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1. Shifting incidence and survival of epithelial ovarian cancer (1995‐2014): A <scp>SurvMark</scp> ‐2 study

Author

Citadel J. Cabasag, Melina Arnold, Mark Rutherford, Jacques Ferlay, Aude Bardot, Eileen Morgan, John Butler, Dianne L. O'Connell, Gregg Nelson, Claus Høgdall, Tine Schnack, Anna Gavin, Mark Elwood, Louise Hanna, Charlie Gourley, Prithwish De, Nathalie Saint‐Jacques, Lina Steinrud Mørch, Ryan R Woods, Alon D. Altman, Peter Sykes, Paul A. Cohen, Orla McNally, Bjørn Møller, Paul Walsh, David S. Morrison, Freddie Bray, and Isabelle Soerjomataram

Subjects
Cancer Research, Oncology
Abstract

The aim of the study is to provide a comprehensive assessment of incidence and survival trends of epithelial ovarian cancer (EOC) by histological subtype across seven high income countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the United Kingdom). Data on invasive EOC diagnosed in women aged 15-99 years during 1995-2014 were obtained from 20 cancer registries. Age standardized incidence rates and average annual percentage change were calculated by subtype for all ages and age groups (15-64 and 65-99 years). Net survival (NS) was estimated by subtype, age group, and 5-year period using Pohar-Perme estimator. Our findings showed marked increase in serous carcinoma incidence was observed between 1995-2014 among women aged 65-99 years with average annual increase ranging between 2.2% and 5.8%. We documented a marked decrease in the incidence of adenocarcinoma 'not otherwise specified' with estimates ranging between 4.4% and 7.4% in women aged 15-64 years and between 2.0% and 3.7% among the older age group. Improved survival, combining all EOC subtypes, was observed for all ages combined over the 20-year study period in all countries with 5-year NS absolute percent change ranging between 5.0 in Canada and 12.6 in Denmark. Several factors such as changes in guidelines and advancement in diagnostic tools may potentially influence the observed shift in histological subtypes and temporal trends. Progress in clinical management and treatment over the past decades potentially plays a role in the observed improvements in EOC survival. This article is protected by copyright. All rights reserved.

Published
2023

2. Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author

Nicola S, Meagher, Kylie L, Gorringe, Matthew, Wakefield, Adelyn, Bolithon, Chi Nam Ignatius, Pang, Derek S, Chiu, Michael S, Anglesio, Kylie-Ann, Mallitt, Jennifer A, Doherty, Holly R, Harris, Joellen M, Schildkraut, Andrew, Berchuck, Kara L, Cushing-Haugen, Ksenia, Chezar, Angela, Chou, Adeline, Tan, Jennifer, Alsop, Ellen, Barlow, Matthias W, Beckmann, Jessica, Boros, David D L, Bowtell, Alison H, Brand, James D, Brenton, Ian, Campbell, Dane, Cheasley, Joshua, Cohen, Cezary, Cybulski, Esther, Elishaev, Ramona, Erber, Rhonda, Farrell, Anna, Fischer, Zhuxuan, Fu, Blake, Gilks, Anthony J, Gill, Charlie, Gourley, Marcel, Grube, Paul R, Harnett, Arndt, Hartmann, Anusha, Hettiaratchi, Claus K, Høgdall, Tomasz, Huzarski, Anna, Jakubowska, Mercedes, Jimenez-Linan, Catherine J, Kennedy, Byoung-Gie, Kim, Jae-Weon, Kim, Jae-Hoon, Kim, Kayla, Klett, Jennifer M, Koziak, Tiffany, Lai, Angela, Laslavic, Jenny, Lester, Yee, Leung, Na, Li, Winston, Liauw, Belle W X, Lim, Anna, Linder, Jan, Lubiński, Sakshi, Mahale, Constantina, Mateoiu, Simone, McInerny, Janusz, Menkiszak, Parham, Minoo, Suzana, Mittelstadt, David, Morris, Sandra, Orsulic, Sang-Yoon, Park, Celeste Leigh, Pearce, John V, Pearson, Malcolm C, Pike, Carmel M, Quinn, Ganendra Raj, Mohan, Jianyu, Rao, Marjorie J, Riggan, Matthias, Ruebner, Stuart, Salfinger, Clare L, Scott, Mitul, Shah, Helen, Steed, Colin J R, Stewart, Deepak, Subramanian, Soseul, Sung, Katrina, Tang, Paul, Timpson, Robyn L, Ward, Rebekka, Wiedenhoefer, Heather, Thorne, Paul A, Cohen, Philip, Crowe, Peter A, Fasching, Jacek, Gronwald, Nicholas J, Hawkins, Estrid, Høgdall, David G, Huntsman, Paul A, James, Beth Y, Karlan, Linda E, Kelemen, Stefan, Kommoss, Gottfried E, Konecny, Francesmary, Modugno, Sue K, Park, Annette, Staebler, Karin, Sundfeldt, Anna H, Wu, Aline, Talhouk, Paul D P, Pharoah, Lyndal, Anderson, Anna, DeFazio, Martin, Köbel, Michael L, Friedlander, and Susan J, Ramus

