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3. ESGO–ESMO–ESP consensus conference recommendations on ovarian cancer: pathology and molecular biology and early, advanced and recurrent disease

Author

Ledermann, J. A., Matias-Guiu, X., Amant, F., Concin, N., Davidson, B., Fotopoulou, C., González-Martin, A., Gourley, C., Leary, A., Lorusso, Domenica, Banerjee, S., Chiva, L., Cibula, D., Colombo, N., Croce, S., Eriksson, A. G., Falandry, C., Fischerova, D., Harter, P., Joly, F., Lazaro, C., Lok, C., Mahner, S., Marmé, F., Marth, C., Mccluggage, W. G., Mcneish, I. A., Morice, P., Nicum, S., Oaknin, A., Pérez-Fidalgo, J. A., Pignata, S., Ramirez, P. T., Ray-Coquard, I., Romero, I., Scambia, Giovanni, Sehouli, J., Shapira-Frommer, R., Sundar, S., Tan, D. S. P., Taskiran, C., van Driel, W. J., Vergote, I., Planchamp, F., Sessa, C., Fagotti, Anna, Lorusso, D., Scambia, G. (ORCID:0000-0003-2758-1063), Fagotti, A. (ORCID:0000-0001-5579-335X), Ledermann, J. A., Matias-Guiu, X., Amant, F., Concin, N., Davidson, B., Fotopoulou, C., González-Martin, A., Gourley, C., Leary, A., Lorusso, Domenica, Banerjee, S., Chiva, L., Cibula, D., Colombo, N., Croce, S., Eriksson, A. G., Falandry, C., Fischerova, D., Harter, P., Joly, F., Lazaro, C., Lok, C., Mahner, S., Marmé, F., Marth, C., Mccluggage, W. G., Mcneish, I. A., Morice, P., Nicum, S., Oaknin, A., Pérez-Fidalgo, J. A., Pignata, S., Ramirez, P. T., Ray-Coquard, I., Romero, I., Scambia, Giovanni, Sehouli, J., Shapira-Frommer, R., Sundar, S., Tan, D. S. P., Taskiran, C., van Driel, W. J., Vergote, I., Planchamp, F., Sessa, C., Fagotti, Anna, Lorusso, D., Scambia, G. (ORCID:0000-0003-2758-1063), and Fagotti, A. (ORCID:0000-0001-5579-335X)

Abstract

The European Society of Gynaecological Oncology, the European Society for Medical Oncology (ESMO) and the European Society of Pathology held a consensus conference (CC) on ovarian cancer on 15-16 June 2022 in Valencia, Spain. The CC panel included 44 experts in the management of ovarian cancer and pathology, an ESMO scientific advisor and a methodologist. The aim was to discuss new or contentious topics and develop recommendations to improve and harmonise the management of patients with ovarian cancer. Eighteen questions were identified for discussion under four main topics: (i) pathology and molecular biology, (ii) early-stage disease and pelvic mass in pregnancy, (iii) advanced stage (including older/frail patients) and (iv) recurrent disease. The panel was divided into four working groups (WGs) to each address questions relating to one of the four topics outlined above, based on their expertise. Relevant scientific literature was reviewed in advance. Recommendations were developed by the WGs and then presented to the entire panel for further discussion and amendment before voting. This manuscript focuses on the recommendation statements that reached a consensus, their voting results and a summary of evidence supporting each recommendation.

Published
2024

4. European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer

Author

Vergote, I., Ausems, M., Brasiuniene, B., Brenton, J., Büttner, R., Colombo, N., González-Martín, A., Harter, P., Lambrechts, D., Lorusso, D., Madry, R., Mirza, M.R., Pujol, P., Ray-Coquard, I., Abreu, M., Balboni, S., Banerjee, S., Barberis, M., Barretina Ginesta, M.P., Baurain, J.-F., Bignami, M., Bjorge, L., Blecharz, P., Bruchim, I., Capilna, M., Cerana, N., Cicchetti, A., Collins, D., Concin, N., D’Incalci, M., Davidson, B., de la Motte Rouge, T., De Iaco, P., Demirkiran, F., Denys, H., Doerk, T., Dorum, A., Ferrero, A., Fidalgo, A.P., Genuardi, M., Gladieff, L., Glasspool, R., Grimm, C., Gultekin, M., Hahnen, E., Hasenburg, A., Hegmane, A., Heinzelmann, V., Hogdall, E., Janavicius, R., Jarmalaite, S., Kalachand, R., Kaneva, R., Kilickap, S., Kocian, R., Kolencik, D., Kristeleit, R., Kryzhanivska, A., Leary, A., Lemley, B., Ligtenberg, M., López-Guerrero, J.A., Lord, C.J., Avall-Lundqvist, E., Maenpaa, J., Mahner, S., Marmé, F., Marth, C., McNeish, I., Merkelbach-Bruse, S., Mourits, M., Normanno, N., Oaknin, A., Ojamaa, K., Papdimitriou, C., Penault-Llorca, F., Perrone, A.M., Pignata, S., Pikarsky, E., Rouleau, E., Rubio, M., Sapino, A., Schmalfeldt, B., Sehouli, J., Shapira, R., Steffensen, K.D., Sukhin, V., Syrios, J., Szallasi, Z., Taskiran, C., Terzic, M., Tischkowitz, M., Toth, I., Van de Vijver, K., Vardar, M.A., Wasag, B., Wimberger, P., Witteveen, E., Brenton, J.D., and Ausems, M.G.E.M.

Published
2022
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6. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Author

Amankwah, EK, Lin, HY, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chen, Z, Chen, YA, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Jim, H, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, Mcguire, V, Mclaughlin, JR, Mcneish, I, Menon, U, Milne, RL, Modugno, F, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, and Weber, RP

Subjects
Epidemiology, Public Health and Health Services, Genetics
Abstract

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value

Published
2015

7. ESMO–ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease

Author

Baert, T., Banerjee, S., Belaroussi, I., Blecharz, P., Bruchim, I., Cibula, D., Colombo, N., Concin, N., Davidson, B., Dashora, A., Devouassoux-Shisheboran, M., du Bois, A., Ferrero, A., Glasspool, R., González-Martin, A., Heinzelmann-Schwarz, V., Joly, F., Kim, J.W., Kridelka, F., Ledermann, J., Lorusso, D., Mahner, S., McCluggage, W.G., McNeish, I., Mikami, M., Mirza, M.R., Morice, P., Nicum, S., Olbrecht, S., O’Donnell, D.M., Pautier, P., Planchamp, F., Pignata, S., Querleu, D., Ray-Coquard, I., Rodolakis, A., Sehouli, J., Selcukbiricik, F., Sessa, C., Singh, N., Tan, D.S.P., Timmerman, D., Tognon, G., van der Velden, J., Vergote, I., Witteveen, P.O., and Zeimet, A.G.

