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Purpose: To summarize the radiotherapy-relevant statements of the 18th St. Gallen Breast Cancer Consensus Conference and interpret the findings in light of German guideline recommendations., Methods: Statements and voting results from the 18th St. Gallen International Breast Cancer Consensus Conference were collected and analyzed according to their relevance for the radiation oncology community. The voting results were discussed in two hybrid meetings among the authors of this manuscript on March 18 and 19, 2023, in light of the German S3 guideline and the 2023 version of the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) guidelines., Results and Conclusion: There was a high level of agreement between the radiotherapy-related statements of the 18th St. Gallen International Breast Cancer Consensus Conference and the German S3 and AGO guidelines. Discrepancies include the impact of number of lymph node metastases for the indication for postmastectomy radiotherapy., (© 2024. The Author(s).)

Background: The GAIN-2 trial was designed to identify a superior intense dose-dense (idd) strategy for high-risk patients with early breast cancer. Here, we report an interim analysis, at which the predefined futility boundary was crossed., Patients and Methods: GAIN-2 was an open-label, randomised, multicentre phase III trial. Two thousand eight hundred and eighty seven patients were randomised 1:1 between three courses each of idd epirubicin (E) 150 mg/m 2 , nab-paclitaxel (nP) 330 mg/m 2 and cyclophosphamide (C) 2000 mg/m 2 (iddEnPC) versus four cycles of leucocyte nadir-based tailored and dose-dense EC (dtEC) followed by four cycles of tailored and dose-dense docetaxel (dtD) (dtEC-dtD)., Results: The duration of median follow-up was 45.8 (range 0.0-88.3) months. Trial objectives included invasive disease-free survival (iDFS) as the primary end-point. A total of 593 patients received the treatment as neoadjuvant chemotherapy. At the time of futility interim analysis, 414 events for iDFS were reported. Overall, there was no difference in iDFS between iddEnPC and dtEC-dtD with 4-year iDFS rates of 84.3% (95% confidence interval (CI) 82.0-86.4%). Among all predefined subgroups, hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-), lobular cancer and ≤50 years subgroups predicted for better iDFS in the dtEC-dtD arm. Overall, 88.1% of patients completed all treatment in both arms. Haematological toxicity grade 3/4 and grade 3/4 non-haematological adverse events were significantly higher with iddEnPC (iddEnPC 50.8% vs dtEC-dtD 45.1%, P = 0.002), especially arthralgia and peripheral sensory neuropathy. Two treatment-related deaths occurred during dtEC-dtD, corresponding to a low mortality rate of 0.07%., Conclusions: iDFS is equal in both regimens, but tailoring dose-dense chemotherapy improved outcomes in HR+/HER2-, lobular cancer and patients ≤50 years., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AS reports grants from Celgene, grants from Roche, grants from AbbVie, personal fees from Roche, personal fees from AstraZeneca, personal fees from Celgene, personal fees from Roche, personal fees from Roche, personal fees from Celgene, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Novartis, personal fees from MSD, personal fees from Tesaro, personal fees from Lilly, personal fees from Pfizer, other from Roche, outside the submitted work; CD reports personal fees from Novartis, Roche, MSD Oncology, Daiichi Sankyo, grants from Myriad Genetics, other from Sividon Diagnostics/Myriad, outside the submitted work and has a patent EP18209672 pending, a patent EP20150702464 pending and a patent Software (VMscope digital pathology) pending. CJ reports honoraria from Roche, Celgene, Novartis, Genomic Health and Amgen; compensation for consulting and advisory role from Roche, Novartis and Pfizer; travel expenses from Roche, Astra Zeneca and Genomic Health; CS reports compensation for consulting and advisory role from Olympus, Hologic; and travel expenses from imed, MedConcept, Medtronic, Diaglog Service, Mentor, mylan, GBG and