AGO Recommendations for the Diagnosis and Treatment of Patients with Advanced and Metastatic Breast Cancer: Update 2014

For the last 13 years, the Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) has issued annually updated evidence-based recommendations for the diagnosis and treatment of patients with early and metastatic breast cancer. The AGO Breast Committee consists of 45 gynecological oncologists specialized in breast cancer and interdisciplinary members specialized in pathology, radiological diagnostics, medical oncology, and radiotherapy. Each update is performed/assembled in accordance with documented rules, by thoroughly reviewing and scoring the recent publications chapter by chapter for their scientific validity (Oxford Level of Evidence, LoE; www.cebm.net [1]) and clinical relevance (AGO grades of recommendation; table 1). All AGO Breast Committee members have declared their potential conflicts of interest. Here, we present the 2014 update of these guidelines, focusing on relevant changes introduced this year. The full version of the updated 2014 slide set is available online as a PDF file [2], in English and German. Moreover, a version for patients is also available at www.ago-online.de.The role of bisphosphonates (BP) in the treatment of hypercalcemia (LoE1a/A/++), the reduction of skeletal events (LoE1a/A/++) in M1oss patients (= patients with 1 bone metastasis), the prevention of antitumor therapy-induced bone loss/osteoporosis (LoE1b/B/++), and in the reduction of bone pain (LoE1a/A/++) is well established. The same is true for denosumab. This antibody causes less nephrotoxicity and less gastrointestinal toxicity, but higher rates of hypocalcemia than BPs. Both denosumab and BPs can cause osteonecrosis of the jaw (ONJ): in the 3-4-weekly treatment of patients in the metastatic setting ONJ has been reported to occur in 1-2% of cases, whereas in the less intense adjuvant setting ONJ is diagnosed only in a rare number of cases (<< 1%). The lowest incidences are reported for oral BPs.The most controversial issue is the use of BPs in adjuvant therapy of patients with breast cancer, where denosumab is still under investigation.One of the highlights of the 2013 San Antonio Breast Cancer Symposium was the presentation of a meta-analysis of the prospective randomized trials evaluating the effect of BPs on survival N as part of the adjuvant treatment of patients with early breast cancer. Coleman [3] presented the analysis done by the Early Breast Cancer Trialists' Collaborative Group. Original data from 22,982 patients who were initially randomized in adjuvant treatment protokolls testing BPs versus nihil were assessable. Primary endpoints of these trials were either survival or bone density. 36 trials were identified, 7 using clodronate and 29 using aminobisphosphonates. Data from 17,709 patients were evaluable, comprising 98% (n = 5,053/5,174) of patients entered into clodronate and 72% (n = 12,738/17,808) entered into aminobisphosphonate trials (zoledronic acid intravenously (i.v.; 65%), oral ibandronate (24%), or oral pamidronate (8% of the study patients). Primary endpoints were time to first recurrence, time to first distant failure, and overall survival (OS). Recurrence rates were 25.4% in the BP arm versus 26.5% for non-BP patients. Distant recurrences occurred in 20.9% (BP) and 22.3% (non-BP), respectively. The corresponding event rates for bone metastases were 6.9% versus 8.4%. In the subset of postmenopausal women (induced menopause or > 55 years if unknown), distant recurrences were observed in 18.4% (BP) versus 21.9% (non-BP) (p = 0.0003), bone metastases in 5.9% versus 8.8% (p < 0.00001) and non-bone metastases in 13.3% versus 14.3% (not significant). Both the 10-year breast cancer mortality rate (18.3% vs. 15.2%, p = 0.004) and the overall mortality rate (21.5% vs. 23.8%, p = 0.007) was significantly reduced by the use of BPs. The results were identical in the clodronate and the aminobisphosphonate group, whether given for cancer or for osteoporosis (n = 4,373). Differences were not significant if premenopausal women were included in the analysis.Based on these data the AGO recommendations have been adjusted, since this meta-analysis shows for the first time a significant 10-year OS benefit in the range of 3% due to postoperative treatment with BPs in postmenopausal women (LoE1a/A/+). This benefit is larger than the one observed after the introduction of aromatase inhibitors (AIs) (vs. tamoxifen) or taxanes (taxane/antracyclines vs. antracyclines). Unconditional recommendation (++) was not given due to the heterogeneity of the study population, the regimen, and of the treatment duration.It has to be acknowledged that expectations and objectives of follow-up are differentially reported by health professionals or patients.The main objective of following patients after the primary treatment of breast cancer is the detection of potentially curable events, particularly the detection of local recurrences and contralateral initially breast cancer. With increasing complexity and time length of primary adjuvant treatment, surveillance and counselling during the follow-up period becomes increasingly important. The psychosocial aspects of support and counselling will gain relevance as more patients survive breast cancer and will encounter long-term treatment.Routine follow-up examinations in asymptomatic patients should comprise history (for specific symptoms), physical examination, mammography, ultrasound of the breast, magnetic resonance imaging (MRI) of the breast in case of inconclusive conventional imaging, and pelvic examination. Breast self-examination