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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: We previously reported that nab-paclitaxel (nP) increases the pathological complete response (pCR, ypT0 ypN0) rate when it replaces solvent-based paclitaxel (P) as part of a sequential taxane followed by epirubicin/cyclophosphamide (EC) neoadjuvant chemotherapy for patients with early breast cancer (Untch et al. SABCS 2014). Here, we report efficacy and safety of patients being treated either with 150 mg/m2 nab-paclitaxel (nP150) before an amendment or with 125 mg/m2 nab-paclitaxel (nP125) thereafter in comparison to solvent-formulated paclitaxel at 80 mg/m2 (P80). Methods: In the GeparSepto study (NCT01583426), 1207 patients were randomized to either nP150 or P80 q1w for 12 weeks followed by 4 cycles of conventionally dosed EC (E: 90mg/m2; C: 600 mg/m2) q3w. The primary objective of the study was to compare the pCR rate (pCR, ypT0 ypN0). Patients with untreated, histologically confirmed uni- or bilateral, cT2- cT4d carcinoma, and no clinically relevant cardiovascular and other co-morbidities were included. Patients with HER2+ tumors received trastuzumab (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly to all chemotherapy cycles. After a safety analysis showed a higher rate of dose reductions and treatment discontinuations with nP150 compared to P80, weekly dose of nP was reduced to 125 mg/m2. Results: nP was given for the majority of cycles at a dose of 150 mg/m2 to 179 patients and at a dose of 125 mg/m2 to 426 patients. Treatment characteristics were fairly balanced between these two sequential cohorts as well as compared to 601 patients receiving P80 except for HER2 status (HER2-positive: nP150 22%, nP125 37% and P80 33%) and Ki67 ( Conclusions: Risk-benefit ratio of nP125 was improved over nP150 with better drug adherence and RTDI, lower frequency of PNP but a higher pCR rate. It should therefore be considered as the preferred schedule when nP is used as neoadjuvant treatment for primary breast cancer. The trial was financially supported by Celgene and Roche. Citation Format: von Minckwitz G, Untch M, Jakisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Weibringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer J-U, Clemens M, Costa SD, Gerber B, Nekljudova V, Loibl S. nab-paclitaxel at a dose of 125 mg/m2 weekly is more efficacious but less toxic than at 150 mg/m2. Results from the neoadjuvant randomized GeparSepto study (GBG 69). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-11.

Introduction Addition of carboplatin to anthracycline/taxane-based neoadjuvant chemotherapy has shown to improve pathological complete response (pCR; ypT0 ypN0) rates in patients with triple-negative breast cancer in two large phase II studies (GeparSixto: von Minckwitz et al. Lancet Oncol 2014; CALGB 40603: Sikov et al. J Clin Oncol 2015). Participants of the GeparSixto study with triple-negative tumors showed an improvement of pCR rate from 36.9 to 53.2% by the addition of carboplatin (p=0.005); however, no statistically significant difference in pCR rate was observed in the HER2-positive subgroup (36.8 vs 32.8%, respectively). A greater benefit with carboplatin was observed in patients with BRCA mutations or a high homologous recombination deficiency (HRD score) in the tumor (pCR rate of 30% compared to 10% for patients without HRD). So far, it is unknown whether these effects on pCR translate into a survival benefit for the patients. We here report an early survival analysis of the GeparSixto study. Patients and Methods In the GeparSixto trial (NCT01426880), patients were treated for 18 weeks with paclitaxel 80mg/m2 q1w and non-pegylated-liposomal doxorubicin (NPLD) 20mg/m2 q1w. Patients with TNBC (N=315) received concurrently bevacizumab 15mg/kg i.v. q2w until surgery. Patients with HER2+ disease (N=273) received concurrently trastuzumab 6(8)mg/kg q3w and lapatinib 750mg daily. All patients were randomized 1:1 to receive concurrently carboplatin AUC 1.5-2.0 q1w vs no carboplatin, stratified by subtype (HER2+ vs TNBC). Carboplatin dose was reduced from AUC 2.0 to 1.5 by an amendment after 330 patients. Primary objective was pCR rate (ypT0 ypN0). Loco-regional invasive recurrence free survival (LRRFS), distant-disease- free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS) were secondary objectives. Results 595 patients were recruited (8/2011 - 12/2012) in 51 German centers. 296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. So far, 82 events have been reported after a median of 28 months follow-up. Analysis of updated events by treatment arm in the full study population as well as in the TNBC and HRD subgroups will be presented. Conclusion Even if the GeparSixto study was not powered to show carboplatin effects on survival, the expected results will help to assess the overall benefit of carboplatin in TNBC and the power of pCR to predict for DFS and OS. Citation Format: von Minckwitz G, Loibl S, Schneeweiss A, Salat CT, Rezai M, Zahm D-M, Klare P, Blohmer J-U, Tesch H, Khandan F, Fasching PA, Jakisch C, Nekljudova V, Untch M. Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-04.

Gynaecologists and oncologists (listed below) met in November 2008 to draw LIP recommendations to be used as guidelines for adjuvant treatment with bisphosphonates for the prevention of tumour progression in receptor positive breast cancer patients based on the Currently available evidence. Malignant epithelial tumours usually disseminate into bone marrow. Because of the abundance of cytokines and the stimulating growth factors found there, this microenvironment is ideal for the survival and growth of cancer cells. A variety of growth factors such as transforming growth factor beta (TGF-beta) or insulin-like growth factor (IGF) are accumulated within the bone matrix and can be released by stimulated osteoclasts and become available for tumour cells. Therefore the bone and its microenvironment play an important role in tumour progression because cancer cells can survive in bone marrow and grow to become bone metastases. In addition, tumour cells can reenter in the circulation and form new metastases in more distant organs. Recently, various Studies have shown that adjuvant bisphosphonate therapy can improve disease-free survival in hormone receptor positive breast cancer patients. Due to medical need and because detailed guidelines for this therapeutic intervention are still lacking, twelve experts have Put together recommendations for adjuvant bisphosphonate therapy based on the currently available evidence. This critical consensus could help to encourage the use of appropriate adjuvant bisphosphonate therapy in these patients.

Preoperative chemotherapy represents the standard procedure in inflammatory breast cancer. However, only recently it could be demonstrated that preoperative chemotherapy is beneficial even for patients with operable primary breast cancer. The number of breast conserving surgeries could be increased significantly. Furthermore this in vivo chemosensitivity assay can provide important prognostic as well as predictivy informations. Preoperative chemotherapy is not associated with an increased risk for the patients as outcome is similar to patients with conventional adjuvant treatment. We investigated new regimens to improve this type of chemotherapy and reached a remission rate of 93% with a combination of adriamycin and docetaxel (ADoc). A randomized study (GEPARDO-study) comparing ADoc with ADoc + tamoxifen has recently been started in Germany by the German Adjuvant Breast Cancer Study Group (GABG).