Pfizer; ES reports honoraria from Roche, Astra Zeneca, Novartis, Pfizer, ESAI, Tesaro and MSD; compensation for consulting and advisory role from Roche and Tesaro; and travel expenses from Roche and Pfizer; FM reports personal fees from Roche, AstraZeneca, Pfizer, Tesaro, Novartis, Amgen, PharmaMar, GenomicHealth, CureVac, EISAI, Celgene, Clovis, Janssen-Cilag, Immunomedics, GSK, MSD, Seagen and Lilly outside the submitted work; JH reports grants and personal fees from Novartis, personal fees from Lilly, personal fees and other from Pfizer, personal fees and other from Roche, personal fees from Abbvie, personal fees from Astra Zeneca, personal fees from Eisai, other from Daichii, grants, personal fees and other from Celgene, personal fees from MSD, grants and personal fees from Hexal, outside the submitted work; JUB reports personal fees from AMGEN, personal fees from ASTRA Zeneca, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from SonoScape, from Sysmex, outside the submitted work; MR reports honoraria from MSD, Astra Zeneca, Lilly, Novartis and SOMATEX; compensation for consulting and advisory role from Roche, Novartis, MSD, Astra Zeneca and Lilly; and travel expenses from Pfizer, Novartis and Celgene; MU reports honoraria paid to his employer by Amgen, Astra Zeneca, Celgene, Daiji Sankyo, Eisai, Lilly, MSD, Mundipharma, Pfizer, Novartis, Roche, Sanofi Aventis and PUMA Biotechnology; compensation for consulting and advisory role to the employer from Amgen, Abbvie, Astra Zeneca, Celgene, Daiji Sankyo, Eisai, Lilly, MSD, Mundipharma, Novartis, Odonate, Pfizer, Roche, PUMA Biotechnology, Sanofi Aventis and Teva; SL reports grants and other from Roche during the conduct of the study; grants and other from Abbvie, grants and other from Amgen, grants and other from Celgene, grants and non-financial support from Immunomedics, grants and other from Novartis, grants and other from Pfizer, other from Seattle Genetics, other from PriME/Medscape, personal fees from Chugai, grants from Teva, grants from Vifor, grants and other from Daiichi-Sankyo, other from Lilly, other from Samsung, other from EirGenix, other from BMS, other from Puma, other from MSD and grants and other from AstraZeneca outside the submitted work; In addition, SL has a patent EP14153692.0 pending. TL reports honoraria from Lilly, Teva, Tesaro, Roche, Novartis, Pfizer, MSD, Amgen and Clovis; compensation for consulting and advisory role from Lilly, Roche, Tesaro, Amgen and MSD; travel expenses from Roche, Pfizer and Celgene; VM reports speaker honoraria from Amgen, Astra Zeneca, Celgene, Roche, TEVA and consultancy honoraria from Roche, Amgen, Tesaro and Myelo Therapeutics; WJ reports grants and personal fees from Sanofi-Aventis, Novartis, Lilly, Pfizer, Roche, Chugai and AstraZeneca during the conduct of the study; No other potential conflict of interest relevant to this article was reported., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: BRCA1 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., Methods: Patients 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., Results: Two 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., Conclusions: gBRCA1/2m 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., Competing Interests: Conflict of interest statement The authors declare the following conflicts of interest: A.S. reports receiving grants from Celgene, Roche, AbbVie; personal fees from Roche, AstraZeneca, Celgene, Roche, Pfizer, Novartis, MSD, Tesaro, Lilly, and others from Roche, outside the submitted work; C.H. reports receiving personal fees from Roche, Novartis, Lilliy, MSD, Astra Zeneca, and Pfizer; C.J. reports personal fees from Roche, AsraZeneca, Celgene, Pfizer, Novartis, and Amgen; F.J.C. reports receiving personal fees from AstraZeneca; receiving grants from GRAIL, others from Qiagen and Ambry Genetics, outside the submitted work; H.T. reports receiving personal fees from Novartis, Pfizer, AstraZeneca, Roche, Eisai, and Lilly, outside the submitted work; J.H. reports receiving grants and personal fees from Novartis, personal fees from Lilly, Astra Zeneca, Eisai, MSD, and