Published
2019
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8. openFrame: A modular, sustainable, open microscopy platform with single‐shot, dual‐axis optical autofocus module providing high precision and long range of operation

Author

Lightley, J., primary, Kumar, S., additional, Lim, M. Q., additional, Garcia, E., additional, Görlitz, F., additional, Alexandrov, Y., additional, Parrado, T., additional, Hollick, C., additional, Steele, E., additional, Roßmann, K., additional, Graham, J., additional, Broichhagen, J., additional, McNeish, I. A., additional, Roufosse, C. A., additional, Neil, M. A. A., additional, Dunsby, C., additional, and French, P. M. W., additional

Published
2023
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9. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Author

Buck, M, Dean, A, Friedlander, M L, Goh, J C, Harnett, P, Kichenadasse, G, Scott, C L, Denys, H, Dirix, L, Vergote, I, Elit, L, Ghatage, P, Oza, A M, Plante, M, Provencher, D, Weberpals, J I, Welch, S, Floquet, A, Gladieff, L, Joly, F, Leary, A, Lortholary, A, Lotz, J, Medioni, J, Tredan, O, You, B, El-Balat, A, Hänle, C, Krabisch, P, Neunhöffer, T, Pölcher, M, Wimberger, P, Amit, A, Kovel, S, Leviov, M, Safra, T, Shapira-Frommer, R, Stemmer, S, Bologna, A, Colombo, N, Lorusso, D, Pignata, S, Sabbatini, R F, Scambia, G, Tamberi, S, Zamagni, C, Fong, P C, O'Donnell, A, Gancedo, M Amenedo, Herraez, A Casado, Garcia-Donas, J, Guerra, E M, Oaknin, A, Palacio, I, Romero, I, Sanchez, A, Banerjee, S N, Clamp, A, Drew, Y, Gabra, H G, Jackson, D, Ledermann, J A, McNeish, I A, Parkinson, C, Powell, M, Aghajanian, C, Armstrong, D K, Birrer, M J, Buss, M K, Chambers, S K, Chen, L-m, Coleman, R L, Holloway, R W, Konecny, G E, Ma, L, Morgan, M A, Morris, R T, Mutch, D G, O'Malley, D M, Slomovitz, B M, Swisher, E M, Vanderkwaak, T, Vulfovich, M, Coleman, Robert L, Oza, Amit M, Lorusso, Domenica, Aghajanian, Carol, Oaknin, Ana, Dean, Andrew, Colombo, Nicoletta, Weberpals, Johanne I, Clamp, Andrew, Scambia, Giovanni, Leary, Alexandra, Holloway, Robert W, Gancedo, Margarita Amenedo, Fong, Peter C, Goh, Jeffrey C, O'Malley, David M, Armstrong, Deborah K, Garcia-Donas, Jesus, Swisher, Elizabeth M, Floquet, Anne, Konecny, Gottfried E, McNeish, Iain A, Scott, Clare L, Cameron, Terri, Maloney, Lara, Isaacson, Jeff, Goble, Sandra, Grace, Caroline, Harding, Thomas C, Raponi, Mitch, Sun, James, Lin, Kevin K, Giordano, Heidi, and Ledermann, Jonathan A

Published
2017
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12. European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer

Author

Vergote, I, Gonzalez-Martin, A, Ray-Coquard, I, Harter, P, Colombo, N, Pujol, P, Lorusso, D, Mirza, M, Brasiuniene, B, Madry, R, Brenton, J, Ausems, M, Buttner, R, Lambrechts, D, Abreu, M, Balboni, S, Banerjee, S, Barberis, M, Barretina Ginesta, M, Baurain, J, Bignami, M, Bjorge, L, Blecharz, P, Bruchim, I, Capilna, M, Cerana, N, Cicchetti, A, Collins, D, Concin, N, D'Incalci, M, Davidson, B, de la Motte Rouge, T, De Iaco, P, Demirkiran, F, Denys, H, Doerk, T, Dorum, A, Ferrero, A, Fidalgo, A, Genuardi, M, Gladieff, L, Glasspool, R, Grimm, C, Gultekin, M, Hahnen, E, Hasenburg, A, Hegmane, A, Heinzelmann, V, Hogdall, E, Janavicius, R, Jarmalaite, S, Kalachand, R, Kaneva, R, Kilickap, S, Kocian, R, Kolencik, D, Kristeleit, R, Kryzhanivska, A, Leary, A, Lemley, B, Ligtenberg, M, Lopez-Guerrero, J, Lord, C, Avall-Lundqvist, E, Maenpaa, J, Mahner, S, Marme, F, Marth, C, Mcneish, I, Merkelbach-Bruse, S, Mourits, M, Normanno, N, Oaknin, A, Ojamaa, K, Papdimitriou, C, Penault-Llorca, F, Perrone, A, Pignata, S, Pikarsky, E, Rouleau, E, Rubio, M, Sapino, A, Schmalfeldt, B, Sehouli, J, Shapira, R, Steffensen, K, Sukhin, V, Syrios, J, Szallasi, Z, Taskiran, C, Terzic, M, Tischkowitz, M, Toth, I, Van de Vijver, K, Vardar, M, Wasag, B, Wimberger, P, Witteveen, E, Vergote I., Gonzalez-Martin A., Ray-Coquard I., Harter P., Colombo N., Pujol P., Lorusso D., Mirza M. R., Brasiuniene B., Madry R., Brenton J. D., Ausems M. G. E. M., Buttner R., Lambrechts D., Ausems M., Brenton J., Abreu M., Balboni S., Banerjee S., Barberis M., Barretina Ginesta M. P., Baurain J. -F., Bignami M., Bjorge L., Blecharz P., Bruchim I., Capilna M., Cerana N., Cicchetti A., Collins D., Concin N., D'Incalci M., Davidson B., de la Motte Rouge T., De Iaco P., Demirkiran F., Denys H., Doerk T., Dorum A., Ferrero A., Fidalgo A. P., Genuardi M., Gladieff L., Glasspool R., Grimm C., Gultekin M., Hahnen E., Hasenburg A., Hegmane A., Heinzelmann V., Hogdall E., Janavicius R., Jarmalaite S., Kalachand R., Kaneva R., Kilickap S., Kocian R., Kolencik D., Kristeleit R., Kryzhanivska A., Leary A., Lemley B., Ligtenberg M., Lopez-Guerrero J. A., Lord C. J., Avall-Lundqvist E., Maenpaa J., Mahner S., Marme F., Marth C., McNeish I., Merkelbach-Bruse S., Mourits M., Normanno N., Oaknin A., Ojamaa K., Papdimitriou C., Penault-Llorca F., Perrone A. M., Pignata S., Pikarsky E., Rouleau E., Rubio M., Sapino A., Schmalfeldt B., Sehouli J., Shapira R., Steffensen K. D., Sukhin V., Syrios J., Szallasi Z., Taskiran C., Terzic M., Tischkowitz M., Toth I., Van de Vijver K., Vardar M. A., Wasag B., Wimberger P., Witteveen E., Vergote, I, Gonzalez-Martin, A, Ray-Coquard, I, Harter, P, Colombo, N, Pujol, P, Lorusso, D, Mirza, M, Brasiuniene, B, Madry, R, Brenton, J, Ausems, M, Buttner, R, Lambrechts, D, Abreu, M, Balboni, S, Banerjee, S, Barberis, M, Barretina Ginesta, M, Baurain, J, Bignami, M, Bjorge, L, Blecharz, P, Bruchim, I, Capilna, M, Cerana, N, Cicchetti, A, Collins, D, Concin, N, D'Incalci, M, Davidson, B, de la Motte Rouge, T, De Iaco, P, Demirkiran, F, Denys, H, Doerk, T, Dorum, A, Ferrero, A, Fidalgo, A, Genuardi, M, Gladieff, L, Glasspool, R, Grimm, C, Gultekin, M, Hahnen, E, Hasenburg, A, Hegmane, A, Heinzelmann, V, Hogdall, E, Janavicius, R, Jarmalaite, S, Kalachand, R, Kaneva, R, Kilickap, S, Kocian, R, Kolencik, D, Kristeleit, R, Kryzhanivska, A, Leary, A, Lemley, B, Ligtenberg, M, Lopez-Guerrero, J, Lord, C, Avall-Lundqvist, E, Maenpaa, J, Mahner, S, Marme, F, Marth, C, Mcneish, I, Merkelbach-Bruse, S, Mourits, M, Normanno, N, Oaknin, A, Ojamaa, K, Papdimitriou, C, Penault-Llorca, F, Perrone, A, Pignata, S, Pikarsky, E, Rouleau, E, Rubio, M, Sapino, A, Schmalfeldt, B, Sehouli, J, Shapira, R, Steffensen, K, Sukhin, V, Syrios, J, Szallasi, Z, Taskiran, C, Terzic, M, Tischkowitz, M, Toth, I, Van de Vijver, K, Vardar, M, Wasag, B, Wimberger, P, Witteveen, E, Vergote I., Gonzalez-Martin A., Ray-Coquard I., Harter P., Colombo N., Pujol P., Lorusso D., Mirza M. R., Brasiuniene B., Madry R., Brenton J. D., Ausems M. G. E. M., Buttner R., Lambrechts D., Ausems M., Brenton J., Abreu M., Balboni S., Banerjee S., Barberis M., Barretina Ginesta M. P., Baurain J. -F., Bignami M., Bjorge L., Blecharz P., Bruchim I., Capilna M., Cerana N., Cicchetti A., Collins D., Concin N., D'Incalci M., Davidson B., de la Motte Rouge T., De Iaco P., Demirkiran F., Denys H., Doerk T., Dorum A., Ferrero A., Fidalgo A. P., Genuardi M., Gladieff L., Glasspool R., Grimm C., Gultekin M., Hahnen E., Hasenburg A., Hegmane A., Heinzelmann V., Hogdall E., Janavicius R., Jarmalaite S., Kalachand R., Kaneva R., Kilickap S., Kocian R., Kolencik D., Kristeleit R., Kryzhanivska A., Leary A., Lemley B., Ligtenberg M., Lopez-Guerrero J. A., Lord C. J., Avall-Lundqvist E., Maenpaa J., Mahner S., Marme F., Marth C., McNeish I., Merkelbach-Bruse S., Mourits M., Normanno N., Oaknin A., Ojamaa K., Papdimitriou C., Penault-Llorca F., Perrone A. M., Pignata S., Pikarsky E., Rouleau E., Rubio M., Sapino A., Schmalfeldt B., Sehouli J., Shapira R., Steffensen K. D., Sukhin V., Syrios J., Szallasi Z., Taskiran C., Terzic M., Tischkowitz M., Toth I., Van de Vijver K., Vardar M. A., Wasag B., Wimberger P., and Witteveen E.

Abstract

Background: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. Design: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts’ consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. Conclusion: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR de

Published
2022

14. Spatial and temporal intra-tumoural heterogeneity in advanced High-Grade Serous Ovarian Cancer: implications for surgical and clinical outcomes

Author

Cunnea, P, Curry, E, Christie, E, Nixon, K, Kwok, CH, Pandey, A, Wulandari, R, Thol, K, Ploski, J, Morera-Albert, C, McQuaid, S, Lozano-Kuehne, J, Clark, JJ, Krell, J, Stronach, E, McNeish, I, Bowtell, D, and Fotopoulou, C

Abstract

Limited evidence exists on the impact of spatial and temporal heterogeneity of high-grade serous ovarian cancer (HGSOC) on tumour evolution, clinical outcomes and surgical operability. We perform systematic multi-site tumour mapping at presentation and matched relapse from 49 high tumour burden patients, operated upfront. From SNP array-derived copy number data, we categorise dendrograms representing tumour clonal evolution as sympodial or dichotomous, noting most chemo-resistant patients favour simpler sympodial evolution. Three distinct tumour evolutionary patterns from primary to relapse are identified, demonstrating recurrent disease may emerge from pre-existing or newly detected clones. Crucially, we identify spatial heterogeneity for clinically actionable homologous recombination deficiency scores, and for poor prognosis biomarkers CCNE1 and MYC. Copy-number signature, phenotypic, proteomic and proliferative-index heterogeneity further highlights HGSOC complexity. This study explores HGSOC evolution and dissemination across space and time, its impact on optimal surgical cytoreductive effort and clinical outcomes, and consequences for clinical decision-making.

Published
2023

19. Preexisting TP53 -Variant Clonal Hematopoiesis and Risk of Secondary Myeloid Neoplasms in Patients with High-grade Ovarian Cancer Treated with Rucaparib

Author

Kwan, T, Oza, A, Tinker, A, Ray-Coquard, I, Oaknin, A, Aghajanian, C, Lorusso, D, Colombo, N, Dean, A, Weberpals, J, Severson, E, Vo, L, Goble, S, Maloney, L, Harding, T, Kaufmann, S, Ledermann, J, Coleman, R, Mcneish, I, Lin, K, Swisher, E, Kwan T. T., Oza A. M., Tinker A. V., Ray-Coquard I., Oaknin A., Aghajanian C., Lorusso D., Colombo N., Dean A., Weberpals J., Severson E., Vo L. -T., Goble S., Maloney L., Harding T., Kaufmann S. H., Ledermann J. A., Coleman R. L., McNeish I. A., Lin K. K., Swisher E. M., Kwan, T, Oza, A, Tinker, A, Ray-Coquard, I, Oaknin, A, Aghajanian, C, Lorusso, D, Colombo, N, Dean, A, Weberpals, J, Severson, E, Vo, L, Goble, S, Maloney, L, Harding, T, Kaufmann, S, Ledermann, J, Coleman, R, Mcneish, I, Lin, K, Swisher, E, Kwan T. T., Oza A. M., Tinker A. V., Ray-Coquard I., Oaknin A., Aghajanian C., Lorusso D., Colombo N., Dean A., Weberpals J., Severson E., Vo L. -T., Goble S., Maloney L., Harding T., Kaufmann S. H., Ledermann J. A., Coleman R. L., McNeish I. A., Lin K. K., and Swisher E. M.

