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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.

Purpose: The heterogeneity of response to anti-HER2 agents represents a major challenge in patients with HER2-positive breast cancer. To better understand the sensitivity and resistance to trastuzumab and lapatinib, we investigated the role of copy number aberrations (CNA) in predicting pathologic complete response (pCR) and survival outcomes in the NeoALTTO trial. Experimental Design: The neoadjuvant phase III NeoALTTO trial enrolled 455 patients with HER2-positive early-stage breast cancer. DNA samples from 269 patients were assessed for genome-wide copy number profiling. Recurrent CNAs were found with GISTIC2.0. Results: CNA estimates were obtained for 184 patients included in NeoALTTO. Among those, matched transcriptome and whole-exome data were available for 154 and 181 patients, respectively. A significant association between gene copy number and pCR was demonstrated for ERBB2 amplification. Nevertheless, ERBB2 amplification ceased to be predictive once ERBB2 expression level was considered. GISTIC2.0 analysis revealed 159 recurrent CNA regions. Lower copy number levels of the 6q23-24 locus predicted absence of pCR in the whole cohort and in the estrogen receptor–positive subgroup. 6q23-24 deletion was significantly more frequent in TP53 wild-type (WT) compared with TP53-mutated, resulting in copy number levels significantly associated with lack of pCR only in the TP53 WT subgroup. Interestingly, a gene-ontology analysis highlighted several immune processes correlated to 6q23-24 copy number. Conclusions: Our analysis identified ERBB2 copy number as well as 6q23-24 CNAs as predictors of response to anti–HER2-based treatment. ERBB2 expression outperformed ERBB2 amplification. The complexity of the 6q23-24 region warrants further investigation.

In der Gruppe der Mammakarzinome hat das triple-negative Mammakarzinom (TNBC, „triple-negative breast cancer“) das heterogenste Outcome und die schlechteste Prognose. Durch das Fehlen von Hormonrezeptoren und des HER2/neu(„human epidermal growth factor receptor 2“)-Rezeptor bestehen in der aktuellen klinischen Routine keine Zielstrukturen fur eine spezifische Therapie. Es erfolgte eine Literaturrecherche zur aktuellen Studienlage und vielversprechenden Therapieansatzen. In der kurativen Situation finden sich neue Ansatze in der Hinzunahme von Checkpointinhibitoren zusatzlich zur Standardchemotherapie. Ebenfalls gibt es mit Capecitabin analog der CREATE-X-Studie bei non-PCR eine postneoadjuvante Therapie. In der palliativen Situation findet man neben verschiedenen Chemotherapien einen Ansatz in der Testung von Tumorgewebe und der Keimbahn. Bei PD-L1(„programmed cell death 1 ligand 1“)-Positivitat kann auf den bereits zugelassenen Checkpointinhibitor Atezolizumab zuruckgegriffen werden. Bevacizumab ist auch bei manchen Patientinnen eine Option. Weitere mogliche Antikorpertherapien umfassen in Zukunft Pembrolizumab sowie die Antikorper-drug-Konjugate Sacituzumab-Govitecan und Trastuzumab-Deruxtecan. Bei einer Aktivierung des AKT/PI3K(Phosphoinositid-3-Kinase)-Signalwegs scheinen AKT-Inhibitoren wie Capivasertib oder Ipatasertib eine Option darzustellen. Bei BRCA-Positivitat stehen PARP(Poly[ADP-ribose]-Polymerasen)-Inhibitoren zur Verfugung. Trotz Fehlens der Hormonrezeptoren und des HER2/neu-Rezeptors bestehen mittlerweile mit der PD-L1-Testung, der Keimbahnanalyse und auch der Testung auf eine Aktivierung des AKT/PI3K-Signalwegs weitere zielgerichtete Therapieoptionen fur das TNBC sowohl in der kurativen als auch in der palliativen Situation.

Lange Zeit war eine Chemotherapie die einzige Therapieoption beim metastasierten triple-negativen Mammakarzinom. Mittlerweile hat sich das Therapiespektrum um die Substanzklasse der Immuntherapeutika erweitert, wobei basierend auf der IMpassion130-Studie der Checkpointinhibitor Atezolizumab bei positivem PD-L1-Status in der ersten Linie mit nab-Paclitaxel die Zulassung hat. Bei Vorliegen einer BRCA-Mutation erweitern die Poly(ADP-Ribose)-Polymerase-Inhibitoren (PARP-Inhibitoren) Olaparib und Talazoparib das therapeutische Spektrum nicht nur beim triple-negativen, sondern auch beim hormonrezeptorpositiven Her2-negativen metastasierten Mammakarzinom. Weitere vielversprechende Substanzen wie AKT-Inhibitoren und das Antikorper-Chemokonjugat Sacituzumab-Govitecan werden aktuell noch im Rahmen klinischer Studien untersucht.

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: Metastatic breast cancer (MBC) is usually an incurable disease and maintenance of quality of life (QoL) is one of the main aims of therapy. In patients with HER2-positive MBC taxane-based chemotherapy in combination with dual HER2 targeted therapy with trastuzumab and pertuzumab,is the standard of care. Adverse events are well-known side effects of any cytostatic treatment and can seriously impact the patients' QoL. The synergistic combination of dual HER2-targeted therapy with trastuzumab and pertuzumab plus endocrine therapy might offer a better treatment option for these patients. First clinical trials suggest an additional benefit when a CDK4/6 inhibitor is added to the combination of endocrine therapy and anti HER2 treatment. DETECT V is a randomized phase III study comparing the safety and efficacy of trastuzumab plus pertuzumab and the CDK 4/6 inhibitor ribociclib in combination with either endocrine therapy or chemotherapy. Trial design: Patients with HER2 positive and hormone-receptor positive MBC are 1:1 randomized to receive trastuzumab and pertuzumab combined with endocrine therapy and ribociclib or to chemotherapy with trastuzumab and pertuzumab followed by maintenance therapy with trastuzumab, pertuzumab, endocrine therapy and ribociclib. Chemotherapy and the endocrine agents can be chosen from a variety of available regimens according to the physicians discretion. Specific aims: The primary objective of this study is to compare safety and tolerability in both arms, as assessed by the occurrence of AEs during the treatment period. Secondary endpoints are progression free survival, overall survival, quality-adjusted survival using the quality-adjusted time without symptoms and toxicity (Q-TWiST) method. A translational program is included investigating detection and phenotyping of circulating tumor cells (CTC)-and the assessment of marker expression on CTCs in order to validate an endocrine responsiveness score. Present accrual and target accrual: The DETECT V trial started 2015 in the Dept. of Gynecology, University of Ulm and at the up to 120 sites in Germany. Until June 2018 97 patients with HER2-positive, hormone-receptor positive metastatic breast cancer have been enrolled. A sample size of 270 patients is planned. Contact information: Jens Huober, University of Ulm, Dept of Gynecology, Breast Center, jens.huober@uniklinik-ulm.de Sabrina Krause, University of Ulm, Dept of Gynecology, sabrina.krause@uniklinik-ulm.de Citation Format: Krause S, Friedl T, Fehm T, Romashova T, Fasching PA, Schneeweiss A, Müller V, Taran F-A, Polasik A, Tzschaschel M, De Gregorio A, Meier-Stiegen F, Janni W, Huober J. DETECT V/CHEVENDO – Comparison of dual HER2-targeted therapy with trastuzumab plus pertuzumab in combination with chemo- or endocrine therapy in addition with CDK4/6 inhibition in patients with HER2-positive and hormone-receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-01.