Abbvie, personal fees and other from Pfizer and Roche, other from Daichii; receiving grants, personal fees and other from Celgene; receiving grants and personal fees from Hexal, outside the submitted work; J.U.B. reports receiving personal fees from AMGEN, ASTRA Zeneca, Novartis, Pfizer, Roche, SonoScape, and Sysmex, outside the submitted work; K.L. reports personal fees and non-financial support from Roche, Lilly, personal fees from Novartis and Genomic Health, outside the submitted work; K.R. reports personal fees from AstraZeneca, Tesaro and Pfizer, outside the submitted work; M.U. reports personal fees and non-financial support from Abbvie, Amgen GmbH, Eisai GmbH, Daiji Sankyo, Celgene GmbH, MSD Merck, Mundipharma, Roche Pharma AG, Odonate, TEVA Pharmaceuticals Ind Ltd., Sanofi Aventis Deutschland GmbH, Pfizer GmbH, Astra Zeneca and Lilly Int., Novartis, Clovis Oncology, and Myriad Genetics; personal fees from BMS, Lilly Deutschland, PUMA Biotechnology, Pierre Fabre, outside the submitted work; P.A.F. reports receiving personal fees from Novartis, Lilly, Pierre Fabre, and Seattle Genetics, Roche, Pfizer, Daiichi-Sankyo, Astra Zeneca, Eisai, Merck Sharp & Dohme; grants from Biontech, Cepheid. R.S. reports receiving grants from Cologne Furtune; S.L. reports receiving grants and other from AstraZeneca, Daiichi-Sankyo, Roche, Pfizer, Novartis, Abbvie, Amgen and Celgene during the conduct of the study; grants and non-financial support from Immunomedics; other from Seattle Genetics, PriME/Medscape, Lilly, Samsung, Eirgenix, BMS, Puma, MSD; personal fees from Chugai; grants from Teva and Vifor; outside the submitted work; In addition, S.L. has a patent EP14153692.0 pending. T.L. reports non-financial support from Pharma Mar, Celgene and Daiichi-Sankyo; personal fees and non-financial support from MSD, Pfizer, Roche, Clovis; personal fees from Amgen, Novartis, Teva, Tesaro, outside the submitted work; V.M. reports speaker honoraria from Amgen, Astra Zeneca, Celgene, Roche, TEVA, and consultancy honoraria from Roche, Amgen, Tesaro and Myelo Therapeutic; No other potential conflict of interest relevant to this article was reported., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background Patients with breast cancer can be affected by cardiotoxic reactions through cancer therapies. Cardiac biomarkers, like NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin T, might have predictive value. Methods and Results Echocardiography, ECG, hemodynamic parameters, NT-proBNP and high-sensitivity cardiac troponin T were assessed in 853 patients with early-stage breast cancer randomized in the German Breast Group GeparOcto-GBG 84 phase III trial. Patients received neo-adjuvant dose-dense, dose-intensified epirubicin, paclitaxel, and cyclophosphamide (iddEPC group, n=424) or paclitaxel, non-pegylated doxorubicin, and in triple negative breast cancer, (paclitaxel, non-pegylated doxorubicin, carboplatin group, n=429) treatment for 18 weeks. Patients positive for human epidermal growth receptor 2 (n=354, 41.5%) received monoclonal antibodies on top of allocated therapy; 119 (12.9%) of all patients showed a cardiotoxic reaction during therapy (15 [1.8%] using a more strict definition). Presence of cardiotoxic reactions was irrespective of treatment allocation ( P =0.31). Small but significant increases in NT-proBNP developed early in patients with a cardiotoxic reaction as compared with those without in whom NT-proBNP rose only towards the end of therapy ( P =0.04). High-sensitivity cardiac troponin T rose early in both groups. Logistic regression showed that NT-proBNP (odds ratio [OR], 1.03; 95% CI, 1.008-1.055; P =0.01) and hemoglobin (OR, 1.31; 95% CI, 1.05-1.63; P =0.02) measured at 6 weeks after treatment initiation were significantly associated with cardiotoxic reactions. Conclusions NT-proBNP and hemoglobin are significantly associated with cardiotoxic reactions in patients with early-stage breast cancer undergoing dose-dense and dose-intensified chemotherapy, but high-sensitivity cardiac troponin T is not. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT02125344.

