المؤلفون: Drew, Y, Kim, J-W, Penson, RT, O'Malley, DM, Parkinson, C, Roxburgh, P, Plummer, R, Im, S-A, Imbimbo, M, Ferguson, M, Rosengarten, O, Steeghs, N, Kim, MH, Gal-Yam, E, Tsoref, D, Kim, J-H, You, B, De Jonge, M, Lalisang, R, Gort, E, Bastian, S, Meyer, K, Feeney, L, Baker, N, Ah-See, M-L, Domchek, SM, Banerjee, S, MEDIOLA Investigators

المساهمون: Banerjee, Susana

مصطلحات موضوعية: Humans, Female, Bevacizumab, Poly(ADP-ribose) Polymerase Inhibitors, Ovarian Neoplasms, Cohort Studies, Germ-Line Mutation, Antineoplastic Agents, Phthalazines, Carcinoma, Ovarian Epithelial, Neoplasm Recurrence, Local

جغرافية الموضوع: United States

الوصف: PURPOSE: Early results from the phase II MEDIOLA study (NCT02734004) in germline BRCA1- and/or BRCA2-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) showed promising efficacy and safety with olaparib plus durvalumab. We report efficacy and safety of olaparib plus durvalumab in an expansion cohort of women with gBRCAm PSROC (gBRCAm expansion doublet cohort) and two cohorts with non-gBRCAm PSROC, one of which also received bevacizumab (non-gBRCAm doublet and triplet cohorts). PATIENTS AND METHODS: In this open-label, multicenter study, PARP inhibitor-naïve patients received olaparib plus durvalumab treatment until disease progression; the non-gBRCAm triplet cohort also received bevacizumab. Primary endpoints were objective response rate (ORR; gBRCAm expansion doublet cohort), disease control rate (DCR) at 24 weeks (non-gBRCAm cohorts), and safety (all cohorts). RESULTS: The full analysis and safety analysis sets comprised 51, 32, and 31 patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively. ORR was 92.2% [95% confidence interval (CI), 81.1-97.8] in the gBRCAm expansion doublet cohort (primary endpoint); DCR at 24 weeks was 28.1% (90% CI, 15.5-43.9) in the non-gBRCAm doublet cohort (primary endpoint) and 74.2% (90% CI, 58.2-86.5) in the non-gBRCAm triplet cohort (primary endpoint). Grade ≥ 3 adverse events were reported in 47.1%, 65.6%, and 61.3% of patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively, most commonly anemia. CONCLUSIONS: Olaparib plus durvalumab continued to show notable clinical activity in women with gBRCAm PSROC. Olaparib plus durvalumab with bevacizumab demonstrated encouraging clinical activity in women with non-gBRCAm PSROC. No new safety signals were identified.

وصف الملف: Print; 62; application/pdf

العلاقة: 730052; Clinical Cancer Research, 2024, 30 (1), pp. 50 - 62; https://repository.icr.ac.uk/handle/internal/6148Test

الإتاحة: https://doi.org/10.1158/1078-0432.CCR-23-2249Test
https://repository.icr.ac.uk/handle/internal/6148Test

المؤلفون: DiSilvestro, P, Banerjee, S, Colombo, N, Scambia, G, Kim, B-G, Oaknin, A, Friedlander, M, Lisyanskaya, A, Floquet, A, Leary, A, Sonke, GS, Gourley, C, Oza, A, Gonzalez-Martin, A, Aghajanian, C, Bradley, W, Mathews, C, Liu, J, McNamara, J, Lowe, ES, Ah-See, M-L, Moore, KN

المساهمون: Banerjee, Susana

مصطلحات موضوعية: Science & Technology, Life Sciences & Biomedicine, Obstetrics & Gynecology

وصف الملف: 27; application/pdf

العلاقة: Obstetrical and Gynecological Survey, 2023, 78 (1), pp. 25 - 27; https://repository.icr.ac.uk/handle/internal/5747Test

