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Background: The GeparOLA study was designed to evaluate the efficacy and safety of the combination of paclitaxel (P) plus olaparib (O) as part of neoadjuvant chemotherapy (NACT) in patients with human epidermal growth factor receptor 2 (HER2)-negative, either hormone receptor (HR)-positive or HR-negative and homologous recombination deficiency (HRD) defined as having a g/tBRCA mutation and/or a high HRD score. Primary analysis showed a pCR rate of 55.1% (90% CI 44.5%-65.3%) with PO and 48.6% (90% CI 34.3%-63.2%) with P plus carboplatinum (Cb). The PO combination could not exclude a pCR rate of ≤55% in the PO arm but was significantly better tolerated. Analysis on the stratified subgroups showed higher pCR rates with PO in the cohorts of patients < 40 years and HR-positive tumors (Fasching Ann Oncol 2020). Here, we report long-term data. Methods: GeparOLA (NCT02789332) was a non-comparative, multicenter, prospective, randomized, open-label, phase II trial. Patients with primary HER2-negative breast cancer, HRD and indication for chemotherapy (cT2-cT4a-d or cT1c and cN+ or cT1c and pNSLN+ or cT1c and TNBC or cT1c and Ki-67 >20%) were randomly assigned to receive either P 80 mg/m2 weekly plus O 100 mg twice daily for 12 weeks or P plus Cb area under the curve 2 (AUC2) weekly for 12 weeks, both followed by four cycles of either 2-weekly or 3-weekly epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2. Primary endpoint was pCR (ypT0/is ypN0) rate after NACT with PO followed by EC. Long-term efficacy endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). The time-to-event endpoints analysis is planned with median follow-up of at least 4 years and a follow-up completeness of at least 80%. Results: Between September 2016 and July 2018, 274 patients were screened, of whom 107 were randomized and 106 (PO N=69; PCb N=37) started treatment. The median age was 47.0 years (range 25.0-71.0); 32 patients were aged < 40 years; 36.2% of patients had cT1 tumors and 31.8% were cN-positive; the majority (86.8%) had grade 3 tumors and a Ki-67>20% (89.6%). Seventy-seven patients (72.6%) had TNBC. After a median follow-up of 49.8 months (range 0.1-69.1), 18 (15 in PO; 3 in PCb) iDFS events and 7 (6 in PO; 1 in PCb) deaths were reported. The 4-year survival rates are shown in the table below. iDFS (HR PO to PCb=2.86 [95%CI 0.83-9.9], log-rank p=0.081), DDFS (HR =3.03 [95%CI 0.67-13.67], log-rank p=0.129), and OS (HR=3.27 [95%CI 0.39-27.2], log-rank p=0.244) tended to be inferior with olaparib. Patients without g/tBRCA mutation seem to benefit from the use of carboplatinum (7/30 iDFS/DDFS events in PO; 0/16 in PCb, log-rank p=0.037, HR n.a.). Conclusions: In patients with HER2-negative and HRD breast cancer the use of olaparib instead of carboplatinum although showing comparable pCR rates, tended to result in an overall inferior outcome. This was mainly driven by the patients without a g/tBRCA mutation. In patients with a g/t BRCA mutation no difference between olaparib and carboplatinum was seen. Key words: Olaparib, HER2-negative breast cancer, HRD, survival Funding: The study was financially supported by AstraZeneca Citation Format: Peter A. Fasching, Sabine Schmatloch, Jan Hauke, Julia Rey, Christian Jackisch, Peter Klare, Theresa Link, Claus Hanusch, Jens Huober, Andrea Stefek, Sabine Seiler, Wolfgang D. Schmitt, Christoph Uleer, Gabriele Doering, Kerstin Rhiem, Andreas Schneeweiss, Carsten Denkert, Rita K. Schmutzler, Eric Hahnen, Michael Untch, Valentina Nekljudova, Jens-Uwe Blohmer, Sibylle Loibl. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency – long-term survival of the GeparOLA study [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 P4-06-13.

