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Addition of immune checkpoint inhibitors to neoadjuvant chemotherapy (NACT) is a promising strategy in early breast cancer, but the optimal duration of therapy is currently unknown. In the GeparNuevo (NCT02685059) trial, addition of durvalumab to NACT as previously reported led to a moderate increase in pathological complete response (pCR) rate by an absolute 9% (P = 0.287).Patients with cT1b-cT4a-d triple-negative breast cancer (TNBC) received durvalumab 1.5 g or placebo every 4 weeks added to nab-paclitaxel 125 mg/mA total of 174 patients were randomised between June 2016 and October 2017. After a median follow-up of 43.7 months, 34 events had occurred. Despite a non-significant increase in the pCR rate, significant differences were observed for 3-year iDFS, DDFS and OS: iDFS was 85.6% with durvalumab versus 77.2% with placebo [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.24-0.97, stratified log-rank P = 0.036]; DDFS 91.7% versus 78.4% (HR 0.31, 95% CI 0.13-0.74, P = 0.005); OS 95.2% versus 83.5% (HR 0.24, 95% CI 0.08-0.72, P = 0.006). pCR patients had 3-year iDFS of 95.5% with durvalumab and 86.1% without (HR 0.22, 95% CI 0.05-1.06). In the non-pCR cohort 3-year iDFS was 76.3% versus 69.7% (HR 0.67, 95% CI 0.29-1.54). Multivariable analysis confirmed a durvalumab effect independent of the pCR effect. No new safety signals occurred.Durvalumab added to NACT in TNBC significantly improved survival despite a modest pCR increase and no adjuvant component of durvalumab. Additional studies are needed to clarify the optimal duration and sequence of checkpoint inhibitors in the treatment of early TNBC.

Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC.GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4 weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0).A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5 years (range 23-76); 47 patients (27%) were younger than 40 years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ2P = 0.287), corresponding to OR = 1.45 (95% CI 0.80-2.63, unadjusted Wald P = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR = 2.22, 95% CI 1.06-4.64, P = 0.035; interaction P = 0.048). In both arms, significantly increased pCR (P 0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P = 0.045) and for PD-L1-immune cell in placebo arm (P = 0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%.Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patients treated with durvalumab alone before start of chemotherapy.ClinicalTrials.gov number: NCT02685059.

Background Patients with invasive residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemo-resistant breast cancer. Bisphosphonates are an established treatment for bone metastases and are of potential benefit as adjuvant treatment in early breast cancer. Patients and methods Patients who had invasive tumour residuals (ypT1-4 and/or ypN+) after a minimum of four cycles of anthracycline-taxane-containing NACT were eligible for the NeoAdjuvant Trial Add-oN study. Patients were randomised within 3 years after surgery to receive zoledronate 4 mg i.v. for 5 years versus observation. Zoledronate was given every 4 weeks for the first 6 months, every 3 months for the following 2 years, and every 6 months for the last 2.5 years. Primary objective was disease-free survival. Results After a median time of 54.7 months no difference in disease-free survival was observed between the zoledronate and observation groups (hazard ratio [HR] 0.960, 95% confidence interval [CI] 0.709–1.30, log rank P = 0.789). Various subgroups were examined without identifying a treatment effect of zoledronate. Patients over 55 years of age showed a HR of 0.832 in favour of zoledronate, but the result was not significant ( P = 0.480). A similar result was obtained for overall survival with a HR of 1.19 (95% CI 0.79–1.79; log rank P = 0.408). Zoledronate was well tolerated and no new toxicity signal was identified. Conclusion Postneoadjuvant treatment with zoledronate does not improve outcome in patients without pathological complete response after neoadjuvant anthracycline-taxane-based chemotherapy for early breast cancer.

