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2. AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer – results of two parallel first-in-human phase I studies

Author

Omlin, A., Jones, R. J., van der Noll, R., Satoh, T., Niwakawa, M., Smith, S. A., Graham, J., Ong, M., Finkelman, R. D., Schellens, J. H. M., Zivi, A., Crespo, M., Riisnaes, R., Nava-Rodrigues, D., Malone, M. D., Dive, C., Sloane, R., Moore, D., Alumkal, J. J., Dymond, A., Dickinson, P. A., Ranson, M., Clack, G., de Bono, J., and Elliott, T.

Published
2015
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4. 230MO First in human, modular study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced solid malignancies

Author

Krebs, M.G., primary, Lord, S., additional, Kenny, L., additional, Baird, R.D., additional, MacPherson, I., additional, Bahl, A., additional, Clack, G., additional, Ainscow, E., additional, Barrett, A.G., additional, Dickinson, P., additional, Fuchter, M.J., additional, Lehnert, M., additional, Ali, S., additional, Mcintosh, S., additional, and Coombes, R.C., additional

Published
2021
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5. 265P Study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in combination with fulvestrant in patients with advanced hormone receptor positive HER2 negative breast cancer (HR+BC)

Author

Howell, S.J., primary, Krebs, M.G., additional, Lord, S., additional, Kenny, L., additional, Bahl, A., additional, Clack, G., additional, Ainscow, E., additional, Arkenau, H-T., additional, Mansi, J.L., additional, Palmieri, C., additional, Richards, P., additional, Jeselsohn, R., additional, Mitri, Z., additional, Gradishar, W.J., additional, Sardesai, S., additional, O'Shaughnessy, J., additional, Lehnert, M., additional, Ali, S., additional, McIntosh, S., additional, and Coombes, R.C., additional

Published
2021
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14. Systems Pharmacology Modeling of Prostate‐Specific Antigen in Patients With Prostate Cancer Treated With an Androgen Receptor Antagonist and Down‐Regulator

Author

Mistry, HB, Fabre, M‐A, Young, J, Clack, G, and Dickinson, PA

Subjects
Male, Systems Analysis, Down-Regulation, Original Articles, Prostate-Specific Antigen, urologic and male genital diseases, Models, Biological, Pyridazines, Prostatic Neoplasms, Castration-Resistant, Treatment Outcome, Receptors, Androgen, Androgen Receptor Antagonists, Humans, Original Article
Abstract

First‐in‐human (FIH) studies with AZD3514, a selective androgen receptor (AR) down‐regulator, showed decreases of >30% in the prostate‐specific antigen (PSA) in some patients. A modeling approach was adopted to understand these observations and define the optimum clinical use hypothesis for AZD3514 for clinical testing. Initial empirical modeling showed that only baseline PSA correlated significantly with this biological response, whereas drug concentration did not. To identify the mechanistic cause of this observation, a mechanism‐based model was first developed, which described the effects of AZD3514 on AR protein and PSA mRNA levels in LNCaP cells with and without dihydrotestosterone (DHT). Second, the mechanism‐based model was linked to a population pharmacokinetic (PK) model; PSA effects of clinical doses were subsequently simulated under different clinical conditions. This model was used to adjust the design of the ongoing clinical FIH study and direct the backup program.

