breast
• Different tumor biology (hormone-receptor status, HER2-receptor status, tumor grade).

Five-year overall survival after an isolated chest wall recurrence is 68%; after intra-breast recurrence it is 81% (e4). Operable breast, chest wall, and axillary recurrences should be excised with tumor-free margins (EL 2b/A; AGO-GR++). For intra-breast recurrence, mastectomy is regarded as the standard treatment, although in some cases repeat breast-preserving surgery and interstitial radiotherapy may be undertaken (EL 3/C; AGO-GR+/–). The rate of repeat intra-breast recurrence is higher after such treatment (e9), but the significance of this for overall survival is unclear (6). Patients who have not yet received radiotherapy should be offered it (EL 2b/B; AGO-GR+).

Antihormonal therapy after R0 resection of a locoregional recurrence with M0 status has prolonged the interval until a repeat recurrence, but without improving overall survival (EL 5/D; AGO-GR++) (10). No valid study results are available for chemotherapy or trastuzumab therapy after R0 resection of a local recurrence, so that these cannot be definitely recommended at present (EL 3b/C; AGO-GR+/–) (e10, e11). The exception to this is in HER2-positive patients who have not yet received anti-HER2-treatment (trastuzumab or lapatinib); in this group anti-HER2-treatment (trastuzumab or lapatinib) can be recommended (EL 5/D; AGO-GR+).

In patients with R1-resection in whom further resection is not possible, and in other cases of locoregional recurrences (lymph nodes, skin), chemotherapy, monoclonal antibody therapy, radiotherapy (EL 2/B; AGO-GR++) and combinations of these (e.g., simultaneous radiochemotherapy, EL 3b/C; AGO-GR+) may be considered (e12, e13). In patients with M1 status and/or inoperable local recurrence, decisions about palliative surgery must be made on an individual basis (e.g., where there is ulceration, unpleasant odor, or pain) (EL 5/D; AGO-GR+/–) (6).

Metastatic breast cancer
Treatment goals
Because metastastic breast cancer is not curable, the primary goals of therapy are restoration of quality of life, reduction of tumor-related symptoms, and maintenance of the patient’s social environment; prolonging life is secondary to these (EL 1a/A; AGO-GR++). The possibility of increasing the overall survival of patients with metastastic breast cancer has been the subject of debate in recent years (e14). However, prospective and retrospective studies show that the treatment options available at present do improve overall survival (EL 2a) (e15). The median survival of patients with metastastic breast cancer is currently given as 20 to 28 months; it depends heavily on the nature of the metastases and the tumor biology (11, 12, e16e18).

Treatment monitoring
To monitor the efficacy of antitumor treatment, a “marker lesion” is chosen. This should be monitored with the simplest method of examination—palpation, ultrasonography, or tumor marker evolution (if raised; CA15–3, CEA, or CA-27–29; HER-2 shed antigen, ECD. Tumor response is “objectified” according to the RECIST criteria (response evaluation criteria in solid tumors), whereby the longest diameter of the target lesion that can be best visualized is monitored over time—depending on the clinical situation, every 2 to 3 months (e19). Side effects must be recognized before they become clinically manifest (e.g., using echocardiography during trastuzumab therapy) (e20).

Available treatments
Currently licensed treatment options have been greatly expanded in recent years (Box 3 gif ppt). In the choice of therapy, previous treatments, comorbidities, side effects, and also the expectations and wishes of the patient must all be taken into account (EL 1c/A; AGO-GR++). More significant than the patient’s actual age is the function of her individual organs (bone marrow, kidneys, liver, heart). Dosages should follow those of the trials on which the licensing was based (EL 1c/A; AGO-GR++). All patients should be offered the chance to participate in clinical studies (AGO-GR++).

Primary metastatic breast cancer
The prognosis of primary metastatic breast cancer depends on the location of the metastases, but is generally regarded as poorer than that of secondary metastatic tumors (EL 4/C). In primary metastatic breast cancer, resection with tumor-free margins (tumorectomy, mastectomy) improves 5-year overall survival by 40% to 50% (13, e21, e22). The role of axillary surgery is unclear.

Endocrine (antihormonal) treatment
Today, endocrine treatment is the first line of therapy for all patients with metastatic breast cancer and positive or unknown hormone receptor status whose disease is not at a life-threatening stage (EL 1a/A; AGO-GR++). A delay of 10 to 12 weeks must be allowed for before the endocrine treatment will start to take effect. Extensive visceral metastases, CNS metastases and/or an urgent need for remission (pain) are reasons not to undertake endocrine treatment. Concurrent chemoendocrine therapy (EL 1b/A; AGO-GR– –) must be avoided, as this is no more effective than the separate therapies but has more side effects (14). Endocrine maintenance therapy following a response to chemotherapy improves not only disease-free survival but also overall survival (EL 3/C; AGO-GR++) (e23).

HER2-positive metastatic breast cancer
HER2 status is not in itself a decision criterion for or against endocrine treatment. All endocrine therapies are less effective when there is overexpression of HER2 than when there is not (15). Compared to anastrozole treatment alone the combination of anastrozole with trastuzumab significantly improved the remission rate (20% versus 7%) and the progression-free interval (5 versus 2 months) (EL 2b/B; AGO-GR+/–) (16).

Compared with an aromatase inhibitor alone, in patients not previously treated with trastuzumab, letrozole combined with the dual tyrosine kinase (HER2, EGFR) inactivator lapatinib showed a significantly higher remission rate (15% versus 28%) and a longer progression-free interval (3 versus 8 months; EL 2b/B; AGO-GR+/–) (17).

Nevertheless, the combination of chemotherapy with trastuzumab remains the standard for all HER2--positive patients. Combinations of hormone therapy and trastuzumab should only be considered for selected patients (e.g., with comorbidities or in whom chemotherapy is contraindicated).

HER2-negative metastatic breast cancer
For premenopausal women, the standard treatment is suppression of ovarian function combined with a second endocrine treatment step (aromatase inhibitor, fulvestrant) by analogy to postmenopausal patients (e24e26). Endocrine treatment in postmenopausal patients with metastatic breast cancer depends on which treatment was previously given, and for how long. At present, there are four clinical situations (Box 4 gif ppt). After treatment with tamoxifen, aromatase inhibitors, and fulvestrant, gestagens (medroxyprogesterone acetate, megestrol acetate), with their anabolic, analgesic, and euphorizing side effects, show positive effects in patients in the final stage of the disease. Otherwise, endocrine treatment starts again from the beginning (EL 5/D; AGO-GR+).