Background: The impact of locoregional radiotherapy (RT) after neoadjuvant chemotherapy (NACT) and mastectomy in breast cancer patients is currently unclear. Several publications have suggested that patients with a favorable response to NACT might not benefit from RT after mastectomy., Methods: A retrospective analysis of three prospective randomized NACT trials was performed. Information on the use of RT was available for 817 breast cancer patients with non-inflammatory breast cancer who underwent mastectomy after NACT within the GeparTrio, GeparQuattro, and GeparQuinto-trials. RT was administered to 676 of these patients (82.7%)., Results: The 5-year cumulative incidence of locoregional recurrence (LRR) was 15.2% (95% confidence interval [CI] 9.0-22.8%) in patients treated without RT and 11.3% in patients treated with RT (95% CI 8.7-14.3%). In the multivariate analysis, RT was associated with a lower risk of LRR (hazard ratio 0.51, 95% CI 0.27-1.0; p = 0.05). This effect was shown especially in patients with cT3/4 tumors, as well as in patients who were cN+ before neoadjuvant therapy, including those who converted to ypN0 after neoadjuvant therapy. In the bivariate analysis, disease-free survival was significantly worse in patients who received RT, however this was not confirmed in the multivariate analysis., Conclusions: Our results suggest that RT reduces the LRR rates in breast cancer patients who receive a mastectomy after NACT without an improvement in DFS. Prospective randomized controlled trials such as the National Surgical Adjuvant Breast and Bowel Project B-51/RTOG 1304 trial will analyze whether RT has any benefit in patients who have a favorable response after NACT.

Background: 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., Methods: 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., Results: 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) ≥ 25 kg/m 2 ; 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., Conclusions: 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.

Background: Immune cell infiltration in breast cancer is important for the patient's prognosis and response to systemic therapies including immunotherapy. We sought to investigate the prevalence of tumour-infiltrating lymphocytes (TILs) and their association with immune checkpoints such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in high-risk, node-positive breast cancer of the adjuvant German Adjuvant Intergroup Node-positive (GAIN-1) trial., Patients and Methods: We evaluated TILs by haematoxylin and eosin staining and PD-1 and PD-L1 (SP263 assay) expression by immunohistochemistry in 1318 formalin-fixed, paraffin-embedded breast carcinomas. The association of TILs with PD-1, PD-L1, molecular intrinsic subtypes, outcome and therapy regimens (dose-dense [dd] epirubicin, paclitaxel and cyclophosphamide [EPC] and dd epirubicin, cyclophosphamide, paclitaxel and capecitabine [EC-PwX]) was statistically tested., Results: Overall TILs density was significantly associated with the expression of PD-1 and PD-L1 in immune cells (each p < 0.0001) and PD-L1 in tumour cells (p = 0.0051). TILs were more common in triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive tumours (each p < 0.0001). On multivariate Cox regression analyses, patients with breast cancer without TILs had an unfavourable disease-free survival (DFS) in the EPC arm compared with the EC-PwX arm (hazard ratio [HR] = 0.69 [0.44-1.06], p = 0.0915); but no differences were seen in tumours with TILs (HR = 1.24 [0.92-1.67], p = 0.1566, interaction p = 0.0336). PD-1-positive immune cells in TNBC were associated with a significantly better DFS (HR = 0.50 [0.25-0.99], p = 0.0457). PD-L1 expression had no impact on patient outcome., Conclusions: TILs predict the benefit of intensified ddEPC compared with ddEC-PwX therapy in node-positive, high-risk breast cancer. TILs, PD-1 and PD-L1 are linked to each other indicating tumour immunogenicity. Moreover, PD-1-positive immune cells have a positive prognostic impact in TNBC., Clinical Trial: NCT00196872., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: GeparOcto compared efficacy and safety of two chemotherapy regimens in high-risk early breast cancer (BC): sequential treatment with intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) and weekly treatment with paclitaxel plus non-pegylated liposomal doxorubicin (M, Myocet®) with additional carboplatin (PM(Cb)) in triple-negative BC (TNBC)., Patients and Methods: Patients with cT1c-cT4a-d and centrally assessed human epidermal growth factor receptor (HER)2-positive BC or TNBC were eligible, irrespective of nodal status, luminal B-like tumours only if pN+. Patients were randomised (stratified by BC subtype, Ki67, lymphocyte-predominant BC) to receive 18 weeks of E (150 mg/m 2 ) followed by P (225 mg/m 2 ) followed by C (2000 mg/m 2 ), each q2w for 3 cycles or weekly P (80 mg/m 2 ) plus M (20 mg/m 2 ) plus, in TNBC, Cb (area under curve (AUC) 1.5). HER2-positive BC patients additionally received trastuzumab (6 [loading dose 8]mg/kg q3w) and pertuzumab (420 [840]mg q3w) with all P and C cycles. Primary end-point was pathological complete response (pCR, ypT0/is ypN0), secondary end-points included other pCR definitions, pCR in stratified subpopulations, tolerability and compliance. This trial is registered with ClinicalTrials.gov number NCT02125344., Results: 945/961 randomised patients started treatment. The median age was 48 years; 7.6% had cT3-4, 46% cN+, 66% G3, 40% HER2-positive, 43% TNBC. pCR rate with iddEPC was 48.3%, with PM(Cb) 48.0%, respectively (PM(Cb) versus iddEPC odds ratio 0.99; 95% confidence interval 0.77-1.28, P = 0.979) with no significant differences observed in TNBC, HER2-positive, luminal B-like subtypes. 16.4% with iddEPC and 34.1% with PM(Cb) discontinued treatment (P < 0.001), mainly due to adverse events; two patients on PM(Cb) died., Conclusions: In high-risk early BC there is no difference in pCR rates following neoadjuvant treatment with iddEPC or weekly PM(Cb), respectively. iddEPC is one of the effective dose-dense regimens feasible in daily practice., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Brain metastases (BMs) have a major impact on life expectancy and quality of life for many breast cancer patients. Knowledge about treatment patterns and outcomes is limited., Methods: We analysed clinical data of 1712 patients diagnosed with BMs from breast cancer between January 2000 and December 2016 at 80 institutions., Results: Median age at diagnosis of BMs was 56 years (22-90 years). About 47.8% (n = 732) of patients had HER2-positive, 21.4% (n = 328) had triple-negative and 30.8% (n = 471) had hormone receptor (HR)-positive, HER2-negative (luminal-like) primary tumours. The proportion of patients with HER2-positive BMs decreased comparing the years 2000-2009 with 2010-2015 (51%-44%), whereas the percentage of patients with luminal-like tumours increased (28%-34%; p = 0.0331). Patients with BMs in the posterior fossa were more often HER2 positive (n = 169/314, 53.8%) than those diagnosed with triple-negative (n = 65/314, 20.7%) or luminal-like primary breast cancer (n = 80/314, 25.5%), (p < 0.0001). Median overall survival (OS) time after development of BMs for the overall cohort was 7.4 months (95% confidence interval [CI]: 6.7-8.0 months). One-year survival rate was 37.7% (95% CI: 35.2-40.1). Patients with HER2-positive tumours had the longest median OS of 11.6 months (95% CI: 10.0-13.4) compared with 5.9 months (95% CI: 5.0-7.2) for patients with luminal-like and 4.6 months (95% CI: 3.9-5.4) for patients with triple-negative tumours. Patients with HER2-positive tumours who received anti-HER2 treatment had longer median OS than those without (17.1 months versus 7.2 months, p < 0.0001)., Conclusions: Prognosis of patients after developing BMs varies significantly according to the subtype. The outcome in this cohort is similarly poor in triple-negative and HR-positive/HER2-negative patients. Our results underline the high medical need for improvement of treatment and prevention strategies for BMs in breast cancer