8 Supplementary Figures and 2 Supplementary Tables

A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21∼22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with ⩾4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21∼22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype.

DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.

529 Background: The optimal way to schedule AIs and/or Tam in the adjuvant treatment of early breast cancer remains uncertain. Methods: ITT meta-analysis of individual patient data on 36 889 post-menopausal women with ER-positive invasive breast cancers in randomised trials of [A] Continuous AI (5yrs) vs Tam (5yrs); [B] Sequential Tam then AI (2-3yrs of Tam then 2-3 yrs AI) vs Tam (5yrs); [C] Continuous AI (5yrs) vs Sequential Tam then AI (5yrs). Results: [A] Fewer women had breast cancer recurrence with Continuous AI than Tam (827/4,970 vs 964/4,915, p<0.0001) and fewer died of breast cancer: 504 vs 562; rate ratio (RR) 0.86 [0.76-0.97], p=0.014. Recurrence RRs were: 0.66 during yrs 0-1 [95%CI 0.54-0.80], 0.75 during yrs 2-4 [0.64-0.88] and 0.90 in yrs 5+ [0.79-1.04]. [B] Recurrence was also lower with Sequential Tam then AI than with Tam alone (753/5,909 vs 863/5,889, p=0.0001) as was breast cancer mortality (361 vs 428 deaths; RR 0.84 [0.73-0.97], p=0.015). Recurrence RRs were 0.56 during yrs 2-4 [0.46-0.67] and 0.97 in yrs 5+ [0.86-1.09]. [C] In trials comparing Continuous AI versus Sequential Tam then AI, recurrence was lower with AI than Tam during yrs 0-1; RR 0.75 [0.62-0.89], but similar during yrs 2-4 (0.99 [0.85-1.15]), when both groups received AI, and in yrs 5+ (0.96 [0.76-1.21]) after treatment completion; overall, there were fewer recurrences with Continuous AI than Sequential Tam then AI (705/6,422 vs 764/6,377, RR 0.90 [0.81-1.00]; 5yr recurrence 9.6% vs 10.7%, p=0.042) and fewer breast cancer deaths (395 vs 432; 0.89 [0.77-1.02], p=0.097). In the 3 comparisons, proportional recurrence reductions did not differ much by age, nodal status, tumour grade, or PR status and, overall, fewer endometrial cancers (0.2% vs 0.6%, RR=0.37 [0.27-0.51]) but more fractures (8.1% vs 5.9%, RR=1.40 [1.27-1.53]) were seen with AIs than Tam; non-breast deaths were similar. Conclusions: AIs, in either Continuous or Sequential regimens, are even more effective than Tam monotherapy in preventing recurrence and breast cancer death, despite substantial cross-over from Tam to AI in some studies. Recurrence reductions are seen mainly while treatments differ, hence somewhat fewer recurrences with Continuous AI than Sequential Tam then AI.

Zielsetzung: In der TARGIT A Studie wurde im Protokoll eine additive Ganzbrustbestrahlung (WBRT) zur intraoperativen Radiotherapie (IORT) bei einem tumorfreien Schnittrand von < 1 mm empfohlen. In Deutschland wurde die WBRT aufgrund der Auflagen vom BFS bei einem tumorfreien Schnittrand < 10 mm ergänzt. Wir analysierten die Auswirkungen dieser Strategie auf die Therapie und die Lokalrezidivrate.

Autologous stem-cell transplantation (autoSCT) is considered a standard treatment of non-frail patients with mantle cell lymphoma (MCL), but little is known about outcome of MCL patients relapsing after autoSCT. We therefore sought to analyse the outcome after autoSCT failure and the efficacy of a rescue stem-cell transplantation (SCT) in this setting.Patients with MCL were eligible if they had relapsed after autoSCT performed between 2000 and 2009. A total of 1054 patients could be identified in the EBMT registry. By contacting the transplant centres, a full dataset could be retrieved for 360 patients.Median overall survival (OS) after relapse of the whole study group was 19 months. A long (> 12 months) interval between autoSCT and relapse [P < 0.001, hazard ratio (HR) 0.62], primary refractory disease (P < 0.02, HR 1.92), prior high-dose ARA-C treatment (P = 0.04, HR 1.43), and the year of relapse (P = 0.02, HR 0.92) significantly influenced OS from relapse in multivariate analysis.Eighty patients (22%) received a rescue allogeneic SCT (alloSCT). Relapse incidence, non-relapse mortality, and OS 2 years after alloSCT was 33% [confidence interval (95% CI 21% to 45%)], 30% (95% CI 19% to 42%), and 46% (95% CI 33% to 59%), respectively. Remission duration after autoSCT was the only variable significantly affecting the outcome of salvage alloSCT. In contrast, rescue autoSCT was not associated with long-term disease control. However, individual patients survived long term even without salvage transplantation.MCL recurrence within 1 year after autoSCT has an extremely dismal outcome, while the prognosis of patients with longer remission durations after autoSCT is significantly better. AlloSCT may offer the possibility of durable survival when performed for patients with a remission duration of more than 12 months after first autoSCT, but the favourable effect of a salvage alloSCT in this setting needs further validation.