Purpose:Next-generation sequencing (NGS) can be used for comprehensive investigation of molecular events in breast cancer. We evaluated the relevance of genomic alterations for response to neoadjuvant chemotherapy (NACT) in the GeparSepto trial.Experimental Design:Eight hundred fifty-one pretherapeutic formalin-fixed paraffin-embedded (FFPE) core biopsies from GeparSepto study were sequenced. The panel included 16 genes for mutational (AKT1, BRAF, CDH1, EGFR, ERBB2, ESR1, FBXW7, FGFR2, HRAS, KRAS, NRAS, SF3B1, TP53, HNF1A, PIK3CA, and PTEN) and 8 genes for copy-number alteration analysis (CCND1, ERBB2, FGFR1, PAK1, PIK3CA, TOP2A, TP53, and ZNF703).Results:The most common genomic alterations were mutations of TP53 (38.4%) and PIK3CA (21.5%), and 8 different amplifications (TOP2A 34.9%; ERBB2 30.6%; ZNF703 30.1%; TP53 21.9%; PIK3CA 24.1%; CCND1 17.7%; PAK1 14.9%; FGFR 12.6%). All other alterations had a prevalence of less than 5%. The genetic heterogeneity in different breast cancer subtypes [lum/HER2neg vs. HER2pos vs. triple-negative breast cancer (TNBC)] was significantly linked to differences in NACT response. A significantly reduced pathologic complete response rate was observed in PIK3CA-mutated breast cancer [PIK3CAmut: 23.0% vs. wild-type (wt) 38.8%, P < 0.0001] in particular in the HER2pos subcohort [multivariate OR = 0.43 (95% CI, 0.24–0.79), P = 0.006]. An increased response to nab-paclitaxel was observed only in PIK3CAwt breast cancer, with univariate significance for the complete cohort (P = 0.009) and the TNBC (P = 0.013) and multivariate significance in the HER2pos subcohort (test for interaction P = 0.0074).Conclusions:High genetic heterogeneity was observed in different breast cancer subtypes. Our study shows that FFPE-based NGS can be used to identify markers of therapy resistance in clinical study cohorts. PIK3CA mutations could be a major mediator of therapy resistance in breast cancer.

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Supplementary Figures

(A) Paired scatter plot demonstrating the correlation between the immune-associated gene expression and PD-L1. (B) PD-L1 immunohistochemistry and mRNA expression in pre-treatment core biopsies. The definition of >= 1 % of positively stained tumor cells is associated with CD274 (=PD-L1) mRNA expression (t-test P-value and area under the curve).

Supplementary materials and tables

Differentially expressed genes according to treatment response

Supplemental Methods, Figures 1-2, Table S1. Supplemental Methods providing details on the study cohort and the image analysis algorithm. Supp. Figure 1: A) Ki67 stained breast cancer tissue. B) Haematoxylin Signal derived from color deconvolution (1) and C) histogram showing frequencies (y axis) of specific heamatoxylin intensities (x axis) of the image background (red) and foreground (green). Arrows show representative locations of different intensity classes: no tissue (red), tissue but no cell nuclei (blue), Ki67 negative cell (green) and Ki67 positive cell nuclei (orange). Figure 2: Construction of the borderline between plausible and non-plausible thresholds by combining the threshold and the resulting ratio of positive cells. Supplementary table S1: Clinico-pathological data of the study cohort

