Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Abstract P6-10-01: Efficacy and safety of the therapeutic cancer vaccine tecemotide (L-BLP25) in early breast cancer: Results from a prospective, randomized, neoadjuvant phase-II study (ABCSG-34)

Abstract Background: Immune-based therapeutic strategies represent a promising approach in early and advanced breast cancer treatment. MUC1 glycoprotein is overexpressed and aberrantly glycosylated in over 90% of malignant breast cancer. It is involved in oncogenesis and confers resistance to anti-cancer therapies, thus representing a particularly promising target. Tecemotide is a MUC1-based therapeutic cancer vaccine. The aim of this trial was to investigate the efficacy and safety of preoperative tecemotide in primary breast cancer patients receiving neoadjuvant Standard-of-Care (SoC) treatment. Patients and Methods: 400 patients with HER2-negative early breast cancer were recruited into this prospective, multicentre randomized 2-arm academic phase-II trial. Patients received preoperative SoC treatment with or without tecemotide therapy. Postmenopausal women with E+++, or E++ and Ki67 &amp;lt;14%, and G1,2,X tumors received 6 months of letrozole as SoC. Postmenopausal patients with triple-negative, E- or E+, or E++ and Ki67 ≥14%, and with G3 tumors, and all premenopausal patients received 4 cycles of epirubicin/cyclophosphamide plus 4 cycles of docetaxel as SoC. Patients were additionally randomized to receive reverse or conventional sequence of epirubicin/cyclophosphamide and docetaxel. Primary endpoint was histopathological response measured by Residual Cancer Burden (RCB0/I vs RCBII/III) at the time of surgery. Secondary endpoints included pCR, efficacy of reverse versus conventional sequence chemotherapy, and safety. Results: We did not observe a significant difference in RCB0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40), and in endocrine and chemotherapy treated subgroups (25.0% vs 13.3%, p = 0.17; 39.6% vs 37.8%, p = 0.75). Similarly, addition of tecemotide did not affect overall pCR rates (22.5% vs 17.4%, p = 0.23). RCB0/I rates were comparable regardless of docetaxel being given before or after epirubicin/cyclophosphamide (37.2% vs 40.1%, p = 0.61). Tecemotide addition was not associated with a worse toxicity profile (178 AEs, 57 SAEs vs 180 AEs, 48 SAEs based on patient incidence). Conclusion: Immune-based targeting of MUC1 by tecemotide is safe but does not improve RCB and pCR rates in early SoC-treated breast cancer. Citation Format: Singer CF, Pfeiler G, Hubalek M, Bartsch R, Stoeger H, Pichler A, Petru E, Greil R, Rudas M, Tea M-KM, Wette V, Petzer AL, Sevelda P, Egle D, Dubsky PC, Balic M, Tinchon C, Bago-Horvath Z, Frantal S, Michael G. Efficacy and safety of the therapeutic cancer vaccine tecemotide (L-BLP25) in early breast cancer: Results from a prospective, randomized, neoadjuvant phase-II study (ABCSG-34) [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 P6-10-01.</jats:p

Abstract S2-02: The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial

Abstract Background: Adjuvant endocrine therapy compromises bone health in pre- and postmenopausal breast cancer (BC) patients. Bisphosphonates have been shown to prevent and counteract these side effects of endocrine therapy, and to improve disease-free and overall survival outcomes in postmenopausal (natural or induced) BC patients (EBCTCG meta-analysis, Lancet 2015). The aim of ABCSG-18 was to investigate the effects of adjuvant anti-RANK-ligand Denosumab on bone health and disease outcomes in postmenopausal patients with early hormone receptor+ (HR+) BC receiving AI treatment. Patients and Methods: 3,425 postmenopausal patients with HR+ BC receiving AI were recruited in 58 trial sites into this prospective, randomized, double-blind, placebo-controlled, phase-III trial. Patients were randomized 1:1 to either Denosumab 60mg or placebo q6mo s.c. Bone end point results showed that adjuvant denosumab significantly reduced clinical fractures (primary endpoint, HR=0.5, p&amp;lt;0.0001), improved bone mineral density, and reduced vertebral fractures without relevant toxicity (Gnant et al., Lancet 2015). Disease-free survival (DFS) is a secondary endpoint. Following an IDMC recommendation based on the results of a protocol-specified interim analysis, a DFS analysis took place in September 2015, before a patients' choice unblinding option will be provided to trial patients in the year 2016. Additional disease outcome related end points (BMFS, OS) will be analysed during further study follow up. Results: With a median follow-up of 4 years, 370 DFS events were recorded. 203 DFS events occurred in the placebo group, and 167 in the Denosumab group (HR 0.816, p=0.051). Subgroup analyses indicate that the Denosumab benefit (overall absolute 2.1% at 5 years) may be particularly driven by tumors larger than 2cm (HR=0.66, p=0.016), ductal breast cancer histology type (HR=0.79, p=0.048), and tumors with both ER and PR positive (HR=0.75, p=0.013). Summary and conclusion: Adjuvant Denosumab 60mg q6mo s.c. improves disease-free survival of HR+ breast cancer patients receiving aromatase inhibitors. Numerically, this benefit of adjuvant Denosumab is at least comparable to the DFS-benefit of adjuvant bisphosphonates. Bases on these results and the previously reported dramatic reduction of fractures, adjuvant Denosumab should be offered to all postmenopausal HR+ breast cancer patients on AI. Citation Format: Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger-Zeinitzer E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer CF, On behalf of the Austrian Breast and Colorectal Cancer Study Group. The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-02.</jats:p