Chemotherapy and targeted therapy
There are no real predictors of responsiveness to chemotherapy. If chemotherapy is indicated (Box 5 gif ppt), it should be continued so long as the therapeutic index is favorable, i.e., so long as the benefit is greater than the side effects (EL 2b/B; AGO-GR+). Disease progression and untreatable side effects are signs that warrant treatment cessation (EL 1c/A; AGO-GR++).

Mono- versus polychemotherapy
A meta-analysis from 1996 that covered 996 patients and two randomized studies (docetaxel, D, versus docetaxel+capecitabine, DC; paclitaxel, P, versus paclitaxel+gemcitabine, PG) compared monochemotherapies to combination chemotherapies (e27e29). This showed the combination to be superior to the monotherapy in respect of response (D versus DC: 30% versus 42%; P versus PG: 26% versus 41%), progression-free interval (4 versus 6 months in both cases), and overall survival (D versus DC: 12 versus 15 months; P versus PG: 16 versus 19 months). However, the combination treatments also led to significantly more side effects. These studies did not address the question of sequential administration of the individual substances. In a multicenter three-arm study, 739 patients were randomized to receive doxorubicin, paclitaxel, or both (A, P, AP) (18). When progression occurred, the patients in the monotherapy arms were treated with the substance they had not received so far. The combination gave rise to higher remission rates (A 34%, P 36%, AP 47%) and a longer progression-free -interval (A 6 months, P 6 months, AP 8 months), though toxicity was also higher. There were no significant differences in total survival in the three arms (A 19 months, P 22 months, AP 22 months). At present there are few indications that justify combination chemotherapy, especially since there is no guarantee of a survival advantage in comparison to sequential monotherapy with the same substances (e30).

HER2-negative metastatic breast cancer
The first-line treatment with the highest recommendation grade for previously untreated metastatic breast cancer is anthracyclines and taxanes (EL 1b/A; AGO-GR++) (6). Docetaxel appears to be better when given at 3-weekly intervals and paclitaxel at weekly intervals (6, 19, e31, e32). Many patients have already received anthracyclines and taxanes as adjuvant treatment. If there has been a long period (more than 2 to 3 years) between the adjuvant treatment and metastatic recurrence, it is certainly acceptable to give a taxane or anthracycline. To reduce the risk of cumulative cardiotoxicity, in this situation the liposomal encapsulation of doxorubicin or epidoxorubicin can be used (EL 1b/A; AGO-GR++). When the patient has been previously treated with anthracyclines, taxanes are indicated (EL 1a/A; AGO-GR++); after previous treatment with anthracyclines and taxanes, capecitabine (EL 2b/B; AGO-GR++), vinorelbine, nab-paclitaxel (nanoparticle-albumin-bound paclitaxel, licensed in the USA), and PEG-liposomal doxorubicin are indicated (EL 2b/B; AGO-GR+). Vinorelbine is indicated above all when there are contraindications to treatment with taxanes (e.g., impaired liver function). Cytostatics not licensed in Germany are nab-paclitaxel and ixabepilone (e33e35) (licensed in the USA; EMEA, the European Medicines Agency, did not approve its licensing in 2008). Ixabepilone works via inhibition of the microtubule system, without the occurrence of cross-resistance with taxanes (e36e38). For off-label use of ixabepilone, neuropathy and the therapeutic index must be monitored. Neither of these substances requires a solubilizer, so premedication is unnecessary. If polychemotherapy is indicated, anthracycline–taxane combinations are recommended in patients not previously treated with anthracycline (EL 1b/A; AGO-GR++), and combinations of taxanes with capecitabine (EL 2b/B; AGO-GR+) or gemcitabine (EL 2b/B; AGO-GR++) in patients who have previously received -anthracyclines (e28, e29).

Vascularization is a necessary part of metastasization. To that extent, inhibition of angiogenesis using the VEGF-specific antibody bevacizumab is a logical therapeutic approach. As first-line treatment in HER2-negative patients, bevacizumab in combination with docetaxel (D, once every 3 weeks) or paclitaxel (P, once a week) led to significantly higher remission rates (D: 63% versus 44%, P: 28% versus 14%) and an increase in progression-free survival (D: 1 month, P: 5 months), although overall survival was not affected (EL 1b/B; AGO-GR+) (20) (Miles et al.: Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer [mBC]: AVADO. Proc Am Soc Clin Oncol 26, abstr. LBA1011. 2008).

The efficacy and side effects of bevacizumab depend on its early use and individual VEGF genotypes (e62). Bevacizumab is licensed for use in combination with taxanes for first-line treatment of HER2-negative metastatic breast cancer.

HER2-positive metastatic breast cancer
Patients who overexpress HER2 benefit from early use of the monoclonal antibody trastuzumab in combination with docetaxel or paclitaxel, with a significant increase in median overall survival (D: 23 versus 31 months, P: 20 versus 25 months; EL 1b/A; AGO-GR++) (21, e40). For this reason, trastuzumab in combination with a cytostatic should be offered as first-line therapy to all patients, with the exception of older patients and those with cardiac morbidity (EL 1b/A; AGO-GR++). Monitoring of heart function is obligatory during trastuzumab therapy. If progression occurs during trastuzumab treatment (± taxane), the present recommendation is to switch to lapatinib+capecitabine (EL 1c/B; AGO-GR+), since the combination of lapatinib+capecitabine is significantly better than chemotherapy alone in terms of tumor response (29% versus 16%) and progression-free survival (37 versus 20 weeks) (e41, e42). Lapatinib (± capecitabine) seems to be effective in the treatment of radiotherapy-resistant brain metastases (EL 2b/B; AGO-GR+/–) (e43). In patients with metastatic breast cancer not previously treated with trastuzumab, the combination of lapatinib+paclitaxel (EL 2b/B; AGO-GR+/–) led to a significant improvement in clinical benefit (69% versus 40%) and progression-free survival (36 versus 25 months) compared to chemotherapy alone, and median overall survival was also increased (105 versus 82 months) (22). Prospective studies on continuing trastuzumab when disease progression occurs during trastuzumab therapy in combination with chemotherapy showed that continuing the antibody treatment and changing the chemotherapy had a significant advantage over chemotherapy alone, leading to a treatment response of 49% versus 25% for the combination (e44). Continuing trastuzumab therapy when disease progression occurs and changing the chemotherapy (EL 2b/B; AGO-GR+) represents an alternative to lapatinib+chemotherapy. Clinical trials are now ongoing into another HER2 monoclonal antibody, pertuzumab (e45).

