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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.

Background: We have previously shown that expression of the IL8/VEGFA-metagene eliminates the good prognostic effect of TILs in TNBC (PMID 21978456, 28750120). We also showed that the VEGFA metagene predicted response to neoadjuvant bevacizumab in the GeparQuinto trial (Karn 2017 SABCS #851166). The main cellular sources of the transcripts that comprise the VEGFA metagene are unknown since mRNA profiling of bulk biopsies contains signals from different cell types. Methods: Individual genes that comprise the VEGFA metagene were measured in bulk tissue- and single cell-RNA-Seq from breast cancer subtypes and normal cells on different platforms (Affymetrix n=4915, Agilent n=597, Illumina n=2433, RNA-Seq n=1215, Exome Capture RNA-Seq n=226, HTG-Seq n=243, sc-RNA-Seq n=24710). For blinded, orthogonal validation we performed immunohistochemistry. Effect of neoadjuvant chemotherapy with or without bevacizumab was studied by RNA-Seq and IHC on samples from GeparQuinto trial. SWOG S0800 (GSE114403), PROMIX (GSE87455), and GeparSixto trials were used for validation. TCGA was mined for mutations and somatic CNA. RNA-Seq from GeparNuevo was used for correlation with checkpoint inhibitor treatment. Results: We identified a stable core of six genes (VEGFA, ANGPTL4, ADM, NDRG1, DDIT4, CSTB) in different cohorts. Strong expression of this signature was mainly restricted to TNBC subtype and associated with poor prognosis within this subgroup. Single cell RNA-Seq of breast epithelial cells from 4 reduction mammoplasties and 4 TNBC revealed that these genes are coexpressed in individual epithelial cells and not associated with endothelial cells. In line with their presumed functions in cellular stress and hypoxia, immunohistochemistry revealed strong para-necrotic expression in TNBC. Moreover, high gene expression in TNBC was associated with mutations in DNA damage control pathways, somatic copy number alterations, and lower TILs. While chemotherapy led to downregulation, bevacizumab increased expression. In multivariate analysis, high pretreatment values predict pCR to both bevacizumab and chemotherapy (OR 2.40, P=0.006), which may be explained by sensitivity of tumors which are already under cellular stress. On the other hand, expression of the VEGFA metagene seems to create an immunosuppressive environment that counteracts the positive prognostic effect of TILs. In pre-treatment biopsies from the GeparNuevo checkpoint inhibitor trial we found a negative correlation of VEGFA metagene expression with the amount of the recently identified tissue-resident memory T cell subset (CD8TRM, PMID 29942092; P=0.002), while the subsequent increase of CD8TRM during treatment was larger in tumors with high VEGFA (P=0.019). Conclusions: Perinecrotic carcinoma cells under stress from hypoxia and or chromosomal instability are the source of the VEGFA metagene signature. Its predictive value in TNBC suggests estimating and reporting the amount of necrosis in the pathology report may be helpful in predicting response to preoperative chemotherapy, and could be used as stratification factor in clinical trials. The signature indicates an immunosuppressive environment and should be further studied in the context of immune therapies in combinations with anti-angiogenic treatment. Citation Format: Karn T, Denkert C, Sinn BV, Weber K, Nekljudova V, Rody A, Meissner T, Hatzis C, El-Balat A, Becker S, Solbach C, Untch M, Schneeweiss A, von Minckwitz G, Loibl S, Pusztai L, Holtrich U. Single-cell profiling identifies hypoxic carcinoma cells as source of an immunosuppressive VEGFA metagene [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 P3-10-01.