Purpose:We evaluated mRNA signatures to predict response to neoadjuvant PD-L1 inhibition in combination with chemotherapy in early triple-negative breast cancer.Experimental Design:Targeted mRNA sequencing of 2,559 transcripts was performed in formalin-fixed, paraffin-embedded samples from 162 patients of the GeparNuevo trial. We focused on validation of four predefined gene signatures and differential gene expression analyses for new predictive markers.Results:Two signatures [GeparSixto signature (G6-Sig) and IFN signature (IFN-Sig)] were predictive for treatment response in a multivariate model including treatment arm [G6-Sig: OR, 1.558; 95% confidence interval (CI), 1.130–2.182; P = 0.008 and IFN-Sig: OR, 1.695; 95% CI, 1.234–2.376; P = 0.002), while the CYT metric predicted pathologic complete response (pCR) in the durvalumab arm, and the proliferation-associated gene signature in the placebo arm. Expression of PD-L1 mRNA was associated with better response in both arms, indicating that increased levels of PD-L1 are a general predictor of neoadjuvant therapy response. In an exploratory analysis, we identified seven genes that were higher expressed in responders in the durvalumab arm, but not the placebo arm: HLA-A, HLA-B, TAP1, GBP1, CXCL10, STAT1, and CD38. These genes were associated with cellular antigen processing and presentation and IFN signaling.Conclusions:Immune-associated signatures are associated with pCR after chemotherapy, but might be of limited use for the prediction of response to additional immune checkpoint blockade. Gene expressions related to antigen presentation and IFN signaling might be interesting candidates for further evaluation.

PDF file, 66K, Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the treatment effect of conventional versus response-guided neoadjuvant chemotherapy as measured by mean disease-free survival according to overlapping subpopulations defined by percentages of Ki67 at surgery in patients with hormone-receptor-positive (A) and hormone-receptor-negative (B) disease.

Purpose: The value of Ki67 measured on residual disease after neoadjuvant chemotherapy is not sufficiently described.Experimental Design: Participants of the GeparTrio study with primary breast cancer randomly received neoadjuvant response-guided [8 cycles TAC (docetaxel/doxorubicin/cyclophosphamide) in responding and TAC-NX (vinorelbine/capecitabine) in nonresponding patients] or conventional (6 cycles TAC) chemotherapy according to interim response assessment. Ki-67 levels were centrally measured immunohistochemically after neoadjuvant treatment if tumor tissue was available. Here, we analyze 1,151 patients having a pathologic complete response (pCR; n, 484), or residual disease with low (0–15%), intermediate (15.1–35%), or high (35.1–100%) posttreatment Ki67 levels in 488, 77, and 102 patients, respectively.Results: Patients with high posttreatment Ki67 levels showed higher risk for disease relapse (P < 0.0001) and death (P < 0.0001) compared with patients with low or intermediate Ki67 levels. Patients with low Ki67 levels showed a comparable outcome to patients with a pCR (P = 0.211 for disease-free and P = 0.779 for overall survival). Posttreatment Ki67 levels provided more prognostic information than pretreatment Ki67 levels or changes of Ki67 from pre- to posttreatment. Information on pCR plus posttreatment Ki67 levels surmount the prognostic information of pCR alone in hormone–receptor-positive disease [hazard ratios (HR), 1.82–5.88] but not in hormone–receptor-negative disease (HR: 0.61–1.73). Patients with conventional and response-guided treatment did not show a different distribution of posttreatment Ki67 (P = 0.965).Conclusions: Posttreatment Ki67 levels provide prognostic information for patients with hormone–receptor-positive breast cancer and residual disease after neoadjuvant chemotherapy. Levels were not prognostic for outcome after response-guided chemotherapy. High posttreatment Ki67 indicates the need for innovative postneoadjuvant treatments. Clin Cancer Res; 19(16); 4521–31. ©2013 AACR.