Bisphosphonates
Bisphosphonates (BPs) are indicated in all patients with bone metastases (EL 1a/A; AGO-GR++). By inhibiting osteoclast activity, BPs lead to bone stabilization, a reduction in serum calcium concentration, and avoidance of skeletal complications (23, e46e51). BPs are given in combination with antitumor therapy and should continue to be given after disease progression (EL 5/D; AGO-GR++). The oral and intravenous routes are equally effective (23, e49e52). Osteonecrosis of the jaw during intravenous administration (EL 2b) can be avoided if dental cleaning and restoration is carried out first, or by oral administration (EL 4/C; AGO-GR+). More recent data suggest that BPs have direct antitumoral and bone-protective effects (EL 1b/A; AGO-GR+) (24). Denusomab (not yet licensed), a subcutaneously administered anti-RANKL (receptor activator of nuclear factor kappaB ligand) antibody, showed a positive effect on bone metabolism with fewer side effects than BP (e53).

Radiotherapy
Irradiation of symptomatic bone metastases leads to an improvement in pain symptoms, in mobility and function, local stabilization, and reduced risk of bone fracture (EL 1a/B; AGO-GR++).

However, in cases where there is spinal compression or risk of fracture, the combination of surgery followed by radiotherapy is superior to radiotherapy alone (EL 3b/C; AGO-GR++) (e54). For this reason, before radiotherapy is started, the question of whether operative stabilization is required should be clarified at a multidisciplinary case conference (e55).

In cases of “small” CNS oligometastases or where there are metastases in an unfavorable (inoperable) location, MRI-guided stereotactic single irradiation (“radiosurgery”) or fractionated irradiation should be carried out (EL 2b/B; AGO-GR++) (e56). After surgery on CNS metastases, percutaneous irradiation of the entire cranium improves local control and overall survival (EL 2b/B; AGO-GR++). Where there are multiple CNS metastases, irradiation of the entire cranium accompanied by antiedema therapy (glucocorticoids) (EL 1a/A; AGO-GR++) or simultaneous radiochemotherapy (temozolomide, topotecan) is an option (EL 3b/C; AGO-GR+/–). For the treatment of skin, lymph node, plexus, and spinal canal metastases, irradiation with or without combined chemotherapy (EL 4/D; AGO-GR+/–) is effective (e12).

Operative/ablative treatment
For patients with “small” oligometastases who are in good general condition and have had a long progression-free interval, operative or ablative procedures (RFA, LITT, cryotherapy) are therapeutic options (EL 3b/C; AGO-GR+/–) that should be carefully weighed in each individual case (e57e59). It should be pointed out that these results come from case series with highly selected patients. In addition, the effect of growth factors on tumor cells after major invasive procedures is unclear (e60).

Other treatment options
At present there are no recommendations for regional chemotherapy or the use of hyperthermia (EL 3b/C; AGO-GR–). The treatment of choice for pleural effusion is pleurodesis with talcum and VATS (video-assisted thoracic surgery) (EL 1b/B; AGO-GR++) (25, e61).

Future prospects
In the present authors’ view, metastatic breast cancer will remain a great challenge for physicians and researchers. Although long-term remissions are possible in individual cases today, no treatment will be available in the foreseeable future that can claim to be curative. For this reason the main aim of current treatment for metastatic breast cancer continues to be, as the authors said at the beginning, to restore and maintain quality of life by the alleviation of symptoms caused by metastases.

Conflict of interest statement
Professor Gerber has received lecture fees and reimbursement of travel expenses from Astra Zeneca, Pfizer, Novartis, Roche, GSK, and Sanofi-Aventis.
Dr. Reimer has received lecture fees and reimbursement of travel expenses from Novartis, Astra Zeneca, Pfizer, Sanofi-Aventis, and Roche.
Professor Freund has received lecture fees and reimbursement of travel expenses from Hoffmann-La Roche, Novartis, Janssen-Cilag, Astra Zeneca, Mundipharma, and Bristol-Myers Squibb.

Manuscript received on 12 January 2009, revised version accepted on
17 June 2009.

Translated from the original German by Kersti Wagstaff, MA.


Corresponding author
Prof. Dr. med. Bernd Gerber
Universitäts-Frauenklinik Rostock
Südring 81
18059 Rostock, Germany
bernd.gerber@med.uni-rostock.de