Abstract GS6-04: The EndoPredict score predicts residual cancer burden after neoadjuvant chemotherapy and after neoendocrince therapy in HR+/HER2- breast cancer patients from ABCSG 34

Abstract Background: In the neoadjuvant treatment setting of ER+/HER2- breast cancer (BC) the choice between preoperative endocrine - (NET) or preoperative chemotherapy (NCT) is largely based on the expression of hormone receptors (HR), grading and possibly Ki-67. The EndoPredict 12-gene molecular score (EP) is a validated prognostic score based on the expression of genes involved in cellular processes including proliferation and ER signaling/differentiation. The application of the EP molecular score may thus provide additional insight into neoadjuvant response of tumors. Methods: This prospective translational study was carried out as an exploratory endpoint within the ABCSG 34 protocol (SABCS 2016, Singer et al.) and included only the HR+ subset of women. ABCSG 34 was a randomized 2-arm academic phase-II trial including 400 patients (250 ER+) with HER2 negative early BC. Patients were selected for either NET or NCT according to the study protocol reflecting standard of care: postmenopausal women with ER+++, or ER++ and Ki67 &amp;lt;14%, and G1,2,X tumors received 6 months of Letrozole. Postmenopausal patients with ER-(and PgR+) or ER low and Ki67 ≥14%, and with G3 tumors, and premenopausal patients, received 8 cycles of anthracycline/taxane based chemotherapy. Primary endpoint was Residual Cancer Burden score (RCB0/I vs RCBII/III) at surgery in women with or without Tecemotide (L-BLP25). EP was assessed from diagnostic cores and the predefined risk groups (EP low-risk vs EP high-risk; cutoff value: 5.0) and the score as a continuous variable (EPc) were applied to all patients with both full molecular - and RCB data (n=217). Results: 134 patients (EP low-risk:9; EP high-risk:125) with HR+ tumors received NCT. Stage I: 14.9%, II/III: 84%; G3: 56%; mean Ki-67: 40.4%. No patient with EP low-risk score showed RCB0/I (NPV: 100%) whereas 26.4% of EP high-risk showed full response. In logistic regression EP as a continuous score (EPc) was a significant predictor of RCB0/I, showed an AUC (95% CI) of 0.736 (0.63 - 0.84) and revealed close correlation with Ki-67. 83 patients (EP low-risk:44; EP high-risk:39) received NET. Stage I: 38.6%, II/III: 60.2%; G3: 4.8%; mean Ki-67: 14.9%. 27.3% (n=12/44) with EP low-risk and 7.7% (n=3/39) with EP high-risk showed RCB0/I. EPc was a significant predictor of RCB0/I with an AUC (95% CI) of 0.726 (0.60 - 0.85). In all multivariate analyses low anatomic stage was the most powerful predictor of RCB0/I. Conclusions: Clinical standard of care separated ABCSG 34 patients into two HR+ cohorts with differing clinical features and treated distinctly with either NET or NCT: In women treated with neoadjuvant Letrozole a high molecular score indicated a very low possibility of endocrine response. In women clinically selected for neoadjuvant chemotherapy, a high EP score was associated with a higher probability of chemotherapy response and the low EP risk group outlined a group of women with very poor tumor response to NCT(NPV 100%). In summary, EP low risk is associated with tumor response to endocrine treatment and predicts resistance in the chemotherapy group. NCT, especially to attain breast conservation in ER+/HER2-/EP low risk should be reconsidered. Citation Format: Dubsky PC, Fesl C, Singer CF, Pfeiler G, Kronenwett R, Hubalek M, Bartsch R, Stoeger H, Pichler A, Petru E, Bjelic-Radisic V, Greil R, Rudas M, Tea M-KM, Wette V, Petzner AL, Sevelda P, Egle D, Fitzal F, Exner R, Jakesz R, Balic M, Tinchon C, Bago-Horvath Z, Lax S, Regitnig P, Gnant M, Filipits M. The EndoPredict score predicts residual cancer burden after neoadjuvant chemotherapy and after neoendocrince therapy in HR+/HER2- breast cancer patients from ABCSG 34 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS6-04.</jats:p