Subjects
Ovarian Neoplasms, Cancer Research, BORDERLINE TUMORS, CARCINOMA, ADENOCARCINOMA, TRANSGELIN, Carcinoma, Ovarian Epithelial, EXPANSILE, Prognosis, INTESTINAL-TYPE, CANCER, Adenocarcinoma, Mucinous, PATTERN, RARE, Oncology, POOR-PROGNOSIS, Humans, Female, Neoplasm Staging, Gastrointestinal Neoplasms
Abstract

Purpose: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04–7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04–1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01–1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Published
2022

3. Overall Survival With Maintenance Olaparib at a 7-Year Follow-up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial

Author

Paul DiSilvestro, Susana Banerjee, Nicoletta Colombo, Giovanni Scambia, Byoung-Gie Kim, Ana Oaknin, Michael Friedlander, Alla Lisyanskaya, Anne Floquet, Alexandra Leary, Gabe S. Sonke, Charlie Gourley, Amit Oza, Antonio González-Martín, Carol Aghajanian, William Bradley, Cara Mathews, Joyce Liu, John McNamara, Elizabeth S. Lowe, Mei-Lin Ah-See, Kathleen N. Moore, Institut Català de la Salut, [DiSilvestro P] Program in Women's Oncology, Women & Infants Hospital, Providence, RI. [Banerjee S] The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, United Kingdom. [Colombo N] University of Milan-Bicocca and Istituto Europeo di Oncologia IRCCS, Milan, Italy. [Scambia G] Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. [Kim BG] Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. [Oaknin A] Gynaecologic Cancer Programme, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d'Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Disilvestro, P, Banerjee, S, Colombo, N, Scambia, G, Kim, B, Oaknin, A, Friedlander, M, Lisyanskaya, A, Floquet, A, Leary, A, Sonke, G, Gourley, C, Oza, A, González-Martín, A, Aghajanian, C, Bradley, W, Mathews, C, Liu, J, Mcnamara, J, Lowe, E, Ah-See, M, and Moore, K

Subjects
Cancer Research, Otros calificadores::/uso terapéutico [Otros calificadores], Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms [DISEASES], Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], Medicaments antineoplàstics - Ús terapèutic, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS], Obstetrics and Gynecology, General Medicine, Ovaris - Càncer - Tractament, neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas [ENFERMEDADES], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Ovarian Cancer, Olaparib, Settore MED/40 - GINECOLOGIA E OSTETRICIA, Anomalies cromosòmiques, Oncology, SOLO1/GOG 3004 Trial, Other subheadings::/therapeutic use [Other subheadings], Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS], BRCA Mutation, fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS]
Abstract

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.