Abstract

Importance: A total of 1% to 3% of patients treated with a poly(adenosine diphosphate-ribose) polymerase inhibitor for high-grade ovarian cancer (HGOC) develop therapy-related myeloid neoplasms (t-MNs), which are rare but often fatal conditions. Although the cause of these t-MNs is unknown, clonal hematopoiesis of indeterminate potential (CHIP) variants can increase the risk of primary myeloid malignant neoplasms and are more frequent among patients with solid tumors. Objectives: To examine whether preexisting CHIP variants are associated with the development of t-MNs after rucaparib treatment and how these CHIP variants are affected by treatment. Design, Setting, and Participants: This retrospective genetic association study used peripheral blood cell (PBC) samples collected before rucaparib treatment from patients in the multicenter, single-arm ARIEL2 (Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer) (n = 491; between October 30, 2013, and August 9, 2016) and the multicenter, placebo-controlled, double-blind ARIEL3 (Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer) (n = 561; between April 7, 2014, and July 19, 2016), which tested rucaparib as HGOC therapy in the treatment and maintenance settings, respectively. The follow-up data cutoff date was September 1, 2019. Of 1052 patients in ARIEL2 and ARIEL3, PBC samples from 20 patients who developed t-MNs (cases) and 44 randomly selected patients who did not (controls) were analyzed for the presence of CHIP variants using targeted next-generation sequencing. Additional longitudinal analysis was performed on available ARIEL2 samples collected during treatment and at the end of treatment. Main Outcomes and Measures: Enrichment analysis of preexisting variants in 10 p

Published
2021

20. OC04.06: A comparison of the homologous recombination deficiency test success rate using samples from ultrasound‐guided biopsies and those obtained during laparotomies in advanced ovarian cancer.

Author

Ditri, D., Hunt, A., Chadha, A., Keogh, G., Thompson, J., Loughborough, W., McNeish, I., Krell, J., McDermott, J., Ghaem‐Maghami, S., and Tookman, L.

Subjects
HOMOLOGOUS recombination, OVARIAN epithelial cancer, OVARIAN cancer, BIOPSY, RETROSPECTIVE studies, CA 125 test
Abstract

This article discusses a study that aimed to identify factors that influence the success rate and time-to-result of testing for tumour homologous recombination deficiency (HRD) in patients with advanced high-grade epithelial ovarian cancer. The study found that samples taken during surgery had a higher test success rate compared to those obtained using ultrasound-guided biopsy. Additionally, diagnostic biopsies taken with a larger needle gauge resulted in greater rates of test success. The article concludes that by optimizing HRD testing, treatment can be optimized at the earliest possible timepoint. [Extracted from the article]

Published
2024
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21. 527MO Rucaparib maintenance treatment in patients (pts) with newly diagnosed ovarian cancer (OC): Defining benefit according to disease risk subgroups within the phase 3 ATHENA–MONO study

Author

Kristeleit, R., primary, Ghamande, S., additional, Lim, M-C., additional, Parkinson, C., additional, Morgan, M., additional, Wilson, M., additional, Oaknin, A., additional, Buscema, J., additional, Bessette, P., additional, Lorusso, D., additional, Ueland, F., additional, Safra, T., additional, Barlin, J., additional, Marmé, F., additional, Herzog, T.J., additional, McNeish, I., additional, Goble, S., additional, Hume, S., additional, Fujiwara, K., additional, and Monk, B.J., additional

Published
2022
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22. 575P Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade serous or endometrioid ovarian cancer: A multi-national observational study

Author

Morgan, R.D., primary, Clamp, A.R., additional, Barnes, B., additional, Schlecht, H., additional, Yarram-Smith, L., additional, Wallis, Y., additional, Morgan, S., additional, Valganon, M., additional, Hudson, E., additional, McKenna, S., additional, Sundar, S., additional, Nicum, S., additional, Brenton, J.D., additional, Kristeleit, R., additional, Banerjee, S., additional, McNeish, I., additional, Ledermann, J.A., additional, Taylor, S., additional, Evans, G., additional, and Jayson, G.C., additional

Published
2022
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24. Overall survival results from ICON8, a GCIG phase 3 randomised controlled trial assessing weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment

Author

McNeish, I, Clamp, A, James, EC, Dean, A, Kim, J-W, O’Donnell, DM, Gallardo-Rincon, D, Blagden, S, Brenton, J, Perren, TJ, Sundar, S, Lord, R, Dark, G, Hall, M, Banerjee, S, Glasspool, RM, Hanna, L, Williams, S, Scratchard, KM, Nam, H, Essapen, S, Parkinson, C, McAvan, L, Swart, AM, Popoola, B, Schiavone, F, Badrock, J, Fananapazir, F, Cook, AD, Parmar, M, Kaplan, R, Ledermann, JA, Ovarian Cancer Action, and National Institute for Health Research

Subjects
1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Background: Standard of care first line chemotherapy for epithelial ovarian cancer (EOC) is carboplatin and paclitaxel administered once every three weeks. The JGOG3016 trial reported significant improvement in progression-free (PFS) and overall survival (OS) with dose-dense weekly paclitaxel and three-weekly carboplatin. However, this benefit was not observed in the progression free survival results of ICON8, previously reported. Here, we present the final co-primary OS and updated PFS outcomes. Methods: Women aged 18 or above with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IC-IV EOC were recruited. Patients were randomly assigned to one of three groups; group 1: 3-weekly carboplatin area under the curve (AUC) 5/6 and 3-weekly paclitaxel 175mg/m2, group 2: 3-weekly carboplatin AUC5/6 and weekly paclitaxel 80mg/m2, group 3: weekly carboplatin AUC2 and weekly paclitaxel 80mg/m2, all administered by intravenous infusion. Patients entered the trial after immediate primary surgery (IPS) or received delayed primary surgery (DPS) during chemotherapy. Randomisation was performed using minimisation with stratification factors of GCIG group, disease stage and outcome and timing of surgery. Co-primary outcomes were PFS and OS, with comparisons performed between group 2 and group 1, and group 3 and group 1. Intention-to-treat analyses were powered to detect a hazard ratio of 0.75 in favour of the experimental groups. The trial is registered on clinicaltrials.gov as NCT01654146 and controlled-trials.com asISRCTN10356387. Findings: Between 6 Jun 2011 and 28 Nov 2014, 1566 women were recruited; group 1 (N=522), group 2 (N=523) and group 3 (N=521). Baseline characteristics include median age 62, 69% high grade serous carcinoma, 72% stage IIIC-IV disease, 48% IPS. By March 2020, with a median follow up of 69 months (IQR 61-75 months), 324, 309 and 313 deaths had occurred in groups 1, 2 and 3 respectively. No significant difference in OS was observed in either comparison: HR 0.87 (97.5% CI 0.73, 1.05) group 2 vs group 1, HR 0.91 (97.5% CI 0.76, 1.09) group 3 vs group 1. Most common G3/4 adverse events were reduced neutrophils (78, 183, 154 in groups 1, 2, 3) reduced white blood cell count (22, 80, 71 In groups 1, 2, 3) and anaemia (26, 66, 25 in groups 1, 2, 3). No new serious adverse events were reported. Interpretation: First-line weekly dose-dense chemotherapy does not improve OS for patients with EOC compared with standard 3-weekly chemotherapy and should not be used as part of standard multimodality ovarian cancer treatment for Caucasian women in the front-line setting. Funding: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia.