Published
2016

16. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years

Author

Pan, H, Gray, R, Braybrooke, J, Davies, C, Taylor, C, Mcgale, P, Peto, R, Pritchard, Ki, Bergh, J, Dowsett, M, Hayes, Df, Albain, K, Anderson, S, Arriagada, R, Barlow, W, Bartlett, J, Bergsten‐nordström, E, Bliss, J, Boccardo, F, Bradley, R, Brain, E, Cameron, D, Clarke, M, Coates, A, Coleman, R, Correa, C, Costantino, J, Cuzick, J, Davidson, N, Dodwell, D, Di Leo, A, Ewertz, M, Forbes, J, Gelber, R, Gnant, M, Goldhirsch, A, Goodwin, P, Hill, C, Ingle, J, Jagsi, R, Janni, W, Loibl, S, Mackinnon, E, Martin, M, Mukai, H, Norton, L, Ohashi, Y, Paik, S, Perez, E, Piccart, M, Pierce, L, Poortmans, P, Raina, V, Ravdin, P, Regan, M, Robertson, J, Rutgers, E, Slamon, D, Sparano, J, Swain, S, Tutt, A, Viale, G, Von Minckwitz, G, Wang, X, Whelan, T, Wilcken, N, Winer, E, Wolmark, N, Wood, W, Zambetti, M, Alberro, Ja, Ballester, B, Deulofeu, P, Fábregas, R, Fraile, M, Gubern, Jm, Janer, J, Moral, A, De Pablo Jl, Peñalva, G, Puig, P, Ramos, M, Rojo, R, Santesteban, P, Serra, C, Solà, M, Solarnau, L, Solsona, J, Veloso, E, Vidal, S, Abe, O, Abe, R, Enomoto, K, Kikuchi, K, Koyama, H, Masuda, H, Nomura, Y, Sakai, K, Sugimachi, K, Toi, M, Tominaga, T, Uchino, J, Yoshida, M, Haybittle, Jl, Leonard, Cf, Calais, G, Garaud, P, Collett, V, Delmestri, A, Sayer, J, Harvey, Vj, Holdaway, Im, Kay, Rg, Mason, Bh, Forbes, Jf, Balic, M, Bartsch, R, Fesl, C, Fitzal, F, Fohler, H, Greil, R, Jakesz, R, Marth, C, Mlineritsch, B, Pfeiler, G, Singer, Cf, Steger, Gg, Stöger, H, Canney, P, Yosef, Hma, Focan, C, Peek, U, Oates, Gd, Powell, J, Durand, M, Mauriac, L, Dolci, S, Larsimont, D, Nogaret, Jm, Philippson, C, Piccart, Mj, Masood, Mb, Parker, D, Price, Jj, Lindsay, Ma, Mackey, J, Hupperets, Psgj, Bates, T, Blamey, Rw, Chetty, U, Ellis, Io, Mallon, E, Morgan, Dal, Patnick, J, Pinder, S, Lohrisch, C, Nichol, A, Bramwell, Vh, Chen, Be, Gelmon, K, Goss, Pe, Levine, Mn, Parulekar, W, Pater, Jl, Shepherd, Le, Tu, D, Berry, D, Broadwater, G, Cirrincione, C, Muss, H, Weiss, Rb, Abu‐zahra, Ht, Portnoj, Sm, Bowden, S, Brookes, C, Dunn, J, Fernando, I, Lee, M, Poole, C, Rea, D, Spooner, D, Barrett‐lee, Pj, Mansel, Re, Monypenny, Ij, Gordon, Nh, Davis, Hl, Sestak, I, Lehingue, Y, Romestaing, P, Dubois, Jb, Delozier, T, Griffon, B, Mace Lesec’h, J, De La Lande, B, Mouret‐fourme, E, Mustacchi, G, Petruzelka, L, Pribylova, O, Owen, Jr, Harbeck, N, Jänicke, F, Meisner, C, Schmitt, M, Thomssen, C, Meier, P, Shan, Y, Shao, Yf, Zhao, Db, Chen, Zm, Howell, A, Swindell, R, Boddington, C, Burrett, Ja, Cutter, D, Duane, F, Evans, V, Gettins, L, Godwin, J, James, S, Kerr, A, Liu, H, Mannu, G, Mchugh, T, Morris, P, Read, S, Wang, Y, Wang, Z, Albano, J, De Oliveira Cf, Gervásio, H, Gordilho, J, Ejlertsen, B, Jensen, Mb, Johansen, H, Mouridsen, H, Palshof, T, Gelman, Rs, Harris, Jr, Henderson, C, Shapiro, Cl, Christiansen, P, Mouridsen, Ht, Fehm, T, Trampisch, Hj, Dalesio, O, De Vries Ege, Rodenhuis, S, Van Tinteren, H, Comis, Rl, Davidson, Ne, Robert, N, Sledge, G, Solin, Lj, Sparano, Ja, Tormey, Dc, Dixon, Jm, Forrest, P, Jack, W, Kunkler, I, Rossbach, J, Klijn, Jgm, Treurniet‐donker, Ad, Van Putten Wlj, Rotmensz, N, Veronesi, U, Bartelink, H, Bijker, N, Bogaerts, J, Cardoso, F, Cufer, T, Julien, Jp, Van De Velde Cjh, Cunningham, Mp, Brufsky, Am, Coleman, Re, Llombart, Ha, Huovinen, R, Joensuu, H, Costa, A, Bonadonna, G, Gianni, L, Valagussa, P, Goldstein, Lj, Bonneterre, J, Fargeot, P, Fumoleau, P, Kerbrat, P, Luporsi, E, Namer, M, Carrasco, E, Segui, Ma, Eiermann, W, Hilfrich, J, Jonat, W, Kaufmann, M, Kreienberg, R, Schumacher, M, Bastert, G, Rauschecker, H, Sauer, R, Sauerbrei, W, Schauer, A, Blohmer, Ju, Costa, Sd, Eidtmann, H, Gerber, B, Jackisch, C, De Schryver, A, Vakaet, L, Belfiglio, M, Nicolucci, A, Pellegrini, F, Pirozzoli, Mc, Sacco, M, Valentini, M, Mcardle, Cs, Smith, Dc, Stallard, S, Dent, Dm, Gudgeon, Ca, Hacking, A, Murray, E, Panieri, E, Werner, Id, Galligioni, E, Leone, B, Vallejo, Ct, Zwenger, A, Lopez, M, Erazo, A, Medina, Jy, Horiguchi, J, Takei, H, Fentiman, Is, Hayward, Jl, Rubens, Rd, Skilton, D, Scheurlen, H, Sohn, Hc, Untch, M, Dafni, U, Markopoulos, C, Fountzilas, G, Mavroudis, D, Klefstrom, P, Blomqvist, C, Saarto, T, Gallen, M, Tinterri, C, Margreiter, R, De