Published
2023

4. Ovarian carcinosarcoma is a distinct form of ovarian cancer with poorer survival compared to tubo-ovarian high-grade serous carcinoma

Author

Robert L. Hollis, Ian Croy, Michael Churchman, Clare Bartos, Tzyvia Rye, Charlie Gourley, and C. Simon Herrington

Subjects
Ovarian Neoplasms, Cancer Research, Carcinosarcoma, endocrine system diseases, Oncology, Chondrosarcoma, Humans, Female, Carcinoma, Ovarian Epithelial, Neoplasm Recurrence, Local, female genital diseases and pregnancy complications, Cystadenocarcinoma, Serous, Neoplasm Staging
Abstract

Background Ovarian carcinosarcoma (OCS) is an uncommon, biphasic and highly aggressive ovarian cancer type, which has received relatively little research attention. Methods We curated the largest pathologically confirmed OCS cohort to date, performing detailed histopathological characterisation, analysis of features associated with survival and comparison against high-grade serous ovarian carcinoma (HGSOC). Results Eighty-two OCS patients were identified; overall survival was poor (median 12.7 months). In all, 79% demonstrated epithelial components of high-grade serous (HGS) type, while 21% were endometrioid. Heterologous elements were common (chondrosarcoma in 32%, rhabdomyosarcoma in 21%, liposarcoma in 2%); chondrosarcoma was more frequent in OCS with endometrioid carcinomatous components. Earlier stage, complete resection and platinum-containing adjuvant chemotherapy were associated with prolonged survival; however, risk of relapse and mortality was high across all patient groups. Histological subclassification did not identify subgroups with distinct survival. Compared to HGSOC, OCS patients were older (P P = 0.025), demonstrated lower chemotherapy response rate (P = 0.001) and had significantly poorer survival (P Conclusion OCS represents a distinct, highly lethal form of ovarian cancer for which new treatment strategies are urgently needed. Histological subclassification does not identify patient subgroups with distinct survival. Aggressive adjuvant chemotherapy should be considered for all cases, including those with early-stage disease.

Published
2022

5. Supplementary Methods 1 from Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author

Susan J. Ramus, Michael L. Friedlander, Martin Köbel, Anna DeFazio, Lyndal Anderson, Paul D.P. Pharoah, Aline Talhouk, Anna H. Wu, Karin Sundfeldt, Annette Staebler, Sue K. Park, Francesmary Modugno, Gottfried E. Konecny, Stefan Kommoss, Linda E. Kelemen, Beth Y. Karlan, Paul A. James, David G. Huntsman, Estrid Høgdall, Nicholas J. Hawkins, Jacek Gronwald, Peter A. Fasching, Philip Crowe, Paul A. Cohen, Heather Thorne, Rebekka Wiedenhoefer, Robyn L. Ward, Paul Timpson, Katrina Tang, Soseul Sung, Deepak Subramanian, Colin J.R. Stewart, Helen Steed, Mitul Shah, Clare L. Scott, Stuart Salfinger, Matthias Ruebner, Marjorie J. Riggan, Jianyu Rao, Ganendra Raj Mohan, Carmel M. Quinn, Malcolm C. Pike, John V. Pearson, Celeste Leigh Pearce, Sang-Yoon Park, Sandra Orsulic, David Morris, Suzana Mittelstadt, Parham Minoo, Janusz Menkiszak, Simone McInerny, Constantina Mateoiu, Sakshi Mahale, Jan Lubiński, Anna Linder, Belle W.X. Lim, Winston Liauw, Na Li, Yee Leung, Jenny Lester, Angela Laslavic, Tiffany Lai, Jennifer M. Koziak, Kayla Klett, Jae-Hoon Kim, Jae-Weon Kim, Byoung-Gie Kim, Catherine J. Kennedy, Mercedes Jimenez-Linan, Anna Jakubowska, Tomasz Huzarski, Claus K. Høgdall, Anusha Hettiaratchi, Arndt Hartmann, Paul R. Harnett, Marcel Grube, Charlie Gourley, Anthony J. Gill, Blake Gilks, Zhuxuan Fu, Anna Fischer, Rhonda Farrell, Ramona Erber, Esther Elishaev, Cezary Cybulski, Joshua Cohen, Dane Cheasley, Ian Campbell, James D. Brenton, Alison H. Brand, David D.L. Bowtell, Jessica Boros, Matthias W. Beckmann, Ellen Barlow, Jennifer Alsop, Adeline Tan, Angela Chou, Ksenia Chezar, Kara L. Cushing-Haugen, Andrew Berchuck, Joellen M. Schildkraut, Holly R. Harris, Jennifer A. Doherty, Kylie-Ann Mallitt, Michael S. Anglesio, Derek S. Chiu, Chi Nam Ignatius Pang, Adelyn Bolithon, Matthew Wakefield, Kylie L. Gorringe, and Nicola S. Meagher