Published
2022

25. Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup

Author

Vergote, I., Gonzalez-Martin, A., Lorusso, D., Gourley, C., Mirza, M.R., Kurtz, J.E., Okamoto, A., Moore, K., Kridelka, F., McNeish, I., Reuss, A., Votan, B., Bois, A. du, Mahner, S., Ray-Coquard, I., Kohn, E.C., Berek, J.S., Tan, D.S.P., Colombo, N., Zang, R., Concin, N., O'Donnell, D., Rauh-Hain, A., Herrington, C.S., Marth, C., Poveda, A., Fujiwara, K., Stuart, G.C., Ottevanger, N., Oza, A.M., Bookman, M.A., Vergote, I., Gonzalez-Martin, A., Lorusso, D., Gourley, C., Mirza, M.R., Kurtz, J.E., Okamoto, A., Moore, K., Kridelka, F., McNeish, I., Reuss, A., Votan, B., Bois, A. du, Mahner, S., Ray-Coquard, I., Kohn, E.C., Berek, J.S., Tan, D.S.P., Colombo, N., Zang, R., Concin, N., O'Donnell, D., Rauh-Hain, A., Herrington, C.S., Marth, C., Poveda, A., Fujiwara, K., Stuart, G.C., Ottevanger, N., Oza, A.M., and Bookman, M.A.

Abstract

Item does not contain fulltext, The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.

Published
2022

26. Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup

Author

Vergote, I, Gonzalez-Martin, A, Lorusso, D, Gourley, C, Mirza, M, Kurtz, J, Okamoto, A, Moore, K, Kridelka, F, Mcneish, I, Reuss, A, Votan, B, du Bois, A, Mahner, S, Ray-Coquard, I, Kohn, E, Berek, J, Tan, D, Colombo, N, Zang, R, Concin, N, O'Donnell, D, Rauh-Hain, A, Herrington, C, Marth, C, Poveda, A, Fujiwara, K, Stuart, G, Oza, A, Bookman, M, Vergote, Ignace, Gonzalez-Martin, Antonio, Lorusso, Domenica, Gourley, Charlie, Mirza, Mansoor Raza, Kurtz, Jean-Emmanuel, Okamoto, Aikou, Moore, Kathleen, Kridelka, Frédéric, McNeish, Iain, Reuss, Alexander, Votan, Bénédicte, du Bois, Andreas, Mahner, Sven, Ray-Coquard, Isabelle, Kohn, Elise C, Berek, Jonathan S, Tan, David S P, Colombo, Nicoletta, Zang, Rongyu, Concin, Nicole, O'Donnell, Dearbhaile, Rauh-Hain, Alejandro, Herrington, C Simon, Marth, Christian, Poveda, Andres, Fujiwara, Keiichi, Stuart, Gavin C E, Oza, Amit M, Bookman, Michael A, Vergote, I, Gonzalez-Martin, A, Lorusso, D, Gourley, C, Mirza, M, Kurtz, J, Okamoto, A, Moore, K, Kridelka, F, Mcneish, I, Reuss, A, Votan, B, du Bois, A, Mahner, S, Ray-Coquard, I, Kohn, E, Berek, J, Tan, D, Colombo, N, Zang, R, Concin, N, O'Donnell, D, Rauh-Hain, A, Herrington, C, Marth, C, Poveda, A, Fujiwara, K, Stuart, G, Oza, A, Bookman, M, Vergote, Ignace, Gonzalez-Martin, Antonio, Lorusso, Domenica, Gourley, Charlie, Mirza, Mansoor Raza, Kurtz, Jean-Emmanuel, Okamoto, Aikou, Moore, Kathleen, Kridelka, Frédéric, McNeish, Iain, Reuss, Alexander, Votan, Bénédicte, du Bois, Andreas, Mahner, Sven, Ray-Coquard, Isabelle, Kohn, Elise C, Berek, Jonathan S, Tan, David S P, Colombo, Nicoletta, Zang, Rongyu, Concin, Nicole, O'Donnell, Dearbhaile, Rauh-Hain, Alejandro, Herrington, C Simon, Marth, Christian, Poveda, Andres, Fujiwara, Keiichi, Stuart, Gavin C E, Oza, Amit M, and Bookman, Michael A

Abstract

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.

Published
2022

27. 44TiP ENGOT-ov65/KEYNOTE-B96: Phase III, randomized, double-blind study of pembrolizumab vs placebo + paclitaxel with optional bevacizumab for platinum-resistant recurrent ovarian cancer

Author

Colombo, N., primary, Coleman, R.L., additional, Wu, X., additional, Kose, F., additional, Wenham, R., additional, Sebastianelli, A., additional, Hasegawa, K., additional, Zsiros, E., additional, De La Motte Rouge, T., additional, Bidzinski, M., additional, McNeish, I., additional, Sehouli, J., additional, Korach, J., additional, Debruyne, P.R., additional, Kim, J-W., additional, De Melo, A.C., additional, Peng, X., additional, Bogusz, A.M., additional, Yamada, K., additional, and Monk, B.J., additional

Published
2022
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28. 4P Targeting PI3K/AKT/mTOR pathway in platinum-resistant ovarian high-grade serous carcinoma: Translational analysis from the randomized phase II OCTOPUS trial

Author

Giannone, G., primary, Ennis, D., additional, Mirza, H.B., additional, Cheng, Z., additional, McDermott, J., additional, Lewsley, L-A., additional, Clamp, A.R., additional, Herbertson, R.A., additional, Glasspool, R.M., additional, Krell, J., additional, Hinsley, S., additional, Banerji, U., additional, Riisnaes, R., additional, Banerjee, S., additional, and McNeish, I., additional

Published
2022
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29. Sixth ovarian cancer consensus conference on clinical research of the gynecologic cancer InterGroup

Author

McNeish, I, Ovarian Cancer Action, and National Institute for Health Research

Subjects
1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research (OCCC6) was held virtually in October 2021 following published consensus guidelines. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within 4 topic groups on clinical research including first line treatment, recurrent disease, disease subgroups and future trials. Unanimous consensus was obtained for 14 of 20 statements, with >90% concordance in the remaining 6 statements. The high acceptance rate following active deliberation amongst the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote harmonisation of international clinical research in ovarian cancer.

Published
2022

32. The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma

Author

Cheng, Z, Mirza, H, Ennis, DP, Smith, P, Morrill Gavarro, L, Sokota, C, Giannone, G, Goranova, T, Bradley, T, Piskorz, A, Lockley, M, For the BriTROC-1 Investigators, Kaur, B, Singh, N, Tookman, L, Krell, J, McDermott, J, Macintyre, G, Markowetz, F, Brenton, JD, McNeish, I, Imperial College Healthcare NHS Trust- BRC Funding, Cancer Research UK, Ovarian Cancer Action, and National Institute for Health Research

Subjects
Ovarian Neoplasms, Cancer Research, BriTROC-1 Investigators, High-Throughput Nucleotide Sequencing, Genomics, Carcinoma, Ovarian Epithelial, Middle Aged, Article, Cystadenocarcinoma, Serous, Oncology, Mutation, Fallopian Tube Neoplasms, Humans, 1112 Oncology and Carcinogenesis, Female, Oncology & Carcinogenesis
Abstract

Purpose: Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors. Experimental Design: We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study. Results: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) samples. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. Conclusions: Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness. See related commentary by Yang et al., p. 2730

Published
2021

33. Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING

Author

Bruand, M., Barras, D., Mina, M., Ghisoni, E., Morotti, M., Lanitis, E., Fahr, N., Desbuisson, M., Grimm, A., Zhang, H., Chong, C., Dagher, J., Chee, S., Tsianou, T., Dorier, J., Stevenson, B.J., Iseli, C., Ronet, C., Bobisse, S., Genolet, R., Walton, J., Bassani-Sternberg, M., Kandalaft, L.E., Ren, B., McNeish, I., Swisher, E., Harari, A., Delorenzi, M., Ciriello, G., Irving, M., Rusakiewicz, S., Foukas, P.G., and Martinon, F.

Subjects
BRCA1, CTLA-4, DNA sensing, ICB, PARPi, PD-L1, STING, T cells, VEGF-A, angiogenesis, dual immune checkpoint blockade, ovarian cancer, type I IFN
Abstract

In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I interferon (IFN) and stimulator of IFN genes (STING). BRCA1-mutated (BRCA1 mut ) tumors are thus T cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5 chemokine is identified as a potential mechanism to attenuate T cell inflammation. Alternatively, in BRCA1 mut cancers retaining inflammation, STING upregulates VEGF-A, mediating immune resistance and tumor progression. Tumor-intrinsic STING elimination reduces neoangiogenesis, increases CD8 + T cell infiltration, and reverts therapeutic resistance to dual immune checkpoint blockade (ICB). VEGF-A blockade phenocopies genetic STING loss and synergizes with ICB and/or poly(ADP-ribose) polymerase (PARP) inhibitors to control the outgrowth of Trp53 -/- Brca1 -/- but not Brca1 +/+ ovarian tumors in vivo, offering rational combinatorial therapies for HRD cancers.

Published
2021

36. ESMO-ESGO consensus conference recommendations on ovarian cancer: Pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease

Author

Colombo, N, Sessa, C, Bois, A, Ledermann, J, Mccluggage, W, Mcneish, I, Morice, P, Pignata, S, Ray-Coquard, I, Vergote, I, Baert, T, Belaroussi, I, Dashora, A, Olbrecht, S, Planchamp, F, Querleu, D, Bois, A du, McCluggage, W G, McNeish, I, Colombo, N, Sessa, C, Bois, A, Ledermann, J, Mccluggage, W, Mcneish, I, Morice, P, Pignata, S, Ray-Coquard, I, Vergote, I, Baert, T, Belaroussi, I, Dashora, A, Olbrecht, S, Planchamp, F, Querleu, D, Bois, A du, McCluggage, W G, and McNeish, I

Abstract

The development of guidelines is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically relevant and evidence-based recommendations in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO-ESGO consensus conference on ovarian cancer was held on April 12-14, 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO-ESGO consensus conference, together with a summary of evidence supporting each recommendation.

Published
2019

37. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease

Author

Selçukbiricik, Fatih, Colombo, N.; Sessa, C.; du Bois, A.; Ledermann, J.; McCluggage, W. G.; McNeish, I.; Morice, P.; Pignata, S.; Ray-Coquard, I.; Vergote, I.; Baert, T.; Belaroussi, I.; Dashora, A.; Olbrecht, S.; Planchamp, F.; Querleu, D.; Baert, T.; Banerjee, S.; Belaroussi, I.; Blecharz, P.; Bruchim, I.; Cibula, D.; Colombo, N.; Concin, N.; Davidson, B.; Dashora, A.; Devouassoux-Shisheboran, M.; du Bois, A.; Ferrero, A.; Glasspool, R.; Gonzalez-Martin, A.; Heinzelmann-Schwarz, V.; Joly, F.; Kim, J. W.; Kridelka, F.; Ledermann, J.; Lorusso, D.; Mahner, S.; McCluggage, W. G.; McNeish, I.; Mikami, M.; Mirza, M. R.; Morice, P.; Nicum, S.; Olbrecht, S.; O'Donnell, D. M.; Pautier, P.; Planchamp, F.; Pignata, S.; Querleu, D.; Ray-Coquard, I.; Rodolakis, A.; Sehouli, J.; Selcukbiricik, F.; Sessa, C.; Singh, N.; Tan, D. S. P.; Timmerman, D.; Tognon, G.; van der Velden, J.; Vergote, I.; Witteveen, P. O.; Zeimet, A. G., Koç University Hospital, Selçukbiricik, Fatih, Colombo, N.; Sessa, C.; du Bois, A.; Ledermann, J.; McCluggage, W. G.; McNeish, I.; Morice, P.; Pignata, S.; Ray-Coquard, I.; Vergote, I.; Baert, T.; Belaroussi, I.; Dashora, A.; Olbrecht, S.; Planchamp, F.; Querleu, D.; Baert, T.; Banerjee, S.; Belaroussi, I.; Blecharz, P.; Bruchim, I.; Cibula, D.; Colombo, N.; Concin, N.; Davidson, B.; Dashora, A.; Devouassoux-Shisheboran, M.; du Bois, A.; Ferrero, A.; Glasspool, R.; Gonzalez-Martin, A.; Heinzelmann-Schwarz, V.; Joly, F.; Kim, J. W.; Kridelka, F.; Ledermann, J.; Lorusso, D.; Mahner, S.; McCluggage, W. G.; McNeish, I.; Mikami, M.; Mirza, M. R.; Morice, P.; Nicum, S.; Olbrecht, S.; O'Donnell, D. M.; Pautier, P.; Planchamp, F.; Pignata, S.; Querleu, D.; Ray-Coquard, I.; Rodolakis, A.; Sehouli, J.; Selcukbiricik, F.; Sessa, C.; Singh, N.; Tan, D. S. P.; Timmerman, D.; Tognon, G.; van der Velden, J.; Vergote, I.; Witteveen, P. O.; Zeimet, A. G., and Koç University Hospital

Abstract

The development of guidelines recommendations is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically relevant and evidence-based recommendations in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO-ESGO consensus conference on ovarian cancer was held on 12-14 April 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO-ESGO consensus conference, together with a summary of evidence supporting each recommendation., ESMO and ESGO funds

Published
2019

38. 722O Randomised phase II trial of olaparib compared to weekly paclitaxel or olaparib plus cediranib in patients with platinum-resistant ovarian cancer (OCTOVA)

Author

Nicum, S., primary, Holmes, J., additional, McGregor, N., additional, Dunn, R., additional, Collins, L., additional, Kaye, S., additional, McNeish, I., additional, Glasspool, R.M., additional, Hall, M., additional, Roux, R., additional, Michael, A., additional, Banerjee, S., additional, Kristeleit, R., additional, Jayson, G., additional, Clamp, A., additional, and Mansouri, A., additional

Published
2021
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39. 751P Survival prognostic and surrogate values of the early modeled CA-125 KELIM in newly diagnosed advanced ovarian cancer: Data from the GCIG meta-analysis group

Author

Corbaux, P., primary, You, B., additional, Glasspool, R.M., additional, Yanaihara, N., additional, Tinker, A.V., additional, Lindemann, K., additional, Ray-Coquard, I.L., additional, Mirza, M.R., additional, Subtil, F., additional, Colomban, O., additional, Peron, J., additional, Karamouza, E., additional, McNeish, I., additional, Hinsley, S., additional, Kagimura, T., additional, Welch, S., additional, Lewsley, L-A., additional, Paoletti, X., additional, and Cook, A., additional

Published
2021
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40. 747P Real-world experience of rucaparib in patients with ovarian cancer: A multicentre United Kingdom study

Author

Lythgoe, M., primary, Cleary, S., additional, Kalofonou, F., additional, Grunewald, T., additional, Miller, R., additional, Cartwright, D., additional, Glasspool, R.M., additional, Jones, R., additional, Rossides, S., additional, Ratnakumaran, R., additional, Michael, A., additional, McNeish, I., additional, Tookman, L., additional, and Krell, J., additional

Published
2021
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42. Characterization of a RAD51C-silenced high-grade serous ovarian cancer model during development of PARP inhibitor resistance.

Author

Hurley R.M., McGehee C.D., Nesic K., Correia C., Weiskittel T.M., Kelly R.L., Venkatachalam A., Hou X., Pathoulas N.M., Meng X.W., Kondrashova O., Radke M.R., Schneider P.A., Flatten K.S., Peterson K.L., Becker M.A., Wong E.M., Southey M.S., Dobrovic A., Lin K.K., Harding T.C., McNeish I., Ross C.A., Wagner J.M., Wakefield M.J., Scott C.L., Haluska P., Hendrickson A.E.W., Karnitz L.M., Swisher E.M., Li H., John Weroha S., Kaufmann S.H., Hurley R.M., McGehee C.D., Nesic K., Correia C., Weiskittel T.M., Kelly R.L., Venkatachalam A., Hou X., Pathoulas N.M., Meng X.W., Kondrashova O., Radke M.R., Schneider P.A., Flatten K.S., Peterson K.L., Becker M.A., Wong E.M., Southey M.S., Dobrovic A., Lin K.K., Harding T.C., McNeish I., Ross C.A., Wagner J.M., Wakefield M.J., Scott C.L., Haluska P., Hendrickson A.E.W., Karnitz L.M., Swisher E.M., Li H., John Weroha S., and Kaufmann S.H.

Abstract

Acquired PARP inhibitor (PARPi) resistance in BRCA1-or BRCA2-mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived ovarian cancer xenograft PH039, which lacks HR gene mutations but harbors RAD51C promoter methylation, was selected for PARPi resistance by cyclical niraparib treatment in vivo. PH039 acquired PARPi resistance by the third treatment cycle and grew through subsequent treatment with either niraparib or rucaparib. Transcriptional profiling throughout the course of resistance development showed widespread pathway level changes along with a marked increase in RAD51C mRNA, which reflected loss of RAD51C promoter methylation. Analysis of ovarian cancer samples from the ARIEL2 Part 1 clinical trial of rucaparib monotherapy likewise indicated an association between loss of RAD51C methylation prior to on-study biopsy and limited response. Interestingly, the PARPi resistant PH039 model remained platinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure can reverse RAD51C methylation and restore RAD51C expression, but also provide a model for studying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.Copyright © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer.

Published
2021

43. Characterization of a RAD51C-silenced high-grade serous ovarian cancer model during development of PARP inhibitor resistance

Author

Hurley, RM, McGehee, CD, Nesic, K, Correia, C, Weiskittel, TM, Kelly, RL, Venkatachalam, A, Hou, X, Pathoulas, NM, Meng, XW, Kondrashova, O, Radke, MR, Schneider, PA, Flatten, KS, Peterson, KL, Becker, MA, Wong, EM, Southey, MS, Dobrovic, A, Lin, KK, Harding, TC, McNeish, I, Ross, CA, Wagner, JM, Wakefield, MJ, Scott, CL, Haluska, P, Hendrickson, AEW, Karnitz, LM, Swisher, EM, Li, H, Weroha, SJ, Kaufmann, SH, Hurley, RM, McGehee, CD, Nesic, K, Correia, C, Weiskittel, TM, Kelly, RL, Venkatachalam, A, Hou, X, Pathoulas, NM, Meng, XW, Kondrashova, O, Radke, MR, Schneider, PA, Flatten, KS, Peterson, KL, Becker, MA, Wong, EM, Southey, MS, Dobrovic, A, Lin, KK, Harding, TC, McNeish, I, Ross, CA, Wagner, JM, Wakefield, MJ, Scott, CL, Haluska, P, Hendrickson, AEW, Karnitz, LM, Swisher, EM, Li, H, Weroha, SJ, and Kaufmann, SH

Abstract

Acquired PARP inhibitor (PARPi) resistance in BRCA1- or BRCA2-mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived ovarian cancer xenograft PH039, which lacks HR gene mutations but harbors RAD51C promoter methylation, was selected for PARPi resistance by cyclical niraparib treatment in vivo. PH039 acquired PARPi resistance by the third treatment cycle and grew through subsequent treatment with either niraparib or rucaparib. Transcriptional profiling throughout the course of resistance development showed widespread pathway level changes along with a marked increase in RAD51C mRNA, which reflected loss of RAD51C promoter methylation. Analysis of ovarian cancer samples from the ARIEL2 Part 1 clinical trial of rucaparib monotherapy likewise indicated an association between loss of RAD51C methylation prior to on-study biopsy and limited response. Interestingly, the PARPi resistant PH039 model remained platinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure can reverse RAD51C methylation and restore RAD51C expression, but also provide a model for studying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.

Published
2021

48. An exploratory analysis of objective responses to neoadjuvant chemotherapy: results from a randomised phase III trial evaluating first-line carboplatin-paclitaxel regimens for ovarian, fallopian tube or primary peritoneal carcinoma (ICON8)

Author

McNeish, I, Morgan, RD, Cook, AD, James, EC, Lord, R, Dark, G, Glasspool, RM, Krell, J, Parkinson, C, Poole, CJ, Hall, M, Gallardo-Rincón, D, Lockley, M, Essapen, S, Summers, J, Anand, A, Zachariah, A, Williams, S, Jones, R, Scatchard, K, Walther, A, Kim, J-W, Sundar, S, Jayson, GC, Ledermann, JA, Clamp, AR, Imperial College Healthcare NHS Trust- BRC Funding, Ovarian Cancer Action, and Cancer Research UK

Subjects
1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundPlatinum-based neoadjuvant chemotherapy (NACT) followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase III trials,evaluation of response to NACT using Response Evaluation Criteria in Solid Tumours (RECIST)and CA125 was not reported. We describeRECIST and Gynecologic Cancer InterGroup (GCIG)CA125 responses in patients receiving platinum-based NACT followed by DPS in the phase III trial, ICON8.MethodsICON8 was an international, multicentre, randomised, phase III trial in which women ≥18 years old with an Eastern Cooperative Oncology Group performance status of 0-2, life expectancy >12 weeks and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO;1988) stage IC-IIA high-grade serous, clear cell or any poorly differentiated/grade 3 histological subtype or any FIGO (1988) stage IIB-IV epithelial cancer of the ovary, fallopian tube or primary peritoneum were randomised (1:1:1) to receive either intravenous (IV) carboplatin (AUC5/6)and IV paclitaxel (175mg/m2by body surface area [BSA])on day 1 of every 21-day cycle(control arm)or IV carboplatin (AUC5/6)on day 1 and IV paclitaxel (80mg/m2by BSA)on days 1, 8 and 15 of every 21-day cycle(dose-fractionated paclitaxelarm) or IV carboplatin (AUC2)and IV paclitaxel (80mg/m2by BSA)on days 1, 8 and 15 of every 21-day cycle(dose-fractionated carboplatin and paclitaxelarm). Randomisation occurred using a minimisation method and patients where stratified according to GCIG group, disease stage and timing and outcome of cytoreductive surgery. Neither patients nor clinicians were masked to their allocated group. The scheduling of surgery and use of NACTwere determined by local multidisciplinary case review. In this post-hoc 5exploratory analysis of ICON8, progression-free survival (PFS) was analysed using the landmark method and defined as the time interval between the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death, whichever occurred first. This is different to the intention-to-treat primary PFS efficacy analysis of ICON8, which definedPFS as the time from randomisation to the date of clinical or radiological progression or death, whichever occurred first. This post-hoc exploratory analysis includes only women recruited to ICON8thatwere planned for NACT followed by DPS and had RECIST v1.1 and/or GCIG CA125 evaluable disease. ICON8isclosed for enrolment and follow-up, and registered with ClinicalTrials.gov, number: NCT01654146. Findings: BetweenJune 6,2011 and November 28,2014,1,566 women were enrolled in ICON8.Seven hundred and seventy-nine women were planned forNACT followed by DPS(NACT-DPS). In the NACT-DPS population,94% had FIGO stage IIIC/IV disease. Five hundred and sixty-four women had RECIST evaluable disease at trial entry and the complete or partial response rate (CR/PR) was 62%(348/564). Seven hundred and twenty-seven women were evaluable by GCIG CA125 criteria at the time of diagnosis and 84%(610/727) had a CA125 response. The median PFS was 14.4 months (95% CI [confidence interval] 9.2-28.0months; 297 events) for RECIST CR/PR and 13.3 months (95% CI 8.1-20.1months; 171 events) for RECIST stable disease(SD). The median PFS for those women with a GCIG CA125 response was 13.8 months (95% CI 8.8-23.4months; 544 events) and 9.7 months (95% CI 5.8-14.5months; 111 events) for those without. Complete cytoreduction(R0) was achieved in 56% (187/335) of women with RECISTCR/PRand42% (73/172) with RECIST SD. Complete cytoreduction (R0) was achieved in50% (290/576) and 30% (30/101) of women 6with and without a GCIG CA125 response, respectively. The median follow-up was 29.5 months (interquartile range:15.6-54.3months) for the NACT-DPS population.InterpretationThe RECIST-defined radiological response was lower than frequently quoted to patients in the clinic. RECIST v1.1 and GCIGCA125 responses to NACT for epithelial ovarian cancer should not be used as individual predictive markers to stratify patients likely to benefit from DPS, but instead used in conjunction with the patient’s clinical capacity to undergo cytoreductive surgery. A patient should not be denied surgery based solely on the lack of a RECIST v1.1 or GCIG CA125 response.

Published
2020

49. Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors

Author

Universitat Rovira i Virgili, Lahiguera Á., Hyroššová P., Figueras A., Garzón D., Moreno R., Soto-Cerrato V., McNeish I., Serra V., Lazaro C., Barretina P., Brunet J., Menéndez J., Matias-Guiu X., Vidal A., Villanueva A., Taylor-Harding B., Tanaka H., Orsulic S., Junza A., Yanes O., Muñoz-Pinedo C., Palomero L., Pujana M.À., Perales J.C., Viñals F., Universitat Rovira i Virgili, and Lahiguera Á., Hyroššová P., Figueras A., Garzón D., Moreno R., Soto-Cerrato V., McNeish I., Serra V., Lazaro C., Barretina P., Brunet J., Menéndez J., Matias-Guiu X., Vidal A., Villanueva A., Taylor-Harding B., Tanaka H., Orsulic S., Junza A., Yanes O., Muñoz-Pinedo C., Palomero L., Pujana M.À., Perales J.C., Viñals F.

Abstract

© 2020 The Authors. Published under the terms of the CC BY 4.0 license Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defective (HRD) cancers rely on oxidative metabolism to supply NAD+ and ATP for poly(ADP-ribose) polymerase (PARP)-dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD+ concentration changes. On the other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patient-derived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors.

Published
2020

50. 323 ENGOT-en9/LEAP-001: a phase 3 study of first-line pembrolizumab plus lenvatinib compared with chemotherapy in advanced or recurrent endometrial cancer

Author

Randall, L, primary, Marth, C, additional, Vulsteke, C, additional, Jesús Rubio, M, additional, Makker, V, additional, Braicu, I, additional, McNeish, I, additional, Madry, R, additional, Ayhan, A, additional, Hasegawa, K, additional, Wu, X, additional, Dutta, L, additional, Xu, C, additional, Keefe, S, additional, Lee, J, additional, and Pignata, S, additional

Published
2020
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