German Breast Group Research Articles

249P Neoadjuvant chemotherapy in inflammatory breast cancer: A meta-analysis of 10 trials of the German Breast Group (GBG)

249P Neoadjuvant chemotherapy in inflammatory breast cancer: A meta-analysis of 10 trials of the German Breast Group (GBG)

Breast-conserving surgery is not associated with increased local recurrence in patients with early-stage node-negative triple-negative breast cancer treated with neoadjuvant chemotherapy

BackgroundNeoadjuvant chemotherapy (NACT) is routinely used for patients with triple-negative breast cancer (TNBC). Upfront breast-conserving therapy (BCT) consisting of breast-conserving surgery (BCS) and adjuvant radiotherapy (RT) has been shown to be associated with improved outcome in patients with early TNBC as compared to mastectomy. MethodsWe identified 2632 patients with early TNBC from the German Breast Group meta-database. Patients with cT1-2 cN0 and ypN0, available surgery and follow-up data were enrolled. Data of 1074 patients from 8 prospective NACT trials were available. Endpoints of interest were locoregional recurrence as first site of relapse (LRR), disease-free survival (DFS) and overall survival (OS). We performed univariate and multivariate Fine-Gray analysis and Cox regression models. ResultsAfter a median follow-up of 64 months, there were 94 (8.8%) locoregional events as first site of relapse. Absence of pathologic complete response (pCR) was associated with increased LRR upon uni- and multivariate analysis (hazard ratio [HR] = 2.28; p < 0.001 and HR = 2.22; p = 0.001). Type of surgery was not associated with LRR. Patients in the BCS-group had better DFS and OS (DFS: HR = 0.47; p < 0.001 and OS: HR = 0.40; p < 0.001). BCS was associated with improved DFS and OS upon multivariate analysis (DFS: HR = 0.51; p < 0.001; and OS HR = 0.43; p < 0.001), whereas absence of pCR was associated with worse DFS and OS (DFS: HR = 2.43; p < 0.001; and OS: HR = 3.15; p < 0.001). ConclusionsIn this retrospective analysis of patients with early stage node-negative TNBC treated with NACT, BCS was not associated with an increased risk of LRR but with superior DFS and OS.

Adjuvant Docetaxel in Node-Negative Breast Cancer Patients: A Randomized Trial of AGO-Breast Study Group, German Breast Group, and EORTC-Pathobiology Group

In node-negative breast cancer (NNBC), a high risk of recurrence is determined by clinico-pathological or tumor-biological assessment. Taxanes may improve adjuvant chemotherapy. NNBC 3-Europe, the first randomized phase-3 trial in node-negative breast cancer (BC) with tumor-biological risk assessment, recruited 4146 node-negative breast cancer patients from 2002 to 2009 in 153 centers. Risk assessment was performed by clinico-pathological factors (43%) or biomarkers (uPA/PAI-1, urokinase-type plasminogen activator/its inhibitor PAI-1). High-risk patients received six courses 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), cyclophosphamide (500 mg/m2) (FEC), or three courses FEC followed by three courses docetaxel 100 mg/m2 (FEC-Doc). Primary endpoint was disease-free survival (DFS). In the intent-to-treat population, 1286 patients had received FEC-Doc, and 1255 received FEC. Median follow-up was 45 months. Tumor characteristics were equally distributed; 90.6% of tested tumors had high uPA/PAI-1-concentrations. Planned courses were given in 84.4% (FEC-Doc) and 91.5% (FEC). Five-year-DFS was 93.2% (95% C.I. 91.1-94.8) with FEC-Doc and 93.7% (91.7-95.3) with FEC. Five-year-overall survival was 97.0% (95.4-98.0) for FEC-Doc and 96.6% % (94.9-97.8) for FEC. With adequate adjuvant chemotherapy, even high-risk node-negative breast cancer patients have an excellent prognosis. Docetaxel did not further reduce the rate of early recurrences and led to significantly more treatment discontinuations.

Abstract PD15-06: PD15-06 Pathologic complete response and breast-conserving surgery are associated with improved prognosis in patients with early-stage triple-negative breast cancer treated with neoadjuvant chemotherapy