Background Even though patients with a pCR following neoadjuvant chemotherapy have an excellent prognosis still some of these patients will eventually relapse. A better identification of pts with an increased risk of relapse despite a pCR would be helpful to select these patients for additional post-neoadjuvant treatment strategies. Thus, the rationale of this retrospective analysis was to identify factors predicting relapse despite a pCR. Methods This pooled retrospective analysis based on the GBG meta-database includes the neoadjuvant trials GeparTrio, GeparQuattro, GeparQuinto, GeparSixto and GeparSepto. In these trials 2188 (27%) of 7933 pts had a pCR according to ypT0/ypTis ypN0 Definition and were included. The primary endpoint was disease-free survival (DFS), secondary endpoints were distant DFS (DDFS) and overall survival (OS). A multivariate Cox proportional hazards model was used to report hazard ratios with 95% confidence interval (CI). The two-sided significance level was set to α=0.05. Endpoints were analysed for all pts and in subgroups defined by intrinsic subtypes. The potential risk factors intrinsic subtype (HER2 negative/hormone receptor (HR) positive, triple negative, HER2 positive/HR positive, HER2 positive/HR negative), histological tumor type (lobular vs other), grade (G1/G2 vs G3), KI67 (≤20% vs higher), initial cT and cN stadium (cT1 vs cT2 vs cT3/4; cN0 vs cN+), age (≤40 vs 41-59 vs ≥60), BMI (< 25 vs 25-29 vs ≥ 30), planned number of cycles of chemotherapy (≤6 vs > 6), menopausal status (pre- vs postmenopausal) and clinical response after 2-4 cycles (SD vs PR vs CR vs PD) were included as covariates in multivariate Cox regression models as well as study identification. Results From 2188 evaluable patients DFS, DDFS and OS events were observed in 290/197/130 pts respectively; the median follow-up over all studies was 59 months. In multivariate analysis including study and all potential risk factors DFS was significantly different with regard to the initial cN status (cN+ vs cN0, hazard ratio (HR) 1.70; 95% CI [1.2, 2.4], p=0.002). Of borderline significance was histological type (non-lobular vs lobular, HR 0.52 95% CI [0.3, 1.1]; p=0.076) and initial tumor stage (cT3/4 vs cT1, HR 1.61 95% CI [1.0, 2.7]; p=0.064). In terms of DDFS significant differences were seen for the initial cN status (cN+ vs cN0, HR 2.34; 95% CI [1.5, 3.6], p Conclusions Initial tumor load before start of neoadjuvant chemotherapy (tumor stage and nodal status) and lobular subtype were predictors of long term outcome after a pCR following neoadjuvant chemotherapy. Intrinsic subtype, KI67, grade and planned number of cycles were not predictive for a relapse. Citation Format: Huober J, Schneeweiss A, Blohmer J-U, Denkert C, Tesch H, Hanusch CA, Salat C, Rhiem K, Rezai M, Solbach C, Fasching PA, Jackisch C, Mehta K, Nekljudova V, Seither F, von Minckwitz G, Loibl S, Untch M. Factors predicting relapse in early breast cancer patients with a pathological complete response after neoadjuvant therapy – Results of a pooled analysis based on the GBG meta-database [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-01.

Background: Further progress in the treatment of breast cancer will likely come from contributions of molecular biology and immunologic approaches. The search for druggable molecular aberrations may enable treatment based on the molecular profile. A better identification of patients with a high risk of relapse facilitates the selection of these pts for clinical trials investigating early therapeutic molecular-based interventions. Trial Design: The BRandO BiO Registry is a multi-center regional registry to record clinical, epidemiological, and biological data from patients with newly diagnosed breast and ovarian cancer at the University of Ulm, Dept. of Gynecology and 19 affiliated network hospitals and practices in the Alb-Allgäu Bodensee region (outreach area of the Comprehensive Cancer Center Ulm). Longitudinal biobanking is included with collection of paraffin-embedded samples of the primary tumor as well as blood samples at first diagnosis, after 6 and 12 months and at first relapse to isolate and investigate cell-free and germline DNA. Epidemiological, life style and quality of life (QOL) questionnaires are collected at first diagnosis, after 12, 36 and 60 months. The follow up is planned for 10 years. Eligibility criteria: Patients with primary newly diagnosed untreated breast or ovarian cancer of ≥ 18 years are eligible; primary metastatic untreated disease is allowed. Exclusion criteria comprise severe neurological or psychiatric disorders interfering with the ability to give an informed consent, no consent for registration, storage and processing of the individual disease characteristics and bio samples, and any malignant tumor in the last 3 years (except in situ disease). Specific aims: To register the majority of patients with newly diagnosed breast or ovarian cancer in all BRandO-BiO participating centers of a well-defined geographical area. To assess clinical characteristics and outcome data (event-free survival, overall survival) of these patients. To evaluate the primary tumor of all patients for mutational (druggable) aberrations. Further to assess cell-free DNA in the serial blood samples at baseline, 6 and 12 months and correlate these results with clinical outcome data as well as tumor and patient characteristics to look for early markers predicting relapse. To perform a longitudinal assessment of the patients' sociodemographic factors, comorbidities, lifestyle and QOL factors by analyzing serial questionnaires collected at recruitment and at 12, 36 and 60 months. Present accrual and target accrual: The BRandO BiO Registry started January 2016 in the Dept. of Gynecology, University of Ulm and February 2017 at the network hospitals and practices. Until June 2018, 1180 patients with primary breast or ovarian cancer have been enrolled. The current adherence to serial blood testing and serial questionnaires is good with a return rate of 90%. A sample size of 3000 patients is planned. Contact information: Jens Huober, University of Ulm, Dept of Gynecology, Breast Center, jens.huober@uniklinik-ulm.de Amelie de Gregorio, University of Ulm, Dept of Gynecology, Breast Center, Amelie.de Gregorio@uniklinik-ulm.de Citation Format: Huober J, Nagel G, Rempen A, Schlicht E, Flock F, Fritz S, Thiel F, Wiesmüller L, Felderbaum R, Heilmann V, Bekes I, Fink V, Albrecht S, De Gregorio N, Tzschaschel M, Ernst K, Wolf C, Kuhn P, Friedl T, Janni W, De Gregorio A. The BRandO BiO registry – A multicenter regional registry for patients with primary breast and ovarian cancer with longitudinal biobanking and evaluation of epidemiological, life style and quality of life factors [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-11-01.

Background: The GeparNuevo trial showed a numerical increase in the pCR rate to 53% vs 44%; p=0.281 compared to placebo in TNBC with the addition of the anti-PD-L1 antibody durvalumab to a neoadjuvant anthracycline-taxane containing chemotherapy (Loibl S et al. ASCO 2018). In a predefined subgroup analysis, a significant increase of the pCR rate was observed for patients that received durvalumab for 2 weeks alone prior to the start of chemotherapy in a window phase (61% vs 41%, p interaction=0.048), while the pCR rate was not increased for the subset of patients that did start durvalumab together with chemotherapy. Here we report the main results of the translational programme for GeparNuevo with a focus on mRNA signatures predictive for pCR in pretherapeutic core biopsies. Methods: A total of 162 baseline FFPE core biopsies were evaluable for expression of 2560 genes using the HTG EdgeSeq® system that combines a modified nuclease protection assay with next generation sequencing. Data was processed as recommended by the HTG and median transformed for further analyses. For differential gene expression analyses, the data was scale-normalized (TMM normalization; EdgeR package) and linear models were fit (limma package). Prior to these analyses, genes were filtered based on minimal expression (> 4) and variability (IQR > 1). As a first step, predefined immune-genes signature (TILs signature) (Denkert et al. JCO 2016) as well as IFN-gamma signatures were evaluated for correlation with pCR in logistic regression models. Subsequently, we performed a differential gene expression analysis according to therapy response for the durvalumab-arm and the placebo arm using the pre-filtered candidate genes. Gene names are not included in this abstract to allow filing of IP, but full gene names will be presented at the SABCS meeting. Results: The predefined TIL- and IFN-gamma signatures were associated with increased pCR rates in the complete cohort (TIL-signature: OR 1.44, 95% CI 1.15-1.82, p=0.002; IFN-Gamma-signature: OR 1.63, 95% CI 1.22-2.24, p=0.002) as well as in the durvalumab arm (p=0.012 and 0.042) and the placebo arm (p=0.050 and 0.011). These signatures were general pCR predictors without specificity for durvalumab response. Additional 44 genes were significantly (p Conclusion: Our results show that specific immune-related gene expression signatures predict response to durvalumab in primary triple negative breast cancer. The trial was financially supported by Astra Zeneca and Celgene Citation Format: Loibl S, Sinn BV, Karn T, Untch M, Treue D, Sinn H-P, Weber KE, Hanusch CA, Fasching PA, Huober J, Zahm D-M, Jackisch C, Thomalla J, Blohmer J-U, Marmé F, Klauschen F, Rhiem K, Felder B, von Minckwitz G, Burchardi N, Schneeweiss A, Denkert C. mRNA signatures predict response to durvalumab therapy in triple negative breast cancer (TNBC)– Results of the translational biomarker programme of the neoadjuvant double-blind placebo controlled GeparNuevo trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-07.

