This first large randomized trial suggests high efficacy and excellent tolerability of a neoadjuvant nab-paclitaxel/carboplatin regimen, superior to nab-paclitaxel/gemcitabine in TNBC. De-escalation of further chemotherapy in patients with early pCR after a short anthracycline-free regimen is a promising field of future research. Early necrotic morphological changes and/or proliferation decrease after the first therapy cycle seem to be associated with subsequent pCR.

The validated EndoPredict assay is a novel tool to predict the risk of metastases of patients with estrogen receptor positive, HER2 negative breast cancer treated with endocrine therapy alone. It has been designed to integrate genomic and clinical information and includes clinico-pathological factors such as tumor size and nodal status. The test is feasible in a decentral setting in molecular pathology laboratories. In this project, we investigated the performance of this test in clinical practice, and performed a retrospective evaluation of its impact on treatment decisions in breast cancer. During one year, EndoPredict assays from 167 patients could be successfully performed. For retrospective evaluation of treatment decisions, a questionnaire was sent to the clinical partner. Regarding the molecular EP class, samples from 56 patients (33.5%) had a low-risk, whereas 111 patients (66.5%) showed a high-risk gene profile. After integration of the clinicopathological factors the combined clinical and molecular score (EPclin) resulted in a low-risk group of 77 patients (46.4%), while 89 (53.6%) had a high risk EPclin score. The EPclin-based estimated median 10-year-risk for metastases with endocrine therapy alone was 11% for the whole cohort. The median handling time averaged three days (range: 0 to 11 days), 59.3% of the tests could be performed in three or less than three days. Comparison of pre- and post-test therapy decisions showed a change of therapy in 37.7% of patients. 16 patients (12.3%) had a change to an additional chemotherapy while 25.4% of patients (n = 33) changed to an endocrine therapy alone. In 73 patients (56.2%) no change of therapy resulted. In 6.1% of patients (n = 8), the patients did not agree to the recommendation of the tumor board. Our results show that the EndoPredict assay could be routinely performed in decentral molecular pathology laboratories and the results markedly change treatment decisions.

Changes in lipid metabolism are an important but not well-characterized hallmark of cancer. On the basis of our recent findings of lipidomic changes in breast cancer, we investigated glycerol-3-phosphate acyltransferase (GPAM), a key enzyme in the lipid biosynthesis of triacylglycerols and phospholipids. GPAM protein expression was evaluated and linked to metabolomic and lipidomic profiles in a cohort of human breast carcinomas. In addition, GPAM mRNA expression was analyzed using the GeneSapiens in silico transcriptiomics database. High cytoplasmic GPAM expression was associated with hormone receptor negative status (p = 0.013). On the protein (p = 0.048) and mRNA (p = 0.001) levels, increased GPAM expression was associated with a better overall survival. Metabolomic analysis by GC-MS showed that sn-glycerol-3-phosphate, the substrate of GPAM, was elevated in breast cancer compared to normal breast tissue. LC-MS based lipidomic analysis identified significantly higher levels of phospholipids, especially phosphatidylcholines in GPAM protein positive tumors. In conclusion, our results suggest that GPAM is expressed in human breast cancer with associated changes in the cellular metabolism, in particular an increased synthesis of phospholipids, the major structural component of cellular membranes.

Background: Paclitaxel chemotherapy frequently induces dose-limiting sensory axonal polyneuropathy. As sensory symptoms are challenging to assess objectively in clinical routine, an easily accessible biomarker for chemotherapy-induced polyneuropathy (CIPN) holds the potential to improve early diagnosis. Here, we describe neurofilament light chain (NFL), a marker for neuroaxonal damage, as translational surrogate marker for CIPN. Methods: NFL concentrations were measured in an in vitro model of CIPN, exposing induced pluripotent stem cell-derived sensory neurons (iPSC-DSN) to paclitaxel. Breast and ovarian cancer patients undergoing paclitaxel chemotherapy, breast cancer control patients without chemotherapy and healthy controls were recruited in a cohort study and examined before chemotherapy (V1) and after 28 weeks (V2, after chemotherapy). CIPN was assessed by the validated Total Neuropathy Score reduced, which combines patient-reported symptoms with data from clinical examinations. Serum NFL (NFLs) concentrations were measured at both visits with single molecule array technology (SIMOA).Results: NFL is released from iPSC-DSN upon paclitaxel incubation in a dose-and time-dependent manner and inversely correlates with iPSC-DSN viability. NFLs strongly increased in paclitaxel-treated patients with CIPN, but not in chemotherapy patients without CIPN or controls, resulting in an 86 % sensitivity and 87 % specificity.A NFLs increase of +36 pg/ml from baseline was associated with a predicted CIPN probability of >0.5. Conclusion:NFLs correlates with CIPN development and severity, which may guide neurotoxic chemotherapy in the future.