Abstract Background: Neoadjuvant chemotherapy (NACT) is standard of care for patients with triple-negative breast cancer (TNBC). Treatment response, especially pathologic complete response (pCR), is a strong predictive factor for treatment outcome. In the setting of up-front surgery, retrospective data have suggested improved outcome in patients with early TNBC that received breast-conserving surgery with adjuvant radiotherapy (BCT) as compared to mastectomy. Methods: We identified 2632 patients with early TNBC from the German Breast Group meta-database. Patients with cT1-2 cN0 and ypN0, available surgery and follow-up data were eligible for this project. A total of 1074 patients from 8 prospective NACT trials were analyzed. Endpoints of interest were locoregional recurrence as first site of relapse (LRR, other sites of recurrence were considered competing events), disease-free survival (DFS) and overall survival (OS); analyses were performed using univariate and multivariate Fine-Gray (for LRR) and Cox models including study, age, cT, surgery type and pCR. For the analyses including pCR as covariable, only patients at risk at the landmark time were evaluated. Results: Median age was 48 years, 69.6% of patients had cT2 tumors and 85.3% underwent BCS. Of the 1074 analyzed patients, 48.8% achieved pCR. After a median follow-up of 64 months, there were 94 (8.8%) locoregional events as first site of relapse. Upon univariate analysis, absence of pCR (hazard ratio [HR]=2.28; 95%CI 1.44-3.61; p&amp;lt; 0.001) and ypT-stage (ypT0/is vs. ypT1-3, HR=0.61; 95%CI 0.40-0.95; p=0.028) were significantly associated with LRR, while type of surgery, age and cT-stage were not. Upon multivariate analysis, absence of pCR was the only factor associated with increased risk of LRR (HR=2.22; 95%CI 1.38-3.58; p=0.001). Patients that underwent mastectomy (N=158) were significantly younger (age ≤ 50 years 72.8% vs. 59.9% for BCT [N=916]; p=0.002) DFS and OS was significantly better in patients who underwent BCT compared to mastectomy (DFS: HR=0.47; 95%CI 0.34-0.66; p&amp;lt; 0.001 and OS: HR=0.40; 95%CI 0.26-0.63; p&amp;lt; 0.001). In multivariate analysis, BCT was associated with a significantly better DFS and OS as compared to mastectomy (DFS: HR=0.51; 95%CI 0.36-0.72; p&amp;lt; 0.001; and OS HR=0.43; 95%CI 0.27-0.68; p&amp;lt; 0.001), whereas absence of pCR was associated with significantly worse DFS and OS (DFS: HR=2.43; 95%CI 1.78-3.31; p&amp;lt; 0.001; and OS: HR=3.15; 95%CI 1.94-5.10; p&amp;lt; 0.001). Conclusions: In this retrospective analysis from the GBG meta-database, treatment response, e.g. pCR, was the main determinant of locoregional recurrence in patients with early stage TNBC treated with NACT. BCT was associated with improved DFS and OS compared to mastectomy, which may at least in part reflect favorable patient selection. Citation Format: David Krug, Valentina Vladimirova, Michael Untch, Thorsten Kühn, Andreas Schneeweiss, Carsten Denkert, Beyhan Ataseven, Christine Solbach, Bernd Gerber, Hans Tesch, Michael Golatta, Sabine Seiler, Jörg Heil, Valentina Nekljudova, Sibylle Loibl. PD15-06 Pathologic complete response and breast-conserving surgery are associated with improved prognosis in patients with early-stage triple-negative breast cancer treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD15-06.

Outcome of breast cancer patients treated with chemotherapy during pregnancy compared with non-pregnant controls

BackgroundA diagnosis of breast cancer during pregnancy (PrBC) does not impact prognosis if standard treatment is offered. However, caution is warranted as gestational changes in pharmacokinetics may lead to reduced chemotherapy concentration. MethodsSurvival of PrBC patients treated with chemotherapy during pregnancy was compared to non-pregnant breast cancer patients treated with chemotherapy, diagnosed after 2000, excluding patients older than 45 years or with a postpartum diagnosis. The data was registered in two multicenter registries (the International Network of Cancer, Infertility and Pregnancy and the German Breast Group). Cox proportional hazards regression was used to compare disease-free (DFS) and overall survival (OS) between both groups, adjusting for age, stage, grade, hormone receptor status, human epidermal growth factor 2 status and histology, weighted by propensity scoring to account for the differences in baseline characteristics between pregnant patients and controls. ResultsIn total, 662 pregnant and 2081 non-pregnant patients were selected. Pregnant patients were more likely to have stage II breast cancer (60.1% vs 56.1%, p = 0.035), grade 3 tumors (74.0% vs 62.2%, p < 0.001), hormone receptor-negative tumors (48.4% vs 34.0%, p < 0.001) or triple-negative breast cancer (38.9% vs 26.9%, p < 0.001). Median follow-up was 66 months. In multivariable analysis, DFS and OS were comparable for pregnant and non-pregnant patients (DFS: HR 1.02, 95% CI 0.82–1.27, p = 0.83; OS: HR 1.08, 95% CI 0.81–1.45, p = 0.59). ConclusionOutcome of women with breast cancer treated with chemotherapy during pregnancy is comparable to young non-pregnant women. These results support chemotherapy for PrBC when indicated.

Abstract OT-04-02: The AXSANA trial (AXillary Surgery After NeoAdjuvant treatment): An international prospective multicenter cohort study of the EUBREAST study group to evaluate different surgical methods of axillary staging (sentinel lymph node biopsy, targeted axillary dissection, axillary dissection) in clinically node-positive breast cancer patients treated with neoadjuvant chemotherapy (NCT04373655)