Purpose: Scoring proliferation through Ki67 immunohistochemistry is an important component in predicting therapy response to chemotherapy in patients with breast cancer. However, recent studies have cast doubt on the reliability of “visual” Ki67 scoring in the multicenter setting, particularly in the lower, yet clinically important, proliferation range. Therefore, an accurate and standardized Ki67 scoring is pivotal both in routine diagnostics and larger multicenter studies.Experimental Design: We validated a novel fully automated Ki67 scoring approach that relies on only minimal a priori knowledge on cell properties and requires no training data for calibration. We applied our approach to 1,082 breast cancer samples from the neoadjuvant GeparTrio trial and compared the performance of automated and manual Ki67 scoring.Results: The three groups of autoKi67 as defined by low (≤15%), medium (15.1%–35%), and high (>35%) automated scores showed pCR rates of 5.8%, 16.9%, and 29.5%, respectively. AutoKi67 was significantly linked to prognosis with overall and progression-free survival P values POS < 0.0001 and PPFS < 0.0002, compared with POS < 0.0005 and PPFS < 0.0001 for manual Ki67 scoring. Moreover, automated Ki67 scoring was an independent prognosticator in the multivariate analysis with POS = 0.002, PPFS = 0.009 (autoKi67) versus POS = 0.007, PPFS = 0.004 (manual Ki67).Conclusions: The computer-assisted Ki67 scoring approach presented here offers a standardized means of tumor cell proliferation assessment in breast cancer that correlated with clinical endpoints and is deployable in routine diagnostics. It may thus help to solve recently reported reliability concerns in Ki67 diagnostics. Clin Cancer Res; 21(16); 3651–7. ©2014 AACR.

R scripts to reproduce the statistical tests for the TCGA survival analyses.

Ovarian cancer is a heterogeneous disease of low prevalence, but poor survival. Early diagnosis is critical for survival, but it is often challenging because the symptoms of ovarian cancer are subtle and become apparent only during advanced stages of the disease. Therefore, the identification of robust biomarkers of early disease is a clinical priority. Metabolomic profiling is an emerging diagnostic tool enabling the detection of biomarkers reflecting alterations in tumor metabolism, a hallmark of cancer. In this study, we performed metabolomic profiling of serum and tumor tissue from 158 patients with high-grade serous ovarian cancer (HGSOC) and 100 control patients with benign or non-neoplastic lesions. We report metabolites of hydroxybutyric acid (HBA) as novel diagnostic and prognostic biomarkers associated with tumor burden and patient survival. The accumulation of HBA metabolites caused by HGSOC was also associated with reduced expression of succinic semialdehyde dehydrogenase (encoded by ALDH5A1), and with the presence of an epithelial-to-mesenchymal transition gene signature, implying a role for these metabolic alterations in cancer cell migration and invasion. In conclusion, our findings represent the first comprehensive metabolomics analysis in HGSOC and propose a new set of metabolites as biomarkers of disease with diagnostic and prognostic capabilities. Cancer Res; 76(4); 796–804. ©2015 AACR.

Results of statistical tests for all metabolites in serum samples.

Supplementary Tables related to clinicopathological data (S1), metabolomics results (S3, S5, S6), gene expression and copy number survival analyses (S7-S8) and gene set enrichment analyses (S9-10) as well as Supplementary Figures (S1-S6) related to metabolomics results.

Supplementary Figure Legends

Salamanders are an important group of living amphibians and model organisms for understanding locomotion, development, regeneration, feeding, and toxicity in tetrapods. However, their origin and early radiation remain poorly understood, with early fossil stem-salamanders so far represented by larval or incompletely known taxa. This poor record also limits understanding of the origin of Lissamphibia (i.e., frogs, salamanders, and caecilians). We report fossils from the Middle Jurassic of Scotland representing almost the entire skeleton of the enigmatic stem-salamanderMarmorerpeton. We use computed tomography to visualize high-resolution three-dimensional anatomy, describing morphologies that were poorly characterized in early salamanders, including the braincase, scapulocoracoid, and lower jaw. We use these data in the context of a phylogenetic analysis intended to resolve the relationships of early and stem-salamanders, including representation of important outgroups alongside data from high-resolution imaging of extant species.Marmorerpetonis united withKaraurus,Kokartus, and others from the Middle Jurassic–Lower Cretaceous of Asia, providing evidence for an early radiation of robustly built neotenous stem-salamanders. These taxa display morphological specializations similar to the extant cryptobranchid “giant” salamanders. Our analysis also demonstrates stem-group affinities for a larger sample of Jurassic species than previously recognized, highlighting an unappreciated diversity of stem-salamanders and cautioning against the use of single species (e.g., Karaurus) as exemplars for stem-salamander anatomy. These phylogenetic findings, combined with knowledge of the near-complete skeletal anatomy ofMamorerpeton,advance our understanding of evolutionary changes on the salamander stem-lineage and provide important data on early salamanders and the origins of Batrachia and Lissamphibia.