Diffuse hair loss begins shortly after initiation of chemotherapy, mainly as anagen effluvium, with a proportion of anagen to telogen conversion. Hair loss is most prominent after 6 weeks of chemotherapy. Within 3 months after cessation of chemotherapy, hair growth rate returns to baseline values. Tamoxifen did not affect hair growth parameters.

These data confirm that the combination of capecitabine and trastuzumab is highly active in patients with HER-2-overexpressing anthracycline- and/or taxane-pretreated breast cancer, with only slight restrictions regarding quality of life.

Recently, it has been demonstrated that calling of copy number alterations (CNAs) from amplicon sequencing (AS) data is feasible. Most approaches, however, require non-tumor (germline) DNA for data normalization. Here, we present the method Ioncopy for CNA detection which requires no normal controls and includes a significance assessment for each detected alteration.Ioncopy was evaluated in a cohort of 184 clinically annotated breast carcinomas. A total number of 252 amplifications were detected, of which 183 (72.6%) could be validated by a call of an additional amplicon interrogating the same gene. Moreover, a total number of 33 deletions were found, whereof 27 (81.8%) could be validated. Analyzing the 16 most frequently amplified genes, validation rates of over 89% could be achieved for 11 of these genes. 11 of the top 16 genes showed significant overexpression in the amplified tumors. 89.5% of the HER2-amplified tumors were GRB7 and STARD3 co-amplified, whereas 68.4% of the HER2-amplified tumors had additional MED1 amplifications. Correlations between CNAs measured by amplicons in HER2 exons 19, 20 and 21 were strong (all R > 0.93). AS based detection of HER2 amplifications had a sensitivity of 90.0% and a specificity of 98.8% compared to the gold standard of HER2 immunohistochemistry combined with in situ hybridization.In summary, we developed and validated a novel method for detection and significance assessment of CNAs in amplicon sequencing data. Using Ioncopy, AS offers a straightforward and efficient approach to simultaneously analyze gene amplifications and gene deletions together with simple somatic mutations in a single assay.

Introduction: Breast cancer (BC) survivors often suffer from disease- and therapy-related long-term side-effects. The study aim was to explore the feasibility, adherence, and individual experiences as well as possible effects of 2 different walking interventions in BC patients. Methods: This randomized controlled, pragmatic pilot trial included a qualitative study component. BC patients were randomized to either mindful walking (MFW) with mindfulness exercises and walking or moderate walking (MW) alone in weekly group sessions over 8 weeks. After 8 and 16 weeks, satisfaction, and self-perceived effectiveness as well as different health-related outcomes including health-related (WHOQOL-BREF) and disease-specific quality of life (FACT-G), perceived stress (PSQ) and cancer-related fatigue (CFS-D) were assessed. ANCOVA was used to evaluate differences in study outcomes. Qualitative data included 4 focus group interviews including 20 patients and were analyzed using a directed qualitative content analysis approach. Results: Altogether, 51 women (mean age 55.8 years (SD 10.9)) were randomized (n = 24 MFW; n = 27 MW). Both groups would recommend the course to other BC patients (MFW 88.9%; MW 95.2%) and showed possible improvements from baseline to week 8, without statistically significant difference between groups: WHOQOL-BREF (MFW: adjusted mean 65.4 (95% confidence interval (CI), 57.1-73.7); MW: 61.6 (53.6-69.6)); FACT-G (MFW: 76.0 (71.5-80.5); MW: 73.0 (68.5-77.4)); PSQ (MFW: 45.3 (40.5-50.1); MW: 45.4 (40.8-50.0)); CFS-D (MFW: 24.3 (20.8-27.8); MW: 25.5 (22.1-28.8)). Improvements lasted until the 16-weeks follow-up. The qualitative analysis suggested that MFW primarily promoted mindfulness, self-care, and acceptability in BC patients, whereas MW activated and empowered the patients as a result of the physical exercise. Conclusion: Both study interventions were positively evaluated by patients and showed possible pre-post effects in disease-specific health-related outcomes without differences between groups. The qualitative analysis results indicate that different resources and coping strategies were addressed by the 2 study interventions. Trial registration: DKRS00011521; prospectively registered 21.12.2016; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011521 .