Abstract Background The optimal surgical staging of the axilla in patients who convert from a clinically positive (cN+) to a clinically negative node status (ycN0) through neoadjuvant chemotherapy is still unclear. Widely diverse techniques such as full Axillary Lymph Node Dissection (ALND), Targeted Axillary Dissection (TAD), Targeted Lymph Node Biopsy (TLNB) and Sentinel Lymph Node Biopsy alone (SLNB) are given preference in different international guidelines. So far, no comparative data on the oncological outcome or the morbidity of the different procedures are available. Further research is needed to safely de-escalate the radicality of axillary surgery in this patient group. Trial design The EUBREAST study group initiated an international prospective cohort study including cN+ patients converting to ycN0 status and treated with different axillary staging techniques according to the standard at their treating institution. Participants are patients with cT1-3 tumors with axillary lymph node metastasis confirmed by core biopsy or fine needle aspiration and scheduled for neoadjuvant systemic therapy. The trial is funded by the AGO-B Study Group, the Claudia von Schilling Foundation for Breast Cancer Research and the AWOgyn (Working Group for Reconstructive Surgery in Oncology-Gynecology) and supported by the NOGGO (North-Eastern German Society of Gynaecologic Oncology) and the German Breast Group. Primary endpoints: 5-year invasive disease-free survival, 3-year axillary recurrence rate and health-related quality of life (HRQoL). HRQoL will be evaluated using four standardized questionnaires (EORTC QLQ-C 30, EORTC QLQ BR 23, Lymph ICF and SOC-13) at baseline and 1, 3 and 5 years after surgery. Secondary endpoints are the feasibility and performance of different axillary staging techniques (detection rate, number of removed lymph nodes and association with complications, arm morbidity and quality of life, operating time and use of clinical and economic resources); impact of learning curve, and the detailed mapping of surgical and oncological treatment standards in different countries. Present accrual (July 7th 2020): 5. The first study participant has been recruited in June 2020. Target accrual: 3000 patients from EUBREAST member states (20) Citation Format: Maggie Banys-Paluchowski, Elmar Stickeler, Jana de Boniface, Oreste Gentilini, Marc Thill, Steffi Hartmann, Marina Mangold, Christine Solbach, Jens-Uwe Blohmer, Michael Untch, Matilda Appelgren, Hans-Christian Kolberg, Thorsten Kühn, EUBREAST. The AXSANA trial (AXillary Surgery After NeoAdjuvant treatment): An international prospective multicenter cohort study of the EUBREAST study group to evaluate different surgical methods of axillary staging (sentinel lymph node biopsy, targeted axillary dissection, axillary dissection) in clinically node-positive breast cancer patients treated with neoadjuvant chemotherapy (NCT04373655) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-04-02.

Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy

BackgroundBRCA1 and BRCA2 play a central role in DNA repair. Therefore, patients harbouring germline (g) BRCA1/2 mutations (m) treated with chemotherapy might be at higher risk of haematological toxicities. MethodsPatients from German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-breast group studies with early triple-negative breast cancer (TNBC) and known gBRCA1/2m status treated with anthracycline-taxane-based neoadjuvant chemotherapy were analysed. Primary objective was the rate of neutropenia grade (G)III–IV in cycle 1 (C1). Secondary objectives included effects on overall and other haematological toxicities GIII-IV in C1, cumulative haematological toxicity across all cycles, relative total dose intensity, and granulocyte-colony stimulating factor prophylaxis. Haematological toxicities under taxanes, carboplatin, and cyclophosphamide were explored. ResultsTwo hundred nine of 1171 (17.8%) evaluated patients had gBRCA1/2m. In C1, 37.4% gBRCA1/2m versus 35.7% wild-type patients had neutropenia GIII-IV (P = 0.683). For C1, gBRCA1/2m predicted neither for neutropenia GIII-IV (odds ratio [OR]: 1.26, 95% confidence intervals [CI]: 0.87–1.82, P = 0.226) nor for other haematological toxicities GIII-IV (OR: 0.91, 95% CI: 0.64–1.31, P = 0.625) in multivariable regression models. Analyses of cumulative toxicities across all cycles yielded similar results except thrombocytopaenia GIII-IV, which was increased in gBRCA1m patients. In patients treated with taxanes, the rate of haematological toxicities GIII-IV was higher in gBRCA1/2m compared with wild-type (59.5% versus 43.1%; p < 0.001). No difference was seen under cyclophosphamide or platinum-containing chemotherapies. ConclusionsgBRCA1/2m was not associated with higher risk of overall severe haematological toxicities in the first cycle or cumulatively across all cycles under standard chemotherapy for TNBC. Under taxane, patients with gBRCA1/2m might have a higher risk of haematological toxicities GIII-IV, requiring further research.

Fatal events during clinical trials: an evaluation of deaths during breast cancer studies.

Information on deaths occurring during oncological clinical trials has never been systematically assessed. Here, we examine the incidence of death and the profile of patients who died during randomized clinical breast cancer (BC) trials. Information on fatal events during German Breast Group (GBG) led BC trials was prospectively captured. Data were derived from the trial databases and death narratives. All deaths were evaluated for possible causes, underlying conditions, treatment relatedness, time point and rate of autopsies. From 12/1996 to 01/2017, 23,387 patients were treated within 32 trials. Of those 88 (0.4%) died on therapy within 17 trials. Median age was 64 [range 35-84] years, 63.2% of patients had a body mass index (BMI) ≥ 25kg/m2; 65.9% 1-3 and 22.7% ≥ 4 comorbidities; 61.4% 1-2 cardiovascular risk factors (CRFs); 26.4% took > 3 drugs; 81.7% had ECOG 0; 50.0% stage III, 76.7% luminal BC. The main causes of death were infection (38.6%; of those, 82.3% sepsis, 17.6% pneumonia), heart failure (14.8%), and pulmonary embolism (13.6%). Fatal events mainly occurred within the first 4 therapy cycles (55.7%), in the investigational arm (66.7%) and under anthracycline-taxane-based chemotherapy (51.1%). A relationship with the treatment was declared in 27.3% of the cases. An autopsy was performed in 13.6% of patients. Death during study treatment was mainly related to infections, and patients with advanced disease, high BMI, underlying comorbidities, CRFs and concomitant medications. If considered for study participation these patients need careful monitoring due to their higher risk for death on study.