BACKGROUND Local treatment of the primary or metastatic sites in urologic malignancies is promising when compared to systemic therapy alone, leading to the definition of a potentially curative oligometastatic state. OBJECTIVES Comparison of imaging modalities regarding local and metastatic tumor sites in urologic cancers. METHODS Review of comparative trials addressing quality criteria of imaging modalities. RESULTS Depending on primary tumor and metastatic site, conventional imaging modalities such as computer tomography (CT) and bone scintigraphy still represent the standard of care in Germany. Due to superior quality criteria, hybrid-imaging techniques were widely adopted for oncological staging and particular due to the new PSMA-ligand (PSMA-PET/CT) in prostate cancer imaging. The development of new radioisotopes as well as their clinical application remains a focus of current research. CONCLUSIONS High-quality diagnostic imaging modalities lay the groundwork for a precise definition of an oligometastatic state. By enabling treatment of the entire tumor burden, a delay of systemic therapy, longer progression-free survival, or even curative treatment may become achievable.

Background Risk assessment on the molecular level is important in predictive pathology to determine the risk of metastatic disease for ERpos, HER2neg breast cancer. The gene expression test EndoPredict (EP) was trained and validated for prediction of a 10-year risk of distant recurrence to support therapy decisions regarding endocrine therapy alone or in combination with chemotherapy. The EP test provides the 12-gene Molecular Score (MS) and the EPclin-Score (EPclin), which combines the molecular score with tumor size and nodal status. In this project we investigated the correlation of 12-gene MS and EPclin scores with classical pathological markers. Methods EndoPredict-based gene expression profiling was performed prospectively in a total of 1652 patients between 2017 and 2020. We investigated tumor grading and Ki67 cut-offs of 20% for binary classification as well as 10% and 30% for three classes (low, intermediate, high), based on national and international guidelines. Results 410 (24.8%) of 1652 patients were classified as 12-gene MS low risk and 626 (37.9%) as EPclin low risk. We found significant positive associations between 12-gene MS and grading (p p = 0.001), 12-gene MS and Ki67 (p p 20% were classified as low risk by EPclin. Same differences were seen comparing EP test results and tumor grading. Conclusion In this study we could show that EP risk scores are distributed differentially among Ki67 expression groups, especially in Ki67 low and high tumors with a substantial proportion of patients with EPclin high risk results in Ki67 low tumors and vice versa. This suggests that classical pathological parameters and gene expression parameters are not interchangeable, but should be used in combination for risk assessment.

The use of Space has drastically evolved these last ten years. Tomorrow will see easier and cheaper access to Space, satellite servicing, in-orbit manufacturing, human private spaceflights to ever increasing number of Orbital Stations, road to the Moon, Asteroids, Mars … It seems fundamental to make sure we can rely on robust, reliable, frequent and affordable access to and from LEO with both automatic systems and human missions; such systems are the bricks with which all the future operations in Space will be built. Independent human access to space from Europe for our astronauts is a key to any future in Space. It has been studied in depth since the 80's with Hermes Spaceplane, then through numerous studies, pre-development activities, and demonstrations such as ARD, X38-CRV or IXV, which now allow Europe to reconsider such an endeavor with a much higher confidence. We have worked during one year on every aspect of a European Human spaceflight system aimed at being launched from Guiana Space Center. It would be a logical addition to new orbital infrastructures in LEO which, following the ISS retirement, are already under deployment by governments and commercial entities in the US, Russia, China, India. We found out that Europe could play a very specific role, deploying a “universal” vehicle capable to visit any future LEO architecture; following its historical tradition, Europe would be in a position to cooperate potentially with everyone in LEO! We traded the various types of potential vehicles dealing with the recovery techniques for both nominal and abort cases. The launch with Ariane 6 has been looked at in detail and a particular effort has been devoted to the adaptation of the Guiana Space Center. A cautious examination of the required technologies shows that European industry is fully ready, and that most of these technologies are available. In particular, we have shown the readiness of Human-Rating systems, based on the ATV, Orion ESM and ISS pressurized modules. Even if the capability requires a significant budget, the question is to know if Europe can be left aside in the future? Such a program would release a very strong positive sign for the young generations cradled with the feats of our astronauts; it would give motivating STEM objectives to the next generation of students. As a major space power it is clearly strategic for Europe to develop independent human access to LEO in the current multipolar world.