Background: In node negative and 1-3 positive nodes breast cancer patients with hormone receptor positive (HR+), HER2-negative (HER2-) early-stage breast cancer the indication for chemotherapy is based on clinical and pathologic risk stratification (tumor size, nodal status, grading, quantitative ER, progesterone receptor and Ki67). For further decision-making, the EndoPredict test, which combines a molecular signature with the clinical risk factors tumor size and nodal status, stratifies patients into “low risk" or “high risk” groups. Level I-B- evidence demonstrates, that EndoPredict predicts the 10 year cumulative risk of relapse and metastases in patients with HR+/HER2- primary breast cancer with endocrine treatment. Aim: In the RESCUE-Trial we document distant metastasis-free survival (DMFS), disease free survival (DFS) and overall survival (OS) events in patients who had an EndoPredict test. The primary objective is to show that 10-year DMFS of patients tested as “low risk” by EndoPredict and treated with adjuvant endocrine therapy alone is >90 %. Secondary endpoints among others include DMFS, DFS, OS in patients with EPclin “low risk” versus “high risk”. Also the proportion of patients whose treatment was concordant and non-concordant with EndoPredict test results, will be analyzed for survival. The prognostic performance of classical prognostic factors (like tumor size, nodal status, grading, quantitative ER, progesterone receptor and Ki67 level) with respect to survival will also be assessed. Eligibility: Patient with HR+/HER2- primary invasive breast cancer stage I/II and T1 to T3 with 0 to 3 positive lymph nodes will be eligible, if they had an EndoPredict test within three months before inclusion. Methods: The EndoPredict test results, tumor board decision and anti-tumor therapy will be assessed. After one year, annually (for 10 years), patients will be evaluated for treatment compliance, recurrence, metastases, and survival. The primary endpoint will be analyzed by a Kaplan-Meyer estimate for which a one-sided lower 95 % confidence interval will be given. Several secondary endpoints will be assessed in three interim analyses after completion of the 1st, 3rd, 5th year and then finally after 10 years. Accrual: Start of accrual is planned for July 2018. At least 26 sites in Germany and one site in Switzerland will be active. Sponsor: The study is sponsored by the North-Eastern-German Society of Gynecological Oncology (NOGGO) e.V. Contact Information: For further information, contact NOGGO via studies@noggo.de or the leading physician Dr. Johannes Ettl via johannes.ettl@tum.de. Citation Format: Ettl J, Blohmer J-U, Denkert C, Keller M, Klein E, Kronenwett R, Neuser P, Paepke S, Schade-Brittinger C, Schnuppe K, Untch M, Wittenberg M, Kiechle M. RESCUE: Reaching for Evidence-baSed Chemotherapy Use in Endocrine sensitive breast cancer - A prospective health care study on risk assessment by the clinicomolecular test EndoPredict® and long-term patient outcome in early luminal 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 OT1-12-03.

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: 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: Currently, patients with breast cancer (BC) with hormone receptor (HR) immunohistochemical expression between 1-9% are eligible to receive endocrine therapy. However, recent data suggest that these tumors express a basal-like molecular phenotype associated with triple negative BC (TNBC) rather than luminal phenotype associated with HR positive BC. Here, we aimed to determine the differences between strong HR positive, low HR positive and negative HR BC, in regard to responsiveness to neoadjuvant chemotherapy (NACT) and disease free survival (DFS) in large cohorts from GBG clinical trials. Methods: In this retrospective analysis of data from women with BC treated in the neoadjuvant GeparQuinto (n=2572), GeparSixto (n=588) and GeparSepto (n=1206) clinical trials, we compared patients with three HR phenotypes: low positive (ER and/or PR= 1-9%), strong positive (ER or PR= 10-100%), and negative (ER and PR= Results: Patients median age was 49 years, the majority had clinical tumor stage 2 (54.1%), negative nodal status (54.7%), and Her2 negative tumors (72.4%). 85.1% of women had BC classified as no special histological type. The pCR rate across the studies was 26.2%. 145 (3.4%) patients had low HR positive, 2417 (57.3%) strong HR positive and 1658 (39.3%) HR negative tumors. After NACT, 16.3% of patients with strong HR positive BC achieved a pCR, while among those with HR negative and low HR positive tumors, pCR rates were 40.2% and 37.9%, respectively (p Conclusions: Similarly to patients with negative HR tumors, patients with low HR positive tumors have a better responsiveness to NACT and worse survival rates, compared to patients with strongly HR positive BC. We suggest that studies on treatment options for basal-like/TNBC, should also consider including patients with low HR positive tumors. Citation Format: Villegas SL, Lederer B, Untch M, Holms F, Ulmer H-U, Diebold K, Fasching PA, Weber K, Schmitt WD, Tesch H, Rezai M, Marmé F, Sinn B, Hackmann J, Schneeweiss A, Tannapfel A, Nekljudova V, Denkert C, Loibl S. Similarities between low hormone receptor positive and hormone receptor negative breast cancer: An analysis of 4366 patients from multicenter clinical trials [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 P2-08-10.