Outcome after neoadjuvant chemotherapy in elderly breast cancer patients - a pooled analysis of individual patient data from eight prospectively randomized controlled trials.

IntroductionRecent studies showed the high and independent impact of age (<40 years) on pathologic complete response (pCR) and prognosis for patients undergoing neoadjuvant chemotherapy (NACT). Some physicians might not consider elderly patients (>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 are investigated in several histological subgroups.MethodsFrom 1998 to 2010, eight prospectively randomized German Breast Group (GBG) trials of anthracycline- and taxane-based NACT were performed and analyzed in this study.ResultsCompared to the overall average, elderly women had significant larger tumors and more overall lymph node involvement. Histologically, they had more G2 tumors, more estrogen-receptor positive tumors. pCR (ypT0 ypN0) was strongly associated with age. The multivariable logistic regression analysis of clinical parameters showed that young age, clinical stage T4, invasive ductal cancer and poor differentiated breast cancer are predictive for high pCR. The multivariate analyses of molecular subgroups showed that age >65years is a predictor of significant lower pCR in HER2− breast cancers. Nonetheless, HER2+ patients showed pCR rates as high− and HR+/HER2+ even higher - pCR rates compared to younger patients.DiscussionThis study underlines the unfavorable impact of higher age on pCR, but it shows a realistic chance for pCR if NACT is applied - especially for HER2+ patients. Furthermore, elderly patients with non-TNBC showed a good prognosis (comparable to younger patients) regarding overall survival, even if they do not have pCR.

Axillary staging for breast cancer during pregnancy: feasibility and safety of sentinel lymph node biopsy.

Safety of sentinel lymph node (SLN) biopsy for breast cancer during pregnancy is insufficiently explored. We investigated efficacy and local recurrence rate in a large series of pregnant patients. Women diagnosed with breast cancer who underwent SLN biopsy during pregnancy were identified from the International Network on Cancer, Infertility and Pregnancy, the German Breast Group, and the Cancer and Pregnancy Registry. Chart review was performed to record technique and outcome of SLN biopsy, locoregional and distant recurrence, and survival. We identified 145 women with clinically N0 disease who underwent SLN during pregnancy. The SLN detection techniques were as follows: 99mTc-labeled albumin nanocolloid only (n=96; 66.2%), blue dye only (n=14; 9.7%), combined technique (n=15; 10.3%), or unknown (n=20; 13.8%). Mapping was unsuccessful in one patient (0.7%) and she underwent an axillary lymph node dissection (ALND). Mean number of SLNs was 3.2 (interquartile range 1-3; missing n=15). Positive SLNs were found in 43 (29.7%) patients and 34 subsequently underwent ALND. After a median follow-up of 48months (range 1-177), 123 (84.8%) patients were alive and free of disease. Eleven patients experienced a locoregional relapse, including 1 isolated ipsilateral axillary recurrence (0.7%). Eleven (7.6%) patients developed distant metastases, of whom 9 (6.2%) died of breast cancer. No neonatal adverse events related to SLN procedure during pregnancy were reported. SLN biopsy during pregnancy has a comparably low axillary recurrence rate as in nonpregnant women. Therefore, this method can be considered during pregnancy instead of standard ALND for early-stage, clinically node-negative breast cancer.

Abstract P2-03-09: Comparison of the mutational landscape of breast cancer during pregnancy and non-pregnant controls

Abstract Background:Currently, breast cancer during pregnancy (BCP) is not believed to be biologically different from breast cancer unrelated to pregnancy based on limited datasets mainly obtained by immunohistochemistry. However, some groups report that BCP patients have an inferior survival compared to young non-pregnant breast cancer patients. The largest analysis based on the BCP registry by the German Breast Group (GBG) revealed however, no difference between pregnant and non-pregnant breast cancer patients, indicating that treatment rather than biology might be the reason for the inferior survival reported by others. Methods: The BCP study (GBG 29/BIG 03-02) is a multicentre observational study for breast cancer during pregnancy. In tumour tissue collected within this study from pregnant M0 patients we investigated the following genes: AKT1, ATM, BRAF, CBFB, CCND1, CDH1, CDKN2A, CTCF, EGFR, ERBB2, ESR1, FGFR2, GATA3, KRAS, MAP2K4, MAP3K1, MDM2, MED12, MYC, PIK3CA, PIK3R1, PTEN, RB1, RUNX1, and TP53 by massive parallel sequencing (MPS). This included patients with all molecular subtypes: HR+/-, HER2+/-. Sequencing was done on an IonTorrent Proton using a custom designed Breast Cancer Panel (BCPv2). This panel comprises 236 amplicons split into two primer pools and covers hotspot regions of 138 exons of the 25 genes. To test the hypothesis that breast cancer diagnosed during pregnancy is biologically not different from breast cancer diagnosed in young non-pregnant women, we compared the molecular profiles obtained, with genetic data from M0 patients not known to be pregnant from TCGA with age &amp;lt;= 45. TCGA data were pre-processed to be compatible to the targeted MPS datasets from pregnant patient. Results: Material from 141 patients from the BCP study was available from which ultimately 109 fully evaluable MPS datasets could be obtained. In the TCGA data set 114 breast cancer patients &amp;lt;= 45 years could be identified. Pregnant patients with breast cancer were significantly younger, had more often HR- tumours (59.6% vs 30.1%) but had less frequently grade 3 tumours (30.6% vs 48.2%). All other clinical variables showed no significant differences between pregnant and non-pregnant patients. In the BCP data, overall 106 mutations could be found. The most frequent mutations were detected in TP53 (62%) and in PIK3CA (11.1%). In non-pregnant patients the mutation rates were different with 32.5% in TP53 and 21.1% in PIK3CA. Exact matching by variables age, HR, HER2 and grade yielded 40 patients from both datasets. In these subcohorts, still divergent mutational rates for TP53 and PIK3CA between pregnant and non-pregnant women were noted, however, the differences failed to reach statistical significance. Conclusions: Overall the mutational landscapes do not seem to be overtly different between pregnant patients and no-pregnant controls, although slight imbalances in mutational rates occurred, which might be partly explained by a selection bias and a small sample size after matching. Further comparisons using other datasets, looking into survival and regarding copy number variation are currently conducted. This research is been funded by the German Cancer Consortium-DKTK and the BANSS Foundation. Citation Format: Loibl S, Pfarr N, Weber K, Neunhöffer T, Villegas S, Stenzinger A, Furlanetto J, Aktas B, Budczies J, Marmé F, Kahmann L, Denkert C, Weichert W. Comparison of the mutational landscape of breast cancer during pregnancy and non-pregnant controls [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 P2-03-09.