Background Studies leading to the approval of trastuzumab emtansine (T-DM1) have been conducted without pertuzumab as previous therapy. Therefore data about patient characteristics and the efficacy of T-DM1 after a treatment with pertuzumab is scarce. Aim of this study was to analyze a real world patient cohort of advanced breast cancer (aBC) patients, who were treated with T-DM1 after a treatment containing pertuzumab in the metastatic setting with regard to patient characteristics and progression free survival (PFS). Methods The PRAEGNANT metastatic breast cancer registry (NCT02338167) is a prospective registry for metastatic breast cancer patients with focus on molecular biomarkers. Patients of all therapy lines with any kind of treatment are eligible for this registry. Collected data comprises all relevant patient and tumor characteristics, therapies, adverse events, quality of life, patient reported outcomes, response and survival (PFS/OS). Here we report on the patient characteristics and PFS data for HER2 positive patients treated with T-DM1 after a treatment with pertuzumab. Patients had to be included before or at the beginning of the T-DM1 therapy. Results A total of 58 patients could be identified, who were suitable for the analysis. Of those 34 were treated in the second line, 14 in the third line and 10 in the fourth line or higher. Most of the pertuzumab therapies before T-DM1 were conducted in first line (n=46; 79.3%). Median PFS for all patients was 4.8 months (95% CI: 3.0-7.8 months). Median PFS for patients treated in the 3rdline and 4thline or higher was 4.2 months(95%CI: 2.3 - NA) and 4.0 months (95%CI: 1.8-N.A.), respectively. In patients treated 2ndline with T-DM1 PFS was 7.7 months (95%CI: 2.8 – 12.2). Conclusion T-DM1 is effective as 2ndand further line therapy following pretreatment with pertuzumab. Overall PFS was about 5 months with 7.7 months as 2nd-line therapy. The PFS in higher therapy lines might be shorter. As the sample size of this real world cohort was rather low and analyses have to be considered exploratory, this data need to be confirmed in studies with a larger sample size. Citation Format: Schneeweiss A, Lux MP, Hartkopf AD, Volz B, Kolberg H-C, Hadji P, Tesch H, Haeberle L, Ettl J, Lüftner DI, Wallwiener M, Müller V, Beckmann MW, Belleville E, Wimberger P, Hielscher C, Geberth M, Lermann J, Abenhardt W, Kurbacher C, Wuerstlein R, Thomssen C, Untch M, Overkamp F, Huober J, Taran F-A, Janni W, Wallwiener D, Brucker SY, Fasching PA, Fehm TN. Progression free survival (PFS) and overall survival (OS) of patients treated with trastuzumab emtansine (T-DM1) after previous treatment with pertuzumab in patients with advanced breast cancer (NCT02338167) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-22.

Purpose: This analysis describes comprehensive real-world data concerning the use of anti-HER2 therapies in HER2 positive metastatic breast cancer (MBC). Specifically, it describes the therapy patterns of treatments with trastuzumab (TZM), pertuzumab+trastuzumab (PTZ/TZM), lapatinib (LAP) and trastuzumab emtansine (T-DM1). Methods: The PRAEGNANT study is a real-time, real-world registry for patients with MBC. Patients can be registered for PRAEGNANT at any time during the course of their metastatic disease and are followed up until death. All therapy lines are documented. This analysis presents the utilization of anti-HER2 therapies as well as therapy sequences. Results: Of 1936 patients within PRAEGNANT at the time of database closure 451 were HER2 positive (23.3%). Within the analysis set (417 patients after an unilateral breast cancer diagnosis), of which 53% were included in PRAEGNANT in the 1stline setting, 241 were treated with TZM (58%), 237 with PTZ (57%), 85 with LAP (20%) and 125 with T-DM1 (30%) during the course of their therapies. The sequence PTZ/TZMàT-DM1 was given to 51 patients (12%). Worse ECOG, negative hormone receptor status, and visceral or brain metastases were associated with a more frequent use of this therapy sequence. Most patients received T-DM1 after a therapy with pertuzumab. Conclusions: Both novel therapies (PTZ/TZM and T-DM1) are utilized in a high proportion of HER2 positive breast cancer patients. As most patients receive T-DM1 after pertuzumab real world data might help to understand whether this sequence has similar efficacy like in the approval study. Citation Format: Lux MP, Hartkopf AD, Huober J, Volz B, Taran F-A, Overkamp F, Hadji P, Tesch H, Haeberle L, Ettl J, Lueftner DI, Wallwiener M, Müller V, Beckmann MW, Belleville E, Wimberger P, Hielscher C, Geberth M, Lermann J, Abenhardt W, Kurbacher C, Wuerstlein R, Thomssen C, Untch M, Fasching PA, Janni W, Fehm TN, Wallwiener D, Brucker SY, Schneeweiss A, Kolberg H-C. Therapy landscape of patients with metastatic, HER2 positive breast cancer - Data from the real world breast cancer registry PRAEGNANT (NCT02338167) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-37.

Background: The collaborative DETECT study program represents one of the largest study program on metastatic breast cancer worldwide. The main objective of the DETECT trial is to evaluate the efficacy of individualized breast cancer treatment based on the presence and phenotype setting of circulating tumor cells (CTCs). Thus, the DETECT study program is one of the first clinical trial translating the role of CTC enumeration/phenotyping directly into treatment intervention within different breast cancer subtypes. Trial design: The DETECT III trial is a multicenter, randomized, phase III study to compare standard therapy alone versus standard therapy plus lapatinib in patients with initially HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. Patients with persisting HER2-negative circulating tumor cells (CTCs) can be included within the DETECT IV trial, a prospective, multicenter, open-label, phase II study including patients with HER2-negative metastatic breast cancer. Within the DETECT IV study setting postmenopausal patients with hormone-receptor positive metastatic breast cancer are treated with everolimus or ribociclib and endocrine therapy, while women with triple negative metastatic breast cancer or a hormone-receptor positive tumor and indication for chemotherapy receive eribulin. Specific aims: The DETECT study program comprises all breast cancer subtypes and therefore offers various up-to-date treatment options, generating a wealth of clinical data including long-term follow-up data, evaluated in a controlled setting of a single large clinical trial. The primary endpoint of the DETECT III trial is the comparison of patients receiving standard anticancer therapy with lapatinib and patients receiving standard anticancer therapy alone, with regard to the CTC clearance rate. The secondary objective of this trial is to assess the level of compliance to study procedures comparing the efficacy of lapatinib between given treatment groups (Progression free survival, overall response rate and dynamic of CTCs). Primary objective of the DETECT IV trial is to evaluate CTC clearance rate within the everolimus/ribociclib cohort and additionally assess progression-free survival defined as time interval from date of recruitment until progressive disease within the eribulin cohort. The main focal point of the extensive collaborative translational oncology research projects is to apply innovative biomarkers and assays focusing on molecular characteristics of CTCs. This “biological status” may give new information about CTCs potential function as liquid biopsy in order to determine their relevance for therapy prediction. Citation Format: Krause S, Friedl T, Romashova T, Fasching PA, Schneeweiss A, Müller V, Taran F-A, Arkadius P, Marie T, De Gregorio A, Meier-Stiegen F, Huober J, Janni W, Fehm T. DETECT III/IV study trial – The multicenter study program in patients with HER2-negative metastatic breast cancer and circulating tumor cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-10-01.