Up to 40% of patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer develop brain metastases (BMs). Understanding of clinical features of these patients with HER2-positive breast cancer and BMs is vital.A total of 2948 patients from the Brain Metastases in Breast Cancer registry were available for this analysis, of whom 1311 had primary tumors with the HER2-positive subtype.Patients with HER2-positive breast cancer and BMs were-when compared with HER2-negative patients-slightly younger at the time of breast cancer and BM diagnosis, had a higher pathologic complete response rate after neoadjuvant chemotherapy and a higher tumor grade. Furthermore, extracranial metastases at the time of BM diagnosis were less common in HER2-positive patients, when compared with HER2-negative patients. HER2-positive patients had more often BMs in the posterior fossa, but less commonly leptomeningeal metastases. The median overall survival (OS) in all HER2-positive patients was 13.2 months (95% confidence interval 11.4-14.4). The following factors were associated with shorter OS (multivariate analysis): older age at BM diagnosis [≥60 versus60 years: hazard ratio (HR) 1.63, P0.001], lower Eastern Cooperative Oncology Group status (2-4 versus 0-1: HR 1.59, P0.001), higher number of BMs (2-3 versus 1: HR 1.30, P = 0.082; ≥4 versus 1: HR 1.51, P = 0.004; global P = 0.015), BMs in the fossa anterior (HR 1.71, P0.001), leptomeningeal metastases (HR 1.63, P = 0.012), symptomatic BMs at diagnosis (HR 1.35, P = 0.033) and extracranial metastases at diagnosis of BMs (HR 1.43, P = 0.020). The application of targeted therapy after the BM diagnosis (HR 0.62, P0.001) was associated with longer OS. HER2-positive/hormone receptor-positive patients showed longer OS than HER2-positive/hormone receptor-negative patients (median 14.3 versus 10.9 months; HR 0.86, P = 0.03), but no differences in progression-free survival were seen between both groups.We identified factors associated with the prognosis of HER2-positive patients with BMs. Further research is needed to understand the factors determining the longer survival of HER2-positive/hormone receptor-positive patients.

Purpose Evaluating consecutive early breast cancer patients, we analyzed both the impact of EndoPredict® on clinical decisions as well as clinico-pathological factors influencing the decision to perform this gene expression test. Methods Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative early breast cancer patients treated between 2011 and 2016 were included in this study to investigate the role of EndoPredict® (EPclin) in the treatment of early breast cancer. A main study aim was to analyze the changes in therapy recommendations with and without EPclin. In addition, the impact of clinico-pathological parameters for the decision to perform EPclin was examined by Pearson's chi-squared test (χ2-test) and Fisher's exact test as well as univariate and multivariate logistic regressions. Results In a cohort of 869 consecutive early HR-positive, HER-negative breast cancer patients, EPclin was utilized in 156 (18.0%) patients. EPclin led to changes in therapy recommendations in 33.3% (n = 52), with both therapy escalation in 19.2% (n = 30) and de-escalation in 14.1% (n = 22). The clinico-pathological factors influencing the use of EPclin were age (P

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.

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.

This abstract was withdrawn by the authors.