Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, ...oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the second of a two part conference scene, consensus recommendations for radiation treatment, primary systemic therapies and management of genetic predisposition are reported and focus on the following topics: influence of both clinical response to PST and stage at presentation on recommendations for postmastectomy radiotherapy; use of regional nodal irradiation in selected node-positive patients and those with adverse pathological factors; extent of surgical resection following downstaging of tumors with PST; use of preoperative hormonal therapy in premenopausal women with larger, node-negative luminal A-like tumors and managing increasing demands for contralateral prophylactic mastectomy in patients with a unilateral sporadic breast cancer.
•This ESO-ESMO ABC 5 Clinical Practice Guideline provides key recommendations for managing advanced breast cancer patients.•It provides updates on managing patients with all breast cancer subtypes, ...LABC, follow-up, palliative and supportive care.•Updated diagnostic and treatment algorithms are also provided.•All recommendations were compiled by a multidisciplinary group of international experts.•Recommendations are based on available clinical evidence and the collective expert opinion of the authors.
We report on the multiwavelength observations of the bright, long gamma-ray burst GRB 110731A, by the Fermi and Swift observatories, and by the MOA and GROND optical telescopes. The analysis of the ...prompt phase reveals that GRB 110731A shares many features with bright Large Area Telescope bursts observed by Fermi during the first three years on-orbit: a light curve with short time variability across the whole energy range during the prompt phase, delayed onset of the emission above 100 MeV, extra power-law component and temporally extended high-energy emission. In addition, this is the first GRB for which simultaneous GeV, X-ray, and optical data are available over multiple epochs beginning just after the trigger time and extending for more than 800 s, allowing temporal and spectral analysis in different epochs that favor emission from the forward shock in a wind-type medium. The observed temporally extended GeV emission is most likely part of the high-energy end of the afterglow emission. Both the single-zone pair transparency constraint for the prompt signal and the spectral and temporal analysis of the forward-shock afterglow emission independently lead to an estimate of the bulk Lorentz factor of the jet Gamma ~ 500-550.
Cosmic rays (CRs) can be studied through the galaxy-wide gamma-ray emission that they generate when propagating in the interstellar medium. The comparison of the diffuse signals from different ...systems may inform us about the key parameters in CR acceleration and transport. We aim to determine and compare the properties of the CR-induced gamma-ray emission of several Local Group galaxies. We use 2 years of nearly continuous sky-survey observations obtained with the Large Area Telescope aboard the Fermi Gamma-ray Space Telescope to search for gamma-ray emission from M31 and M33. We compare the results with those for the Large Magellanic Cloud, the Small Magellanic Cloud, the Milky Way, and the starburst galaxies M82 and NGC253. We detect a gamma-ray signal at 5sigma significance in the energy range 200 MeV-20 GeV that is consistent with originating from M31. The integral photon flux above 100MeV amounts to 9.1 +/- 1.9 (stat) +/- 1.0 (sys) x10e-9 ph/cm2/s. We find no evidence for emission from M33 and derive an upper limit on the photon flux >100MeV of 5.1 x10e-9 ph/cm2/s (2sigma). Comparing these results to the properties of other Local Group galaxies, we find indications for a correlation between star formation rate and gamma-ray luminosity that also holds for the starburst galaxies. The gamma-ray luminosity of M31 is about half that of the Milky Way, which implies that the ratio between the average CR densities in M31 and the Milky Way amounts to 0.35 +/- 0.25. The observed correlation between gamma-ray luminosity and star formation rate suggests that the flux of M33 is not far below the current upper limit from the LAT observations.
In this paper, we present the Fermi All-sky Variability Analysis (FAVA), a tool to systematically study the variability of the gamma-ray sky measured by the Large Area Telescope on board the Fermi ...Gamma-ray Space Telescope.For each direction on the sky, FAVA compares the number of gamma-rays observed in a given time window to the number of gamma-rays expected for the average emission detected from that direction. This method is used in weekly time intervals to derive a list of 215 flaring gamma-ray sources. We proceed to discuss the 27 sources found at Galactic latitudes smaller than 10 and show that, despite their low latitudes, most of them are likely of extragalactic origin.