is encouraged by experts especially for self-awareness, but no survival benefit has so far been scientifically substantiated.Additional examination modalities or shorter examination intervals are explicitly discouraged for the time being, since although intensified surveillance has proved to decrease the lead time until the detection of distant metastases in comparison to conventional surveillance, it has not been shown to improve OS. In the context of novel treatment modalities for distant disease, however, this objective should be reexamined. There are indications that physical activity (as for example walking or yoga) and weight reduction during follow-up can improve quality of life and physical performance, reduce fatigue, and optimize outcome. Therefore, during follow-up, patients should be encouraged to take and supported in keeping up measures to achieve these goals. Intervention in order to treat comorbidities and to counsel for lifestyle risks is recommended in order to reduce unfavorable effects on the course of the breast cancer disease.During follow-up, compliance with endocrine therapies should be monitored. Predictors for the discontinuation of treatment are young age and old age, breast-conserving therapy (vs. mastectomy), more than 2 comorbidities, higher copayment required, smaller blister pack, and prescription by general practitioners. Predictors of good compliance are marriage, adjuvant chemotherapy, and adjuvant radiotherapy.Very limited data have been reported in this context and none has been considered to justify a change in treatment recommendation. It has to be emphasized that based on current evidence, the AGO discourages additional follow-up examinations in asymptomatic patients, but encourages the performance of future studies on the relevance of additional tests in the context of modern imaging and treatment modalities.About 10% (2-20) of patients who undergo breast-conserving surgery and radiation therapy will subsequently develop ipsilateral breast tumor recurrence. Chest wall recurrences after mastectomy and isolated axillary recurrences are relatively rare events. Although the local outcome following salvage therapy is favorable in the majority of cases, the risk of distant metastases for patients with local recurrence is 3-5 times greater than for those without recurrence. The reason for this association has been controversially discussed. However, it now has become an acknowledged fact that local recurrence is both a marker of the underlying biological aggressiveness of the tumor and a possible source for further tumor dissemination.Only few relevant new data have been reported over the past 12 months. Saigal et al. [4] could show that inflammatory breast cancer at primary diagnosis correlated with increased risk of locoregional recurrence. A meta-analysis reported by Wang et al. [5] confirmed earlier data that triple-negative and/or human epidermal growth factor receptor 2 (HER2)-positive breast cancer is also associated with increased locoregional recurrence risk. The hazard ratio was 1.88 (1.58-2.22) for triple-negative breast cancer (TNBC) as compared to any other HER2-negative subtypes. However, in comparison to HER2-positive breast cancer, TNBC showed a lower risk with an hazard ratio of 0.69 (0.53-0.91).Complete resection of the locally recurrent tumor is the treatment of choice whenever possible. Radiotherapy is needed if there has been no prior irradiation. Hormone receptor (HR)-positive isolated locoregional recurrences should receive endocrine treatment. HR-negative patients should receive an effective adjuvant-analogue chemotherapeutic regimen. In case of HER2 positivity, a HER2-targeting procedure should be added, since isolated locoregional recurrence offers the last chance for breast cancer cure. New radiotherapy data published by Skinner et al. [6] showed no benefit of moderate dose escalation (+10%) after mastectomy. So far, the standard dose regimen remains the radiotreatment of choice. Based on this limited novel evidence, no relevant changes of the AGO recommendations have been made.Endocrine therapy is the backbone of and first choice for the treatment of HR-positive metastatic breast cancer. Therefore, metastatic lesions should be reanalyzed by biopsy and immunohistological staining, if possible. However, even if the analysis may show persisting HR positivity, the tumor cells may have generated resistance against endocrine treatment.In peri- and premenopausal patients, the induction of ovarian function suppression (gonadotropin-releasing hormone (GnRH) analogue or luteinizing hormone (LH) analogue) is the first step in endocrine treatment. If possible, it should be combined with tamoxifen 20 mg/day [7]. An AI can be used if there are contraindications against tamoxifen. However, mono therapy with ovarian function suppression or tamoxifen alone is also an option.In postmenopausal patients, endocrine treatment should be selected depending on previous medication and time line. The first choice of endocrine treatment should be an AI if either tamoxifen has already been used in the primary setting (fig. 1) or an AI treatment was terminated more than 1 year before [8]. If the cancer progressed on therapy with non-steroidal AI (letrozole or anastrozole) or if an AI therapy was terminated less than 1 year ago, two distinct options for endocrine treatment may be considered, i.e. (i) fulvestrant (500 mg every 4 weeks) [9] or (ii) a combination of exemestane plus everolimus [10] (fig. 2). In case of disease progression on either one of these two agents at later stages the other agent may be used. Importantly, in selected patients