IMPORTANCE: Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) likely benefits a subset of patients; however, determinants of benefit are poorly understood. OBJECTIVE: To define the association of molecular subtype, tumor proliferation, and immunophenotype with benefit of carboplatin added to NAC for patients with stages II to III TNBC. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of a phase 3, double-blind, randomized clinical trial (BrighTNess) that enrolled 634 women across 145 centers in 15 countries. Women with clinical stages II to III TNBC who had undergone pretreatment biopsy were eligible to participate. Whole transcriptome RNA sequencing was performed on the biopsy specimens. The prespecified end point was association of pathologic complete response (pCR) with gene expression–based molecular subtype, with secondary end points investigating established signatures (proliferation, immune) and exploratory analyses of immunophenotype. Data were collected from April 2014 to March 2016. The study analyses were performed from January 2018 to March 2019. INTERVENTIONS: Neoadjuvant chemotherapy with paclitaxel followed by doxorubicin and cyclophosphamide, or this same regimen with carboplatin or carboplatin plus veliparib. MAIN OUTCOMES AND MEASURES: Association of gene expression–based molecular subtype (PAM50 and TNBC subtypes) with pCR. RESULTS: Of the 634 women (median age, 51 [range, 22-78] years) enrolled in BrighTNess, 482 (76%) patients had evaluable RNA sequencing data, with similar baseline characteristics relative to the overall intention-to-treat population. Pathologic complete response was significantly more frequent in PAM50 basal-like vs nonbasal-like cancers overall (202 of 386 [52.3%] vs 34 of 96 [35.4%]; P = .003). Carboplatin benefit was not significantly different in basal-like vs nonbasal-like subgroups (P = .80 for interaction). In multivariable analysis, proliferation (hazard ratio, 0.36; 95% CI, 0.21-0.61; P

Abemaciclib; Adjuvant; Early breast cancer Abemaciclib; Adjuvant; Càncer de mama precoç Abemaciclib; Adyuvante; Cáncer de mama precoz Background Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. Patients and methods This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. Results At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. Conclusion Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period. This work was supported by the sponsor (Eli Lilly and Company) and designed together with the study Executive Committee (no grant number).

Background The efficacy and toxicity of olaparib as combination therapy in early breast cancer (BC) patients with homologous recombinant deficiency (HRD) [score high and/or germline (g) or tumour (t) BRCA1/2 mutation] is not well described. GeparOLA ( ClinicalTrials.gov , NCT02789332 ) investigated olaparib in combination with paclitaxel in HER2-negative early BC with HRD. Patients and methods Patients with untreated primary HER2-negative cT2-cT4a-d or cT1c with either cN+ or pNSLN+ or cT1c and triple-negative breast cancer (TNBC) or cT1c and Ki-67>20% BC with HRD were randomised either to paclitaxel (P) 80 mg/m2 weekly plus olaparib (O) 100 mg twice daily for 12 weeks or P plus carboplatinum (Cb) area under the curve 2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). Stratification factors were hormone receptor (HR) status (HR+ versus HR−) and age ( Results A total of 107 patients were randomised between September 2016 and July 2018; 106 (PO N = 69; PCb N = 37) started treatment. Median age was 47.0 years (range 25.0-71.0); 36.2% had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumours; grade 3 tumours: 86.8%; Ki-67>20%: 89.6%; TNBC: 72.6%; confirmed gBRCA1/2 mutation: 56.2%. The pCR rate with PO was 55.1% [90% confidence interval (CI) 44.5% to 65.3%] versus PCb 48.6% (90% CI 34.3% to 63.2%). Analysis for the stratified subgroups showed higher pCR rates with PO in the cohorts of patients Conclusion GeparOLA could not exclude a pCR rate of ≤55% in the PO arm. PO was significantly better tolerated and the combination merits further evaluation.

Background The predictive value of tumor mutational burden (TMB), alone or in combination with an immune gene expression profile (GEP), for response to neoadjuvant therapy in early triple negative breast cancer (TNBC) is currently not known, either for immune checkpoint blockade (ICB) or conventional chemotherapy. Patients and methods We obtained both whole exome sequencing and RNA-Seq data from pretreatment samples of 149 TNBC of the recent neoadjuvant ICB trial, GeparNuevo. In a predefined analysis, we assessed the predictive value of TMB and a previously developed immune GEP for pathological complete remission (pCR). Results Median TMB was 1.52 mut/Mb (range 0.02–7.65) and was significantly higher in patients with pCR (median 1.87 versus 1.39; P = 0.005). In multivariate analysis, odds ratios for pCR per mut/Mb were 2.06 [95% confidence intervals (CI) 1.33–3.20, P = 0.001] among all patients, 1.77 (95% CI 1.00–3.13, P = 0.049) in the durvalumab treatment arm, and 2.82 (95% CI 1.21–6.54, P = 0.016) in the placebo treatment arm, respectively. We also found that both continuous TMB and immune GEP (or tumor infiltrating lymphocytes) independently predicted pCR. When we stratified patients in groups based on the upper tertile of TMB and median GEP, we observed a pCR rate of 82% (95% CI 60% to 95%) in the group with both high TMB and GEP in contrast to only 28% (95% CI 16% to 43%) in the group with both low TMB and GEP. Conclusions TMB and immune GEP add independent value for pCR prediction. Our results recommend further analysis of TMB in combination with immune parameters to individually tailor therapies in breast cancer.

Background A-to-I RNA editing, a post-transcriptional modification of the RNA catalyzed by the ADAR family of enzymes, is emerging as a widespread phenomenon in breast cancer (BC). A-to-I RNA editing is more frequent in the highly repetitive Alu regions but can affect both coding and non-coding regions. It has been shown to greatly impact cell functionality. In a recent report, we have shown that A-to-I RNA editing is regulated both by ADAR copy number and type I interferon response (Fumagalli et al. Cell Rep 2015). The main aim of the current study was to investigate the extent and profile of A-to-I RNA editing in HER2+ BC patients (pts) treated in the NeoALTTO trial, and to explore its impact on pathologic complete response (pCR) and survival. Methods Aligned RNAseq reads of sufficient quality and quantity were obtained for 252 of the 455 pts enrolled in the study, as described previously (Fumagalli et al. JAMA Oncol 2016). Editing sites from the rediPortal database were assessed. The editing level at a given site was computed by counting the number of Gs and As. Sites with coverage more than 10 were considered for further analyses. Editing in normal tissues was obtained from the GTEx project of the rediPortal database. Tumor infiltrating lymphocytes (TILs) and copy number aberrations were previously reported. Correlations between different parameters were assessed using Spearman correlations (ρ). The Mann-Whitney test was used to relate binary and numerical features. Event-free survival (EFS) analysis was performed using the Cox proportional hazard model. Results There was a median of 71470 edited sites per sample. As expected, mean editing per sample correlated with ADAR expression (ρ=59%, p Conclusions Our study shows for the first time that deregulated RNA editing, as compared to editing in normal tissues, is a widespread phenomenon in HER2+ BC patients treated in the NeoALTTO trial and is associated with poor outcome. These results may provide new perspectives for the treatment of HER2+ disease by developing therapies targeting RNA editing. Citation Format: Venet D, Rothé F, Dupont F, Maetens M, Fumagalli D, Salgado R, Bradbury I, Pusztai L, Harbeck N, Izquierdo M, de la Pena L, Ignatiadis M, de Azambuja E, Huober J, Nuciforo P, Baselga J, Piccart M, Loi S, Sotiriou C. Deregulation of A-to-I RNA editing is associated with poor prognosis in HER2+ breast cancers in the neoALTTO trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-05-04.