Lafontan, B, Mihura, J, Roché, H, Asselain, B, Salmon, Rj, Vilcoq, Jr, André, F, Delaloge, S, Koscielny, S, Michiels, S, Rubino, C, A'Hern, R, Ellis, P, Kilburn, L, Yarnold, Jr, Benraadt, J, Kooi, M, Van De Velde Ao, Van Dongen Ja, Vermorken, Jb, Castiglione, M, Colleoni, M, Collins, J, Gelber, Rd, Lindtner, J, Price, Kn, Regan, Mm, Rudenstam, Cm, Senn, Hj, Thuerlimann, B, Bliss, Jm, Chilvers, Ced, Coombes, Rc, Hall, E, Marty, M, Buyse, M, Possinger, K, Schmid, P, Wallwiener, D, Bighin, C, Bruzzi, P, Del Mastro, L, Dozin, B, Pastorino, S, Pronzato, P, Sertoli, Mr, Foster, L, George, Wd, Stewart, Hj, Stroner, P, Borovik, R, Hayat, H, Inbar, Mj, Peretz, T, Robinson, E, Camerini, T, Formelli, F, Martelli, G, Di Mauro Mg, Perrone, F, Amadori, D, Martoni, A, Pannuti, F, Camisa, R, Musolino, A, Passalacqua, R, Iwata, H, Shien, T, Ikeda, T, Inokuchi, K, Sawa, K, Sonoo, H, Sadoon, M, Tulusan, Ah, Kohno, N, Miyashita, M, Takao, S, Ahn, Jh, Jung, Kh, Korzeniowski, S, Skolyszewski, J, Ogawa, M, Yamashita, J, Bastiaannet, E, Liefers, Gj, Christiaens, R, Neven, P, Paridaens, R, Van Den Bogaert, W, Braun, S, Martin, P, Romain, S, Janauer, M, Seifert, M, Sevelda, P, Zielinski, Cc, Hakes, T, Hudis, Ca, Wittes, R, Giokas, G, Kondylis, D, Lissaios, B, De La Huerta, R, Sainz, Mg, Ro, J, Camphausen, K, Danforth, D, Lichter, A, Lippman, M, Smart, D, Steinberg, S, D’Amico, C, Lioce, M, Paradiso, A, Ohno, S, Bass, G, Brown, A, Bryant, J, Dignam, J, Fisher, B, Geyer, C, Mamounas, Ep, Redmond, C, Wickerham, L, Aihara, T, Hozumi, Y, Baum, M, Jackson, Im, Palmer, Mk, Ingle, Jn, Suman, Vj, Bengtsson, No, Emdin, S, Jonsson, H, Venturini, M, Lythgoe, Jp, Kissin, M, Erikstein, B, Hannisdal, E, Jacobsen, Ab, Reinertsen, Kv, Varhaug, Je, Gundersen, S, Hauer‐jensen, M, Høst, H, Nissen‐meyer, R, Mitchell, Ak, Robertson, Jfr, Ueo, H, Di Palma, M, Mathé, G, Misset, Jl, Levine, M, Morimoto, K, Takatsuka, Y, Crossley, E, Harris, A, Talbot, D, Taylor, M, Cocconi, G, Di Blasio, B, Ivanov, V, Paltuev, R, Semiglazov, V, Brockschmidt, J, Cooper, Mr, Falkson, Ci, Hadji, P, A’Hern, R, Makris, A, Parton, M, Pennert, K, Powles, Tj, Smith, Ie, Gazet, Jc, Browne, L, Graham, P, Corcoran, N, Clack, G, Van Poznak, C, Deshpande, N, Di Martino, L, Douglas, P, Lindtner, A, Notter, G, Bryant, Ajs, Ewing, Gh, Firth, La, Krushen‐kosloski, Jl, Anderson, H, Killander, F, Malmström, P, Rydén, L, Arnesson, Lg, Carstensen, J, Dufmats, M, Fohlin, H, Nordenskjöld, B, Söderberg, M, Carpenter, Jt, Murray, N, Royle, Gt, Simmonds, Pd, Crowley, J, Gralow, J, Hortobagyi, G, Livingston, R, Martino, S, Osborne, Ck, Ravdin, Pm, Bondesson, T, Celebioglu, F, Dahlberg, K, Fornander, T, Fredriksson, I, Frisell, J, Göransson, E, Iiristo, M, Johansson, U, Lenner, E, Löfgren, L, Nikolaidis, P, Perbeck, L, Rotstein, S, Sandelin, K, Skoog, L, Svane, G, Af Trampe, E, Wadström, C, Maibach, R, Thürlimann, B, Holli, K, Rouhento, K, Safra, T, Brenner, H, Hercbergs, A, Yoshimoto, M, Paterson, Ahg, Fyles, A, Meakin, Jw, Panzarella, T, Bahi, J, Lemonnier, J, Martin, Al, Reid, M, Spittle, M, Bishop, H, Bundred, Nj, Forsyth, S, Pinder, Se, Deutsch, Gp, Kwong, Dlw, Pai, Vr, Senanayake, F, Rubagotti, A, Hackshaw, A, Houghton, J, Ledermann, J, Monson, K, Tobias, Js, Carlomagno, C, De Laurentiis, M, De Placido, S, Williams, L, Bell, R, Hinsley, S, Marshall, Hc, Pierce, Lj, Solomayer, E, Horsman, Jm, Lester, J, Winter, Mc, Buzdar, Au, Hsu, L, Love, Rr, Ahlgren, J, Garmo, H, Holmberg, L, Liljegren, G, Lindman, H, Wärnberg, F, Asmar, L, Jones, Se, Aft, R, Gluz, O, Liedtke, C, Nitz, U, Litton, A, Wallgren, A, Karlsson, P, Linderholm, Bk, Chlebowski, Rt, Caffier, H., Guided Treatment in Optimal Selected Cancer Patients (GUTS), Other departments, CCA - Cancer Treatment and Quality of Life, Radiotherapy, Pan, Hongchao, Gray, Richard, Braybrooke, Jeremy, Davies, Christina, Taylor, Carolyn, Mcgale, Paul, Peto, Richard, Pritchard, Kathleen I, Bergh, Jona, Dowsett, Mitch, Hayes, Daniel F, De Laurentiis, Michelino, MUMC+: MA Medische Oncologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, and Interne Geneeskunde