@For e-references please refer to:
www.aerzteblatt-international.de/ref0610
1.
Jemal A, Thun MJ, Ries LA, et al.: Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 2008; 100: 1672–94 MEDLINE
2.
Kamby C, Vejborg I, Kristensen B, Olsen LO, Mouridsen HT: Metastatic pattern in recurrent breast cancer. Special reference to intrathoracic recurrences. Cancer 1988; 62: 2226–33 MEDLINE
3.
Rhee J, Han SW, Oh DY, et al.: The clinicopathologic characteristics and prognostic significance of triple-negativity in node-negative breast cancer. BMC Cancer 2008; 8: 307 MEDLINE
4.
Kamby C, Ejlertsen B, Andersen J, et al.: The pattern of metastases in human breast cancer. Influence of systemic adjuvant therapy and impact on survival. Acta Oncol 1988; 27: 715–9 MEDLINE
7.
NCCN (National Comprehensive Cancer Network): NCCN Practice Guidelines in Oncology: Breast Cancer 2009
9.
Wapnir IL, Anderson SJ, Mamounas EP, et al.: Prognosis after ipsilater-al breast tumor recurrence and locoregional recurrences in five National Surgical Adjuvant Breast and Bowel Project node-positive adjuvant breast cancer trials. J Clin Oncol 2006; 24: 2028–37 MEDLINE
10.
Waeber M, Castiglione-Gertsch M, Dietrich D, et al.: Adjuvant therapy after excision and radiation of isolated postmastectomy locoregional breast cancer recurrence: definitive results of a phase III randomized trial (SAKK 23/82) comparing tamoxifen with observation. Ann Oncol 2003; 14: 1215–21 MEDLINE
11.
Mauri D, Polyzos NP, Salanti G, Pavlidis N, Ioannidis JP: Multiple-treatments meta-analysis of chemotherapy and targeted therapies in advanced breast cancer. J Natl Cancer Inst 2008; 17: 1780–91 MEDLINE
12.
Gennari A, Conte P, Rosso R, Orlandini C, Bruzzi P: Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies. Cancer 2005; 104: 1742–50 MEDLINE
13.
Ruiterkamp J, Ernst MF, van de Poll-Franse LV, et al.: Surgical resection of the primary tumour is associated with improved survival in patients with distant metastatic breast cancer at diagnosis. Eur J Surg Oncol 2009; 35: 1146–51 MEDLINE
14.
Sledge GWJ, Hu P, Falkson G, Tormey D, Abeloff M: Comparison of chemotherapy with chemohormonal therapy as first-line therapy for metastatic, hormone-sensitive breast cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 2000; 18: 262–6. MEDLINE
15.
Rasmussen BB, Regan MM, Lykkesfeldt AE, et al.: Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1–98 randomised trial. Lancet Oncol 2008; 9: 23–8. MEDLINE
16.
Kaufman B, Mackey JR, Clemens MR, et al.: Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer. Results from the randomized phase III TAnDEM study. J Clin Oncol 2009; 27: 5529–37. MEDLINE
17.
Johnston S, Pippen J Jr, Pivot X, et al.: Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 2009; 27: 5538–46. MEDLINE
18.
Sledge GW, Neuberg D, Bernardo P, et al.: Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 2003; 21: 588–92 MEDLINE
19.
Jones SE, Erban J, Overmoyer B, et al.: Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 2005; 23: 5542–51. MEDLINE
20.
Miller K, Wang M, Gralow J, et al.: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357: 2666–76. MEDLINE
21.
Slamon DJ, Leyland-Jones B, Shak S, 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. MEDLINE
22.
Di Leo A, Gomez HL, Aziz Z, et al.: Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 2008; 26: 5544–52. MEDLINE
23.
Hillner BE, Ingle JN, Chlebowski RT, et al.: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003; 21: 4042–57. MEDLINE
24.
Gnant M, Mlineritsch B, Schippinger W, et al.: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360: 679–91. MEDLINE
25.
Tan C, Sedrakyan A, Browne J, Swift S, Treasure T: The evidence on the effectiveness of management for malignant pleural effusion: a systematic review. Eur J Cardiothorac Surg 2006; 29: 829–38. MEDLINE
e2.
e3.
Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 1996; 14: 2738–46. MEDLINE
e4.
Christiansen P, Al Suliman N, Bjerre K, Moller S: Recurrence pattern and prognosis in low-risk breast cancer patients–data from the DBCG 89-A programme. Acta Oncol 2008; 47: 691–703. MEDLINE
e5.
Lin NU, Claus E, Sohl J, et al.: Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system me-tastases. Cancer 2008; 113: 2638–45. MEDLINE
e6.
Kaplan HG, Malmgren JA: Impact of triple negative phenotype on breast cancer prognosis. Breast J 2008; 14: 456–63. MEDLINE
e7.
Oxford Centre for Evidence-based Medicine Levels of Evidence: Levels of evidence and grades of recommendation.
e8.
Broom RJ, Tang PA, Simmons C, et al.: Changes in estrogen receptor, progesterone receptor and her-2/neu status with time: discordance rates between primary and metastatic breast cancer. Anticancer Res 2009; 29: 1557–62. MEDLINE
e9.
Wurschmidt F, Dahle J, Petersen C, et al.: Reirradiation of recurrent breast cancer with and without concurrent chemotherapy. Radiat Oncol 2008; 3: 28. MEDLINE
e10.
Wapnir IL, Aebi S, Geyer CE, et al.: A randomized clinical trial of adjuvant chemotherapy for radically resected locoregional relapse of breast cancer: IBCSG 27–02, BIG 1–02, and NSABP B-37. Clin Breast Cancer 2008; 8: 287–92. MEDLINE
e11.
Rauschecker H, Clarke M, Gatzemeier W, Recht A: Systemic ther-apy for treating locoregional recurrence in women with breast cancer. Cochrane Database Syst Rev 2001; CD002195.
e12.
Semrau S, Gerber B, Reimer T, Klautke G, Fietkau R: Concurrent radiotherapy and taxane chemotherapy in patients with locore-gional recurrence of breast cancer. A retrospective analysis. Strahlenther Onkol 2006; 182: 596–603. MEDLINE
e13.
Pergolizzi S, Adamo V, Russi E, et al.: Prospective multicenter study of combined treatment with chemotherapy and radiotherapy in breast cancer women with the rare clinical scenario of ipsilateral supraclavicular node recurrence without distant metastases. Int J Radiat Oncol Biol Phys 2006; 65: 25–32. MEDLINE
e14.
Schlesinger-Raab A C, Eckel R, Engel J, Sauer H, Löhrs U, Molls M, Hölzel D: Metastasiertes Mammakarzinom: Keine Lebensverlängerung seit 20 Jahren. Dtsch Arztebl 2005; 102(40): A 2706–14. VOLLTEXT
e15.
Wilcken N, Dear R: Chemotherapy in metastatic breast cancer: A summary of all randomized trials reported 2000–2007. Eur J Cancer 2008; 44: 2218–25. MEDLINE