Background In the NeoALTTO trial, the combination of trastuzumab and lapatinib for the neoadjuvant treatment of HER2 positive early breast cancer patients (pts) nearly doubled the rate of pathological complete response (pCR) compared with either anti-HER2 treatment alone. In the same trial, pCR was shown to be a surrogate for long-term outcome. Expression of ERBB2, ESR1 and immune signatures were the main drivers of pCR (Fumagalli et al. JAMA Oncol 2016). The main aim of the current study was to investigate the relevance of copy number aberrations (CNAs) for pCR and event-free survival (EFS). Methods For 271 out of the 455 pts enrolled in the study with sufficient tumour content, DNA was hybridized on CytoScan HD arrays. The log2 ratio intensities and B allele frequencies were segmented jointly using the multitrack segmentation algorithm. Integer level estimates of total copy number and major allele were obtained using GAP. Recurrent CNAs were found with GISTIC2. The genome instability index (GII) was defined as the median absolute deviation of the normalized copy number. Tumor infiltrating lymphocytes (TILs) and gene expression were obtained as described previously. The correlations between differents parameters were assessed using Spearman correlations (ρ). The Mann-Whitney test was used to relate binary and numerical features. EFS analysis was performed using the Cox proportional hazard model. Results CNAs estimates were obtained for 185 out of 271 pts. CNA distribution was similar to the ones observed in HER2+ pts from the METABRIC and the TCGA datasets. There were 64% of diploid pts, 26% of triploid and 9% of tetraploid or more. Aneuploidy level was not associated with pCR or EFS. Of interest, there were many significant differences in CNA profiles between ER+ and ER- pts. Those differences mirror those observed between ER+ and ER- among HER2- pts in TCGA (ρ=63%) and METABRIC (ρ=56%). ERBB2 amplification was predictive of high pCR (p=0.0007), albeit less so than ERBB2 expression, and ceased to be significant correcting for ERBB2 expression. The pCR rate increased with the GII (p=0.03), independently of ERBB2 amplification. The effect was stronger in ER+ patients (p=0.01). GISTIC analysis revealed 159 recurrent CNA regions. Amplification of 2 regions on 6q23-24 was significantly associated with higher pCR (p=0.00005 and p=0.00087, FDR=0.006 and 0.05). The most significant segment of 6q23-24 contained 39 genes, some whose expression level also predicted pCR (e.g. MAP3K5, p=10-4). Gene ontology analysis of the genes correlated with this segment highlighted the category 'response to interferon-alpha' (p=4.3x10-7). No amplified region or gene was found to be predictive of EFS, after multiple testing correction. Conclusions The amplification of ERBB2 was shown to be predictive of pCR, however its expression was more predictive. High genomic instability was associated with higher rate of pCR in ER+ subgroup. Of interest, a novel amplified region, involving chromosome 6 was shown to be predictive of pCR, which may warrant further investigation. Citation Format: Sotiriou C, Rothé F, Maetens M, Fumagalli D, Brown DN, Salgado R, Bradbury I, Pusztai L, Harbeck N, Ignatiadis M, Sarp S, de la Pena L, de Azambuja E, Huober J, Nuciforo P, Baselga J, Piccart M, Loi S, Venet D. Copy number aberration analysis to predict response to neoadjuvant anti-HER2 therapy: Results from the NeoALTTO phase III trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS1-04.

Introduction: Recent studies showed the high and independent impact of age (65 years) for NACT due to poor prognosis or higher toxicity. The aim of this analysis is to help selecting appropriately elderly women who would benefit from NACT. Secondly, survival parameters will be investigated in several clinical and histological subgroups. Methods: From 1998 to 2010, eight prospectively randomized German Breast Group (GBG) trials of anthracycline- and taxane-based NACT were performed and analyzed in this study. Results: Compared to the overall average, women older than 65 years had significant larger tumors and more overall lymph node involvement. Also, compared to patients younger than 51 years, they had more lobular invasive tumors. Histologically, they had more G2 tumors, more estrogen-receptor positive tumors. PCR (ypT0 ypN0) was strongly associated with age: >65y: 11.7%; 51-65y: 14.1%; 40-50y: 17.3%; 65years is a predictor of significant (p Discussion: This study underlines the unfavorable impact of higher age on pCR, but it shows nevertheless a realistic chance for pCR if NACT is applied - especially for HER2+ patients. Furthermore, elderly patients in this analysis with non-TNBC have a good prognosis (comparable to younger patients) regarding OS, even if they do not have pCR. Citation Format: von Waldenfels G, Loibl S, Furlanetto J, Anna M, Lederer B, Denkert C, Hanusch C, Huober J, Jackisch C, Kümmel S, von Minckwitz G, Schneeweiss A, Untch M, Rhiem K, Fasching PA, Blohmer JU. Outcome after neoadjuvant chemotherapy in elderly breast cancer patients – a pooled analysis of individual patient data from eight prospectively randomized controlled trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-15-03.

Background: Preclinical models suggest that in some HER2 overexpressed breast cancer cases, the extracellular domain of HER2, containing the binding region for trastuzumab (T) is not present due to proteolytic cleavage. Previous measurement of HER2 ECD and ICD in HeCOG 10/05 suggested that breast cancer cases that have low levels of ECD show decreased benefit from adjuvant T therapy (Carvajal et al, 2015). These cases may be more likely to show benefit from lapatinib(L), a small molecular tyrosine kinase inhibitor. NeoALTTO, an international multi-institutional trial comparing pre-surgical treatment with L vs T vs both, showed that pCR rates were around 25-30% for L or T but increased to 50% for both. This cohort allows us to test the hypothesis that patients with low ECD may benefit more from L than T. Methods: ECD and ICD were measured 382 cases using quantitative immunofluorescence (QIF) with domain specific antibodies (SP3, Spring biosciences for ECD and CB11, Biocare for ICD). Slides were stained and scanned, then measured using the AQUA method of QIF. All fields of view were scored and FOVs were averaged to generate a QIF score for each case. Index TMAs were used to standardize all autostainer runs and to define the QIF score cut-point that is equivalent to the clinical cut-point for the index TMA cases. Each case was then assigned to one of three groups; 1) High ECD and ICD, 2) Low ECD but High ICD, and 3) low ICD. Results: In the lapatinib arm, both group 1 and 2 showed a pCR rate of 25% (p>0.99), but in the trastuzumab arm, Group 1 pCR rate was 34% compared to 19% for group 2 (p=0.38). In the combination arm, group 1 showed a pCR rate of 59% compared to 29% for group 2 (p=0.046). In a logistic regression model for pCR, after adjustment for treatment arm and HR status the ECD/ICD status shows a significant predictive value (p = 0.002). Although this study is not powered for event free survival (EFS), at 6 years of follow up we found that patients in group 2 on the lapatinib arm show 92% EFS compared to 69% EFS in group 1 (p=0.17). The opposite trend is seen in both trastuzumab arms where EFS for group 1 on T showed 70% vs 62% for group 2 (p=0.57) and 77% vs 71% on the T+L arm (p=0.74). In a Cox regression model for EFS after adjustment for treatment arm and HR status, the ECD/ICD status is not significant (p=0.88) Conclusions: Cases with low levels of ECD compared to ICD appear benefit less than those with high levels of both ECD and ICD as assessed by pCR from treatments containing T. In contrast, those same patients also appear to benefit more, as assessed by EFS, on the L arm. These observations are consistent with the hypothesis that this assay could stratify benefit from L vs T based on the status of the ECD. Further assessment using this assay on the ALTTO cases is currently underway and may help confirm this observation. Citation Format: Rimm DL, Carvajal-Hausdorf D, Harbeck N, Fumagalli D, Rodrik-Outmezguine V, delaPena L, deAzambuja E, Huober J, Baselga J, Piccart M, Holmes E, Pusztai L. Low levels of HER2 extracellular domain (ECD) compared to intracelluar domain (ICD) in NeoALTTO may segregate benefit from lapatinib and trastuzumab in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-07.