patients., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Human epidermal growth factor receptor 2 (HER2) is a central predictive biomarker in breast cancer. Inaccurate HER2 results in different laboratories could be as high as 20%. However, this statement is based on data generated more than 13 years ago and may not reflect the standards of modern diagnostic pathology. We compared central and local HER2 testing in a total of 1581 HER2-positive tumors from five clinical trials. We evaluated the clinical relevance for pathological complete response (pCR) and disease-free survival in a subgroup of 677 tumors, which received an anti-HER2 therapy. Over the period of 12 years, the discordance rate for HER2 decreased from 52.4 (GeparTrio) to 8.4% (GeparSepto). Discordance rates were significantly higher in hormone receptor (HR)-positive tumors (26.6%), compared to HR-negative tumors (16.3%, P<0.0001), which could be explained by a different distribution of HER2 mRNA levels in HR-positive and HR-negative tumors. pCR rates were significantly lower in discordant tumors (13.7%) compared to concordant tumors (32.2%, GeparQuattro and GeparQuinto, P<0.001). In survival analysis, tumors with discordant HER2 testing had a reduced overall survival (OS) in the HR-negative group (P=0.019) and a trend for improved OS in the HR-positive group (P=0.125). The performance of local HER2 testing was considerably improved over time and has reached a 92% concordance, which shows that quality initiatives in diagnostic pathology are working. Tumors with discordant HER2 testing had a reduced therapy response and different survival rates.

Background: 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., Patients and Methods: 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., Results: We identified 145 women with clinically N0 disease who underwent SLN during pregnancy. The SLN detection techniques were as follows: 99m Tc-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 48 months (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., Conclusions: 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.

Background: The individual risk of recurrence in hormone receptor-positive primary breast cancer patients determines whether adjuvant endocrine therapy should be combined with chemotherapy. Clinicopathological parameters and molecular tests such as EndoPredict(®) (EPclin) can support decision making in patients with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative cancer., Objective: Using a life-long Markov state transition model, we determined the health economic impact and incremental cost effectiveness of EPclin-based risk stratification in combination with clinical guidelines [German-S3, National Comprehensive Cancer Center Network (NCCN), and St. Gallen] to decide on chemotherapy use., Methods: Information on overall and metastasis-free survival came from Austrian Breast & Colorectal Cancer Study Group clinical trials 6/8 (n = 1,619) and published literature. Effectiveness was assessed as quality-adjusted life-years (QALYs). Costs (2010) were assessed from a German third-party payer perspective., Results: Lifetime costs per patient ranged from 28,268 (St.Gallen and EPclin) to 33,756 (NCCN). Due to an imperfect prognostic value and differences in chemotherapy use, strategies achieved between 13.165 QALYs (NCCN) and 13.173 QALYs (EPclin alone) per patient. Using German-S3 as reference, three strategies showed dominant results (St. Gallen and EPclin, German-S3 and EPclin, EPclin alone). Compared to German-S3, the addition of EPclin saved 3,388 and gained 0.002 QALYs per patient. Combining guidelines with EPclin remained preferable in sensitivity analysis., Conclusion: Our study suggests that molecular markers can be sensibly combined with clinical guidelines to determine the risk profile of adjuvant breast cancer patients. Compared with the current German best practice (German-S3), combinations of EPclin with the St. Gallen, German-S3 or NCCN guideline and EPclin alone were dominant from the perspective of the German healthcare system.