Background Use of parenteral (IV) ferric carboxymaltose (FCM) has been shown to be an efficient treatment of iron deficiency anaemia that can prevent blood transfusion. This substudy compared use of FCM with physician’s choice (PhCh) anaemia therapy in breast cancer (BC). Methods In GeparOcto trial pts with primary BC were randomised to receive sequential, intensified, dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) or weekly paclitaxel/liposomal doxorubicin +/- carboplatin (PM(Cb)) (Schneeweiss et al. Eur J Cancer). Pts with anaemia grade ≥2 (haemoglobin (Hb) Results Less than anticipated pts had CT-induced anaemia. 125 pts were randomised (62 in FCM, 63 in PhCh arm). Median age was 46 years (range 26-66); median levels of Hb, serum ferritin and TSAT were 9.6 (7.6-11.8)g/dl, 201 (3.0-551)ng/ml and 14.0% (4.0%-76.0%), respectively. After 6 wks, overall 40 (32.0%) pts (22 in FCM and 18 in PhCh arm; p = 0.447) reached Hb ≥ 11g/dl. Median time to achieve Hb ≥ 11g/dl was 9.0 wks with FCM vs 10.6 wks by PhCh. Median Hb changes vs baseline were comparable in both arms during the treatment. 2 pts in FCM and 5 in PhCh arm (p = 0.246) received blood transfusions until 6 wks of therapy. Conclusions This is the first study investigating IV iron treatment for dose-dense CT-induced anaemia in BC. 32% of pts reached Hb ≥ 11g/dl at 6 wks. FCM treatment was not different than PhCh for anaemia therapy. Clinical trial identification NCT02125344. Legal entity responsible for the study German Breast Group (GBG). Funding The anaemia supportive treatment substudy was financially supported by Vifor Pharma Ltd and the GeparOcto trial by Amgen, Roche and TEVA. Disclosure H. Tesch: Honoraria (self): Vifor; Honoraria (self): Roche; Honoraria (self): Amgen. S. Loibl: Honoraria (institution), Research grant / Funding (institution): Roche; Honoraria (institution), Research grant / Funding (institution): Amgen GmbH; Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): Celgene; Honoraria (institution), Research grant / Funding (institution): Novartis; Honoraria (institution), Research grant / Funding (institution): Pfizer; Honoraria (institution), Research grant / Funding (institution): Seattle Genetics; Honoraria (institution), Research grant / Funding (institution): Teva; Honoraria (institution), Research grant / Funding (institution): Vifor; Honoraria (institution), Research grant / Funding (institution): PRIME; Honoraria (institution), Research grant / Funding (institution): Daiichi; Licensing / Royalties: EP14153692.0 pending. V. Mobus: Honoraria (self): Amgen; Honoraria (self): Celgene; Honoraria (self): Myelotherapeutics; Honoraria (self): AstraZeneca. M. Untch: Honoraria (institution), Non-remunerated activity/ies: Abbvie; Honoraria (institution), Non-remunerated activity/ies: Amgen GmbH; Honoraria (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (institution): BMS; Honoraria (institution), Non-remunerated activity/ies: Celgene GmbH; Honoraria (institution), Non-remunerated activity/ies: Daiji Sankyo; Honoraria (institution), Non-remunerated activity/ies: Eisai GmbH; Honoraria (institution), Non-remunerated activity/ies: Janssen Cilag; Honoraria (institution), Non-remunerated activity/ies: Lilly; Honoraria (institution), Non-remunerated activity/ies: MSD Merck; Honoraria (institution), Non-remunerated activity/ies: Mundipharma; Honoraria (institution), Non-remunerated activity/ies: Myriad Genetics; Honoraria (institution), Non-remunerated activity/ies: Odonate; Honoraria (institution), Non-remunerated activity/ies: Pfizer GmbH; Honoraria (institution): PUMA Biotechnology; Honoraria (institution), Non-remunerated activity/ies: Novartis; Honoraria (institution), Non-remunerated activity/ies: Roche Pharma AG; Honoraria (institution), Non-remunerated activity/ies: Sanofi Aventis Deutschland GmbH; Honoraria (institution), Non-remunerated activity/ies: Sividon Diagnostics; Honoraria (institution), Non-remunerated activity/ies: TEVA Pharmaceuticals Ind Ltd. C. Hanusch: Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Celgene; Honoraria (self): Lilly; Honoraria (self): AstraZeneca. S. Seiler: Honoraria (self), presentations: Roche; Honoraria (self), Advisory / Consultancy: Amgen GmbH; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: Mundipharma; Advisory / Consultancy: Novartis. P.A. Fasching: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Biontech; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Celgene; Honoraria (self): Daiichi-Sankyo; Honoraria (self): TEVA; Honoraria (self): AstraZeneca; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Myelo Therapeutics; Honoraria (self): Macrogenics; Honoraria (self): Eisai; Honoraria (self): PUMA; Research grant / Funding (institution): Cepheid. K. Rhiem: Honoraria (self): Tesaro; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer. J. Huober: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: MSD Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Travel / Accommodation / Expenses: Abbvie. C. Denkert: Shareholder / Stockholder / Stock options: Sividon Diagnostics; Honoraria (self): Teva; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Amgen; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Daiichi Sankyo; Licensing / Royalties: VMScope digital pathology software; Licensing / Royalties: Patent application: EP18209672 - cancer immunotherapy; Licensing / Royalties: Patent application EP20150702464 - therapy response; Licensing / Royalties: Patent application EP20150702464 - therapy response. T. Link: Honoraria (self): Amgen; Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Pfizer; Non-remunerated activity/ies: Pharma Mar; Non-remunerated activity/ies: Daiichi Sankyo; Honoraria (self): MSD Oncology; Honoraria (self): Novartis; Honoraria (self): Teva; Honoraria (self): Tesaro; Honoraria (self), Non-remunerated activity/ies: Roche. A. Schneeweiss: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Molecular Partner; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): MSD Oncology; Honoraria (self): Tesaro; Honoraria (self): Lilly. All other authors have declared no conflicts of interest.

Background LRR after neoadjuvant chemotherapy (NACT) for BC may impact patient's outcome. This study aimed to evaluate the rates of LRR as first event after NACT and to identify independent predictors of LRR. Methods A total of 10075 women with primary BC and available follow-up from 9 prospective neoadjuvant trials were included in the pooled analysis. The main endpoint was cumulative incidence rates of LRR as first event after NACT; distant recurrence, secondary malignancy or death was defined as competing event. To identify predictors of LRR, surgery type, pathological complete response (pCR=ypT0 ypN0), BC subtypes and other risk factors were evaluated using Fine-Gray's regression model. The two-sided significance level was set to α=0.05. Results After a median follow-up in the entire cohort of 67 months (range 0-215 months), 959 (9.5%) LRRs as first event were observed. Age ( 50 years; p Conclusions Young age, node-positive and G3 tumours as well as non-pCR status and TNBC were found to significantly increase the risk of LRR as first event after NACT. Pts with HR-/HER2+ and TNBC not achieving pCR were at highest risk of LRR. Hence, these BC subtypes might be considered for additional post-neoadjuvant treatment approaches. Legal entity responsible for the study German Breast Group (GBG). Funding Has not received any funding. Disclosure M. Untch: Honoraria (institution), non-financial support: Abbvie; Honoraria (institution), non-financial support: Amgen GmbH; Honoraria (institution), non-financial support: AstraZeneca; Honoraria (institution): BMS; Honoraria (institution), non-financial support: Celgene GmbH; Honoraria (institution), non-financial support: Daiji Sankyo; Honoraria (institution), non-financial support: Eisai GmbH; Honoraria (institution), non-financial support: Janssen Cilag; Honoraria (institution), non-financial support: TEVA Pharmaceuticals Ind Ltd; Honoraria (institution): Lilly Deutschland; Honoraria (institution), non-financial support: Sividon Diagnostics; Honoraria (institution), non-financial support: MSD Merck; Honoraria (institution), non-financial support: Mundipharma; Honoraria (institution), non-financial support: Myriad Genetics; Honoraria (institution), non-financial support: Odonate; Honoraria (institution), non-financial support: Pfizer GmbH; Honoraria (institution): PUMA Biotechnology; Honoraria (institution), non-financial support: Novartis; Honoraria (institution), non-financial support: Roche Pharma AG; Honoraria (institution), non-financial support: Sanofi Aventis Deutschland GmbH. C. Hanusch: Honoraria (self), Outside the submitted work: Roche; Honoraria (self), Outside the submitted work: Pfizer; Honoraria (self), Outside the submitted work: Novartis; Honoraria (self), Outside the submitted work: Celgene; Honoraria (self), Outside the submitted work: Lilly; Honoraria (self), Outside the submitted work: AstraZeneca. P.A. Fasching: Research grant / Funding (institution), The Work Under Consideration for Publication: Novartis; Research grant / Funding (institution), The Work Under Consideration for Publication: Biontech; Honoraria (self), The Work Under Consideration for Publication: Novartis; Honoraria (self), The Work Under Consideration for Publication: Roche; Honoraria (self), The Work Under Consideration for Publication: Pfizer; Honoraria (self), The Work Under Consideration for Publication: Celgene; Honoraria (self), The Work Under Consideration for Publication: Daiichi-Sankyo; Honoraria (self), The Work Under Consideration for Publication: TEVA; Honoraria (self), The Work Under Consideration for Publication: AstraZeneca; Honoraria (self), The Work Under Consideration for Publication: Merck Sharp & Dohme; Honoraria (self), The Work Under Consideration for Publication: Myelo Therapeutics; Honoraria (self), The Work Under Consideration for Publication: Macrogenics; Honoraria (self), The Work Under Consideration for Publication: Eisai; Honoraria (self), The Work Under Consideration for Publication: Puma; Research grant / Funding (institution), The Work Under Consideration for Publication: Cepheid. S. Seiler: Honoraria (self), presentations: Roche; Advisory / Consultancy: Amgen GmbH; Advisory / Consultancy: Hexal; Honoraria (self): Mundipharma; Non-remunerated activity/ies: Novartis. C. Denkert: Shareholder / Stockholder / Stock options: Sividon Diagnostics; Honoraria (self): Teva; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Amgen; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Daiichi Sankyo; Licensing / Royalties: VMScope digital pathology software; Licensing / Royalties: Patent application: EP18209672 - cancer immunotherapy; Licensing / Royalties: Patent application EP20150702464 - therapy response; Licensing / Royalties: Patent application EP20150702464 - therapy response. H. Tesch: Honoraria (self): Vifor; Honoraria (self): Roche; Honoraria (self): Amgen. C. Jackisch: Honoraria (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self): Roche. A. Schneeweiss: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Molecular Partner; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Honoraria (self): Lilly. T. Link: Honoraria (self): Amgen; Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Pfizer; Non-remunerated activity/ies: Pharma Mar; Non-remunerated activity/ies: Daiichi Sankyo; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Teva; Honoraria (self): Tesaro; Honoraria (self), Non-remunerated activity/ies: Roche. J. Huober: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: MSD Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy: Abbvie. K. Rhiem: Honoraria (self): Tesaro; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca. S. Loibl: Honoraria (institution), Research grant / Funding (institution), The Work Under Consideration for Publication: Roche; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: AbbVie; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Amgen; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: AstraZeneca; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Celgene; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Novartis; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Pfizer; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Seattle Genetics; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Teva; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Vifor; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: PRIME; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Daiichi; Licensing / Royalties, Intellectual Property - Patents & Copyrights: EP14153692.0 pending. All other authors have declared no conflicts of interest.