e16.
Giordano SH, Buzdar AU, Smith TL, et al.: Is breast cancer survival improving? Cancer 2004; 100: 44–52. MEDLINE
e17.
Andre F, Slimane K, Bachelot T, et al: Breast cancer with synchronous metastases: trends in survival during a 14-year period. J Clin Oncol 2004; 22: 3302–8. MEDLINE
e18.
Chia SK, Speers CH, D’yachkova Y, et al.: The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic brest cancer. Cancer 2007; 110: 973–9. MEDLINE
e19.
Therasse P, Arbuck SG, Eisenhauer EA, et al.: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–16. MEDLINE
e20.
Telli ML, Hunt SA, Carlson RW, Guardino AE: Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. J Clin Oncol 2007; 25: 3525–33. MEDLINE
e21.
Rapiti E, Verkooijen HM, Vlastos G, et al.: Complete excision of primary breast tumor improves survival of patients with metastat-ic breast cancer at diagnosis. J Clin Oncol 2006; 24: 2743–9. MEDLINE
e22.
Babiera GV, Rao R, Feng L, et al.: Effect of primary tumor extirpation in breast cancer patients who present with stage IV disease and an intact primary tumor. Ann Surg Oncol 2006; 13: 776–82. MEDLINE
e23.
Montemurro F, Rondon G, Ueno NT, et al.: Factors affecting progression-free survival in hormone-dependent metastatic breast cancer patients receiving high-dose chemotherapy and hematopoietic progenitor cell transplantation: role of maintenance endocrine therapy. Bone Marrow Transplant 2002; 29: 861–6. MEDLINE
e24.
Carlson RW: Sequencing of endocrine therapies in breast cancer—integration of recent data. Breast Cancer Res Treat 2002; 75 Suppl 1: S27–S32. MEDLINE
e25.
Klijn JG, Blamey RW, Boccardo F, et al.: Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 2001; 19: 343–53. MEDLINE
e26.
Forward DP, Cheung KL, Jackson L, Robertson JF: Clinical and endocrine data for goserelin plus anastrozole as second-line endocrine therapy for premenopausal advanced breast cancer. Br J Cancer 2004; 90: 590–4. MEDLINE
e27.
Fossati R, Confalonieri C, Torri V, et al.: Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol 1998; 16: 3439–60. MEDLINE
e28.
Albain KS, Nag SM, Calderillo-Ruiz G, et al.: Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol 2008; 26: 3950–7. MEDLINE
e29.
O’Shaughnessy J, Miles D, Vukelja S, et al.: Superior survival with capecitabine plus docetaxel combination therapy in anthracy-cline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20: 2812–23. MEDLINE
e30.
Jones D, Ghersi D, Wilcken N: Addition of drug/s to a chemother-apy regimen for metastatic breast cancer. Cochrane Database Syst Rev 2006; 3: CD003368.
e31.
Sparano JA, Wang M, Martino S, et al.: Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 2008; 358: 1663–71. MEDLINE
e32.
Seidman AD, Berry D, Cirrincione C, et al.: Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 non-overexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 2008; 26: 1642–9. MEDLINE
e33.
Gradishar WJ, Tjulandin S, Davidson N, et al.: Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 2005; 23: 7794–803. MEDLINE
e34.
Perez EA: Novel enhanced delivery taxanes: an update. Semin Oncol 2007; 34: suppl-5. MEDLINE
e35.
Robinson DM, Keating GM: Albumin-bound Paclitaxel: in metastatic breast cancer. Drugs 2006; 66: 941–8. MEDLINE
e36.
Bhushan S, Walko CM: Ixabepilone: a new antimitotic for the treatment of metastatic breast cancer. Ann Pharmacother 2008; 42: 1252–61. MEDLINE
e37.
Lechleider RJ, Kaminskas E, Jiang X, et al.: Ixabepilone in combination with capecitabine and as monotherapy for treatment of advanced breast cancer refractory to previous chemotherapies. Clin Cancer Res 2008; 14: 4378–84. MEDLINE
e38.
Bunnell C, Vahdat L, Schwartzberg L, et al.: Phase I/II study of ixabepilone plus capecitabine in anthracycline-pretreated/resistant and taxane-resistant metastatic breast cancer. Clin Breast Cancer 2008; 8: 234–41. MEDLINE
e39.
Schneider BP, Wang M, Radovich M, et al.: Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 2008; 26: 4672–8. MEDLINE
e40.
Marty M, Cognetti F; D Maraninchi D, 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 Oncol 2005; 23: 4247–50. MEDLINE
e41.
Geyer CE, Forster J, Lindquist D, et al.: Lapatinib plus capecita-bine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355: 2733–43. MEDLINE
e42.
Press MF, Finn RS, Cameron D, et al.: HER-2 Gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res 2008; 14: 7861–70. MEDLINE
e43.
Cameron D, Casey M, Press M, et al.: A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008; 112: 533–43. MEDLINE
e44.
von Minckwitz G, du BA, Schmidt M, et al.: Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03–05 study. J Clin Oncol 2009; 27: 1999–2006. MEDLINE
e45.
Portera CC, Walshe JM, Rosing DR, et al.: Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with [corrected] human epidermal growth factor receptor 2-positive metastatic breast cancer. Clin Cancer Res 2008; 14: 2710–6. MEDLINE
e46.
Diel IJ, Body JJ, Lichinitser MR, et al.: Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer. Eur J Cancer 2004; 40: 1704–12. MEDLINE
e47.
Diel IJ: Effectiveness of bisphosphonates on bone pain and quality of life in breast cancer patients with metastatic bone disease: a review. Support Care Cancer 2007; 15: 1243–9. MEDLINE
e48.
Ha TC, Li H: Meta-analysis of clodronate and breast cancer surviv-al. Br J Cancer 2007; 96: 1796–801. MEDLINE
e49.
Aapro M, Abrahamsson PA, Body JJ, et al.: Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2008; 19: 420–32. MEDLINE
e50.
Pavlakis N, Schmidt R, Stockler M: Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2005; CD003474. MEDLINE
e51.
Ross JR, Saunders Y, Edmonds PM, et al.: Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003; 327: 469. MEDLINE
e52.
Body JJ, Diel IJ, Bell R, et al.: Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer. Pain 2004; 111: 306–12. MEDLINE
e53.
Lipton A, Steger GG, Figueroa J, et al.: Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol 2007; 25: 4431–7. MEDLINE
e54.
Patchell RA, Tibbs PA, Regine WF, et al.: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomized trial. Lancet 2005; 366: 643–8. MEDLINE
e55.