Purpose: We aimed to determine the prognosis of patients with breast cancer diagnosed during pregnancy (BCP)., Patients and Methods: In this cohort study, a multicentric registry of patients with BCP (from Cancer in Pregnancy, Leuven, Belgium, and GBG 29/BIG 02-03) compiled pro- and retrospectively between 2003 and 2011 was compared with patients who did not have associated pregnancies, using an age limit of 45 years. Patients with a diagnosis postpartum were excluded. The main analysis was performed using Cox proportional hazards regression of disease-free survival (DFS) and overall survival (OS) on exposure (pregnant or not), adjusting for age, stage, grade, hormone receptor status, human epidermal growth factor 2 status, histology, type of chemotherapy, use of trastuzumab, radiotherapy, and hormone therapy., Results: The registry contained 447 women with BCP, mainly originating from Germany and Belgium, of whom 311 (69.6%) were eligible for analysis. The nonpregnant group consisted of 865 women. Median age was 33 years for the pregnant and 41 years for the nonpregnant patients. Median follow-up was 61 months. The hazard ratio of pregnancy was 1.34 (95% CI, 0.93 to 1.91; P = .14) for DFS and 1.19 (95% CI, 0.73 to 1.93; P = .51) for OS. Cox regression estimated that the 5-year DFS rate for pregnant patients would have increased from 65% to 71% if these patients had not been pregnant. Likewise, the 5-year OS rate would have increased from 78% to 81%., Conclusion: The results show similar OS for patients diagnosed with BCP compared with nonpregnant patients. This information is important when patients are counseled and supports the option to start treatment with continuation of pregnancy.

The advantages of neoadjuvant chemotherapy are the ability to 1) increase the rate of breast conservation and improve operability, 2) to reduce mortality by recognizing resistance mechanisms early, and 3) to investigate the activity of new agents by assessing the pathological complete response rate as a surrogate marker for clinical efficacy. The German Breast Group (GBG) is a cooperative study group which focuses on neoadjuvant therapy for breast cancer. This group cooperates closely with the German Gynecological Oncology Working Group-Breast (AGO-B). Additionally, these two German study groups maintain close ties with other national and international study groups, such as the Breast International Group (BIG), Austrian Breast and Colorectal Cancer Study Group (ABCSG), Central European Cooperative Oncology Group (CECOG), International Cooperative Cancer Group (ICCG) and National Surgical Adjuvant Breast Project (NSABP). A series of clinical trials evaluating the role of neoadjuvant therapy in women with primary breast cancer have been designed, performed and published over the last 10 years. This article summarizes the results of the neoadjuvant trials that have been conducted by the German study groups, outlines ongoing clinical research projects, and discusses concepts for future clinical trials.

Pathological complete response (pCR) to neoadjuvant treatment correlates with outcome in breast cancer. We determined whether characteristics of neoadjuvant therapy are associated with pCR. We used multi-level models, which accounted for heterogeneity in pCR across trials and trial arms, to analyze individual patient data from 3332 women included in 7 German neoadjuvant trials with uniform protocols. PCR was associated with an increase in number of chemotherapy cycles (odds ratio [OR] 1.2 for every two additional cycles; P = 0.009), with higher cumulative anthracycline doses (OR 1.6; P = 0.002), higher cumulative taxane doses (OR 1.6; P = 0.009), and with capecitabine containing regimens (OR 1.62; P = 0.022). Association of pCR with increase in number of cycles appeared more pronounced in hormone receptor (HR)-positive tumors (OR 1.35) than in HR-negative tumors (OR 1.04; P for interaction = 0.046). Effect of anthracycline dose was particularly pronounced in HER2-negative tumors (OR 1.61), compared to HER2-positive tumors (OR 0.83; P for interaction = 0.14). Simultaneous trastuzumab treatment in HER2-positive tumors increased odds of pCR 3.2-fold (P < 0.001). No association of pCR and number of trastuzumab cycles was found (OR 1.20, P = 0.39). Dosing characteristics appear important for successful treatment of breast cancer. Longer treatment, higher cumulative doses of anthracyclines and taxanes, and the addition of capecitabine and trastuzumab are associated with better response. Tailoring according to breast cancer phenotype might be possible: longer treatment in HR-positive tumors, higher cumulative anthracycline doses for HER2-negative tumors, shorter treatment at higher cumulative doses for triple-negative tumors, and limited number of preoperative trastuzumab cycles in HER2-positive tumors.