الإتاحة: https://doi.org/10.1097/OGX.0000000000001120Test
https://repository.icr.ac.uk/handle/internal/5747Test

المؤلفون: DiSilvestro, P, Banerjee, S, Colombo, N, Scambia, G, Kim, B-G, Oaknin, A, Friedlander, M, Lisyanskaya, A, Floquet, A, Leary, A, Sonke, GS, Gourley, C, Oza, A, González-Martín, A, Aghajanian, C, Bradley, W, Mathews, C, Liu, J, McNamara, J, Lowe, ES, Ah-See, M-L, Moore, KN, SOLO1 Investigators

المساهمون: Banerjee, Susana

مصطلحات موضوعية: SOLO1 Investigators

جغرافية الموضوع: United States

الوصف: PURPOSE: In SOLO1/GOG 3004 (ClinicalTrials.gov identifier: NCT01844986), maintenance therapy with the poly(ADP-ribose) polymerase inhibitor olaparib provided a sustained progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 (BRCA) mutation. We report overall survival (OS) after a 7-year follow-up, a clinically relevant time point and the longest follow-up for any poly(ADP-ribose) polymerase inhibitor in the first-line setting. METHODS: This double-blind phase III trial randomly assigned patients with newly diagnosed advanced ovarian cancer and a BRCA mutation in clinical response to platinum-based chemotherapy to maintenance olaparib (n = 260) or placebo (n = 131) for up to 2 years. A prespecified descriptive analysis of OS, a secondary end point, was conducted after a 7-year follow-up. RESULTS: The median duration of treatment was 24.6 months with olaparib and 13.9 months with placebo, and the median follow-up was 88.9 and 87.4 months, respectively. The hazard ratio for OS was 0.55 (95% CI, 0.40 to 0.76; P = .0004 [P < .0001 required to declare statistical significance]). At 7 years, 67.0% of olaparib patients versus 46.5% of placebo patients were alive, and 45.3% versus 20.6%, respectively, were alive and had not received a first subsequent treatment (Kaplan-Meier estimates). The incidence of myelodysplastic syndrome and acute myeloid leukemia remained low, and new primary malignancies remained balanced between treatment groups. CONCLUSION: Results indicate a clinically meaningful, albeit not statistically significant according to prespecified criteria, improvement in OS with maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation and support the use of maintenance olaparib to achieve long-term remission in this setting; the potential for cure may also be enhanced. No new safety signals were observed during long-term follow-up.

وصف الملف: Print-Electronic; application/pdf

العلاقة: Journal of Clinical Oncology, 2022, pp. JCO2201549 -; https://repository.icr.ac.uk/handle/internal/5598Test

الإتاحة: https://doi.org/10.1200/JCO.22.01549Test
https://repository.icr.ac.uk/handle/internal/5598Test

المؤلفون: Lord, SR, Cheng, W-C, Liu, D, Gaude, E, Haider, S, Metcalf, T, Patel, N, Teoh, EJ, Gleeson, F, Bradley, K, Wigfield, S, Zois, C, McGowan, DR, Ah-See, M-L, Thompson, AM, Sharma, A, Bidaut, L, Pollak, M, Roy, PG, Karpe, F, James, T, English, R, Adams, RF, Campo, L, Ayers, L, Snell, C, Roxanis, I, Frezza, C, Fenwick, JD, Buffa, FM, Harris, AL

المساهمون: Haider, Syed

مصطلحات موضوعية: Mitochondria, Humans, Breast Neoplasms, Metformin, Glucose, Antineoplastic Agents, Hypoglycemic Agents, Gene Expression Regulation, Neoplastic, Adult, Aged, Middle Aged, Female, Metabolic Networks and Pathways, Transcriptome, Positron Emission Tomography Computed Tomography

الوصف: Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect.

