The impact of genomic context on outcomes of solid cancer patients treated with genotype-matched targeted therapies:a comprehensive review

INTRODUCTION: A critical need in the field of genotype-matched targeted therapy in cancer is to identify patients unlikely to respond to precision medicines. This will manage expectations of individualised therapies and avoid clinical progression to a point where institution of alternative treatments might not be possible. We examined the evidence base of the impact of genomic context on which targeted alterations are inscribed to identify baseline biomarkers distinguishing those obtaining the expected response from those with less benefit from targeted therapies.METHODS: A comprehensive narrative review was conducted: scoping searches were undertaken in PubMed, Cochrane Database of Systematic Reviews, and PROSPERO. Outcomes included in meta-analysis were progression-free and overall survival. Data were extracted from Kaplan-Meier and used to calculate hazard ratios. Studies presenting data on two molecular subcohorts (e.g. co-mutation versus no co-mutation) were included in fixed meta-analysis. Other studies were used for descriptive purposes.RESULTS: The presence of concomitant driver mutations, higher tumour mutational burden (TMB), greater copy number burden, and APOBEC signatures significantly reduces benefits of targeted therapy in lung cancers in never smokers (LCINS - less than 100 cigarettes per lifetime) and breast cancer, cancers with low TMB. LCINS have significantly poorer outcomes if their cancers harbour p53 co-mutations, an effect also seen in human epidermal growth factor receptor 2-positive (HER2+) breast cancer patients (trastuzumab) and head and neck cancer patients [phosphoinositide 3-kinase (PI3K) inhibition]. PI3K co-alterations have less impact when targeting epidermal growth factor receptor mutations and anaplastic lymphoma kinase fusions, but significantly reduce the impact of targeting HER2 and MET amplifications. SMARCA4 co-mutations predict for poor outcome in patients treated with osimertinib and sotorasib. In BRAF-mutant melanoma, whilst there are no genomic features distinguishing exceptional responders from primary progressors, there are clear transcriptomic features dichotomising these outcomes.CONCLUSION: To our knowledge, this is the most comprehensive review to date of the impact of genomic context on outcomes with targeted therapy. It represents a valuable resource informing progress towards contextualised precision medicine.</p

First Observation of Υ(1S)→γππ\Upsilon(1S)\to \gamma\pi\pi

We report on a study of exclusive radiative decays of the Upsilon(1S) resonance collected with the CLEO-II detector operating at CESR. We present the first observation of the radiative decays Upsilon(1S)->gamma pi+pi- and Upsilon(1S)->gamma pi0pi0. For the dipion mass regime m(pipi)>1.0 GeV, we obtain Br(Upsilon(1S)->gamma pi+pi-=(6.3+/-1.2+/-1.3) x 10^(-5), and Br(Upsilon(1S)->gamma pi0pi0=(1.7+/-0.6+/-0.3) x 10^(-5). The observed gamma pipi events are consistent with the hypothesis Upsilon(1S)->gamma f2(1270).Comment: 9 pages, postscript file also available through http://w4.lns.cornell.edu/public/CLN

Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model

Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures

Measurement of the Inclusive Semi-electronic D0D^0 Branching Fraction

Using the angular correlation between the $\pi^+$ emitted in a $D^{*+} \rightarrow D^0 \pi^+$ decay and the $e^+$ emitted in the subsequent $D^0 \rightarrow Xe^+\nu$ decay, we have measured the branching fraction for the inclusive semi-electronic decay of the $D^0$ meson to be: {\cal B}(D^0 \rightarrow X e^+ \nu) = [6.64 \pm 0.18 (stat.) \pm 0.29 (syst.)] \%. The result is based on 1.7 fb$^{-1}$ of $e^+e^-$ collisions recorded by the CLEO II detector located at the Cornell Electron Storage Ring (CESR). Combining the analysis presented in this paper with previous CLEO results we find, \frac{{\cal B} (D^0 \rightarrow X e^+ \nu)} {{\cal B} (D^0 \rightarrow K^- \pi^+)} = 1.684 \pm 0.056 (stat.) \pm 0.093(syst.) and \frac{{\cal B}(D\rightarrow K^-e^+\nu)} {{\cal B}(D\rightarrow Xe^+\nu)} = 0.581 \pm 0.023 (stat.) \pm 0.028(syst.). The difference between the inclusive rate and the sum of the measured exclusive branching fractions (measured at CLEO and other experiments) is $(3.3 \pm 7.2) \%$ of the inclusive rate.Comment: Latex file, 33pages, 4 figures Submitted to PR

Limit on the Two-Photon Production of the Glueball Candidate fJ(2220)f_{J}(2220) at CLEO

We use the CLEO detector at the Cornell electron-positron storage ring, CESR, to search for the two-photon production of the glueball candidate f_J(2220) in its decay to K_s K_s. We present a restrictive upper limit on the product of the two-photon partial width and the K_s K_s branching fraction. We use this limit to calculate a lower limit on the stickiness, which is a measure of the two-gluon coupling relative to the two-photon coupling. This limit on stickiness indicates that the f_J(2220) has substantial glueball content.Comment: 9 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN

Tau Neutrino Helicity from h±h^{\pm} Energy Correlations

We report a measurement of the magnitude of the tau neutrino helicity from tau-pair events taken with the CLEO detector at the CESR electron-positron storage ring. Events in which each tau undergoes the decay tau -> h nu, with h a charged pion or kaon, are analyzed for energy correlations between the daughter hadrons, yielding |xi| = 2*|h_nu| = 1.03 +/- 0.06 +/- 0.04, with the first error statistical and the second systematic.Comment: 11 pages, postscript file also available through http://w4.lns.cornell.edu/public/CLN

Measurement of the Branching Ratios for the Decays of Ds+→ηπ+,η′π+,ηρ+D_{s}^{+}\to \eta\pi^{+}, \eta^{'}\pi^{+}, \eta\rho^{+}, and eta′ρ+eta^{'}\rho^{+}

Using a data sample with integrated luminosity of about 3.9 fb^{-1} collected in e+ e- annihilation with the CLEO-II detector at the Cornell Electron Storage Ring, we have measured the branching ratios for the decay modes Ds -> (eta, eta') pi and Ds -> (eta, eta') rho relative to Ds -> phi pi. These decay modes are among the most common hadronic decays of the Ds's and can be related by factorization to the semileptonic decays Ds -> (eta,eta') l nu. The results obtained are compared with previous CLEO results and with the branching ratios measured for the related semileptonic decays. We also report results on the Cabibbo-suppressed decays of the D+ to the same final states.Comment: 18 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN

Search for the Decays B^0 -> D^{(*)+} D^{(*)-}

Using the CLEO-II data set we have searched for the Cabibbo-suppressed decays B^0 -> D^{(*)+} D^{(*)-}. For the decay B^0 -> D^{*+} D^{*-}, we observe one candidate signal event, with an expected background of 0.022 +/- 0.011 events. This yield corresponds to a branching fraction of Br(B^0 -> D^{*+} D^{*-}) = (5.3^{+7.1}_{-3.7}(stat) +/- 1.0(syst)) x 10^{-4} and an upper limit of Br(B^0 -> D^{*+} D^{*-}) D^{*\pm} D^\mp and B^0 -> D^+ D^-, no significant excess of signal above the expected background level is seen, and we calculate the 90% CL upper limits on the branching fractions to be Br(B^0 -> D^{*\pm} D^\mp) D^+ D^-) < 1.2 x 10^{-3}.Comment: 12 page postscript file also available through http://w4.lns.cornell.edu/public/CLNS, submitted to Physical Review Letter

Study of the B^0 Semileptonic Decay Spectrum at the Upsilon(4S) Resonance

We have made a first measurement of the lepton momentum spectrum in a sample of events enriched in neutral B's through a partial reconstruction of B0 --> D*- l+ nu. This spectrum, measured with 2.38 fb**-1 of data collected at the Upsilon(4S) resonance by the CLEO II detector, is compared directly to the inclusive lepton spectrum from all Upsilon(4S) events in the same data set. These two spectra are consistent with having the same shape above 1.5 GeV/c. From the two spectra and two other CLEO measurements, we obtain the B0 and B+ semileptonic branching fractions, b0 and b+, their ratio, and the production ratio f+-/f00 of B+ and B0 pairs at the Upsilon(4S). We report b+/b0=0.950 (+0.117-0.080) +- 0.091, b0 = (10.78 +- 0.60 +- 0.69)%, and b+ = (10.25 +- 0.57 +- 0.65)%. b+/b0 is equivalent to the ratio of charged to neutral B lifetimes, tau+/tau0.Comment: 14 page, postscript file also available at http://w4.lns.cornell.edu/public/CLN