Abstract

Supplementary Methods

Published
2023

6. Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

Author

Elli Papaemmanuil, Ellen L. Goode, Kate Lawrenson, Francesmary Modugno, Jason Konner, Simon Gayther, David Huntsman, Michael S. Anglesio, Britta Weigelt, James D. Brenton, Beth Karlan, Anna DeFazio, Charlie Gourley, Michael Churchman, Ronny Drapkin, Kevin M. Elias, Paul Pharoah, Yoke-Eng Chiew, Alison H. Brand, Magdalena Sekowska, Anna Piskorz, Catherine J. Kennedy, Angela Laslavic, Esther Elishaev, Jenny Lester, Sebastian M. Armasu, Stacey J. Winham, Lea A. Moukarzel, Brian J. Wiley, Irenaeus C.C. Chan, Julie M. Cunningham, Yanis Tazi, Martin Köbel, Rajmohan Murali, Zhuxuan Fu, Rosario Corona de la Fuente, Denise Chen, and Kelly L. Bolton

Abstract

Purpose:To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.Experimental Design:We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival.Results:We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy.Conclusions:Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness.See related commentary by Lheureux, p. 4838

Published
2023

7. Supplementary Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

Author

Elli Papaemmanuil, Ellen L. Goode, Kate Lawrenson, Francesmary Modugno, Jason Konner, Simon Gayther, David Huntsman, Michael S. Anglesio, Britta Weigelt, James D. Brenton, Beth Karlan, Anna DeFazio, Charlie Gourley, Michael Churchman, Ronny Drapkin, Kevin M. Elias, Paul Pharoah, Yoke-Eng Chiew, Alison H. Brand, Magdalena Sekowska, Anna Piskorz, Catherine J. Kennedy, Angela Laslavic, Esther Elishaev, Jenny Lester, Sebastian M. Armasu, Stacey J. Winham, Lea A. Moukarzel, Brian J. Wiley, Irenaeus C.C. Chan, Julie M. Cunningham, Yanis Tazi, Martin Köbel, Rajmohan Murali, Zhuxuan Fu, Rosario Corona de la Fuente, Denise Chen, and Kelly L. Bolton