Subjects
0301 basic medicine, Oncology, medicine.medical_treatment, Kaplan-Meier Estimate, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Recurrence, Receptors, Neoplasm Metastasis, AMERICAN SOCIETY, Adjuvant, CLINICAL-PRACTICE GUIDELINE, Absolute risk reduction, Estrogen Antagonists, General Medicine, Estrogen Antagonist, CHEMOTHERAPY, Middle Aged, Prognosis, Neoplasm Metastasi, Local, POSTMENOPAUSAL WOMEN, Receptors, Estrogen, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Meta-analysis, Lymphatic Metastasis, Female, Human, Estrogen Antagonists/therapeutic use, Adult, Risk, medicine.medical_specialty, Prognosi, medicine.drug_class, DISCONTINUATION, Breast Neoplasms, Article, Drug Administration Schedule, LATE DISTANT RECURRENCE, 03 medical and health sciences, Breast cancer, Breast Neoplasms/drug therapy, Internal medicine, SCORE, medicine, Humans, SURGICAL ADJUVANT BREAST, Aged, Proportional Hazards Models, Chemotherapy, business.industry, Proportional hazards model, Lymphatic Metastasi, TAMOXIFEN THERAPY, ta3122, medicine.disease, Estrogen, RANDOMIZED-TRIALS, Discontinuation, Surgery, Neoplasm Recurrence, 030104 developmental biology, Proportional Hazards Model, Neoplasm Grading, Neoplasm Recurrence, Local, business
Abstract