This abstract was withdrawn by the authors.

BACKGROUND: As a neoadjuvant regimen for HER2-positive early breast cancer (BC), the use of two HER2-directed agents is more effective in producing pathological complete (pCR) responses than trastuzumab alone. Nevertheless, highly effective dual anti-HER2 combination may be unnecessary in patients who already benefit from a single agent. We previously reported that our 41-gene TRAR score is an accurate predictor of response to trastuzumab, with low scores being predictive of response to trastuzumab and favorable prognosis (Triulzi T. et al., 2015). PATIENTS AND METHODS: Tissue specimens from HER2-positive BC patients of Neo-ALTTO trial who received neoadjuvant trastuzumab and/or lapatinib plus paclitaxel were included in this study. Analysing RNA from fresh tissue using the 41-gene signature test, the area under the ROC curve (AUC) and the corresponding 95% confidence interval was computed to evaluate the predictive ability of TRAR score with respect to pCR, the primary endpoint of Neo-ALTTO. The prognostic role of TRAR score was investigated using a Cox regression model in univariate fashion. The patterns of Event Free Survival (EFS) according to the dichotomized TRAR score were estimated using the Kaplan–Meier method. RESULTS: The TRAR score was assessed for 226 of the 455 (49.7%) patients enrolled in the Neo-ALTTO study: 136 (60%) presented with T2 tumors, 188 (83%) with N0/1 and 128 (56.6%) with estrogen receptor negative BC. In details, basal TRAR score was available for 69, 79 and 78 patients assigned to neoadjuvant trastuzumab, lapatinib, and their combination, respectively. Overall, patients achieving a pCR showed significantly lower levels of TRAR score than those with residual disease (p CONCLUSION: Overall, we show that our 41-gene signature is accurate in predicting patient response to neoadjuvant HER2 targeted therapy in terms of pCR. In particular, low levels of TRAR score can identify a HER2-positive breast cancer subgroup highly responsive to trastuzumab as monotherapy for whom combination with other HER2-targeted drugs does not appear justified and may be one tool used for exploring de-escalating strategies without sacrificing outcomes. Citation Format: Di Cosimo S, Triulzi T, De Cecco L, Pizzamiglio S, de Azambuja E, Fumagalli D, Pusztai L, Harbeck N, Izquierdo M, de la Pena L, Huober J, Baselga J, Piccart M, Verderio P, Tagliabue E. Identifying clinically relevant subgroups of women with HER2-positive breast cancer: An analysis of Neo-ALTTO using the 41-gene TRAR score [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-03.

Background: The incidence of brain metastases (BM) in breast cancer patients is rising and has become a major clinical challenge. So far, the incidence of BM after modern neoadjuvant treatment is not clear. Materials and Methods: In Geparquinto, patients with untreated HER2-positive breast cancer (n=615) received either lapatinib or trastuzumab, patients with HER2 negative breast cancer (n=1925) received bevacizumab in addition to an anthracycline and taxane-containing regimen and those not responding paclitaxel and everolimus (n=32). In Geparsixto, patients with HER2-positive tumors (n=273) received trastuzumab and lapatinib and patients with triple-negative tumors (n=315) received bevacizumab in addition to chemotherapy. We analyzed clinical factors associated with the occurrence of BM as first site of metastatic relapse after neoadjuvant treatment in both trials (n=3160). Results: After a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed BM as first site of recurrence and 411 (13%) patients had distant metastases outside the brain. Brain metastases as first site of recurrence occurred later than other metastases (3--year-relapse free-rate 96.7% for patients who developed BM and 89.5% for patients who developed metastases outside the brain). Regarding subtypes of the primary tumor, 1% of luminal A (11/954), 2% of luminal B (7/381), 4% of HER2 positive (34/809) and 6% of triple-negative patients (56/1008) developed BM as first site of recurrence. In multivariate analysis, risk factors for the development of BM were larger tumor size (cT3-4; HR 1.9, 95%-CI 1.3-2.8, p=0.0022), node positive disease (HR 2.8, 95% CI 1.8-4.4, p Conclusion: Especially patients with HER2-positive and triple negative tumors are at risk of developing BM despite active systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies. Citation Format: Witzel ID, Laakmann E, Fasching PA, Rezai M, Schem C, Solbach C, Tesch H, Klare P, Schneeweiss A, Zahm D, Blohmer J, Ingold-Heppner B, Huober J, Hanusch C, Jackisch C, Reinisch M, Untch M, von Minckwitz G, Müller V, Loibl S. Development of brain metastases in breast cancer patients treated in the neoadjuvant trials Geparquinto and Geparsixto [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-17-01.

Background Breast Cancer registries can help to understand how patient groups are treated outside clinical trials and what outcome is to expected for specific patient groups and therapy lines, which are not included into clinical trials. Here we present overall survival data according to therapy lines, patient and tumor characteristics. Methods The PRAEGNANT metastatic breast cancer registry (NCT02338167) is a prospective registry for breast cancer patients with focus on molecular biomarkers. Patients of all therapy lines with any kind of treatment are eligible for this registry. Collected data comprises therapies, adverse events, quality of life and other patient reported outcomes. Here we report on the comparison of overall survival data for different patient groups. For that analysis was restricted to patients included in the first therapy line for subgroup comparisons. Only for the analysis of the effect of therapy line on overall survival the complete dataset was used. Results A total of 1854 patients took part in this analysis. Of those 1016 were included first line, and 340, 213 and 285 patients 2nd line, 3rd lin4 and 4th line or higher respectively. A total of 339 deaths were observed. Two year survival rates (2Y-OS) for these groups were 75%, 65%, 57% and 36% (p(log-rank) Conclusion This breast registry included patients over all therapy lines however mainly during the 1st line of therapy. Simple patient and tumor characteristics can classify patients into patients with differently favourable prognosis. Patients with HER2 positive disease had the best overall survival, while TNBC and luminal B like patients had the worst prognosis. As most of the patients were luminal A like 43% of all deaths occured within the group of luminal A like patients, which will need further focus for therapy development in the future. Citation Format: Taran F-A, Fasching PA, Volz B, Huober J, Overkamp F, Kolberg HC, Hadji P, Tesch H, Haeberle L, Ettl J, Lux MP, Hartkopf AD, Lueftner D, Wallwiener M, Müller V, Beckmann MW, Belleville E, Wimberger P, Hielscher C, Geberth M, Fersis N, Abenhardt W, Kurbacher C, Wuerstlein R, Thomssen C, Untch M, Janni W, Fehm TN, Wallwiener D, Brucker SY, Schneeweiss A. Overall survival of metastatic breast cancer patients – data from the PRAEGNANT breast cancer registry [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-09.