Ibrahim A, Crockard A, Antonietti P, et al.: Does spinal surgery improve the quality of life for those with extradural (spinal) osseous metastases? An international multicenter prospective observation-al study of 223 patients. Invited submission from the Joint Sec-tion Meeting on Disorders of the Spine and Peripheral Nerves, March 2007. J Neurosurg Spine 2008; 8: 271–8. MEDLINE
e56.
Chinot OL: Cerebral metastases. Rev Prat 2006; 56: 1799–804. MEDLINE
e57.
Rath GK, Julka PK, Thulkar S, et al.: Radiofrequency ablation of hepatic metastasis: results of treatment in forty patients. J Cancer Res Ther 2008; 4: 14–7. MEDLINE
e58.
Vogl TJ, Naguib NN, Eichler K, et al.: Volumetric evaluation of liver metastases after thermal ablation: long-term results following MR-guided laser-induced thermotherapy. Radiology 2008; 249: 865–71. MEDLINE
e59.
Kuvshinoff B, Fong Y: Surgical therapy of liver metastases. Semin Oncol 2007; 34: 177–85. MEDLINE
e60.
Demicheli R, Retsky MW, Hrushesky WJ, Baum M, Gukas ID: The effects of surgery on tumor growth: a century of investigations. Ann Oncol 2008; 19: 1821–8. MEDLINE
e61.
Shaw P, Agarwal R: Pleurodesis for malignant pleural effusions. Cochrane Database Syst Rev 2004; CD002916.
e62.
Gibson LJ, Dawson CK, Lawrence DH, Bliss JM: Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane Database Syst Rev 2007; CD003370. MEDLINE
e63.
Ingle JN: Sequencing of endocrine therapy in postmenopausal women with advanced breast cancer. Clin Cancer Res 2004; 10: 362S–7S. MEDLINE
e64.
Iaffaioli RV, Formato R, Tortoriello A, et al.: Phase II study of sequential hormonal therapy with anastrozole/exemestane in ad-vanced and metastatic breast cancer. Br J Cancer 2005; 92: 1621–5. MEDLINE
e65.
Carlini P, Michelotti A, Ferretti G, et al.: Clinical evaluation of the use of exemestane as further hormonal therapy after nonsteroidal aromatase inhibitors in postmenopausal metastatic breast cancer patients. Cancer Invest 2007; 25: 102–5. MEDLINE
e66.
Gennatas C, Michalaki V, Carvounis E, et al.: Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on letrozole or anastrozole. A phase II trial conducted by the Hellenic Group of Oncology (HELGO). Tumori 2006; 92: 13–7. MEDLINE
e67.
Vergote I, Amant F, Leunen K, et al.: Metastatic breast cancer: sequencing hormonal therapy and positioning of fulvestrant. Int J Gynecol Cancer 2006; 16 Suppl 2: 524–6. MEDLINE
e68.
Bartsch R, Mlineritsch B, Gnant M, et al.: The Austrian fulvestrant registry: results from a prospective observation of fulvestrant in postmenopausal patients with metastatic breast cancer. Breast Cancer Res Treat 2009; 115: 373–80. MEDLINE
e69.
Chia S, Gradishar W, Mauriac L, et al.: Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 2008; 26: 1664–70. MEDLINE
e70.
Vergote I, Abram P: Fulvestrant, a new treatment option for advanced breast cancer: telerability versus existing agents. Ann Oncol 2006; 17: 200–4. MEDLINE
Universitätsfrauenklinik am Klinikum Südstadt der Hansestadt Rostock: Prof. Dr. med. Gerber, PD Dr. med. Reimer
Klinik und Poliklinik für Innere Medizin, Abteilung Hämatologie und Onkologie der Universität Rostock: Prof. Dr. med. Freund
1. Jemal A, Thun MJ, Ries LA, et al.: Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 2008; 100: 1672–94 MEDLINE
2. Kamby C, Vejborg I, Kristensen B, Olsen LO, Mouridsen HT: Metastatic pattern in recurrent breast cancer. Special reference to intrathoracic recurrences. Cancer 1988; 62: 2226–33 MEDLINE
3. Rhee J, Han SW, Oh DY, et al.: The clinicopathologic characteristics and prognostic significance of triple-negativity in node-negative breast cancer. BMC Cancer 2008; 8: 307 MEDLINE
4. Kamby C, Ejlertsen B, Andersen J, et al.: The pattern of metastases in human breast cancer. Influence of systemic adjuvant therapy and impact on survival. Acta Oncol 1988; 27: 715–9 MEDLINE
5. DGS: S3-Leitlinie der Deutschen Gesellschaft für Senologie. (2008)
6. AGO (Arbeitsgemeinschaft Gynäkologische Onkologie, Organgruppe Mamma); 2009
7. NCCN (National Comprehensive Cancer Network): NCCN Practice Guidelines in Oncology: Breast Cancer 2009
8. Cochrane Collaboration 2009
9. Wapnir IL, Anderson SJ, Mamounas EP, et al.: Prognosis after ipsilater-al breast tumor recurrence and locoregional recurrences in five National Surgical Adjuvant Breast and Bowel Project node-positive adjuvant breast cancer trials. J Clin Oncol 2006; 24: 2028–37 MEDLINE
10. Waeber M, Castiglione-Gertsch M, Dietrich D, et al.: Adjuvant therapy after excision and radiation of isolated postmastectomy locoregional breast cancer recurrence: definitive results of a phase III randomized trial (SAKK 23/82) comparing tamoxifen with observation. Ann Oncol 2003; 14: 1215–21 MEDLINE
11. Mauri D, Polyzos NP, Salanti G, Pavlidis N, Ioannidis JP: Multiple-treatments meta-analysis of chemotherapy and targeted therapies in advanced breast cancer. J Natl Cancer Inst 2008; 17: 1780–91 MEDLINE
12. Gennari A, Conte P, Rosso R, Orlandini C, Bruzzi P: Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies. Cancer 2005; 104: 1742–50 MEDLINE
13. Ruiterkamp J, Ernst MF, van de Poll-Franse LV, et al.: Surgical resection of the primary tumour is associated with improved survival in patients with distant metastatic breast cancer at diagnosis. Eur J Surg Oncol 2009; 35: 1146–51 MEDLINE
14. Sledge GWJ, Hu P, Falkson G, Tormey D, Abeloff M: Comparison of chemotherapy with chemohormonal therapy as first-line therapy for metastatic, hormone-sensitive breast cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 2000; 18: 262–6. MEDLINE
15. Rasmussen BB, Regan MM, Lykkesfeldt AE, et al.: Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1–98 randomised trial. Lancet Oncol 2008; 9: 23–8. MEDLINE
16. Kaufman B, Mackey JR, Clemens MR, et al.: Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer. Results from the randomized phase III TAnDEM study. J Clin Oncol 2009; 27: 5529–37. MEDLINE
17. Johnston S, Pippen J Jr, Pivot X, et al.: Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 2009; 27: 5538–46. MEDLINE
18. Sledge GW, Neuberg D, Bernardo P, et al.: Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 2003; 21: 588–92 MEDLINE
19. Jones SE, Erban J, Overmoyer B, et al.: Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 2005; 23: 5542–51. MEDLINE