2-Methoxyestradiol (2ME) is an endogenous estradiol metabolite, which acts antiproliferative in various tumor cell lines independent of the hormone receptor status. We investigated whether combinations of 2ME with various chemotherapeutic or endocrine compounds may result in an additive effect on the proliferation of human breast cancer cells. The breast cancer cell lines MCF-7 (receptor-positive), BM (receptor-negative) and a MCF-7 line transfected with the aromatase gene were used. All cell lines were incubated in the concentration range of 0.8 microM to 25 microM with 2ME alone and in equimolar combinations with the following compounds: epirubicine, daunorubicine, paclitaxel, docetaxel, carboplatin, vinorelbine, 5-fluorouracil, mafosfamide and 4-OH tamoxifen. The effect of letrozole and 2ME alone and in equimolar combinations was tested in the concentration range of 0.6 to 1 microM. Proliferation was measured after 4 days using the ATP-chemosensitivity test. In MCF-7 cells 2ME in combination with 4OH-tamoxifen, epirubicine, docetaxel, 5-fluoprouracil, mafosfamide and carboplatin led to an additive effect. In BM cells only 2ME combined with 4OH-tamoxifen, daunorubicine and mafosfamide showed an additive action. Both letrozole and 2ME were nearly similar effective in inhibition of the aromatase gene. Here no additive effect was found. 2ME displayed antiproliferative actions in various human breast cancer cells. In addition 2ME was able to increase the antiproliferative property of certain antihormones and cytostatic substances. Furthermore 2ME exhibits a similar property as compared to letrozole in inhibiting the aromatase activity. Since 2ME was well tolerated in a recently conducted phase II trial in patients with refractory metastatic breast cancer, the combination of 2ME with chemotherapeutics or antihormones may offer a new clinically relevant treatment regimen.

Genetic heterogeneity of breast cancer involves multiple alterations of oncogenes and tumour suppressor genes. These genetic alterations may be important for initiation and progression of this malignancy. In order to find a parameter useful for the prognosis of breast cancer, allelic imbalance at five loci on chromosome 17q was examined in 63 sporadic primary breast tumours. The loci are located in three distinct regions frequently deleted in sporadic breast tumours. Allelic imbalance was found in 48–62% of cancers. A significant correlation between allelic imbalance and five parameters associated with aggressive tumour behaviour was observed. Allelic imbalance was associated with aneuploidy, oestrogen and progesterone receptor negativity, positive lymph node status and high tumour grading. Our results support the evidence for the existence of several tumour suppressor genes on chromosome 17q and allow the presumption that allelic imbalance at chromosome 17q loci may be a useful prognostic parameter in breast cancer.

Aim: In locally advanced breast cancer pts (≥pN2), adjuvant iddETC resulted in superior disease-free (DFS) and overall survival (OS) compared to conventionally dosed EC > Tq3w (AGO-ETC; Mobus JCO 2010). In the GAIN trial, iddETC was compared to a 4-drug dose-dense regimen with capecitabine (ddEC > TwX). Using the GAIN data, here we want to confirm the iddETC-results of the AGO-ETC trial with regard to DFS, OS, and toxicity. Methods: In the AGO-ETC trial (1998-2003) 681 of 1,284, and in GAIN (2004-2008) 1,498 of 3,023 pts were treated with iddETC. Pts were included in AGO-ETC if ≥pN2 and in GAIN if ≥pN1; median number of positive nodes was 8 and 5, respectively; all other inclusion criteria were comparable. Median follow-up was 62 and 74 months, respectively, in both trials primary end point was DFS. IddETC consists of a sequence of 3 x E 150mg/m2, 3 x T 225 mg/m2, and 3 x C 2,5 g/m2 q2w, with primary G-CSF support. After 40% accrual in GAIN, a reduced dose of C (2,0 g/m2) and antibiotic prophylaxis was implemented. Pts were randomly assigned to anemia prophylaxis with ESF in AGO-ETC, and to adjuvant ibandronate in GAIN (von Minckwitz JCO 2013). Results: In the iddETC-arm of AGO-ETC, 5y-DFS was 70% (95% CI 68% - 75%) and 5y-OS was 82% (95% CI, 79%to 85%). Comparing to conventional EC > Tq3w, HR for DFS was 0.69 (95% CI, 0.57 - 0.84). In GAIN, 5y-DFS was 80% (95% CI 78% - 82%) and 5y-OS was 85%. DdEC > TwX was not superior to iddETC. Evaluating GAIN pts with ≥pN2 (n = 923) separately, in order to match with the AGO-ETC inclusion criteria, results were comparable: 5yr-DFS was 75% (95% CI 72% - 78%) and 5y-OS was 85% (95% CI 83% - 88%). In AGO-ETC, 47 pts (7%) had at least one episode of febrile neutropenia during iddETC, no toxic death was observed. In GAIN, three pts (0,2%) died from therapy related septicaemia during iddETC. In both trials, paclitaxel induced neuropathy was in the expected range, and no grade 3 congestive heart failure occurred. Treatment induced MDS/AML was rare in both, AGO-ETC (0,6%) and GAIN (0,3%). Conclusions: We consistently show high efficacy of adjuvant iddETC for node-positive breast cancer pts (≥pN2) in two consecutive prospective trials: DFS and OS-results were superior to those with conventionally dosed therapy. In the reported studies, iddETC was feasible without excessive toxicity. We suggest to add iddETC to the group of preferred regimens in current guidelines. Disclosure: C. Thomssen: has received compensated honoraria for presentations and participating in advisory boards from Roche, Amgen, Pfizer; G. von Minckwitz: has received research funds from Roche, BMS, Amgen, Speaker and consultancy honoraria from Roche and Amgen; H. Tesch: has received compensated honoraria from Roche; N. Harbeck has received compensated honoraria from Roche; V. Muller: has received speaker honoraria from Amgen, Celgene, Glaxo Smith Kline, Pierre-Fabre, Roche, Jannsen-Cilag I. Bauerfeind: speakers honoraria from Amgen and Bristol Myers Squibb; S. Loibl: has received compensated honoraria for presentations and participating in advisory boards from Roche, Amgen V. Moebus: has receivedCompensated honoraria from Amgen, Jannsen-Cilag, Roche for presentations and participation in advisory boards. All other authors have declared no conflicts of interest.

Aim: Neoadjuvant chemotherapy uses anthracycline/taxane based combinations of ≥18 weeks as standard treatment. Concurrent administration of trastuzumab in HER2+ disease achieves a pCR rate (ypT0 ypN0) of approx. 40%. Dual anti-HER2 blockade can increase the rate by another 20%. DAFNE (NCT015591477) investigates the combination of afatinib (BIBW 2992), an irreversible ErbB-family blocker with trastuzumab. Methods: DAFNE is a multicenter, prospective, open-label phase II study evaluating efficacy and safety of afatinib in combination with weekly paclitaxel + trastuzumab followed by epirubicin/cyclophosphamide/trastuzumab (ECH) as neoadjuvant therapy in untreated, centrally HER2 + , operable or locally advanced breast cancer patients. All patients were treated for 30 weeks: 6 weeks with afatinib (20mg) and trastuzumab (8/6mg/kg); 12 weeks with additional weekly paclitaxel (80mg/m2); and 12 weeks with ECH according to standard. Afatinib was given every other day for the first 2 weeks to reduce the risk of diarrhea and skin toxicities. Primary prophylaxis with loperamide 2x2mg daily was mandatory for the first 4 weeks of afatinib/trastuzumab and the first 2 weeks of paclitaxel. Primary objective is pCR rate (ypT0/is ypN0). Assuming a pCR rate of 70% with a = 0.1 and 80% power, a pCR of ≤55% should be excluded. Secondary objectives are pCR by other definitions, clinical response rates, rate and type of surgery, toxicity, compliance, pCR related to skin toxicity and diarrhea and pre-specified molecular markers. Results: 65 patients were recruited (5/2012 - 7/2013) in 11 German centers. Median age was 50 years. 9.4% had T3/4, 48.5% N + , 89.2% ductal invasive, 60% G3 and 70.8% HR+ tumors. Of the 22 SAEs (in 16 patients), 27.3% were gastrointestinal, 18.2% hematologic, 13.6% infections and 9.1% related to the nervous system. pCR rate was 49.2% (90% CI: 38.5; 60.1). Conclusions: Despite a tolerable safety profile of the dual blockade with afatinib, the pCR rate was lower than expected. A subsequent phase 3 study cannot be supported. Boehringer Ingelheim, Germany supported this trial. Disclosure: G. von Minckwitz: Research Grants: Boehringer-Ingelheim. All other authors have declared no conflicts of interest.