BACKGROUND:In this study, we examined patients who had non-progressive disease for at least 2 years after diagnosis of inoperable locoregional recurrent or metastatic breast cancer under continuous trastuzumab treatment. Our primary goal was to assess the long-term outcome of patients with durable response to trastuzumab.METHODS:268 patients with HER2-positive inoperable locally recurrent or metastatic breast cancer and non-progressive disease for at least 2 years under trastuzumab treatment were documented retrospectively or prospectively in the HER-OS registry, an online documentation tool, between December 2006 and September 2010 by 71 German oncology centers. The study end point was time to tumor progression.RESULTS:Overall, 47.1% of patients (95% confidence interval (CI): 39.9-54.1%) remained in remission for more than 5 years, while the median time to progression was 4.5 years (95% CI: 4.0-6.6 years). Lower age (<50 years) and good performance status (ECOG 0) at time of trastuzumab treatment initiation as well as complete remission after initial trastuzumab treatment were associated with longer time to progression. Interruption of trastuzumab therapy correlated with shorter time to progression.CONCLUSIONS:HER2-positive patients, who initially respond to palliative treatment with trastuzumab, can achieve a long-term tumor remission of several years.

1121 Background: In 2010, we reported data on local control and early toxicity for the TARGIT-A trial of intraoperative radiotherapy after lumpectomy for early breast cancer. The updated results and first analysis of survival of the whole cohort (n = 3,451) were presented at San Antonio Breast Cancer Symposium in December 2012. We analysed the German cohort of patients, which was supposed to be more homogeneous (prepathology IORT only, homogeneous treatment in EBRT arm) and lower risk (older, smaller tumors, larger margin) than the international cohort of patients due to legal restrictions for radiotherapy studies in Germany. Methods: TARGIT-A was a randomised trial in patients >=50 years with invasive ductal carcinoma (<= 2cm) undergoing breast conserving surgery comparing standard fractionated whole breast EBRT (56 Gy) with single dose TARGIT (20 Gy) immediately after tumor excision / at the time of the primary operation. The experimental arm mandated additional EBRT (46 Gy, excluding a boost, n = 126) if adverse features were detected on final pathology (EIC, N+, margin < 1 cm) making this a “risk-adapted policy”. Median follow-up was 2 years and 5 months. Results: 734 patients recruited from 7 centres in Germany. Patient’s ages were <=50y 3%, 51-60y 33%, 61-70y 51%, >70y 12%. Tumour sizes were 0-1cm 35%, 1.1-2cm 55% and >2cm 11%. Grade I 29%, II 59%, III 12% and nodes negative 81%, 1-3 nodes 16%, >3 nodes 3%. At 5-years, the absolute number of events in TARGIT vs. EBRT were as follows: Primary outcome: IBR 4 vs. 1, Exploratory outcome: All recurrences (breast +axilla+contralateral+distant recurrence) 11 vs. 7, Secondary outcome: All deaths 6 vs. 12, Breast Cancer deaths 3 vs. 5, Non-Breast Cancer deaths 3 vs. 7. Conclusions: Patients in the TARGIT-A trial have excellent 5 year outcomes (local control > 97%, overall survival >= 94%) in both arms of the trial. Clinical trial information: protocol 99PRT/47.