وصف الملف: Print-Electronic; 688.e4; application/pdf

العلاقة: Cell metabolism, 2018, 28 (5), pp. 679 - 688.e4; https://repository.icr.ac.uk/handle/internal/4626Test

الإتاحة: https://doi.org/10.1016/j.cmet.2018.08.021Test
https://repository.icr.ac.uk/handle/internal/4626Test

المؤلفون: Krebs, Matthew G, Delord, J. P., Jeffry Evans, T. R., De Jonge, M., Kim, S. W., Meurer, M., Postel-Vinay, S., Lee, J. S., Angell, H. K., Rocher-Ros, V., Meyer, K., Ah-See, M. L., Herbolsheimer, P., Lai, Z., Nunes, A., Domchek, S. M.

المساهمون: Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester and The Christie NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK

الوصف: Introduction: Preclinical studies have demonstrated increased efficacy with combined DNA damage response inhibition and immune checkpoint blockade compared with either alone. We assessed olaparib in combination with durvalumab in patients with relapsed small cell lung cancer (SCLC). Methods: Patients with previously treated limited or extensive-stage SCLC received oral olaparib 300 mg twice daily, as run-in for 4 weeks, then with durvalumab (1500 mg intravenously every 4 weeks) until disease progression. Primary endpoints were safety, tolerability, and 12-week disease control rate (DCR). Secondary endpoints included 28-week DCR, objective response rate (ORR), duration of response, progression-free survival, overall survival, change in tumor size, and programmed death-ligand 1 (PD-L1) expression subgroup analyses. Results: Forty patients were enrolled and analyzed for safety; 38 were analyzed for efficacy. Eleven patients (28.9% [90% confidence interval (CI), 17.2-43.3]) had disease control at 12 weeks. ORR was 10.5% (95% CI, 2.9-24.8). Median progression-free and overall survival were 2.4 (95% CI, 0.9-3.0)months and 7.6(95% CI, 5.6-8.8)months, respectively. The most common adverse events (≥40.0%) were anemia, nausea, and fatigue. Grade ≥ 3 adverse events occurred in 32 patients (80.0%). PD-L1 levels, tumor mutational burden, and other genetic mutations were evaluated, but no significant correlations with clinical outcomes wereobserved. Conclusions: Tolerability of olaparib with durvalumab was consistent with the safety profile of each agent alone. Although the 12-week DCR did not meet the prespecified target (60%), four patients responded, and median overall survival was promising for a pretreated SCLC population. Further analyses are required to identify patients most likely to benefit from this treatment approach.

العلاقة: https://dx.doi.org/10.1016/j.lungcan.2023.107216Test; Krebs MG, Delord JP, Jeffry Evans TR, De Jonge M, Kim SW, Meurer M, et al. Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA): An open-label, multicenter, phase 1/2, basket study. Lung cancer (Amsterdam, Netherlands). 2023 Jun;180:107216. PubMed PMID: 37146473. Epub 2023/05/06. eng.; http://hdl.handle.net/10541/626294Test; Lung Cancer

الإتاحة: https://doi.org/10.1016/j.lungcan.2023.107216Test
http://hdl.handle.net/10541/626294Test

المؤلفون: Kosmin, M., Padhani, A.R., Gogbashian, A., Woolf, D., Ah-See, M.-L., Ostler, P., Sutherland, S., Miles, D., Noble, J., Marshall, A., Dunn, J., Makris, A.

المصدر: Annals of Oncology ; volume 29, page viii102-viii103 ; ISSN 0923-7534

مصطلحات موضوعية: Oncology, Hematology

الإتاحة: https://doi.org/10.1093/annonc/mdy272.311Test
https://api.elsevier.com/content/article/PII:S0923753419487401?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0923753419487401?httpAccept=text/plainTest
http://academic.oup.com/annonc/article-pdf/29/suppl_8/mdy272.311/26139660/mdy272.311.pdfTest

المؤلفون: Oza, A. M., Pierce, A., Lau, A., Kurian, N., Parr, G., Lao-Sirieix, S. H., Ah-See, M. L. W., Dean, Emma J, Loembe, B.