Background The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)–positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment. Methods In this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, we used Kaplan–Meier and Cox regression analyses, stratified according to trial and treatment, to assess the associations of tumor diameter and nodal status (TN), tumor grade, and other factors with patients’ outcomes during the period from 5 to 20 years. Results Breast-cancer recurrences occurred at a steady rate throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status. Among the patients with stage T1 disease, the risk of distant recurrence was 13% with no nodal involvement (T1N0), 20% with one to three nodes involved (T1N1–3), and 34% with four to nine nodes involved (T1N4–9); among those with stage T2 disease, the risks were 19% with T2N0, 26% with T2N1–3, and 41% with T2N4–9. The risk of death from breast cancer was similarly dependent on TN status, but the risk of contralateral breast cancer was not. Given the TN status, the factors of tumor grade (available in 43,590 patients) and Ki-67 status (available in 7692 patients), which are strongly correlated with each other, were of only moderate independent predictive value for distant recurrence, but the status regarding the progesterone receptor (in 54,115 patients) and human epidermal growth factor receptor type 2 (HER2) (in 15,418 patients in trials with no use of trastuzumab) was not predictive. During the study period from 5 to 20 years, the absolute risk of distant recurrence among patients with T1N0 breast cancer was 10% for low-grade disease, 13% for moderate-grade disease, and 17% for high-grade disease; the corresponding risks of any recurrence or a contralateral breast cancer were 17%, 22%, and 26%, respectively. Conclusions After 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade. (Funded by Cancer Research UK and others.)

Published
2017

18. Systems Pharmacology Modeling of Prostate-Specific Antigen in Patients With Prostate Cancer Treated With an Androgen Receptor Antagonist and Down-Regulator

Author

Mistry, Hitesh, Fabre, M-A, Young, J., Clack, G., and Dickinson, P.A.

Subjects
urologic and male genital diseases
Abstract

First-in-human (FIH) studies with AZD3514, a selective androgen receptor (AR) down-regulator, showed decreases of >30% in the prostate-specific antigen (PSA) in some patients. A modeling approach was adopted to understand these observations and define the optimum clinical use hypothesis for AZD3514 for clinical testing. Initial empirical modeling showed that only baseline PSA correlated significantly with this biological response, whereas drug concentration did not. To identify the mechanistic cause of this observation, a mechanism-based model was first developed, which described the effects of AZD3514 on AR protein and PSA mRNA levels in LNCaP cells with and without dihydrotestosterone (DHT). Second, the mechanism-based model was linked to a population pharmacokinetic (PK) model; PSA effects of clinical doses were subsequently simulated under different clinical conditions. This model was used to adjust the design of the ongoing clinical FIH study and direct the backup program.

Published
2016
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19. Identification of an RNF43 mutated gastric cancer patient population with potential sensitivity to porcupine inhibitor RXC004 and development of a complimentary ctDNA liquid biopsy assay for patient screening

Author

Bingham, M., primary, Bhamra, I., additional, Armer, R., additional, Thompson, B., additional, Woodcock, S., additional, Thomason, A., additional, Phillips, C., additional, McKeever, H., additional, Bradford, J., additional, Chaffey, B., additional, Little, L., additional, and Clack, G., additional

Published
2017
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20. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

Author

Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Coleman, R, Powles, T, Paterson, A, Gnant, M, Anderson, S, Diel, I, Gralow, J, von Minckwitz, G, Moebus, V, Bergh, J, Pritchard, KI, Bliss, J, Cameron, D, Evans, V, Pan, H, Peto, R, Bradley, R, Gray, R, Bartsch, R, Dubsky, P, Fesl, C, Fohler, H, Greil, R, Jakesz, R, Lang, A, Luschin-Ebengreuth, G, Marth, C, Mlineritsch, B, Samonigg, H, Singer, CF, Steger, GG, Stoger, H, Olivotto, I, Ragaz, J, Christiansen, P, Ejlertsen, B, Ewertz, M, Jensen, M-B, Moller, S, Mouridsen, HT, Eiermann, W, Hilfrich, J, Jonat, W, Kaufmann, M, Kreienberg, R, Schumacher, M, Blohmer, JU, Costa, SD, Eidtmann, H, Gerber, B, Jackisch, C, Loibl, S, Dafni, U, Markopoulos, C, Blomqvist, C, Saarto, T, Ahn, J-H, Jung, KH, Perrone, F, Bass, G, Brown, A, Bryant, J, Costantino, J, Dignam, J, Fisher, B, Geyer, C, Mamounas, EP, Paik, S, Redmond, C, Swain, S, Wickerham, L, Wolmark, N, Perez, E, Ingle, JN, Suman, VJ, Hadji, P, A'Hern, R, Dowsett, M, Makris, A, Parton, M, Pennert, K, Powles, TJ, Smith, IE, Yarnold, JR, Clack, G, Van Poznak, C, Safra, T, Bell, R, Coleman, RE, Dodwell, D, Hinsley, S, Marshall, HC, Solomayer, E, Fehm, T, Lester, J, Winter, MC, Horsman, JM, Aft, R, Brufsky, AM, and Llombart, HA

Abstract

Background Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer. Methods We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs). Findings We received data on 18 766 women (18 206 [97%] in trials of 2–5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87–1·01; 2p=0·08), distant recurrence (0·92, 0·85–0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83–0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73–0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78–0·94; 2p=0·002), distant recurrence (0·82, 0·74–0·92; 2p=0·0003), bone recurrence (0·72, 0·60–0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73–0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75–0·97; 2p=0·02). Interpretation Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began. Funding Cancer Research UK, Medical Research Council.