Abstract ES4-3: Tumor-infiltrating lymphocytes (TILs) and genomic signatures of immune cells

Abstract Increased levels of tumor-infiltrating lymphocytes have been described in subsets of breast cancer, in particular triple-negative (TNBC) and HER2-positive (HER2+) tumors. Neoadjuvant therapy approaches in breast cancer have been used as a strategy to characterize subgroups of tumors with increased tumor-infiltrating lymphocytes (TILs). We have described tumor-infiltrating lymphocytes (TILs) as predictors of pathological complete response to neoadjuvant chemotherapy in breast cancer trials conducted by the German Breast Group. It has been shown that increased TILs are linked to an increased response rate to neoadjuvant therapy and improved prognosis after adjuvant therapy, in particular in triple-negative and HER2 positive breast cancer. In addition to tumor-infiltrating lymphocytes, immune mRNA markers have been studied in breast cancer and are associated with increased chemotherapy response and improved prognosis. These results suggest that some subtypes of breast cancer are immunogenic and that there is an ongoing low-level immune response present even in clinically progressing tumors. Therapeutic approaches to modulate tumor-associated inflammation by immune checkpoint inhibitors have shown clinical responses in a subset of triple-negative breast cancers, and some of these responses were durable. These targeted therapies have stimulated interest in the interaction between immune cells and tumor cells. Based on the concept that conventional chemotherapy might be immunogenic, some studies are evaluating the combination of an immune checkpoint inhibitor and a chemotherapy. Considering the fact that responses to immune checkpoint inhibitors are observed in only a subset of tumors, biomarkers that will be able to identify those tumors are needed. Possible biomarkers include the therapeutic targets, in particular PD-L1 and PD1, tumor-infiltrating lymphocytes, predictive mRNA signatures, immunogenic neoepitope signatures that are generated by mutations as well as other factors. Due to the low costs of a simple H&amp;E based test, tumor infiltrating lymphocytes might become a promising biomarker as part of the pathology report. In preparation for this, the international immune-oncology working group (TIL working group) has published standardized guidelines for TIL evaluation in breast cancer, and has conducted a first international TIL ring trial. This ring trial suggests that decentral TIL evaluation is feasible. In some situations, in particular in tumors with intermediate and heterogeneous TILs, additional tests, including gene expression signatures might be necessary. It should be emphasized that the clinical utility of TILs for current medical decisions is very limited at the present time, and the ultimate usefulness of these biomarker concepts will be obtained in the ongoing and future clinical immunotherapy trials. The presentation will provide an overview on recent results on immune markers for prediction of response to neoadjuvant chemotherapy and prognosis with a focus in standardized histomorphological evaluation of tumor-infiltrating lymphocytes as well as clinical trials concepts and biomarker strategies for future immune checkpoint inhibitor therapies in breast cancer. Citation Format: Denkert C. Tumor-infiltrating lymphocytes (TILs) and genomic signatures of immune cells [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 ES4-3.

Pathologic Complete Response with Neoadjuvant Doxorubicin and Cyclophosphamide Followed by Paclitaxel with Trastuzumab and Pertuzumab in Patients with HER2-Positive Early Stage Breast Cancer: A Single Center Experience.