Breast cancer has become curable for the majority of women in Western Europe and North America. Advances have been made in imaging diagnostics as well as the implementation of nationwide screening programmes. Nowadays, we talk about prevention as well as treatment. Pathology has moved from pure morphology (tumour type, grade and stage) to biological characterisation of the tumour. Treatment has changed considerably through a better understanding of the disease; from a local disease predominated by extensive and mutilating surgical techniques to a point where breast cancer has come into its own as a systemic disease with equal “rights” to local as well as systemic treatment. This paradigm shift has led to a multidisciplinary approach of the understanding and treatment of breast cancer. Molecular classification has changed the understanding of breast cancer and will be the basis for an even more individualised treatment. New (biological) agents will help to further tailor treatment to response or resistance. While systemic treatment has been increased in number and duration surgical/local strategies have been reduced to minimum. Evidence-based medicine has helped to improve and standardise treatment of breast cancer. This review summarises the 10th Biedenkopf meeting that was held to review the advances in breast cancer understanding and treatment.

Signifikante Verlängerung des medianen PFS in allen Subgruppen Alle Patientinnen profitieren signifikant bezüg­ lich des medianen progressionsfreien Über­ lebens (PFS) von der Therapie mit Everolimus plus Exemestan (HR = 0,45; 95%­KI: 0,38–0,54; p < 0,0001) – unabhängig von Alter, Anzahl der Vortherapien sowie Ort der Metastasierung. So­ wohl Patientinnen mit viszeralen Metastasen (medianes PFS 8,31 Monate unter Everolimus plus Exemestan vs. 2,89 Monate bei Placebo plus Exemestan; HR = 0,46) als auch Patientinnen ohne viszerale Beteiligung (medianes PFS 16,59 vs. 5,82 Monate bei Placebo plus Exemes­ derter Appetit [1]. Die häufigsten Nebenwir­ kungen vom Grad 3/4 (Inzidenz ≥2%) waren Stomatitis, Hyperglykämie, Fatigue, nicht­in­ fektiöse Pneumonitis und Diarrhö [2]. BOLERO­2 ist eine zulassungsrelevante rando­ misierte, doppelblinde, Placebo­kontrollierte, multizentrische Phase­III­Studie. In dieser Studie wurden 724 postmenopausale Frauen mit Hor­ monrezeptor­positivem, HER2/neu­negativem, fortgeschrittenem Brustkrebs und einem Durch­ schnittsalter von 62 Jahren untersucht, die ein Re­ zidiv oder eine Progression nach einer Therapie mit Letrozol oder Anastrozol vorwiesen. Der mTOR­Inhibitor wird in Kombination mit Exemestan bei postmenopausalen Frauen zur Therapie des Hormonrezeptor­positiven, HER2/ neu­negativen fortgeschrittenen Mammakarzi­ noms ohne symptomatische viszerale Metasta­ sierung angewendet, nachdem es zu einem Rezi­ div oder einer Progression unter einem nicht­ steroidalen Aromataseinhibitor gekommen ist [3]. Die Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) hat die Kombinationstherapie bereits als Empfehlung in ihre Leitlinien für 2012 aufgenommen [4].

Background: Elderly breast cancer patients are underrepresented in clinical trials and this leads to a lack of knowledge regarding the tolerance and side effects of modern chemotherapy regimens, especially in dose-dense (dd) or dose-intensified combination. Patients and Methods: In this analysis, data from 4 German, randomized (neo-)adjuvant trials, including anthracycline-based chemotherapy, were evaluated for toxicity, compliance and feasibility. Patients were grouped according to age. Results: Of the 4,775 patients, 73.6% were < 60 years, 15.8% were 60-64 years and 10.6% were > 64 years. The patients' compliance decreased with increasing age, the rate of therapy discontinuations was 10.3%; 16.0% were > 64 years old (p < 0.001). The rate of dose reductions also increased with increasing age in the docetaxel/doxorubicin/cyclophosphamide (TAC) (p overall = 0.02) and 5-fluorouracil/epirubicin-cyclophosphamide (FE120C) (p overall < 0.001) treatment groups. Neutropenia grade 3 + 4 in patients of > 64 years was 77% in FE120C- compared to 55% in TAC-treated patients (with primary granulocyte colony-stimulating factors (G-CSFs)). The incidence of febrile neutropenia (FN) was lowest in the regimens without additional taxanes. FN in patients aged > 64 years was lower in the FE120C- than in TAC- and dd-doxorubicin/docetaxel-treated groups. Conclusion: The range and intensity of toxicity increased with age. Neutropenia did not increase significantly in the dd groups; the highest rate was seen in FE120C-treated patients. FE120C without G-CSFs is not an option in patients older than 64 years.