20. Miller K, Wang M, Gralow J, et al.: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357: 2666–76. MEDLINE
21. Slamon DJ, Leyland-Jones B, Shak S, 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. MEDLINE
22. Di Leo A, Gomez HL, Aziz Z, et al.: Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 2008; 26: 5544–52. MEDLINE
23. Hillner BE, Ingle JN, Chlebowski RT, et al.: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003; 21: 4042–57. MEDLINE
24. Gnant M, Mlineritsch B, Schippinger W, et al.: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360: 679–91. MEDLINE
25. Tan C, Sedrakyan A, Browne J, Swift S, Treasure T: The evidence on the effectiveness of management for malignant pleural effusion: a systematic review. Eur J Cardiothorac Surg 2006; 29: 829–38. MEDLINE
e1. Robert Koch Institut: Evaluation of cancer incidence in germany (2003–2004); 2009
e2. SEER, 2009: http://seer.cancer.gov/
e3. Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 1996; 14: 2738–46. MEDLINE
e4. Christiansen P, Al Suliman N, Bjerre K, Moller S: Recurrence pattern and prognosis in low-risk breast cancer patients–data from the DBCG 89-A programme. Acta Oncol 2008; 47: 691–703. MEDLINE
e5. Lin NU, Claus E, Sohl J, et al.: Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system me-tastases. Cancer 2008; 113: 2638–45. MEDLINE
e6. Kaplan HG, Malmgren JA: Impact of triple negative phenotype on breast cancer prognosis. Breast J 2008; 14: 456–63. MEDLINE
e7. Oxford Centre for Evidence-based Medicine Levels of Evidence: Levels of evidence and grades of recommendation.
e8. Broom RJ, Tang PA, Simmons C, et al.: Changes in estrogen receptor, progesterone receptor and her-2/neu status with time: discordance rates between primary and metastatic breast cancer. Anticancer Res 2009; 29: 1557–62. MEDLINE
e9. Wurschmidt F, Dahle J, Petersen C, et al.: Reirradiation of recurrent breast cancer with and without concurrent chemotherapy. Radiat Oncol 2008; 3: 28. MEDLINE
e10. Wapnir IL, Aebi S, Geyer CE, et al.: A randomized clinical trial of adjuvant chemotherapy for radically resected locoregional relapse of breast cancer: IBCSG 27–02, BIG 1–02, and NSABP B-37. Clin Breast Cancer 2008; 8: 287–92. MEDLINE
e11. Rauschecker H, Clarke M, Gatzemeier W, Recht A: Systemic ther-apy for treating locoregional recurrence in women with breast cancer. Cochrane Database Syst Rev 2001; CD002195.
e12. Semrau S, Gerber B, Reimer T, Klautke G, Fietkau R: Concurrent radiotherapy and taxane chemotherapy in patients with locore-gional recurrence of breast cancer. A retrospective analysis. Strahlenther Onkol 2006; 182: 596–603. MEDLINE
e13. Pergolizzi S, Adamo V, Russi E, et al.: Prospective multicenter study of combined treatment with chemotherapy and radiotherapy in breast cancer women with the rare clinical scenario of ipsilateral supraclavicular node recurrence without distant metastases. Int J Radiat Oncol Biol Phys 2006; 65: 25–32. MEDLINE
e14. Schlesinger-Raab A C, Eckel R, Engel J, Sauer H, Löhrs U, Molls M, Hölzel D: Metastasiertes Mammakarzinom: Keine Lebensverlängerung seit 20 Jahren. Dtsch Arztebl 2005; 102(40): A 2706–14. VOLLTEXT
e15. Wilcken N, Dear R: Chemotherapy in metastatic breast cancer: A summary of all randomized trials reported 2000–2007. Eur J Cancer 2008; 44: 2218–25. MEDLINE
e16. Giordano SH, Buzdar AU, Smith TL, et al.: Is breast cancer survival improving? Cancer 2004; 100: 44–52. MEDLINE
e17. Andre F, Slimane K, Bachelot T, et al: Breast cancer with synchronous metastases: trends in survival during a 14-year period. J Clin Oncol 2004; 22: 3302–8. MEDLINE
e18. Chia SK, Speers CH, D’yachkova Y, et al.: The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic brest cancer. Cancer 2007; 110: 973–9. MEDLINE
e19. Therasse P, Arbuck SG, Eisenhauer EA, et al.: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–16. MEDLINE
e20. Telli ML, Hunt SA, Carlson RW, Guardino AE: Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. J Clin Oncol 2007; 25: 3525–33. MEDLINE
e21. Rapiti E, Verkooijen HM, Vlastos G, et al.: Complete excision of primary breast tumor improves survival of patients with metastat-ic breast cancer at diagnosis. J Clin Oncol 2006; 24: 2743–9. MEDLINE
e22. Babiera GV, Rao R, Feng L, et al.: Effect of primary tumor extirpation in breast cancer patients who present with stage IV disease and an intact primary tumor. Ann Surg Oncol 2006; 13: 776–82. MEDLINE
e23. Montemurro F, Rondon G, Ueno NT, et al.: Factors affecting progression-free survival in hormone-dependent metastatic breast cancer patients receiving high-dose chemotherapy and hematopoietic progenitor cell transplantation: role of maintenance endocrine therapy. Bone Marrow Transplant 2002; 29: 861–6. MEDLINE
e24. Carlson RW: Sequencing of endocrine therapies in breast cancer—integration of recent data. Breast Cancer Res Treat 2002; 75 Suppl 1: S27–S32. MEDLINE
e25. Klijn JG, Blamey RW, Boccardo F, et al.: Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 2001; 19: 343–53. MEDLINE
e26. Forward DP, Cheung KL, Jackson L, Robertson JF: Clinical and endocrine data for goserelin plus anastrozole as second-line endocrine therapy for premenopausal advanced breast cancer. Br J Cancer 2004; 90: 590–4. MEDLINE
e27. Fossati R, Confalonieri C, Torri V, et al.: Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol 1998; 16: 3439–60. MEDLINE
e28. Albain KS, Nag SM, Calderillo-Ruiz G, et al.: Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol 2008; 26: 3950–7. MEDLINE
e29. O’Shaughnessy J, Miles D, Vukelja S, et al.: Superior survival with capecitabine plus docetaxel combination therapy in anthracy-cline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20: 2812–23. MEDLINE
e30. Jones D, Ghersi D, Wilcken N: Addition of drug/s to a chemother-apy regimen for metastatic breast cancer. Cochrane Database Syst Rev 2006; 3: CD003368.
e31. Sparano JA, Wang M, Martino S, et al.: Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 2008; 358: 1663–71. MEDLINE
e32. Seidman AD, Berry D, Cirrincione C, et al.: Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 non-overexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 2008; 26: 1642–9. MEDLINE