Trastuzumab (H) and pertuzumab (P) with standard chemotherapy is approved for use in the neoadjuvant setting for human epidermal growth receptor 2 -positive patients. A retrospective analysis was performed of patients treated with dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T), trastuzumab, and pertuzumab (THP) in the neoadjuvant setting. Here, the pathologic complete response (pCR) rates are reported. An electronic medical record review was conducted of patients treated with HP-based therapy in the neoadjuvant setting from September 1, 2013, to March 1, 2015. Data on patient demographics, stage of breast cancer, pathology reports, surgical data, and information on systemic therapy were collected. The pCR was defined as total (tpCR, ypT0/is ypN0), German Breast Group (GBG) pCR (ypT0 ypN0), breast pCR (bpCR) with in situ disease (ypT0/is) and without in situ disease (ypT0), and explored axillary pCR (ypN0). Charts from 66 patients were reviewed, and 57 patients were evaluable for pCR. Median age was 46 years (range 26-68 years). Median tumor size was 4 cm. Of 57 patients, 53 (93%) had operable breast cancer (T1-3, N0-1, M0). Three patients (5.3%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 1 (1.7%) had inflammatory breast cancer (T4d, any N, M0). Overall, 44 (77%) and 13 (23%) had hormone receptor (HR)-positive and negative diseases, respectively. Median numbers of cycles of neoadjuvant treatment were as follows: AC (4, range 1-4), T (4, range 1-4), trastuzumab (6, range 3-8), and pertuzumab (6, range 2-8). In these 57 patients, the rates of tpCR and bpCR with in situ disease were demonstrated in 41/57 (72%) patients, and the rates of GBG pCR and bpCR without in situ disease were found in 30/57 (53%) patients. Of 26 patients with biopsy-proven lymph nodal involvement, axillary pCR occurred in 22 (85%) patients. At a single center, the tpCR and GBG pCR rates of dd AC followed by THP are high at 72% and 53%, respectively. The Oncologist 2017;22:139-143Implications for Practice: This is the first study describing the role of doxorubicin and cyclophosphamide followed by paclitaxel and dual anti-HER2 therapy with trastuzumab and pertuzumab (ACTHP) in patients with early stage HER2-positive breast cancer. Total (breast + lymph node) pathological complete remission (pCR) remission (ypT0/is ypN0) and German Breast Group pCR rates (ypT0/ ypN0) were high at 72% and 53%, respectively, with the ACTHP regimen. Rate of axillary clearance in patients with known axillary involvement was high at 85%, which may translate into less extensive axillary surgeries in this subset in the future.

39O - Constitutively activated STAT3 is predictive for trastuzumab resistance in primary HER2 positive breast cancer

A. Sonnenblick1, S. Brohee1, R.F. Salgado1, G. Van den Eynden1, P. Neven2, S. Loibl3, C. Denkert4, H. Joensuu5, M. Piccart6, C. Sotiriou7 Breast Cancer Translational Research Laboratory (BCTL), Institute Jules Bordet, Brussels, Belgium Breast Center, Multidisciplinary Breast Center, KULeuven, Brussels, Belgium Medicine and Research, German Breast Group (GBG) Forschungs GmbH, Neu-Isenburg, Germany Pathology, Institute of Pathology, Charite Hospital, Berlin, Germany Oncology, HUCH Helsinki University Central Hospital, Helsinki, Finland Medicine, Institute Jules Bordet, Brussels, Belgium BCTL Breast Cancer Translational Research Laboratory, Institute Jules Bordet, Brussels, Belgium The likelihood of recurrence in patients with breast cancer who have HER2 positive tumors is relatively high, although trastuzumab is remarkably effective drug in this setting. Signal Transducer and Activator of Transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine phosphorylated (P-STAT3) in response to numerous oncogenic signaling pathways, inhibits anti-tumor immunity and activates downstream proliferative and anti-apoptotic pathways. We hypothesized that specimens expressing P-STAT3 will confer trastuzumab resistance and thus predict resistance to trastuzumab therapy. By integrating protein (reverse phase protein array) and gene expression data from 95 HER2 positive breast cancers treated with trastuzumab in the adjuvant setting, we show that a P-STAT3 associated gene signature (P-STAT3-GS) is able to predict P-STAT3 status in an independent dataset (TCGA) (AUC = 0.78, p = 0.01), suggesting a characteristic set of STAT3 dependent induced changes in HER2 positive cancers. High P-STAT3-GS tumors were associated with trastuzumab resistance (log rank p = 0.49). These results were confirmed in the setting of the fin-HER prospective randomised controlled study, where the effect was especially prominent in ER negative tumors (interaction test p = 0.02). Of interest, constitutively activated P-STAT3 tumors were associated with loss of PTEN (r = -0.4, fdr = 0.025), elevated IL6 (r = 0.4, p = 4.72e) and stromal reactivation. In conclusion this study provides compelling evidence for a link between P-STAT3 and trastuzumab resistance in HER2 positive primary breast cancers. Our results suggest that addition of agents targeting the STAT3 pathway may provide valuable addition to trastuzumab for treatment of HER2 positive breast cancer.

Abstract OT2-5-01: Brain metastases in breast cancer network Germany (BMBC, GBG 79): Multicentric, retro- and prospective collection of patient data and biomaterial from breast cancer patients with brain metastases

