Description: Deep focus earthquakes within the underthrust Indian lower crust beneath the Himalaya occur in very specific regions and have distinct source characteristics. The study of the source mechanisms of these earthquakes provides valuable constraints on the kinematics of deformation of the underthrust Indian Plate, and its influence on the active deformation of the overlying Himalayan wedge. One of the most significant regions of these deep focus earthquakes is beneath the Sikkim and Bhutan Himalaya. We study the source characteristics of the 2011 September 18 ( M w 6.9) deep focus Sikkim main shock and its major aftershocks using global, regional and local waveform data. We determined the focal mechanism of the main shock using moment tensor inversion of global P and SH waveforms, and ascertained the earthquake fault plane using rupture directivity from regional P -wave spectra. The main shock originated at 53 ± 4 km depth and ruptured at least 20 km thickness of the underthrust Indian lower crust. Faulting occurred on a near vertical dextral strike-slip fault oriented NW-SE (strike 127°, dip 81° and rake 167°), oblique to the local strike of the Himalayan arc. The rupture initiated from the SE end of the fault and propagated to the northwest. The main shock was followed by 20 small-to-moderate aftershocks ( m b  〉 3.0), which we relocated using phase arrival times. We computed the focal mechanisms of the larger ones ( m b  ≥ 3.5) using local waveform inversion. We find that all aftershocks originated SE of the main shock, between depths of 12 and 50 km, and have dominantly strike-slip mechanisms. Our results, combined with the source mechanisms of earthquakes from previous studies, reveals that the entire underthrust Indian crust is seismogenic and deforms by dextral strike-slip motion on oblique structures beneath the Sikkim and Bhutan Himalaya. These active oblique structures with transverse motion possibly mark the western boundary of the clock-wise rotating ‘microplates’ in northeast India observed from GPS geodesy.

Description: Deep focus earthquakes within the underthrust Indian lower crust beneath the Himalaya occur in very specific regions and have distinct source characteristics. The study of the source mechanisms of these earthquakes provides valuable constraints on the kinematics of deformation of the underthrust Indian Plate, and its influence on the active deformation of the overlying Himalayan wedge. One of the most significant regions of these deep focus earthquakes is beneath the Sikkim and Bhutan Himalaya. We study the source characteristics of the 2011 September 18 ( M w 6.9) deep focus Sikkim main shock and its major aftershocks using global, regional and local waveform data. We determined the focal mechanism of the main shock using moment tensor inversion of global P and SH waveforms, and ascertained the earthquake fault plane using rupture directivity from regional P -wave spectra. The main shock originated at 53 ± 4 km depth and ruptured at least 20 km thickness of the underthrust Indian lower crust. Faulting occurred on a near vertical dextral strike-slip fault oriented NW-SE (strike 127°, dip 81° and rake 167°), oblique to the local strike of the Himalayan arc. The rupture initiated from the SE end of the fault and propagated to the northwest. The main shock was followed by 20 small-to-moderate aftershocks ( m b  〉 3.0), which we relocated using phase arrival times. We computed the focal mechanisms of the larger ones ( m b  ≥ 3.5) using local waveform inversion. We find that all aftershocks originated SE of the main shock, between depths of 12 and 50 km, and have dominantly strike-slip mechanisms. Our results, combined with the source mechanisms of earthquakes from previous studies, reveals that the entire underthrust Indian crust is seismogenic and deforms by dextral strike-slip motion on oblique structures beneath the Sikkim and Bhutan Himalaya. These active oblique structures with transverse motion possibly mark the western boundary of the clock-wise rotating ‘microplates’ in northeast India observed from GPS geodesy.

Description: Introduction Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2– BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1–3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC). Methods In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology ( n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade ( n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2– patients ( n = 459). Results Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2– patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors. In unselected and HR+/HER2– patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2– (H.R. = 5.36; P 〈 0.001), GGI was the only remaining prognostic factor. In multivariate interaction analysis (including central and genomic grade), luminal-B-like subtype [HR+ and (Ki-67 ≥20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2– patients. Conclusion In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone. Trial registration The WSG-AGO/EC-Doc is registered at ClinicalTrials.gov, NCT02115204.

Description: Background The prognostic value of histologic grade (HG) in invasive lobular carcinoma (ILC) remains uncertain, and most ILC tumors are graded as HG2. Genomic grade (GG) is a 97-gene signature that improves the prognostic value of HG. This study evaluates whether GG may overcome the limitations of HG in ILC. Methods Gene expression data were generated from frozen tumor samples, and GG calculated according to the expression of 97 genes. The prognostic value of GG was assessed in a stratified Cox regression model for invasive disease-free survival (IDFS) and overall survival (OS). Results A total of 166 patients were classified by GG. HG classified 33 (20%) tumors as HG1, 120 (73%) as HG2 and 12 (7%) as HG3. GG classified 106 (64%) tumors as GG low (GG1), 29 (17%) as GG high (GG3) and 31 (19%) as equivocal (cases not classified as GG1 or GG3). The median follow-up time was 6.5 years. In multivariate analyses, GG was associated with IDFS [HR GG3 vs GG1 5.6 (2.1–15.3); P 〈 0.001] and OS [HR GG3 vs GG1 7.2, 95% CI (1.6–32.2); P = 0.01]. Conclusions GG outperformed HG in ILC and added prognostic value to classic clinicopathologic variables, including nodal status.

Description: Background The genomic grade index (GGI) completes the prognostic value of histological grade (HG). Other proliferation markers include the mitotic activity index (MAI) and the Ki67 immunohistochemistry (IHC) status. We compared the prognostic value of GGI, HG, MAI, Ki67 IHC and messenger RNA (mRNA) status in node-positive breast cancer (BC) patients treated with adjuvant anthracycline-based chemotherapy in the prospective PACS01 trial. Patients and methods The five proliferation-related parameters (GGI, Ki67 mRNA expression and centrally determined HG, MAI, and Ki67 IHC status) of tumours were available for 204 cases and analysed as continuous values. We compared the correlations of each one with the other proliferation-related parameters and with histoclinical variables including the disease-free survival (DFS). Results Expected correlations were observed between the five parameters and for each parameter with biological features (hormone-receptor and HER2 status, molecular subtypes), but the GGI displayed the strongest correlations. The GGI outperformed the prognostic performance of the four other proliferation-related parameters for the DFS in all 204 patients and in the 95 HG2 patients. In multivariate analysis including the classical prognostic factors, only GGI remained significant. Finally, the GGI outperformed the prognostic performance of MKI67 mRNA expression in a series of 1599 samples and 656 HG2 cases. Conclusions In this small pilot biomarker study ancillary to the PACS01 trial, the GGI outperforms the prognostic performance of centrally determined HG, MAI, Ki67 IHC status and mRNA expression. Further validation is warranted in larger series.