e33. Gradishar WJ, Tjulandin S, Davidson N, et al.: Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 2005; 23: 7794–803. MEDLINE
e34. Perez EA: Novel enhanced delivery taxanes: an update. Semin Oncol 2007; 34: suppl-5. MEDLINE
e35. Robinson DM, Keating GM: Albumin-bound Paclitaxel: in metastatic breast cancer. Drugs 2006; 66: 941–8. MEDLINE
e36. Bhushan S, Walko CM: Ixabepilone: a new antimitotic for the treatment of metastatic breast cancer. Ann Pharmacother 2008; 42: 1252–61. MEDLINE
e37. Lechleider RJ, Kaminskas E, Jiang X, et al.: Ixabepilone in combination with capecitabine and as monotherapy for treatment of advanced breast cancer refractory to previous chemotherapies. Clin Cancer Res 2008; 14: 4378–84. MEDLINE
e38. Bunnell C, Vahdat L, Schwartzberg L, et al.: Phase I/II study of ixabepilone plus capecitabine in anthracycline-pretreated/resistant and taxane-resistant metastatic breast cancer. Clin Breast Cancer 2008; 8: 234–41. MEDLINE
e39. Schneider BP, Wang M, Radovich M, et al.: Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 2008; 26: 4672–8. MEDLINE
e40. Marty M, Cognetti F; D Maraninchi D, 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 Oncol 2005; 23: 4247–50. MEDLINE
e41. Geyer CE, Forster J, Lindquist D, et al.: Lapatinib plus capecita-bine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355: 2733–43. MEDLINE
e42. Press MF, Finn RS, Cameron D, et al.: HER-2 Gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res 2008; 14: 7861–70. MEDLINE
e43. Cameron D, Casey M, Press M, et al.: A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008; 112: 533–43. MEDLINE
e44. von Minckwitz G, du BA, Schmidt M, et al.: Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03–05 study. J Clin Oncol 2009; 27: 1999–2006. MEDLINE
e45. Portera CC, Walshe JM, Rosing DR, et al.: Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with [corrected] human epidermal growth factor receptor 2-positive metastatic breast cancer. Clin Cancer Res 2008; 14: 2710–6. MEDLINE
e46. Diel IJ, Body JJ, Lichinitser MR, et al.: Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer. Eur J Cancer 2004; 40: 1704–12. MEDLINE
e47. Diel IJ: Effectiveness of bisphosphonates on bone pain and quality of life in breast cancer patients with metastatic bone disease: a review. Support Care Cancer 2007; 15: 1243–9. MEDLINE
e48. Ha TC, Li H: Meta-analysis of clodronate and breast cancer surviv-al. Br J Cancer 2007; 96: 1796–801. MEDLINE
e49. Aapro M, Abrahamsson PA, Body JJ, et al.: Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2008; 19: 420–32. MEDLINE
e50. Pavlakis N, Schmidt R, Stockler M: Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2005; CD003474. MEDLINE
e51. Ross JR, Saunders Y, Edmonds PM, et al.: Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003; 327: 469. MEDLINE
e52. Body JJ, Diel IJ, Bell R, et al.: Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer. Pain 2004; 111: 306–12. MEDLINE
e53. Lipton A, Steger GG, Figueroa J, et al.: Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol 2007; 25: 4431–7. MEDLINE
e54. Patchell RA, Tibbs PA, Regine WF, et al.: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomized trial. Lancet 2005; 366: 643–8. MEDLINE
e55. Ibrahim A, Crockard A, Antonietti P, et al.: Does spinal surgery improve the quality of life for those with extradural (spinal) osseous metastases? An international multicenter prospective observation-al study of 223 patients. Invited submission from the Joint Sec-tion Meeting on Disorders of the Spine and Peripheral Nerves, March 2007. J Neurosurg Spine 2008; 8: 271–8. MEDLINE
e56. Chinot OL: Cerebral metastases. Rev Prat 2006; 56: 1799–804. MEDLINE
e57. Rath GK, Julka PK, Thulkar S, et al.: Radiofrequency ablation of hepatic metastasis: results of treatment in forty patients. J Cancer Res Ther 2008; 4: 14–7. MEDLINE
e58. Vogl TJ, Naguib NN, Eichler K, et al.: Volumetric evaluation of liver metastases after thermal ablation: long-term results following MR-guided laser-induced thermotherapy. Radiology 2008; 249: 865–71. MEDLINE
e59. Kuvshinoff B, Fong Y: Surgical therapy of liver metastases. Semin Oncol 2007; 34: 177–85. MEDLINE
e60. Demicheli R, Retsky MW, Hrushesky WJ, Baum M, Gukas ID: The effects of surgery on tumor growth: a century of investigations. Ann Oncol 2008; 19: 1821–8. MEDLINE
e61. Shaw P, Agarwal R: Pleurodesis for malignant pleural effusions. Cochrane Database Syst Rev 2004; CD002916.
e62. Gibson LJ, Dawson CK, Lawrence DH, Bliss JM: Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane Database Syst Rev 2007; CD003370. MEDLINE
e63. Ingle JN: Sequencing of endocrine therapy in postmenopausal women with advanced breast cancer. Clin Cancer Res 2004; 10: 362S–7S. MEDLINE
e64. Iaffaioli RV, Formato R, Tortoriello A, et al.: Phase II study of sequential hormonal therapy with anastrozole/exemestane in ad-vanced and metastatic breast cancer. Br J Cancer 2005; 92: 1621–5. MEDLINE
e65. Carlini P, Michelotti A, Ferretti G, et al.: Clinical evaluation of the use of exemestane as further hormonal therapy after nonsteroidal aromatase inhibitors in postmenopausal metastatic breast cancer patients. Cancer Invest 2007; 25: 102–5. MEDLINE
e66. Gennatas C, Michalaki V, Carvounis E, et al.: Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on letrozole or anastrozole. A phase II trial conducted by the Hellenic Group of Oncology (HELGO). Tumori 2006; 92: 13–7. MEDLINE
e67. Vergote I, Amant F, Leunen K, et al.: Metastatic breast cancer: sequencing hormonal therapy and positioning of fulvestrant. Int J Gynecol Cancer 2006; 16 Suppl 2: 524–6. MEDLINE
e68. Bartsch R, Mlineritsch B, Gnant M, et al.: The Austrian fulvestrant registry: results from a prospective observation of fulvestrant in postmenopausal patients with metastatic breast cancer. Breast Cancer Res Treat 2009; 115: 373–80. MEDLINE
e69. Chia S, Gradishar W, Mauriac L, et al.: Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 2008; 26: 1664–70. MEDLINE
e70. Vergote I, Abram P: Fulvestrant, a new treatment option for advanced breast cancer: telerability versus existing agents. Ann Oncol 2006; 17: 200–4. MEDLINE