tamoxifen may be given in case of oligosymptomatic disease before chemotherapy is considered.According to clinical symptoms and endocrine responsiveness, endocrine treatment should be stopped and chemotherapy should be considered for further treatment. However, this should be discussed individually with every patient in shared decision-making.In HER2-positive HR-positive advanced breast cancer a combination of anastrozol or letrozole and trastuzumab or letrozole and lapatinib can be considered as a choice [11]. However, the progression-free survival (PFS) was quite short in clinical trials. Combination therapies of chemotherapy and HER2-directed treatment should be considered as a more effective option. Again, no significant changes as to the recommendations in this chapter have been considered necessary.Treatment selection in the advanced situation is based on tumor biology to a similar extent as in the curative setting with the choice of treatment depending on hormone receptor and HER2 status. Other parameters guiding treatment selection are (i) possible combination with compounds of targeted treatment; (ii) previous treatments (and their toxicities); (iii) the aggressiveness of the disease and localization of metastases; (iv) the biologic age; (v) comorbidities (including organ dysfunction); and (vi) the patient's preference and expectations.The first-line therapy in hormone receptor-positive tumors is generally endocrine therapy. If the leading site of metastasis has been proven to be hormone receptor-negative (preferentially diagnosed by biopsy of at least 1 metastatic lesion) or if the course of the disease suggests endocrine resistance or urgent need of response, cytotoxic chemotherapy is indicated (LoE 1aA, AGO++). This is in accordance with the recently published First International Consensus Guidelines for Advanced Breast Cancer (ABC 1) [12]. The use of anthracyclines (including liposomal anthracyclines) and taxanes remains state of the art in first-line therapy of metastatic breast cancer. Vinorelbine, capecitabine, and nanoparticle albumin-bound (nab)-paclitaxel are reasonable alternatives. Monotherapy is preferred over polychemotherapy in non-life-threatening situations. Particularly in single-agent therapy, it is recommended to treat as long as the therapeutic index remains positive (LoE 2bB, AGO+). Monitoring of the treatment response should be performed by assessing the tumor burden at baseline and approximately every 2 months, i.e. every 2-4 cycles of treatment. Assessment of a target lesion may be sufficient. In slow growing disease, longer intervals are acceptable (AGO++). Although some evidence is already available, determination of circulating tumor cells is still considered experimental and recommended preferentially within clinical trials (LoE 1bA, AGO+).In some situations, e.g. in TNBC or other aggressive conditions, combination of chemotherapy with bevacizumab may be recommended to increase the response rate and PFS, although not to prolong survival (LoE 2bB, AGO+) [13]. The combination of chemotherapy with other targeted drugs (e.g. sunitinib, sorafinib, vantetanib) is experimental and should not be performed outside of clinical trials. Platinum-based chemotherapy may be useful as further-line treatment, especially in TNBC (LoE 2bB, AGO+/-), even though data from prospective randomized trials are still lacking.The biggest step forward in the treatment of metastatic breast cancer has been achieved in HER2-overexpressing disease. Pertuzumab in combination with trastuzumab and docetaxel has shown benefit in PFS as well as OS as first-line therapy compared to docetaxel and trastuzumab alone [14] (fig. 3). Furthermore, trastuzumab emtansine (T-DM1) is approved as a further HER2-targeted treatment option in metastatic breast cancer (figs. 4 and 5) and has shown to enhance treatment efficacy (with respect to PFS and OS) in heavily pretreated patients in comparison to lapatinib and capecitabine at favorable toxicity [15,16]. Therefore, T-DM1 represents a recommendable treatment option for Patients with HER2-positive metastatic breast cancer in (i) the first line setting diagnosed ≤ 6 months after adjuvant therapy using taxane and trastuzumab (LoE 2b B, AGO +) or (ii) at second line or further (LoE 1bA, AGO ++).Specific sites of breast cancer metastases are liver, lung, pleura, pericardium, peritoneum, bone marrow, or any soft tissue. Other rare localizations like adrenals, ovaries, uterus, stomach, colon, or placenta have also been reported, however, in such rare cases, controlled trials are not feasible, and treatment options must be discussed individually.Management of primary stage IV breast cancer focuses primarily on systemic therapy. The impact of the extent of local treatment on patient survival is still a matter of debate. Although some trials suggested an association between local treatment (surgery or radiotherapy) of the primary tumor and prolonged survival, recent reports do not these Therefore, remains as to (i) whether these results a selection of women with good for primary site (ii) of women in published studies were diagnosed with metastatic disease after (iii) whether specific of metastases and biological greater and (iv) whether local therapy has been performed with to and If surgery of the primary tumor is performed in the metastatic local or mastectomy should be done with surgery is only indicated for treatment of metastatic disease is the therapy of choice. treatment, metastases should be confirmed by to HR and HER2 status. may occur in of patients and may have impact on systemic treatment. 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