Abstract

Supplementary Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

Published
2023

8. Supplementary Figures S1-S13 from Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author

Susan J. Ramus, Michael L. Friedlander, Martin Köbel, Anna DeFazio, Lyndal Anderson, Paul D.P. Pharoah, Aline Talhouk, Anna H. Wu, Karin Sundfeldt, Annette Staebler, Sue K. Park, Francesmary Modugno, Gottfried E. Konecny, Stefan Kommoss, Linda E. Kelemen, Beth Y. Karlan, Paul A. James, David G. Huntsman, Estrid Høgdall, Nicholas J. Hawkins, Jacek Gronwald, Peter A. Fasching, Philip Crowe, Paul A. Cohen, Heather Thorne, Rebekka Wiedenhoefer, Robyn L. Ward, Paul Timpson, Katrina Tang, Soseul Sung, Deepak Subramanian, Colin J.R. Stewart, Helen Steed, Mitul Shah, Clare L. Scott, Stuart Salfinger, Matthias Ruebner, Marjorie J. Riggan, Jianyu Rao, Ganendra Raj Mohan, Carmel M. Quinn, Malcolm C. Pike, John V. Pearson, Celeste Leigh Pearce, Sang-Yoon Park, Sandra Orsulic, David Morris, Suzana Mittelstadt, Parham Minoo, Janusz Menkiszak, Simone McInerny, Constantina Mateoiu, Sakshi Mahale, Jan Lubiński, Anna Linder, Belle W.X. Lim, Winston Liauw, Na Li, Yee Leung, Jenny Lester, Angela Laslavic, Tiffany Lai, Jennifer M. Koziak, Kayla Klett, Jae-Hoon Kim, Jae-Weon Kim, Byoung-Gie Kim, Catherine J. Kennedy, Mercedes Jimenez-Linan, Anna Jakubowska, Tomasz Huzarski, Claus K. Høgdall, Anusha Hettiaratchi, Arndt Hartmann, Paul R. Harnett, Marcel Grube, Charlie Gourley, Anthony J. Gill, Blake Gilks, Zhuxuan Fu, Anna Fischer, Rhonda Farrell, Ramona Erber, Esther Elishaev, Cezary Cybulski, Joshua Cohen, Dane Cheasley, Ian Campbell, James D. Brenton, Alison H. Brand, David D.L. Bowtell, Jessica Boros, Matthias W. Beckmann, Ellen Barlow, Jennifer Alsop, Adeline Tan, Angela Chou, Ksenia Chezar, Kara L. Cushing-Haugen, Andrew Berchuck, Joellen M. Schildkraut, Holly R. Harris, Jennifer A. Doherty, Kylie-Ann Mallitt, Michael S. Anglesio, Derek S. Chiu, Chi Nam Ignatius Pang, Adelyn Bolithon, Matthew Wakefield, Kylie L. Gorringe, and Nicola S. Meagher

Abstract

Supplementary Figures S1-S13

Published
2023

9. Data from Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author

Susan J. Ramus, Michael L. Friedlander, Martin Köbel, Anna DeFazio, Lyndal Anderson, Paul D.P. Pharoah, Aline Talhouk, Anna H. Wu, Karin Sundfeldt, Annette Staebler, Sue K. Park, Francesmary Modugno, Gottfried E. Konecny, Stefan Kommoss, Linda E. Kelemen, Beth Y. Karlan, Paul A. James, David G. Huntsman, Estrid Høgdall, Nicholas J. Hawkins, Jacek Gronwald, Peter A. Fasching, Philip Crowe, Paul A. Cohen, Heather Thorne, Rebekka Wiedenhoefer, Robyn L. Ward, Paul Timpson, Katrina Tang, Soseul Sung, Deepak Subramanian, Colin J.R. Stewart, Helen Steed, Mitul Shah, Clare L. Scott, Stuart Salfinger, Matthias Ruebner, Marjorie J. Riggan, Jianyu Rao, Ganendra Raj Mohan, Carmel M. Quinn, Malcolm C. Pike, John V. Pearson, Celeste Leigh Pearce, Sang-Yoon Park, Sandra Orsulic, David Morris, Suzana Mittelstadt, Parham Minoo, Janusz Menkiszak, Simone McInerny, Constantina Mateoiu, Sakshi Mahale, Jan Lubiński, Anna Linder, Belle W.X. Lim, Winston Liauw, Na Li, Yee Leung, Jenny Lester, Angela Laslavic, Tiffany Lai, Jennifer M. Koziak, Kayla Klett, Jae-Hoon Kim, Jae-Weon Kim, Byoung-Gie Kim, Catherine J. Kennedy, Mercedes Jimenez-Linan, Anna Jakubowska, Tomasz Huzarski, Claus K. Høgdall, Anusha Hettiaratchi, Arndt Hartmann, Paul R. Harnett, Marcel Grube, Charlie Gourley, Anthony J. Gill, Blake Gilks, Zhuxuan Fu, Anna Fischer, Rhonda Farrell, Ramona Erber, Esther Elishaev, Cezary Cybulski, Joshua Cohen, Dane Cheasley, Ian Campbell, James D. Brenton, Alison H. Brand, David D.L. Bowtell, Jessica Boros, Matthias W. Beckmann, Ellen Barlow, Jennifer Alsop, Adeline Tan, Angela Chou, Ksenia Chezar, Kara L. Cushing-Haugen, Andrew Berchuck, Joellen M. Schildkraut, Holly R. Harris, Jennifer A. Doherty, Kylie-Ann Mallitt, Michael S. Anglesio, Derek S. Chiu, Chi Nam Ignatius Pang, Adelyn Bolithon, Matthew Wakefield, Kylie L. Gorringe, and Nicola S. Meagher