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The human frontal cortex and hippocampus play critical roles in learning and cognition. We investigated the epigenomic and 3D chromatin conformational reorganization during the development of the frontal cortex and hippocampus, using more than 53,000 joint single-nucleus profiles of chromatin conformation and DNA methylation (sn-m3C-seq). The remodeling of DNA methylation predominantly occurs during late-gestational to early-infant development and is temporally separated from chromatin conformation dynamics. Neurons have a unique Domain-Dominant chromatin conformation that is different from the Compartment-Dominant conformation of glial cells and non-brain tissues. We reconstructed the regulatory programs of cell-type differentiation and found putatively causal common variants for schizophrenia strongly overlap with chromatin loop-connected, cell-type-specific regulatory regions. Our data demonstrate that single-cell 3D-regulome is an effective approach for dissecting neuropsychiatric risk loci.

Summary Background The development of anti-HER2 antibody–drug conjugates opens new therapeutic options for patients with breast cancer, including patients with low expression of HER2. To characterise this new breast cancer subtype, we have compared the clinical and molecular characteristics of HER2-low-positive and HER2-zero breast cancer, including response to neoadjuvant chemotherapy and prognosis. Methods In this pooled analysis of individual patient data, we evaluated a cohort of 2310 patients with HER2-non-amplified primary breast cancer that were treated with neoadjuvant combination chemotherapy in four prospective neoadjuvant clinical trials (GeparSepto, NCT01583426 ; GeparOcto, NCT02125344 ; GeparX, NCT02682693 ; Gain-2 neoadjuvant, NCT01690702 ) between July 30, 2012, and March 20, 2019. Central HER2 testing was done prospectively before random assignment of participants in all trials. HER2-low-positive status was defined as immunohistochemistry (IHC) 1+ or IHC2+/in-situ hybridisation negative and HER2-zero was defined as IHC0, based on the American Society of Clinical Oncology/College of American Pathologists guidelines. Disease-free survival and overall survival data were available for 1694 patients (from all trials except GeparX) with a median follow-up of 46·6 months (IQR 35·0–52·3). Bivariable and multivariable logistic regression models and Cox-proportional hazards models were performed based on a predefined statistical analysis plan for analysis of the endpoints pathological complete response, disease-free survival, and overall survival. Findings A total of 1098 (47·5%) of 2310 tumours were HER2-low-positive and 1212 (52·5%) were HER2-zero. 703 (64·0%) of 1098 patients with HER2-low-positive tumours were hormone receptor positive, compared with 445 (36·7%) of 1212 patients with HER2-zero tumours (p Interpretation Our results show that HER2-low-positive tumours can be identified as new subgroup of breast cancer by standardised IHC, distinct from HER2-zero tumours. HER2-low-positive tumours have a specific biology and show differences in response to therapy and prognosis, which is particularly relevant in therapy-resistant, hormone receptor-negative tumours. Our results provide a basis for a better understanding of the biology of breast cancer subtypes and the refinement of future diagnostic and therapeutic strategies. Funding German Cancer Aid (Deutsche Krebshilfe).