In current clinical practice, the use of neoadjuvant chemotherapy for the treatment of breast cancer is well established. Once reserved for the treatment of locally advanced inoperable tumors, the neoadjuvant treatment strategy has been increasingly employed in operable breast cancer with good reason. This strategy offers a number of advantages over adjuvant therapy, with in vivo assessment of tumor response ranking among the most important. The neoadjuvant strategy has shown great potential as a platform for drug development, and this has led the US Food and Drug Administration to recently strongly consider pathologic response to neoadjuvant therapy as an end point to support accelerated drug approval in high-risk early-stage breast cancer. 1 Historical results from a series of important neoadjuvant trials have shaped our current thinking. It has been clearly established that long-term outcomes are similar whether treatment is given preoperatively or postoperatively and that a pathologic complete response (pCR) at the time of surgery is associated with a favorable outcome in all patients who achieve it. 2-4 Failure to achieve a pCR is clearly associated with worse long-term outcomes in triple-negative and human epidermal growth factor receptor 2 (HER2) –positive breast cancer, though this negative prognostic association is not observed for the majority of hormone receptor–positive breast cancers. 5-7 Rates of pCR following neoadjuvant chemotherapy in hormone responsive breast cancer are uniformly low and because these patients arguably receive their most important therapy, endocrine therapy, after chemotherapy, the focus of current neoadjuvant chemotherapy trials has shifted away from this group of patients in large part. Instead, neoadjuvant endocrine therapy strategies have been increasingly investigated for these patients and the field has moved more generally toward strategies to omit chemotherapy in hormone receptor–positive patients unlikely to derive benefit based on results of multiplex gene expression assays. In the article that accompanies this editorial, von Minckwitz et al 8 report survival outcomes after response-guided neoadjuvant chemotherapy in the German Breast Group GeparTrio study. In the German Breast Group tradition, this phase III study represents an enormous effort that tests an interesting strategy of response-guided chemotherapy treatment. More than 2,000 patients with stage II/III breast cancer were treated with an initial two cycles of docetaxel 75 mg/m 2 , doxorubicin 50 mg/m 2 , and cyclophosphamide 500 mg/m 2 on day 1 every 21 days (TAC). Patients achieving clinical response were then randomly assigned to continuing the same therapy for four or six additional cycles and nonresponders were randomly assigned to continue the same therapy or sequence to an alternate chemotherapy combination of navelbine 25 mg/m 2 days 1 and 8 and capecitabine 1,000 mg/m 2 orally twice per day on days 1 through 14 of a 21-day cycle (NX) for four cycles. Patients were accrued from 2002 to 2005 and the patient characteristics and therapies are reflective of the times. Notably, HER2 status was unknown in approximately 20% and no patient received neoadjuvant or adjuvant trastuzumab. The primary end points of the study were to compare pCR rates in early responders and clinical response in early nonresponders. The previously reported primary results showed a nonstatistically significant difference in pCR among early responders treated with TAC 6 compared with TAC 8 (21% v 23.5%; P .27) 9 and similar clinical responses were observed among early nonresponders with TAC 6 compared with TAC NX (50.5% v 51.2%; P .008 for noninferiority). 10 In the article accompanying this editorial, von Minckwitz et al 8 report on the predefined secondary end points of disease-free survival (DFS) and overall survival (OS). At a median follow-up of 62 months, DFS was significantly longer in early responders treated with TAC 8 compared with TAC 6 (hazard ratio [HR], 0.78; 95% CI, 0.62 to 0.97; P .026) and in early nonresponders treated with TAC NX compared with TAC 6 (HR, 0.59; 95% CI, 0.49 to 0.82; P .001). No significant difference in OS was observed in these two groups, though there was a trend toward improved OS in responders receiving TAC 8 compared with TAC 6 (HR, 0.76; 95% CI, 0.57 to 1.01; P .060). As the sample size was calculated to provide adequate power for the primary end point, the study is underpowered for the end points of DFS and OS. In addition, though the groups were reasonably balanced in terms of baseline characteristics, there were fewer patients with grade 3 tumors in the nonresponder group treated with TAC NX (25%) compared with TAC 6 (36%), and this difference was statistically significant. The unexpected finding, namely, that response-guided therapy influences disease-free survival only in hormone receptor– positive and not hormone receptor–negative breast cancer, rests on a secondary exploratory subgroup analysis and therefore needs to