Abstract Background: The incidence of brain metastases in breast cancer patients is rising and has become a major clinical challenge in the last years. So far, limited therapeutic options and insights into the biology of brain metastases exist. Most reports include patients with brain metastases from different tumor entities and few studies so far analyzed exclusively patient data or tumor samples from breast cancer patients. In this context, an open, multicenter registry and biobank should be helpful for analysis of a large number of breast cancer patients with brain metastases. Therefore, we initiated the Brain Metastases in Breast Cancer Network Germany (BMBC; GBG79). Trial design and eligibility criteria: Patients with brain metastases from breast cancer are eligible. Registration of patient data is allowed retrospectively and prospectively. To enable an easy access, an internet-based database was chosen ("MedCodes" by the German Breast Group). Specific aims: Documented data cover incidence, symptoms, number and localization of brain metastases, histopathology, imaging methods, outcome, therapy, and quality of life measurement. Tissue of brain metastases and primary tumors will be collected for translational research projects. Planned analyses include treatment patterns in Germany, patient outcome, as well as validation of prognostic scoring systems in a multicenter setting and in the context of new targeted therapies. Translational research projects investigate the impact of glycosylation, resistance mechanisms against HER2-targeted therapies, role of the blood brain barrier, evaluation of markers of radioresistance and specific genomic alterations associated with brain tropism of breast cancer cells. The registry and biobank should be also open for cooperation with other groups. Present accrual and target accrual: The accrual target is app. 1000 patients in the database and app. 400 tissues of brain metastases from German centers. The study was opened for documentation in April 2014 with more than 50 participating centers as of June 2014. Citation Format: Isabell Witzel, Elena Laakmann, Tanja Fehm, Volker Möbus, Gunter vonMinckwitz, Julia Kaiser, Sibylle Loibl, Volkmar Müller. Brain metastases in breast cancer network Germany (BMBC, GBG 79): Multicentric, retro- and prospective collection of patient data and biomaterial from breast cancer patients with brain metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-5-01.

ASCO 2014: highlights in breast cancer

While in general, not immediately praxis changing, results of various relevant clinical trials were presented at the 2014 ASCO Annual Meeting. Indeed, the ALTTO study provided first (albeit negative) data on the activity of dual Her2 inhibition with trastuzumab and lapatinib (either sequentially or concomitantly) in the adjuvant setting, while a combined analysis of the SOFT and TEXT studies suggested, for the first time, that a combination of ovarian function suppression (OFS) plus exemestane might be superior to OFS plus tamoxifen in premenopausal early breast cancer patients. Results of the POEMS trial investigating the role of the gonadotropin-releasing hormone-analog goserelin in the prevention of chemotherapy-induced amenorrhea led to lengthy debates, as the trial reported a survival benefit in hormone-receptor-negative breast cancer patients receiving goserelin. A subgroup analysis of German Breast Group trial GeparSixto as well as several other phase II trials again emphasized the role of carboplatin in neoadjuvant therapy of triple-negative breast cancer patients. These and other studies will be reviewed within this article.

Sentinel Lymph Node Biopsy for Breast Cancer Treatment During Pregnancy - on Behalf of the International Network of Cancer, Infertility and Pregnancy (Incip) and the German Breast Group (Gbg)

ABSTRACT Aim: The long term safety of sentinel lymph node (SLN) biopsy during pregnancy is insufficiently explored, mainly due to fear for fetal safety. Studies have shown that fetal risk is minimal. We aimed to investigate maternal safety (efficacy and outcome). Methods: Women diagnosed with breast cancer who underwent SLN biopsy during pregnancy were identified from prospective European databases. Chart review was performed to record technique and outcome of SLN biopsy, local and distant recurrence, and survival. Results: We identified a total of 97 women (INCIP n = 83; GBG n = 14). Breast cancer diagnosis was made before pregnancy, in the first, second, and third trimester in 2, 34, 36 and 19 patients respectively (unknown n = 6). Median age at diagnosis was 35 years (range 28-45). All patients had clinically N0 disease (cT1-2: 95.9%; cT3-4: 4.1%). The SLN detection techniques were as follows: 99mTC albumin nanocolloid-only (n = 71; 73.2%), blue dye-only (n = 1; 1.0%), combined technique (n= 9; 9.3%), and unknown (n = 16; 16.5%). Mapping was unsuccessful in one patient, who had subsequent axillary lymph node dissection (ALND). Mean number of SLN's was 2.2 (range 0-7). Positive SLN's were found in 22 patients (6 micrometastases and 2 isolated tumor cells, of which 4 patients did not undergo ALND), 18 subsequent ALND's were performed. The median follow-up was 35 months (range 1 to 148), and median disease free survival was 40.8 months. Eight patients experienced a loco-regional relapse: contralateral breast (n = 1; 1.0%), ipsilateral breast (n = 4; 4.1%), chest wall (n = 1; 1.0%), axilla (n = 2; 2.1%). Four (4.1%) patients developed distant metastases, of whom 3 (3.1%) died of breast cancer. Of the 2 patients who had an axillary recurrence, one patient refused all further adjuvant treatment after primary surgery, one patient had standard adjuvant treatment and ipsilateral axillary recurrence occurred 12 months after diagnosis. Conclusions: SLN biopsy during pregnancy has a low axillary recurrence rate. This staging method can be considered during pregnancy instead of standard ALND for early stage, clinically node negative breast cancer. Disclosure: All authors have declared no conflicts of interest.

Bevacizumab in neoadjuvant chemotherapy increases the pathological complete response rate in patients with triple‐negative breast cancer

Bevacizumab in neoadjuvant chemotherapy increases the pathological complete response rate in patients with triple‐negative breast cancer

Association between Pathological Complete Response and Outcome Following Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients.