Vascular endothelial growth factor (VEGF) was identified as a heparin-binding polypeptide mitogen with a target cell specificity restricted to vascular endothelial cells. Molecular cloning reveals ...the existence of four species of VEGF having 121, 165, 189, and 206 amino acids. These have strikingly different secretion patterns, which suggests multiple physiological roles for this family of polypeptides. The two shorter forms are efficiently secreted, while the longer ones are mostly cell-associated. Alternative splicing of mRNA, rather that transcription from different genes, is the mechanism for their generation. In situ hybridization reveals that the VEGF mRNA is widely distributed in most tissues and organs and expressed at particularly high levels in areas of active vascular proliferation, like the ovarian corpus luteum. Ligand autoradiography on rat tissue sections demonstrates that VEGF binding sites are associated with vascular endothelial cells of both fenestrated and non-fenestrated capillaries and with the endothelium of large vessels, while no displaceable binding is evident on non-endothelial cell types. These findings support the hypothesis that VEGF plays a highly specific role in the maintenance and in the induction of growth of vascular endothelial cells.
Abstract
Background: Discordance in hormone receptor (HR) status between primary (p) tumors and metastatic (m) recurrences has been widely described. Loss of estrogen and progesterone receptor ...expression occurs in ˜12% of asynchronous recurrences, leading to triple-negative (TN) status in the metastasis. Genomic mechanisms driving HR loss and its prognostic and therapeutic implications have not been fully elucidated.
Methods: Targeted NGS (Oncopanel, OP) at Dana-Farber Cancer Institute using multiplexed copy number variation and mutation (mut) detection across the full coding regions of 300 genes and selected intronic regions of 35 genes was prospectively performed on either archival primary or metastatic samples collected in patients (pts) with metastatic breast cancer (MBC). Receptor status at initial diagnosis and recurrence were reviewed using a 1% cutoff to define HR-positivity and excluding HER2+ cases. Fisher´s exact test was used to compare frequency of alterations. Tumor mut burden (TMB) was computed normalizing the sum of reported exon mut in each pt by the exonic-bait-set size of the panel.
Results: Between 8/2013-9/2016, 929 pts with MBC underwent OP testing. Of 517 pts diagnosed with primary HR+/HER2- breast cancer, at time of recurrence 388 remained HR+/HER2- (pHR+/mHR+), 39 switched to HR-/HER2- (pHR+/mTN, of which 23 (59%) had initial HR expression >10%), 10 switched to HER2+ and 80 had unknown metastatic receptor status. Comparison between primary samples in pHR+/mHR+ (n=245) and pHR+/mTN (n=24) showed that pHR+/mTN was significantly more likely to harbor mut in TP53, STK11 and MSH6, amplifications (amp) in CCNE1 and FGFR2, and less likely to have PIK3CA mut or CCND1 amp. Median TMB in primary pHR+/mHR+ was 6.05 mut/Mb (0-37.5) and 5.68 mut/Mb (1.2-10.9) in pHR+/mTN (p=0.45). Metastatic samples in pHR+/mTN (n=15) were enriched in ARID1A, CRTC2 and CDH1 mut compared to metastases (n=40) in pts who remained TN (pTN/mTN). Deletions in CDKN2A/2B and RB1, and mut in TP53, NOTCH2 and ERCC2 were more prevalent in recurrent tumors of pHR+/mTN than pHR+/mHR+. In metastases, TMB was higher in pHR+/mTN than pTN/mTN or pHR+/mHR+ (10.9 vs. 7.0 vs. 7.3 mut/Mb, respectively; p=0.002). Median OS from initial diagnosis was 9.4 yrs in pHR+/mTN, less than pHR+/mHR+ (15.9 yrs; p=0.009) and greater than pTN/mTN (4.3 yrs; p=0.008). Median OS from MBC diagnosis was 1.8 yrs in pHR+/mTN, less than pHR+/mHR+ (6.4 yrs; p=0.001) but not significantly different than pTN/mTN (1.5 yrs, p=0.3).