Published
2015

21. AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer - Results of two parallel first-in-human phase I studies

Author

Pharmacoepidemiology and Clinical Pharmacology, Sub Clinical Pharmacology, Omlin, A., Jones, R. J., Van Der Noll, R., Satoh, T., Niwakawa, M., Smith, S. A., Graham, J., Ong, M., Finkelman, R. D., Schellens, J. H M, Zivi, A., Crespo, M., Riisnaes, R., Nava-Rodrigues, D., Malone, M. D., Dive, C., Sloane, R., Moore, D., Alumkal, J. J., Dymond, A., Dickinson, P. A., Ranson, M., Clack, G., De Bono, J., Elliott, T., Pharmacoepidemiology and Clinical Pharmacology, Sub Clinical Pharmacology, Omlin, A., Jones, R. J., Van Der Noll, R., Satoh, T., Niwakawa, M., Smith, S. A., Graham, J., Ong, M., Finkelman, R. D., Schellens, J. H M, Zivi, A., Crespo, M., Riisnaes, R., Nava-Rodrigues, D., Malone, M. D., Dive, C., Sloane, R., Moore, D., Alumkal, J. J., Dymond, A., Dickinson, P. A., Ranson, M., Clack, G., De Bono, J., and Elliott, T.

Published
2015

22. ATR inhibitor AZD6738

Author

Clack, G., primary, Lau, A., additional, Pierce, A., additional, Smith, S., additional, and Stephens, C., additional

Published
2015
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24. The ATAC ('Arimidex', tamoxifen, alone or in combination) adjuvant breast cancer trial: First results of the endometrial sub-protocol following 2 years of treatment.

Author

Jones A., Omara-Boto T.A., Onwude J., Phillips K., Price J., Samtaney N., Seif M., Doe A., Foster E., Woolas R., Buyse M., Wale C., Margolese R., Body J.J., Duffy S., Jackson T.L., Lansdown M., Philips K., Wells M., Pollard S., Clack G., Coibion M., Bianco A.R., Adams J., Baum M., Buzdar A., Cella D., Coleman R., Constenla M., Cuzick J., Distler W., Dowset M., Eastell R., Fallowfield L.J., Forbes J., George W.D., Gray J., Guastalla J.-P., Hellmund R., Hoctin-Boes G., Houghton J., Williams N., Howell A., Klijn J.G.M., Locker G.Y., Mackey J., Mansel R.E., Nabholtz J.M., Naglkalnai T., Nicolucci A., Nylen U., Sainsbury R., Sapunar F., Suarez-Mendez V.J., Tobias J.S., Friedlander M., Richardson G., Makar A., Neven P., Mention J., Distler D.W., Eiermann W., Mouritis M., Wamsteker, Campos O., Candeias O.R., Landers G., Llombart A., Menjon S., Repolles M., Lindahl B., Ingvar C., Bharbra K., Bjornsson S., Charnock F., Cutner A., De Bono M., Evans-Jones J., Glass M., Holt S., Kremer, O'Donovan P., Jones A., Omara-Boto T.A., Onwude J., Phillips K., Price J., Samtaney N., Seif M., Doe A., Foster E., Woolas R., Buyse M., Wale C., Margolese R., Body J.J., Duffy S., Jackson T.L., Lansdown M., Philips K., Wells M., Pollard S., Clack G., Coibion M., Bianco A.R., Adams J., Baum M., Buzdar A., Cella D., Coleman R., Constenla M., Cuzick J., Distler W., Dowset M., Eastell R., Fallowfield L.J., Forbes J., George W.D., Gray J., Guastalla J.-P., Hellmund R., Hoctin-Boes G., Houghton J., Williams N., Howell A., Klijn J.G.M., Locker G.Y., Mackey J., Mansel R.E., Nabholtz J.M., Naglkalnai T., Nicolucci A., Nylen U., Sainsbury R., Sapunar F., Suarez-Mendez V.J., Tobias J.S., Friedlander M., Richardson G., Makar A., Neven P., Mention J., Distler D.W., Eiermann W., Mouritis M., Wamsteker, Campos O., Candeias O.R., Landers G., Llombart A., Menjon S., Repolles M., Lindahl B., Ingvar C., Bharbra K., Bjornsson S., Charnock F., Cutner A., De Bono M., Evans-Jones J., Glass M., Holt S., Kremer, and O'Donovan P.