PurposeWe aimed to determine the rate of pathological complete response (pCR), clinicopathological factors associated with pCR, and clinical outcomes following neoadjuvant chemotherapy in locally advanced breast cancer.MethodsMedical records of patients who had undergone neoadjuvant chemotherapy for breast cancer between January 2007 and September 2011 were retrospectively reviewed, and the pCR rates were calculated according to three sets of criteria: the National Surgical Adjuvant Breast and Bowel Project (NSABP), the MD Anderson Cancer Center (MDACC), and the German Breast Group (GBG). Tumors were classified as luminal A like, luminal B like, human epidermal growth factor receptor 2 (HER2), or triple-negative. pCR and clinical outcome, including overall survival (OS) and disease-free survival (DFS) rates were analyzed at the median follow-up of 54.2 months.ResultsOf a total of 179 patients who had received neoadjuvant chemotherapy, 167 patients (93.3%) had locally advanced breast cancer and 12 patients (6.7%) had early-stage breast cancer. The majority of patients (152 patients, 89.4%) received anthracycline-based neoadjuvant chemotherapy. The objective clinical response rate was 61.5%, comprising clinical partial response in 5.5% and clinical complete response in 3.9% of patients. Twenty-one (11.7%), 20 (11.2%), and 17 patients (9.5%) achieved pCR according to NSABP, MDACC, and GBG definitions, respectively. pCR rates, as defined by NSABP, according to breast cancer subtype were 4.4%, 9.7%, 24.2%, and 19.2% in luminal A like, luminal B like, HER2, and triple-negative subtypes, respectively. Patients who achieved pCR had significantly better DFS (5-year DFS rates, 80% vs. 53%, p=0.030) and OS (5-year OS rates, 86% vs. 54%, p=0.042) than those who did not.ConclusionThe pCR rate following neoadjuvant chemotherapy for breast cancer in Thai women attending our institution was 11.7%; pCR was more frequently observed in HER2 and triple-negative breast tumor subtypes. Patients who achieved pCR had significantly improved survival.

Abstract PD2-3: High body mass index (BMI) and worse response to neoadjuvant chemotherapy (NACT) by breast cancer phenotype: Own data and external validation on German breast group (GBG) patients

Abstract Introduction It remains controversial to what extent BMI predicts pathologic complete response (pCR) following NACT. We evaluated pCR by ‘BMI category’ in different breast cancer subtypes and validated our findings in a larger dataset from the GBG. Patients and methods A retrospective study from UZL with consecutive breast cancer patients treated between 01-01-2000 and 31-12-2011 with different types of NACT +/- trastuzumab (dose capping BSA≥2m2) followed by surgery. pCR1 (ypT0N0) and pCR2 (ypT0/isN0) were reported in each of the intrinsic breast cancer subtypes based on ER and HER-2 expression. The effect of BMI [BMI 1(≤25kg/m2), BMI 2 (&amp;gt;25-29,9 kg/m2) and BMI 3 (≥ 30 kg/m2)] on both pCR definitions was analyzed in univariate (Chi square test) and multivariate (logistic regression) model. Negative ER and HER-2 status were defined according to ASCO/CAP guidelines (e.g. &amp;lt;1% ER positive tumor cells). Data were validated by GBG using different NACT +/- trastuzumab regimen (no dose capping BSA≥2m2) and similar biomarkers for defining breast cancer subtypes although ER-negative status was defined as &amp;lt;10% ER positive tumor cells. Results We included 267 breast cancer cases while the GBG validation was done in 8874 cases. Multivariate model for UZL patients didn't retain ‘BMI category’ as a predictor for any of the pCR definitions. However, univariate analysis found a significant association between BMI and pCR2 (p = 0,048). The tables show the numerical differences for pCR2 in each BMI category by breast cancer subtype for UZL and GBG patients. UZL data suggest a numerical trend with lower pCR2 rate in obese women, which seems more pronounced in ER-negative breast cancer. Results from the much larger GBG dataset with more power to assess ‘BMI category’ for pCR2 in different breast cancer subtypes using a multivariate model are presented in another abstract. Conclusion Despite the small cohort of patients, our data suggest a lower pCR rate in obese women. External validation by GBG confirms a significant association between BMI and pCR2 in uni- and multivariate model, which is also significant for luminal A/B breast cancer. The most obvious reason for our observation was dose capping but based on the GBG dataset where dose capping was avoided where possible, we speculate that immunologic factors, the microenvironment or alternative signaling pathways may affect sensitivity to NACT +/- trastuzumab. Numerical pCR2 differences by BMI category and breast cancer subtype for UZL patients Luminal A/BLuminal HER2HER 2 likeTNBCTotalUZLn = 111n = 40n = 39n = 75n = 267BMI 16.6% (4/61)35.0% (7/20)63.2% (12/19)31.4% (11/35)25.2% (34/135)BMI 23.1% (1/32)50.0% (7/14)56.3% (9/16)27.3% (6/22)27.3% (23/84)BMI 30% (0/18)33.3% (2/6)50.0% (2/4)15.8% (3/19)16.6% (8/48) Numerical pCR2 differences by BMI category and breast cancer subtype for GBG patients Luminal A/BLuminal HER2HER 2 likeTNBCTotalGBGn = 3250n = 1077n = 806n = 1570n = 8847BMI 111.6%(187/1618)26.7%(147/550)47.3%(191/404)38.9%(300/772)22.5%(982/4358)BMI 210.5%(128/1026)24.9% (81/325)44.2%(111/251)37.4% (187/500)21.2%(596/2813)BMI 37.9% (48/606)22.8%(46/202)41.1%(62/151)31.9%(95/298)18.3%(312/1703) Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD2-3.