In the context of neoadjuvant therapy (NT) for breast cancer patients, different targeted therapy approaches are currently evaluated in clinical trials. Serum markers could help to monitor and optimize such treatment strategies. We investigated human epidermal growth factor receptor 2 serum (sHER2) levels in 175 breast cancer patients participating in the GeparQuattro trial. This study incorporated NT approaches and additional trastuzumab treatment for all patients with HER2-positive tumors. Human epidermal growth factor receptor 2 serum levels were measured by enzyme-linked immunosorbent assay (ELISA) before initiation of NT and after NT (pre-surgery) in a HER2-positive (n = 90) and a HER2-negative patient cohort (n = 85). Median pre-chemotherapy sHER2 levels were higher in patients with positive HER2 status of the primary tumor than in patients with negative HER2 status (14.9 ng/ml vs. 7.7 ng/ml, P < 0.001). A pre-chemotherapy sHER2 cut-off level of 10 ng/ml had the best sensitivity and specificity in discriminating between HER2-positive and HER2-negative primary tumors. In HER2-positive patients, we found a significant positive association between pathological complete remission (pCR) and elevated sHER2 levels (above 15 ng/ml, P = 0.045) and a decrease of sHER2 levels during NT (P = 0.02), which was also significant in multivariate analysis (OR = 3.29, 95% CI 1.001-10.89, P = 0.049). In HER2-negative patients, we observed no association between sHER2 levels and pCR (P > 0.05). Monitoring sHER2 levels in the presence of anti-HER2 treatment might be an adjunct to the clinical evaluation during NT.

Background: The purpose of the study was to evaluate first-line platinum/paclitaxel (Taxol) under phase III trial conditions in ovarian cancer (OC) patients aged >or=70 years., Patients and Methods: Phase III results of 779 patients with OC International Federation of Gynecology and Obstetrics (FIGO) stage IIB/IV treated with cisplatin/paclitaxel versus carboplatin/paclitaxel were retrospectively analyzed according to feasibility, toxicity (National Cancer Institute Common Toxicity Criteria) and quality of life (QoL) [European Organization for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ-C30)] in patients aged <70 or >or=70 years., Results: One hundred and three (13%) patients were aged >or=70 years. Patient characteristics (<70 versus >or=70 years) showed significant differences with regard to Eastern Cooperative Oncology Group performance status, residual disease and constitutional factors but not to FIGO stage, histology or grading. Elderly patients received 98%, 100% and 96% of the recommended paclitaxel, carboplatin and cisplatin dose, respectively, per cycle. Early discontinuation was more frequent in elderly, although QoL, nonhematological and hematological toxicity were comparable between elderly and younger patients, except for febrile neutropenia (5% versus <1%, P = 0.005). There were no significant differences with regard to cycle delays, dose reductions or the use of granulocyte colony-stimulating factor and antibiotics., Conclusion: Platinum/paclitaxel appeared to be feasible and tolerable in elderly patients under clinical trial conditions, but there seems to be a different investigators' estimation of toxicity and less intention to maintain trial treatment in elderly.