Abstract

Background: Tamoxifen treatment results in a doubling of the risk of endometrial cancer after 1-2 years of treatment and a quadrupling after 5 years. Anastrozole, a third-generation aromatase inhibitor, with superior efficacy to tamoxifen, may also offer tolerability benefits in terms of effects on the endometrium. Methods and Results: A sub-protocol of the ATAC trial compared the incidence/type of intrauterine changes following treatment with these agents in a subgroup of patients (n = 285) from the main trial. After 2 years anastrozole treatment, endometrial thickness remained <= 5 mm (baseline: 3.0 mm); in patients receiving tamoxifen, endometrial thickness increased by 3.2 mm to 7.0 mm, with a similar trend in the combination group. At baseline, 26/285 patients (9.1%) had endometrial abnormalities, most commonly polyps. After 2 years the number of endometrial abnormalities appeared lower with anastrozole treatment compared with tamoxifen although these differences were not statistically significant (odds ratio: 0.44; 95% confidence interval 0.146, 1.314; P = 0.14). Most abnormalities occurred within the first year of treatment (anastrozole: 4/6; tamoxifen: 7/10; combination: 10/16; total: 21/32). Fewer patients in the anastrozole group (1.4%) required medical intervention (tamoxifen 12.5%; combination 13.6%). Conclusion(s): Fewer endometrial abnormalities occurred during 2 years treatment with anastrozole compared with tamoxifen although statistical significance was not reached in this sub-protocol analysis. © The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Published
2006

25. The ATAC ('Arimidex', tamoxifen, alone or in combination) adjuvant breast cancer trial: First results of the endometrial sub-protocol following 2 years of treatment

Author

Duffy, Sean, Jackson, Tracy, Lansdown, M., Philips, K., Wells, Michael, Pollard, S., Clack, G., Coibion, Michel, Bianco, André Macedo, Duffy, Sean, Jackson, Tracy, Lansdown, M., Philips, K., Wells, Michael, Pollard, S., Clack, G., Coibion, Michel, and Bianco, André Macedo

Abstract

SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2006

26. The ATAC ('Arimidex', Tamoxifen, Alone or in Combination) adjuvant breast cancer trial: Baseline endometrial sub-protocol data on the effectiveness of transvaginal ultrasonography and diagnostic hysteroscopy

Author

Duffy, Sean, Jackson, Tracy, Lansdown, M., Philips, K., Wells, Michael, Pollard, S., Clack, G., Coibion, Michel, Bianco, André Macedo, Duffy, Sean, Jackson, Tracy, Lansdown, M., Philips, K., Wells, Michael, Pollard, S., Clack, G., Coibion, Michel, and Bianco, André Macedo

Abstract

Background: The 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial is a randomized, double-blind trial comparing anastrozole ('Arimidex'), alone or in combination with tamoxifen, relative to tamoxifen alone as 5 year adjuvant treatment for post-menopausal women with early breast cancer. Since tamoxifen is associated with endometrial pathology, the ATAC endometrial sub-protocol was initiated to establish the background prevalence of intrauterine pathology, and to assess prospectively the incidence and nature of intrauterine changes following endocrine therapy. Another aim was to provide data from which advice could be generated on the best endometrium screening method for patients receiving tamoxifen. Methods: Patients underwent endometrial assessments at entry to the sub-protocol. The baseline investigations comprised transvaginal ultrasound scanning (TVUS), a hysteroscopy and an endometrial biopsy. Results: A total of 285 gynaecologically asymptomatic women from 31 centres in 10 countries entered the endometrial sub-protocol. The mean uterine volume was 47.7 cm3. The median endometrial thickness overall was 3 mm. Twenty-four histologically confirmed, pathological changes were observed. Twenty-three pathologies were confirmed by TVUS, and 21 were identified by hysteroscopy and confirmed by histopathology. Women with or without intrauterine pathology had median endometrial thickness of 5 and 3 mm respectively. Conclusions: The presence of pathology was associated with increased endometrial thickness. The relative sensitivity and specificity of hysteroscopy and endometrial thickness for the diagnosis of endometrial pathology was comparable to other studies. If screening of the endometrium prior to treatment is appropriate, this study supports the use of an endometrial thickness of 3 mm, as assessed by TVUS, as a threshold for needing further investigation. This study demonstrates that if the endometrial thickness is > 3 mm, hysteroscopy and biopsy is the opti, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2005