Abstract

Purpose:Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.Experimental Design:Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).Results:Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04–7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04–1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01–1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%).Conclusions:An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Published
2023

10. Supplementary Tables S1-S11 from Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author

Susan J. Ramus, Michael L. Friedlander, Martin Köbel, Anna DeFazio, Lyndal Anderson, Paul D.P. Pharoah, Aline Talhouk, Anna H. Wu, Karin Sundfeldt, Annette Staebler, Sue K. Park, Francesmary Modugno, Gottfried E. Konecny, Stefan Kommoss, Linda E. Kelemen, Beth Y. Karlan, Paul A. James, David G. Huntsman, Estrid Høgdall, Nicholas J. Hawkins, Jacek Gronwald, Peter A. Fasching, Philip Crowe, Paul A. Cohen, Heather Thorne, Rebekka Wiedenhoefer, Robyn L. Ward, Paul Timpson, Katrina Tang, Soseul Sung, Deepak Subramanian, Colin J.R. Stewart, Helen Steed, Mitul Shah, Clare L. Scott, Stuart Salfinger, Matthias Ruebner, Marjorie J. Riggan, Jianyu Rao, Ganendra Raj Mohan, Carmel M. Quinn, Malcolm C. Pike, John V. Pearson, Celeste Leigh Pearce, Sang-Yoon Park, Sandra Orsulic, David Morris, Suzana Mittelstadt, Parham Minoo, Janusz Menkiszak, Simone McInerny, Constantina Mateoiu, Sakshi Mahale, Jan Lubiński, Anna Linder, Belle W.X. Lim, Winston Liauw, Na Li, Yee Leung, Jenny Lester, Angela Laslavic, Tiffany Lai, Jennifer M. Koziak, Kayla Klett, Jae-Hoon Kim, Jae-Weon Kim, Byoung-Gie Kim, Catherine J. Kennedy, Mercedes Jimenez-Linan, Anna Jakubowska, Tomasz Huzarski, Claus K. Høgdall, Anusha Hettiaratchi, Arndt Hartmann, Paul R. Harnett, Marcel Grube, Charlie Gourley, Anthony J. Gill, Blake Gilks, Zhuxuan Fu, Anna Fischer, Rhonda Farrell, Ramona Erber, Esther Elishaev, Cezary Cybulski, Joshua Cohen, Dane Cheasley, Ian Campbell, James D. Brenton, Alison H. Brand, David D.L. Bowtell, Jessica Boros, Matthias W. Beckmann, Ellen Barlow, Jennifer Alsop, Adeline Tan, Angela Chou, Ksenia Chezar, Kara L. Cushing-Haugen, Andrew Berchuck, Joellen M. Schildkraut, Holly R. Harris, Jennifer A. Doherty, