PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients

Introduction: Inhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway can overcome endocrine resistance in estrogen receptor (ER) α-positive breast cancer, but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently endocrine resistance are lacking. PIK3CA mutations frequently occur in ERα-positive breast cancer and result in PI3K/AKT/mTOR activation in vitro. Nevertheless, the prognostic and treatment-predictive value of these mutations in ERα-positive breast cancer is contradictive. We tested the clinical validity of PIK3CA mutations and other canonic pathway drivers to predict intrinsic resistance to adjuvant tamoxifen. In addition, we tested the association between these drivers and downstream activated proteins.Methods: Primary tumors from 563 ERα-positive postmenopausal patients, randomized between adjuvant tamoxifen (1 to 3 years) versus observation were recollected. PIK3CA hotspot mutations in exon 9 and exon 20 were assessed with Sequenom Mass Spectometry. Immunohistochemistry was performed for human epidermal growth factor receptor 2 (HER2), phosphatase and tensin homolog (PTEN), and insulin-like growth factor 1 receptor (IGF-1R). We tested the association between these molecular alterations and downstream activated proteins (like phospho-protein kinase B (p-AKT), phospho-mammalian target of rapamycin (p-mTOR), p-ERK1/2, and p-p70S6K). Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of canonic pathway drivers, by using Cox proportional hazard models, including a test for interaction.Results: PIK3CA mutations (both exon 9 and exon 20) were associated with low tumor grade. An enrichment of PIK3CA exon 20 mutations was observed in progesterone receptor- positive tumors. PIK3CA exon 20 mutations were not associated with downstream-activated proteins. No significant interaction between PIK3CA mutations or any of the other canonic pathway drivers and tamoxifen-treatment benefit was found.Conclusion: PIK3CA mutations do not have clinical validity to predict intrinsic resistance to adjuvant tamoxifen and may therefore be unsuitable as companion diagnostic for PI3K/AKT/mTOR inhibitors in ERα- positive, postmenopausal, early breast cancer patients

Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment

Contains fulltext : 136517.pdf (publisher's version ) (Open Access)INTRODUCTION: Activation of the phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways results in anti-estrogen resistance in vitro, but a biomarker with clinical validity to predict intrinsic resistance has not been identified. In metastatic breast cancer patients with previous exposure to endocrine therapy, the addition of a mammalian target of rapamycine (mTOR) inhibitor has been shown to be beneficial. Whether or not patients on adjuvant endocrine treatment might benefit from these drugs is currently unclear. A biomarker that predicts intrinsic resistance could potentially be used as companion diagnostic in this setting. We tested the clinical validity of different downstream-activated proteins in the PI3K and/or MAPK pathways to predict intrinsic tamoxifen resistance in postmenopausal primary breast cancer patients. METHODS: We recollected primary tumor tissue from patients who participated in a randomized trial of adjuvant tamoxifen (1-3 years) versus observation. After constructing a tissue micro-array, cores from 563 estrogen receptor alpha positive were immunostained for p-AKT(Thr308), p-AKT(Ser473), p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interactions between these markers and tamoxifen treatment efficacy. RESULTS: Interactions were identified between tamoxifen and p-AKT(Thr308), p-mTOR, p-p70S6K and p-ERK1/2. Applying a conservative level of significance, p-p70S6K remained significantly associated with tamoxifen resistance. Patients with p-p70S6K negative tumors derived significant benefit from tamoxifen (HR 0.24, P < 0.0001), while patients whose tumor did express p-p70S6K did not (HR = 1.02, P =0.95), P for interaction 0.004. In systemically untreated breast cancer patients, p-p70S6K was associated with a decreased risk for recurrence. CONCLUSIONS: Patients whose tumor expresses p-p70S6K, as a marker of downstream PI3K and/or MAPK pathway activation, have a favorable prognosis, but do not benefit from adjuvant tamoxifen. A potential benefit from inhibitors of the PI3K/Akt/mTOR pathway in these patients needs to be further explored

PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients

Contains fulltext : 136461.pdf (publisher's version ) (Open Access)INTRODUCTION: Inhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway can overcome endocrine resistance in estrogen receptor (ER) alpha-positive breast cancer, but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently endocrine resistance are lacking. PIK3CA mutations frequently occur in ERalpha-positive breast cancer and result in PI3K/AKT/mTOR activation in vitro. Nevertheless, the prognostic and treatment-predictive value of these mutations in ERalpha-positive breast cancer is contradictive. We tested the clinical validity of PIK3CA mutations and other canonic pathway drivers to predict intrinsic resistance to adjuvant tamoxifen. In addition, we tested the association between these drivers and downstream activated proteins. METHODS: Primary tumors from 563 ERalpha-positive postmenopausal patients, randomized between adjuvant tamoxifen (1 to 3 years) versus observation were recollected. PIK3CA hotspot mutations in exon 9 and exon 20 were assessed with Sequenom Mass Spectometry. Immunohistochemistry was performed for human epidermal growth factor receptor 2 (HER2), phosphatase and tensin homolog (PTEN), and insulin-like growth factor 1 receptor (IGF-1R). We tested the association between these molecular alterations and downstream activated proteins (like phospho-protein kinase B (p-AKT), phospho-mammalian target of rapamycin (p-mTOR), p-ERK1/2, and p-p70S6K). Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of canonic pathway drivers, by using Cox proportional hazard models, including a test for interaction. RESULTS: PIK3CA mutations (both exon 9 and exon 20) were associated with low tumor grade. An enrichment of PIK3CA exon 20 mutations was observed in progesterone receptor- positive tumors. PIK3CA exon 20 mutations were not associated with downstream-activated proteins. No significant interaction between PIK3CA mutations or any of the other canonic pathway drivers and tamoxifen-treatment benefit was found. CONCLUSION: PIK3CA mutations do not have clinical validity to predict intrinsic resistance to adjuvant tamoxifen and may therefore be unsuitable as companion diagnostic for PI3K/AKT/mTOR inhibitors in ERalpha- positive, postmenopausal, early breast cancer patients

Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment

Introduction: Activation of the phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways results in anti-estrogen resistance in vitro, but a biomarker with clinical validity to predict intrinsic resistance has not been identified. In metastatic breast cancer patients with previous exposure to endocrine therapy, the addition of a mammalian target of rapamycine (mTOR) inhibitor has been shown to be beneficial. Whether or not patients on adjuvant endocrine treatment might benefit from these drugs is currently unclear. A biomarker that predicts intrinsic resistance could potentially be used as companion diagnostic in this setting. We tested the clinical validity of different downstream-activated proteins in the PI3K and/or MAPK pathways to predict intrinsic tamoxifen resistance in postmenopausal primary breast cancer patients.Methods: We recollected primary tumor tissue from patients who participated in a randomized trial of adjuvant tamoxifen (1-3 years) versus observation. After constructing a tissue micro-array, cores from 563 estrogen receptor α positive were immunostained for p-AKT(Thr308), p-AKT(Ser473), p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interactions between these markers and tamoxifen treatment efficacy.Results: Interactions were identified between tamoxifen and p-AKT(Thr308), p-mTOR, p-p70S6K and p-ERK1/2. Applying a conservative level of significance, p-p70S6K remained significantly associated with tamoxifen resistance. Patients with p-p70S6K negative tumors derived significant benefit from tamoxifen (HR 0.24, P < 0.0001), while patients whose tumor did express p-p70S6K did not (HR = 1.02, P =0.95), P for interaction 0.004. In systemically untreated breast cancer patients, p-p70S6K was associated with a decreased risk for recurrence.Conclusions: Patients whose tumor expresses p-p70S6K, as a marker of downstream PI3K and/or MAPK pathway activation, have a favorable prognosis, but do not benefit from adjuvant tamoxifen. A potential benefit from inhibitors of the PI3K/Akt/mTOR pathway in these patients needs to be further explored

The VHMPID RICH upgrade project for ALICE at LHC

RHIC results have shown the importance of high momentum particles as hard probes and the need for particle identification (PID) in a very large momentum range. A Very High Momentum PID (VHMPID) detector has been proposed as upgrade of ALICE to extend the track-by-track identification capabilities for charged hadrons from the presents GeV/c limit to the momentum range 10-30 GeV/c. The VHMPID detector is a focusing RICH using C(4)F(10) gaseous radiator coupled to a CsI-based photon detector. Detector design studies, achievable Cherenkov angle resolution, expected performance and high momentum triggering will be discussed. (C) 2010 Elsevier B.V. All rights reserved

R&D studies of a RICH detector using pressurized C4F8O radiator gas and a CsI-based gaseous photon detector

We report on studies of layout and performance of a new Ring Imaging Cherenkov detector using for the fi rst time pressurized C 4 F 8 O radiator gas and a photon detector consisting of a MWPC equipped with a CsI photocathode. In particular, we present here the results of beam tests of a MWPC having an adjustable anode – cathode gap, aiming at the optimization of single photoelectron detection and Cherenkov angle resolution. This system was proposed as a Very High Momentum Particle Identi fi cation (VHMPID) upgrade for the ALICE experiment at LHC to provide charged hadron track-by-track identi fi cation in the momentum range 5 – 25 GeV/c

R&D studies of a RICH detector using pressurized C4_{4}F8_{8}O radiator gas and a CsI-based gaseous photon detector

We report on studies of layout and performance of a new Ring Imaging Cherenkov detector using for the fi rst time pressurized C 4 F 8 O radiator gas and a photon detector consisting of a MWPC equipped with a CsI photocathode. In particular, we present here the results of beam tests of a MWPC having an adjustable anode – cathode gap, aiming at the optimization of single photoelectron detection and Cherenkov angle resolution. This system was proposed as a Very High Momentum Particle Identi fi cation (VHMPID) upgrade for the ALICE experiment at LHC to provide charged hadron track-by-track identi fi cation in the momentum range 5 – 25 GeV/c

A Very High Momentum Particle Identification Detector

A new detector concept has been investigated to extend the capabilities of heavy-ion collider experiments, represented here through the ALICE detector, in the high transverse momentum (pT region. The resulting Very High Momentum Particle Identification Detector (VHMPID) performs charged hadron identification on a track-by-track basis in the 5 GeV/c &lt; p &lt; 25 GeV/c momentum range and provides heavy-ion experiments with new opportunities to study parton-medium interactions at RHIC and LHC energies, where the creation of deconfined quark-gluon matter has been established. The detector is based on novel advances to the pressurized gaseous ring imaging Cherenkov (RICH) concept, which yield a very compact, high resolution addition to existing heavy-ion experiments. We conclude that in order for the device to yield statistically significant results not only for single particle measurements, but also for di-hadron and jet-tagged correlation studies, it has to cover contiguously up to 30% of a central barrel detector in radial direction. This will allow, for the first time, identified charged hadron measurements in jets. In this paper we summarize the physics motivations for such a device, as well as its conceptual design, layout, and integration into ALICE.1295DE-FG02-07ER41521; DOE; National Research Foundation of Korea; NRF; National Research Foundation of Korea; NSF-PHY-0968903; NSF; National Research Foundation of Korea; NSF-PHY-1305280; NSF; National Research Foundation of Korea(2006) J. Phys. G, 32, p. 1295Sapeta, S., Wiedemann, U.A., (2008) Eur. Phys. J. C, 55, p. 293Liu, W., Fries, R., (2008) Phys. Rev. C, 77, p. 054902Hwa, R.C., Yang, C.B., (2006) Phys. Rev. Lett., 97, p. 042301Lévai, P., Berényi, D., Pásztor, A., Skokov, V.V., (2011) J. Phys. G, 38, p. 124155Aurenche, P., Zakharov, B.G., (2011) Eur. Phys. J. C, 71, p. 1829Bellwied, R., Markert, C., (2010) Phys. Lett. B, 691, p. 208Xu, Y., (2010) J. Phys. G, 37, p. 094059for the STAR Collaboration (L. Ruan), (2010) J. Phys. G, 37, p. 094013(2011) Phys. Rev. C, 83, p. 024909(2013) Phys. Lett. B, 719, p. 18Barile, F., (2011) AIP Conf. Proc., 1317, p. 71HMPID Technical Design Report CERN/LHCC 98-19 ALICE TDR 1DiMauro, A., (2010) Nucl. Instrum Methods A, 617, p. 424Albrecht, E., (2003) Nucl. Instrum Methods A, 510, p. 262Ando, S., (2006) J. Photopolym. Sci. Technol., 19, p. 351Artuso, M., (2006) Nucl. Instrum Methods A, 558, p. 373Barber, G.J., (2008) Nucl. Instrum Methods A, 593, p. 624Baillon, P., (1989) Nucl. Instrum Methods A, 277, p. 338G. Volpe, Proceedings of the RICH2010 Conference, to be published in Nucl. Instrum Methods ACozza, D., (2003) Nucl. Instrum Methods A, 502, p. 101Santiard, J.-C., (2004) Nucl. Instrum Methods A, 518, p. 498Abbon, P., (2007) Nucl. Instrum Methods A, 577, p. 455Abbon, P., (2008) Nucl. Instrum Methods A, 589, p. 362Hamar, G., Kiss, G., Varga, D., (2011) Nucl. Instrum Methods A, 648, p. 163Varga, D., Kiss, G., Hamar, G., Bencédi, G., (2013) Nucl. Instrum Methods A, 698, p. 11G. Volpe, PhD thesis, Study of Cherenkov detectors for high momentum charged particles identification in the ALICE experiment at LHC, Università degli Studi di Bari, Facolta di Scienze Matematiche, Fisiche e Naturali, Dottorato di ricerca in Fisica XIX ciclo, Anno accademico 2005-2006G. Volpe, PoS HIGH-pTLHC, 022 (2008) The VHMPID detector in the ALICE experiment at LHCD. Cozza, Internal Note RICH-ALICE/98-39(2003) Nucl. Instrum Methods A, 502, p. 300Di Mauro, A., (1999) Nucl. Instrum Methods A, 433, p. 190Hirai, M., Kumano, S., (2010) Prog. Theor. Phys. Suppl., 186, p. 252Albino, S., (2010) Rev. Mod. Phys., 82, p. 2489(2009) Phys. Rev. D, 79, p. 112005Albino B.A. Kniehl, S., Kramer, G., (2010) Phys. Rev. Lett., 104, p. 242001Albino, S., Kniehl, B.A., Kramer, G., (2008) Nucl. Phys. B, 803, p. 42De Florian, D., Sassot, R., Stratman, M., (2007) Phys. Rev. D, 76, p. 074033Albino, S., Kniehl, B.A., Kramer, G., (2008) Nucl. Phys. B, 803, p. 42Hirai, M., Kumano, S., Nagai, T.H., Sudoh, K., (2007) Phys. Rev. D, 75, p. 094009(2009) Eur. Phys. J. C, 62, p. 187Grigoryan, L., (2011) Phys. Rev. C, 83, p. 014904Nagy, Z., Soper, D.E., (2012) JHEP, 6, p. 044Gang, C., Hui-Ling, W., (2011) Int. J. Mod. Phys. E, 20, p. 667Pronko, A., (2005) Int. J. Mod. Phys. A, 20, p. 3723Kaidalov, A.B., (1987) Sov. J. Nucl. Phys., 45, p. 902Kraan, A.C., (2008) AIP Conf. Proc., 1038, p. 45(2007) PoS C, POD07, p. 027(2008) J. Phys. G, 35, p. 104096M. Purschke (for the PHENIX Collaboration), QM 2011 proceedingsH. Appelshaeuser (for the ALICE Collaboration), QM 2011 proceedingsY.J. Lie (for the CMS Collaboration), QM 2011 proceedings(2008) J. Phys. G, 35, p. 044027Wang, X.N., Gyulassy, M., (1991) Phys. Rev. D, 44, p. 3501Gyulassy, M., Lévai, P., Vitev, I., (2000) Phys. Rev. Lett., 85, p. 5535Gyulassy, M., Lévai, P., Vitev, I., (2000) Nucl. Phys. B, 571, p. 197Gyulassy, M., Lévai, P., Vitev, I., (2001) Nucl. Phys. B, 594, p. 371Barnafoldi, G., (2004) Prog. Part. Nucl. Phys., 53, p. 257Jia, J., Lacey, R., (2009) Phys. Rev. C, 79, p. 011901Markert, C., Bellwied, R., Vitev, I., (2008) Phys. Lett. B, 669, p. 92Alver, B., Roland, G., (2010) Phys. Rev. C, 81, p. 054905Gavin, S., McLerran, L., Moschelli, G., (2009) Phys. Rev. C, 79, p. 051902Nagle, J., McCumber, M., (2011) Phys. Rev. C, 83, p. 044908(2004) Eur. Phys. J. C, 33, p. S425G. Paić, A. Ortiz (for the ALICE Collaboration), ALICE-INT-2009-015, PoS(High-pT physics09)007(2011) EPJ Web of Conferences, 13, p. 03004for the ALICE Collaboration (S. Pochybova), (2009) PoS High-pT, physics09, p. 045Ellis, J.R., Geiger, K., Kowalski, H., (1996) Phys. Rev. D, 54, p. 5443(2007) J. Phys. G, 34, p. S685(2000) Eur. Phys. J. C, 17, p. 207(2009) Molnár (for the ALICE Collaboration), Proceedings of the High-$p_T$ Physics for the LHC Workshop, 4-7. , February, PraguearXiv:1008.0413, ALICE-EMCal Physics Performance Report, R. Bellwied(2013) Phys. Lett. B, 718, p. 795(2013) Phys. Lett. B, 719, p. 29for the ALICE Collaboration (Y. Belikov), (2011) J. Phys. G, 38, p. 124078Lin, Z.-W., Ko, C.M., Li, B.-A., Zhang, B., Pal, S., (2005) Phys. Rev. C, 72, p. 064901Pierog, T., Werner, K., (2009) Nucl. Phys. Proc. Suppl., 196, p. 102Mikhailov, K., Werner, K., Karpenko, I., Pierog, T., (2011) Phys. Part. Nucl. Lett., 8, p. 989Appelshauser, H., (2011) J. Phys. G, 38, p. 124014Kraan, A.C., (2008) AIP Conf. Proc., 1038, p. 45Grigoryan, L., (2011) Phys. Rev. C, 83, p. 014904Aurenche, P., Zhakarov, B., (2011) Eur. Phys. J. C, 71, p. 1829arXiv:1208.0448, D. BerenyiKaidalov, A.B., (1987) Yad. Fiz., 45, p. 1452Kaidalov, A.B., (1987) Sov. J. Nucl. Phys., 45, p. 1452Tsallis, C., (2009) Eur. Phys. J. A, 40, p. 257Biro, T.S., (2008) EPL, 84, p. 56003Biro, T.S., Urmossy, K., Schram, Z., (2010) J. Phys. G, 37, p. 094027Biro, T.S., (2013) Physica A, 392, p. 3132Biro, T.S., Barnafoldi, G.G., Van, P., (2013) Eur. Phys. J. A, 49, p. 110(2012) Eur. Phys. J. C, 72, p. 2164(2010) Eur. Phys. J. C, 68, p. 345(2010) Eur. Phys. J. C, 68, p. 89Cleymans, J., Worku, D., (2012) J. Phys. G, 39, p. 025006Cleymans, J., Worku, D., (2012) Eur. Phys. J. A, 48, p. 160Becattini, F., Ferroni, L., (2004) Eur. Phys. J. C, 35, p. 243Becattini, F., Ferroni, L., (2004) Eur. Phys. J. C, 38, p. 225Wilk, G., Wlodarczyk, Z., (2009) Eur. Phys. J. A, 40, p. 299Begun, V.V., Gazdzicki, M., Gorenstein, M.I., (2008) Phys. Rev. C, 78, p. 024904Urmossy, K., Barnaföldi, G.G., Biró, T.S., (2012) Phys. Lett. B, 718, p. 12