30. The ATAC adjuvant breast cancer trial in postmenopausal women: Baseline endometrial subprotocol data

Author

Duffy, Sean, Jackson, Tracy, Lansdown, M., Philips, K., Wells, Michael, Pollard, S., Clack, G., Cuzick, Jack, Coibion, Michel, Bianco, André Macedo, Duffy, Sean, Jackson, Tracy, Lansdown, M., Philips, K., Wells, Michael, Pollard, S., Clack, G., Cuzick, Jack, Coibion, Michel, and Bianco, André Macedo

Abstract

Objective: The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial is a randomised, double-blind trial comparing 'Arimidex' (anastrozole), alone or in combination with tamoxifen, relative to tamoxifen alone as a five year adjuvant treatment for postmenopausal women with early breast cancer. Because tamoxifen is associated with endometrial pathology, the ATAC endometrial subprotocol was initiated to establish the background prevalence of pathology, and to assess prospectively the incidence and nature of intrauterine changes before and following endocrine therapy. Setting: International. Population and Study Design: Two hundred and eighty-five women entered the subprotocol: the mean age was 60 years (range 44-80 years); 113 women (40%) had taken hormone replacement therapy prior to randomisation, and 238 women were parous (84%). The age at onset of the menopause was 32-58 years, with the majority becoming menopausal between 46 and 55 years of age. Two hundred and seventy-two women had a hysteroscopy before they commenced trial medication. Hysteroscopy was performed successfully in 265 women. In six women, failure of hysteroscopy at baseline led to withdrawal from the study. Three of the women who withdrew had a pipelle biopsy taken. Therefore, the total number of endometrial biopsies at baseline was 268. Main outcome measures: To assess the demographic characteristics of women entering the endometrial subprotocol and their hysteroscopic and histological findings before commencing trial medication. Results: At hysteroscopy, there was a diagnosis of endometrial polyps in 34 women (13%), fibroids in 16 women (6%) and one case of suspicious endometrium, which was confirmed as a polyp on histology. Only 21 of the 34 polyps seen hysteroscopically were proven histologically (62% accuracy of hysteroscopy). Final histology found the prevalence of endometrial diagnostic categories as follows: 123 inactive endometrium (46%), 20 benign polyps (7%), 17 secretory endometrium, SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published

Published
2003

34. A Prototypical Process for Creating Evidentiary Standards for Biomarkers and Diagnostics

Author

Altar, CA, primary, Amakye, D, additional, Bounos, D, additional, Bloom, J, additional, Clack, G, additional, Dean, R, additional, Devanarayan, V, additional, Fu, D, additional, Furlong, S, additional, Hinman, L, additional, Girman, C, additional, Lathia, C, additional, Lesko, L, additional, Madani, S, additional, Mayne, J, additional, Meyer, J, additional, Raunig, D, additional, Sager, P, additional, Williams, SA, additional, Wong, P, additional, and Zerba, K, additional

Published
2007
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50. A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker.

Author

Khoja, L, Backen, A, Sloane, R, Menasce, L, Ryder, D, Krebs, M, Board, R, Clack, G, Hughes, A, Blackhall, F, Valle, J W, and Dive, C

Subjects
PANCREATIC cancer diagnosis, TUMORS, TUMOR markers, HIGH throughput screening (Drug development), CANCER patients, CELL adhesion molecules
Abstract

Background:Obtaining tissue for pancreatic carcinoma diagnosis and biomarker assessment to aid drug development is challenging. Circulating tumour cells (CTCs) may represent a potential biomarker to address these unmet needs. We compared prospectively the utility of two platforms for CTC enumeration and characterisation in pancreatic cancer patients in a pilot exploratory study.Patients and methods:Blood samples were obtained prospectively from 54 consenting patients and analysed by CellSearch and isolation by size of epithelial tumour cells (ISET). CellSearch exploits immunomagnetic capture of CTCs-expressing epithelial markers, whereas ISET is a marker independent, blood filtration device. Circulating tumour cell expression of epithelial and mesenchymal markers was assessed to explore any discrepancy in CTC number between the two platforms.Results:ISET detected CTCs in more patients than CellSearch (93% vs 40%) and in higher numbers (median CTCs/7.5 ml, 9 (range 0-240) vs 0 (range 0-144)). Heterogeneity observed for epithelial cell adhesion molecule, pan-cytokeratin (CK), E-Cadherin, Vimentin and CK 7 expression in CTCs may account for discrepancy in CTC number between platforms.Conclusion:ISET detects more CTCs than CellSearch and offers flexible CTC characterisation with potential to investigate CTC biology and develop biomarkers for pancreatic cancer patient management. [ABSTRACT FROM AUTHOR]

Published
2012
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