Background: The GeparNuevo trial is a randomized, double-blind, multi-center phase II trial of neoadjuvant therapy in patients with early-stage triple negative breast cancer (TNBC) investigating the role of durvalumab, an anti-PD-L1 antibody, which blocks PD-L1 binding to PD1 and CD80, in addition to standard anthracycline/taxane based chemotherapy (Loibl S et al. ASCO 2018). Methods: In order to determine possible predictive and / or prognostic biomarkers, blood samples were taken before and during the different treatment phases (3 or 4 time points) and evaluated by multicolor flow cytometry by monitoring the absolute cell counts of T cells, B cells and NK cells as well as the frequency, composition and functionality of different immune cell populations using a panel of 35 distinct antibodies. Results: Overall 174 patients were randomized into the GeparNuevo study. 117 patients participated in the window phase of this study and 49 patients provided evaluable material for flow cytometric analyses for material at the above specified time points. Evaluation of the absolute cell count in the whole blood prior and after therapy highlighted a mixed behavior of the total leukocytes. Overall, there was a statistically significant reduction in the lymphocyte count, particularly during the last phase of the treatment (ECdd +/- durvalumab). Further dissection into the different immune populations highlighted an almost complete loss of B cells, which in some patients was also accompanied by a reduction of NK cells, mainly of the CD16+ subset. The loss of CD4+ and CD8+ T cells was less pronounced resulting overall in an enhancement of their percentages within the total lymphocytes. In addition, the different populations have also been evaluated for the expression of PD-L1 activation and exhaustion markers. A pre-specified analysis clearly demonstrated a specific effect of durvalumab during the window phase with mean decreases of 21.7% and 15.0 % in PDL1+ lymphocytes in the CD4+ and CD8+ subgroups, respectively (P Conclusion: Using this approach we hope to identify biomarkers, which will allow a better selection of TNBC patients undergoing specific immunotherapies. Final data will be presented at the meeting. The trial and this translational research project were funded by AstraZeneca and Celgene, Germany. Citation Format: Massa C, Schneeweiss A, Karn T, Hanusch CA, Blohmer J-U, Fasching PA, Jackisch C, van Mackelenbergh M, Marmé F, Müller V, Schem C, Stickeler E, Huober J, Weber KE, Untch M, Denkert C, Loibl S, Mueller A, Biehl K, Seliger B. Immunomonitoring of triple negative breast cancer patients undergoing neoadjuvant therapy with durvalumab - Results from the prospectively randomized GeparNuevo trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-01.

Background Reduced quality of life during chemotherapy is often due to fatigue and dyspnea caused by chemotherapy-induced anemia. In breast cancer patients the incidence is estimated to be above 50% and rising during the course of treatment resulting as well in therapy delays. Despite red blood cell transfusion the administration of erythrocyte stimulating factors (ESF) serves as a treatment option. In comparison with conventional chemotherapy intense dose dense regimens have proven to be beneficial in high-risk breast cancer patients, but higher incidences of anemia have been reported. In the GAIN trial two dose dense regimens were evaluated and patients received either Darbepoetin alfa or Epoetin beta. The aim of this subanalysis was to analyse the efficacy and safety of the application of two different ESF during adjuvant chemotherapy for primary node positive breast cancer. Methods Patients were randomly assigned to receive three courses each of epirubicin (E), paclitaxel (T), cyclophosphamide (C) all given at 2-week intervals i.v. (idd ETC-regimen) or ddEC followed by paclitaxel weekly (Tw) plus capecitabine (X)(EC-TX-regimen).All patients received either primary prophylaxis with Epoetin beta (Epo) (450IE/kg weekly) or Darbepoetin alfa (D) (4,5μg/kg biweekly).Allocation happened alternately by date of randomization. Patient outcome (rate of anemia and thromboembolic events, disease free survival (DFS), overall survival (OS)), overall and by regimen were compared according to ESF type applied and in subgroups defined by age. Results 2994 patients were randomized to receive one of the dose dense chemotherapies and of these 1482 patients were given Darbepoetin alfa and 1512 received Epoetin beta. In the trial 84.7% of patients suffered from anemia in the Darbepoetin as well as in the Epoetin group and grade 3/4 anemia was observed in 3.6% vs 3.1% of patients, respectively. In the ETC arm anemia rates, especially grade 3/4 were slightly higher, but there was no significant difference within the treatment arms according to ESF applied (anemia any grade: D 86.1% vs. Epo 87.2%; EC-TX: D 83.2% vs. Epo 82.3%). In the ETC arm anemia was most frequently observed in patients aged 60+ years, but there was no significant difference between the ESF (D 90.5% vs. Epo 89.8%). No significant differences in the incidence of anemia by ESF treatment were observed in various age groups of the EC-TX arm. Thromboembolic events occurred in 9.1% in the Darbepoetin group and in 10.1% of patients treated with Epoetin (p=0.355). Interestingly there were more thromboembolic events in the EC-TX arm compared to the ETC arm (p OS and DFS analyses showed no difference between ESF treatment overall as well as stratified by chemotherapy regimen. Conclusion High risk breast cancer patients treated with two different dose dense chemotherapy schedules have comparable incidences of anemia, thromboembolic events and a similar long term outcome if they receive a preventive treatment with either Darbepoetin alfa or Epoetin beta. The trial is financially supported by Amgen and Roche. Citation Format: van Mackelenbergh M, Loibl S, Jackisch C, Lück H-J, Schneeweiss A, Tesch H, Harbeck N, Schmatloch S, Fehm T, Huober J, Müller V, Bauerfeind I, Untch M, von Minckwitz G, Nekljudova V, Möbus V. Efficacy and safety of darbepoetin alfa or epoetin beta in 2994 high risk early breast cancer patients participating in the German adjuvant intergroup node-positive study (GAIN) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-04.

This abstract was withdrawn by the authors.

Background:Anti-HER2 agents are associated with an increased risk of cardiotoxicity, occurring mostly during treatment and being generally reversible. To date, no cardiac biomarkers have been validated as predictive markers of cardiotoxicity in patients (pts) receiving anti-HER2 therapies. We evaluated high sensitivity (HS) troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in pts treated with neoadjuvant anti-HER2 therapies to evaluate if early elevation of cardiac biomarkers predicts early or late cardiac events. Material and Methods: 455 pts were randomized to receive either lapatinib (154 pts), trastuzumab weekly (149 pts), or lapatinib with trastuzumab for a total of 6 weeks (152 pts). After this biological window, pts continued on the same targeted therapy plus 12-weekly paclitaxel until definitive surgery. After surgery, patients received adjuvant FEC (3x) followed by the same HER2 therapy as in the neoadjuvant phase for further 34 weeks (to complete 52 weeks in total). Eligible pts had an LVEF ≥50%. Cardiac biomarkers were centrally tested in plasma samples collected at baseline, week 2 (W2) and at surgery. Elevated biomarker was defined as either TNT >0.015 μg/L or NT-proBNP >125 pg/mL. The small number of pts and rarity of marker elevations allowed only descriptive analyses. Results: At a median follow-up of 3.8 years, 280 pts had cardiac biomarkers tested at baseline (61.5%) and NT-proBNP was elevated in 39 pts (13.9%) while TNT was elevated in only 1 pt (0.35%). From those 39 pts with NT-proBNP elevated at baseline, only 1 pt experienced a cardiac event. Also, hypertension was presented in 14 pts (24.5%) with elevated NT-proBNP. Serial measurements were available in 173 pts (61.7%) and NT-proBNP was elevated in 25, 10 and 21 pts at baseline, W2 and at surgery, respectively, while among 171 pts (61%) TNT was elevated in 1, 1 and 5 pts, respectively. There were 13 cardiac events in 11 pts in the entire trial. Five of these pts had a measurement of cardiac biomarkers at baseline (non-elevated NT-prBNP and TNT were observed in 4 and 5 pts), 9 of them had a measurement at week 2 (non-elevated NT-prBNP and TNT were observed in 8 and 9 pts) and 3 of them at surgery (non-elevated NT-prBNP and TNT were observed in 3 and 3 pts), respectively. The following table show the low specificity of the cardiac biomarkers. Patients without cardiac event (N)Patients with cardiac event (N)Patients with elevated markerElevated NT-proBNP Baseline38139Week 229130Surgery40040Elevated TNT Baseline101Week 2101Surgery606 During adjuvant phase, 13 pts experienced LVEF drop to Conclusions: Despite the small sample size, we demonstrated that cardiac biomarkers are rarely elevated in pts receiving anti-HER2 therapies, which is probably due to the absence of myocyte necrosis with respect to TNT, and the lack of chamber dilation in the case of NT-proBNP after exposure to these drugs. In addition, few cardiac events were present in this population not previously exposed to anthracycline-based chemotherapy; therefore the use of cardiac biomarkers in this population may be unnecessary. Citation Format: de Azambuja E, Bradbury I, Ewer M, Campbell C, Zardavas D, Ameels H, Baselga J, Huober J, Izquierdo M, Bozovic-Spasojevic I, Maetens M, Harbeck N, Pusztai L, Piccart M, Rodeheffer R, Sutter T. Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib-induced cardiotoxicity in patients with HER2 positive early breast cancer (BIG 1-06) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-09.

Background: Tumor-infiltrating lymphocytes (TILs) have been shown to be predictive for response to neoadjuvant therapy, in particular in triple-negative and HER2 positive breast cancer, suggesting that subtypes of breast cancer are immunogenic. The role of TILs in luminal breast cancer as well as the impact on prognosis in the different subtypes is less clear. In this study we evaluated TILs in a total of 3771 breast carcinomas from 6 prospective neoadjuvant clinical trials and evaluated their relevance for pCR, DFS and OS in different molecular subtypes. Methods: A total of 3771 tumors from the clinical studies GeparDuo, GeparTrio, GeparQuattro, GeparQuinto, GeparSixto, GeparSepto were evaluated for stromal TILs by standardized methodology. Data on pCR were available for all tumors, DFS and OS was available for 2560 tumors. Logistic regressions, Cox regressions and Kaplan-Meier analyses were performed. In addition, a combined analysis of pCR, survival and TILs in different subtypes was performed. Results: In the complete cohort of 3771 tumors, increased TILs (>=60%) were observed in 19% of tumors, these tumors with >=60% TILs had a pCR rate of 44% (p=60%) were observed in 30% of TNBC (n=906), in 19% of HER2+ tumors (n=1379) and in 13% of HR+/HER2- tumors (n=1366). In all three subtypes, increased TILs were significantly associated with increased pCR rates (p=60%) were associated with worse survival in Kaplan-Meier analysis in luminal tumors (DFS: p=0.04, OS: p Conclusion: Our results suggest that tumor-infiltrating lymphocytes are a strong predictive marker for response to neoadjuvant chemotherapy in all molecular subtypes, and this predictive effect is translated into a survival benefit in HER2+ BC and TNBC. In contrast, a survival benefit is not observed in luminal BC, suggesting a different biology of the immunological infiltrate in this subtype. Citation Format: Denkert C, von Minckwitz G, Darb-Esfahani S, Ingold Heppner B, Klauschen F, Furlanetto J, Pfitzner B, Huober J, Schmitt W, Blohmer J-U, Kümmel S, Engels K, Lederer B, Schneeweiss A, Hartmann A, Jakisch C, Untch M, Hanusch C, Weber K, Loibl S. Evaluation of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarker in different subtypes of breast cancer treated with neoadjuvant therapy - A metaanalysis of 3771 patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-09.

Background The estrogen receptor (ER) as a nuclear transcription factor alters the transcription of estrogen sensitive genes to which the progesterone receptor gene belongs. The ER has also been described to exert non genomic effects by interacting with several cell signalling pathways that do not initially involve increases in gene transcription. These different patterns of action of the ER lead to the assumption that in tumors that utilize the non-genomic ER activity in order to stimulate tumorigenesis and proliferation progesterone receptor (PgR) expression would be decreased or absent. Therefore lack of PgR expression could be a surrogate marker of altered growth factor signalling. The aim of this study was to investigate if PgR expression may act as a predictive factor for response to neoadjuvant chemotherapy and long-term outcome in breast cancer patients. Methods 5613 patients with primary breast cancer, follow-up, positive ER expression; HER2+ and HER2- from overall 10 (n=9785) German neoadjuvant trials receiving an anthracycline and taxane based chemotherapy were included. The pathologic complete response (pCR)(ypT0, ypN0), long term survival data (disease free survival (DFS), distant disease free survival (DDFS), overall survival (OS) and local recurrence free survival (LRFS)) and early relapse, defined as DFS Results Tumors lacking PgR expression (1172 patients) were more often of grade 3 (38.4% v 26.3%; p pCR rates were significantly higher in PgR negative patients in the entire cohort (13.8% v 7.5%; p PgR negativity was also significantly associated with an early relapse overall (32.8% v 25.7%; p Patients with PgR negative disease had a significantly worse DFS, OS, DDFS and LRFS (p Conclusion This analysis demonstrates that ER positive and PgR negative tumors represent a specific subset in primary breast cancer patients associated with higher response but also worse long term outcome after neoadjuvant chemotherapy. Interestingly, PgR negativity served as an independent predictive factor for achieving a pCR after neoadjuvant chemotherapy and therefore its status should be considered when deciding on systemic treatment. Citation Format: van Mackelenberg M, Denkert C, Nekljudova V, Karn T, Schem C, Marme F, Stickeler E, Jackisch C, Hanusch C, Huober J, Fasching P, Blohmer J-U, Kümmel S, Müller V, Schneeweiss A, Untch M, von Minckwitz G, Weber K, Loibl S. Outcome after neoadjuvant chemotherapy in progesterone receptor negative breast cancer patients – A pooled analysis of individual patient data from ten prospectively randomized controlled neoadjuvant trials [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-11.

Background: We previously demonstrated that the majority of women ≤45 years experienced chemotherapy-induced ovarian failure (CIOF) after CT for EBC. Age, CT regimen, duration and dose-density influenced the rate of CIOF. The regain of premenopausal Follicle-Stimulating Hormone (FSH) and Estradiol (E2) levels after chemotherapy is not equivalent to fertility restoration. The Anti-Muellerian Hormone (AMH) assessment seems to be more accurate than other hormones in predicting the ovarian reserve. FSH, E2 and AMH have been prospectively assessed in young patients receiving (neo)adjuvant CT. Methods: 740 patients (pts) aged ≤45yrs treated with anthracycline or taxane-based CT for EBC from 4 German neoadjuvant/adjuvant trials were included. Blood samples were collected at baseline before CT (N=740), end of treatment (EOT n=740), 6 (n=177), 12 (n=113), 18 (n=69), 24 (n=47) months (m) after EOT. Only the full set of samples of a given patient was included. FSH, E2 and AMH were centrally assessed. Postmenopausal hormone levels of FSH and E2 according to the central laboratory were defined as FSH>12.4IU/l and E2 Results: Median age was 40yrs (range 21-45); 57.2% had BMI 18.5- Conclusion: Nearly 70% of women regain premenopausal hormone levels of FSH and E2 within 2 years after end of CT. Despite that, only less than one third maintain their fertility potential as predicted by AMH. AMH is a very sensitive marker for the prediction of fertility function after CT for EBC. Table 1 Median and range of FSH, E2 and AMH levels per time pointsTimepointFSH,IU/lE2, ng/mLAMH, ng/ml% of pts with AMH levels above dtBaseline6.0 [dt-142.7]88.0 [dt-2375.0]0.96 [dt-16.18]95.4EOT76.1 [1.9-225.0]dt [dt-632.0]dt [dt -3.11]15.66 m41.4 [1.1-190.6]10.0 [dt-929.0]dt [dt -3.11]26.112 m28.7 [1.1-146.0]11.0 [dt-947.0]dt [dt -2.81]29.218 m20.6 [0.8-172.3]19.0 [dt-624.0]dt [dt -1.89]34.824 m16.30 [dt-93.9]44.0 [dt-11795.0]dt [dt -1.75]38.3Abbreviations: dt, detectable threshold, EOT, end of treatment; m, month; pts, patients. Detectable threshold: FSH Citation Format: Furlanetto J, Thode C, Huober J, Denkert C, Bassy M, Hanusch C, Jackisch C, Kümmel S, Schneeweiss A, Untch M, Fasching PA, Karn T, Marmé F, van Mackelenbergh M, Müller V, Schem C, von Minckwitz G, Strik D, Nekljudova V, Loibl S. Changes in hormone levels (E2, FSH, AMH) and fertility of young women treated with neoadjuvant chemotherapy (CT) for early breast cancer (EBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD7-09.