pHR+/mHR+ (n=245)pHR+/mTN (n=24)p value NFreq (%)NFreq (%) MutTP536325.72083.3<0.00001PIK3CA9438.4000GATA33514.3000.053STK1152.0312.50.026MSH641.6312.50.017AmpFGFR20028.30.008CCNE10028.30.008CCND14418.0000.018
Conclusion: Targeted NGS shows that alterations in DNA damage and cell-cycle regulation pathways in primary HR+ tumors are associated with HR loss in the metastatic setting. Primary tumors that lose HR appear more similar to basal-like than luminal tumors, despite >10% baseline HR expression in most pts, and once metastatic, survival is comparable to pTN/mTN. Metastases with HR loss have higher TMB than those that remain HR+ or TN throughout the course of the disease. These findings, if confirmed, may influence treatment and pt selection for clinical trials.
Citation Format: Garrido-Castro AC, Hughes ME, Cherniack A, Barroso-Sousa R, Bychkovsky BL, Di Lascio S, Berger A, Mittendorf EA, Files JL, Guo H, Kumari P, Cerami E, Krop IE, Wagle N, Lindeman NI, MacConaill LE, Dillon DA, Winer EP, Lin NU. Genomic alterations associated with loss of HR expression in metastatic breast cancer abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD9-01.
GRB110721A was observed by the Fermi Gamma-ray Space Telescope using its two instruments, the Large Area Telescope (LAT) and the Gamma-ray Burst Monitor (GBM). The burst consisted of one major ...emission episode which lasted for ~24.5 s (in the GBM) and had a peak flux of (5.7 + or - 0.2) x 10 super(?5) erg s super(?1) cm super(?2). The time-resolved emission spectrum is best modeled with a combination of a Band function and a blackbody spectrum. The peak energy of the Band component was initially 15 + or - 2 MeV, which is the highest value ever detected in a GRB. This measurement was made possible by combining GBM/BGO data with LAT Low Energy events to achieve continuous 10-100 MeV coverage. The peak energy later decreased as a power law in time with an index of -1.89 + or - 0.10. The temperature of the blackbody component also decreased, starting from ~80 keV, and the decay showed a significant break after ~2 s. The spectrum provides strong constraints on the standard synchrotron model, indicating that alternative mechanisms may give rise to the emission at these energies.
The 15th St. Gallen International Breast Cancer Conference 2017 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Treatments were ...assessed in light of their intensity, duration and side-effects, seeking where appropriate to escalate or de-escalate therapies based on likely benefits as predicted by tumor stage and tumor biology. The Panel favored several interventions that may reduce surgical morbidity, including acceptance of 2 mm margins for DCIS, the resection of residual cancer (but not baseline extent of cancer) in women undergoing neoadjuvant therapy, acceptance of sentinel node biopsy following neoadjuvant treatment of many patients, and the preference for neoadjuvant therapy in HER2 positive and triple-negative, stage II and III breast cancer. The Panel favored escalating radiation therapy with regional nodal irradiation in high-risk patients, while encouraging omission of boost in low-risk patients. The Panel endorsed gene expression signatures that permit avoidance of chemotherapy in many patients with ER positive breast cancer. For women with higher risk tumors, the Panel escalated recommendations for adjuvant endocrine treatment to include ovarian suppression in premenopausal women, and extended therapy for postmenopausal women. However, low-risk patients can avoid these treatments. Finally, the Panel recommended bisphosphonate use in postmenopausal women to prevent breast cancer recurrence. The Panel recognized that recommendations are not intended for all patients, but rather to address the clinical needs of the majority of common presentations. Individualization of adjuvant therapy means adjusting to the tumor characteristics, patient comorbidities and preferences, and managing constraints of treatment cost and access that may affect care in both the developed and developing world.
PDF