المساهمون: Princess Margaret Cancer Centre, Toronto, ON, Canada

الوصف: Background: Ovarian cancer is the leading cause of death from gynecological cancers in the USA, and the fifth most common cause of cancer death in women. Ola is a PARPi approved for first-line maintenance treatment of BRCA-mutated advanced ovarian cancer in women who achieve a complete or partial response to platinum-based chemotherapy. Ola is also efficacious in combination with bevacizumab in the same population, independent of BRCA mutation status. Cer is a potent, oral, selective inhibitor of ATR. ATR is a critical DDR kinase that is activated in response to replication stress and stalled replication forks. There is no second maintenance standard of care for patients with PSR ovarian cancer who have previously received a PARPi in the maintenance setting. Pre-clinical models have shown that several mechanisms of PARPi resistance may be overcome by ATR inhibition, such as BRCA reversion, replication fork protection and DDR rewiring. DUETTE will select pts with tumor response or stable disease after second or third-line platinum-based treatment, with the expectation to enrich for non-BRCA reversion PARPi resistance mechanisms. The study will address the role of a second maintenance treatment following prior 1L or 2L maintenance, an emerging population of unmet need, and includes translational studies that aim to further our knowledge of clinical PARPi resistance mechanisms and predictors of treatment response. Methods: DUETTE is a global, multi-center, phase II study. 192 pts with PSR epithelial ovarian cancer who have previously received PARPi maintenance treatment, will be retreated with platinum and those who have not progressed after ≥ 4 cycles will be randomized (1:1:1) to 3 treatment arms: Arm 1, open-label: cer 160 mg once daily (qd) days 1 to 7 plus ola 300 mg twice daily (bd); Arm 2, blinded: ola monotherapy 300 mg bd and Arm 3, blinded: ola-placebo. Treatment is administered in 28-day cycles. All pts will be stratified by BRCA status (mutation or wildtype) and response to most recent line of ...

العلاقة: https://dx.doi.org/10.1200/JCO.2020.38.15_suppl.TPS6104Test; Oza AM, Pierce A, Lau A, Kurian N, Parr G, Lao-Sirieix S-H, et al. DUETTE: A randomized phase II study to assess a second maintenance treatment with olaparib (ola) or ola+ceralasertib (cer), in patients (pts) with platinum-sensitive relapsed (PSR) epithelial ovarian cancer who have previously received PARP inhibitor maintenance treatment (NCT04239014). Journal of Clinical Oncology. 2020;38(15_suppl):TPS6104-TPS.; http://hdl.handle.net/10541/623880Test; Journal of Clinical Oncology

الإتاحة: https://doi.org/10.1200/JCO.2020.38.15_suppl.TPS6104Test
http://hdl.handle.net/10541/623880Test

المؤلفون: Woolf, D K, Beresford, M, Li, S P, Dowsett, M, Sanghera, B, Wong, W L, Sonoda, L, Detre, S, Amin, V, Ah-See, M-L, Miles, D, Makris, A

المصدر: British Journal of Cancer ; volume 110, issue 12, page 2847-2854 ; ISSN 0007-0920 1532-1827

مصطلحات موضوعية: Cancer Research, Oncology

الإتاحة: https://doi.org/10.1038/bjc.2014.207Test
http://www.nature.com/articles/bjc2014207.pdfTest
http://www.nature.com/articles/bjc2014207Test

المؤلفون: Lord S. R., Cheng W. -C., Liu D., Gaude E., Haider S., Metcalf T., Patel N., Teoh E. J., Gleeson F., Bradley K., Wigfield S., Zois C., McGowan D. R., Ah-See M. -L., Thompson A. M., Sharma A., Bidaut L., Pollak M., Roy P. G., Karpe F., James T., English R., Adams R. F., Campo L., Ayers L., Snell C., Roxanis I., Frezza C., Fenwick J. D., Buffa F. M., Harris A. L.

المساهمون: Lord, S. R., Cheng, W. -C., Liu, D., Gaude, E., Haider, S., Metcalf, T., Patel, N., Teoh, E. J., Gleeson, F., Bradley, K., Wigfield, S., Zois, C., Mcgowan, D. R., Ah-See, M. -L., Thompson, A. M., Sharma, A., Bidaut, L., Pollak, M., Roy, P. G., Karpe, F., James, T., English, R., Adams, R. F., Campo, L., Ayers, L., Snell, C., Roxanis, I., Frezza, C., Fenwick, J. D., Buffa, F. M., Harris, A. L.

مصطلحات موضوعية: cancer metabolism, gene expression profiling, metabolomic, mitochondria, positron emission tomography

الوصف: Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect. Using dynamic PET imaging, metabolomics, and transcriptomics in breast cancer patients, Lord et al. find that metformin increases 18-FDG flux into tumors and activates mitochondrial metabolism genes. Two distinct metabolic responses are observed and linked to differing proliferation signatures, suggesting that a reactive increase in OXPHOS is linked to metformin resistance.

وصف الملف: PRINT + ONLINE

العلاقة: info:eu-repo/semantics/altIdentifier/wos/WOS:000449440000005; volume:28; issue:5; firstpage:679; lastpage:688; journal:CELL METABOLISM; https://hdl.handle.net/11565/4061219Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85054023859

الإتاحة: https://doi.org/10.1016/j.cmet.2018.08.021Test
https://hdl.handle.net/11565/4061219Test

المؤلفون: Earl HM, Hiller L, Vallier A-L, Loi S, McAdam K, Hughes-Davies L, Harnett AN, Ah-See M-L, Simcock R, Rea D, Raj S, Woodings P, Harries M, Howe D, Raynes K, Higgins HB, Wilcox M, Plummer C, Mansi J, Gounaris I, Mahler-Araujo B, Provenzano E, Chhabra A, Abraham JE, Caldas C, Hall PS, McCabe C, Hulme C, Miles D, Wardley AM, Cameron DA, Dunn JA, Agarwal R, Algurafi H, Allerton R, Archer C, Armstrong A, Bale C, Barraclough L, Barthakur U, Bedi C, Benstead K, Bloomfield D, Bowen R, Bradley C, Brown J, Butt M, Churn M, Cleator S, Cliff J, Crellin P, Daly M, De Silva-Minor S, Dhadda A, Din O, Down S, Earl H, Eaton D, Eichholz A, Epurescu D, Goh C, Goodman A, Grieve R, Hadaki M, Harper-Wynne C, Hayward L, Humphreys A, Innes H, Jafri M, Jegannathen A, Kelleher M, Kristeleit H, Lee D, Lupton S, MacGregor C, Malik Z, Marshall J, McGolick T, Mehra R, Mithal N, Moss C, Moss A, Mukesh M, Neal A, Nelmes D, Neville-Webbe H, Newby J, O'Reilly S, Ostler P, Persic M, Pettit L, Raja F, Reed C, Rigg A, Roe H, Shah N, Simmonds P, Sims E, Smith S, Storey N, Taylor W, Thanvi N, Tipples K, Vaidya J, Varughese M, Vinayan A, Walji N, Waters S, Wright K, Yahya S

المصدر: The Lancet, 29 June - 5 July 2019

الوصف: © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. Methods: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006–007018–39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). Findings: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6–6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9–90·7) in the 6-month group and 89·8% (88·3–91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93–1·24], non-inferiority ...

وصف الملف: application/pdf

الإتاحة: https://eprint.ncl.ac.uk/fulltext.aspx?url=258584/8EB34366-D8C9-4498-9728-D2D1595C4BA9.pdf&pub_id=258584Test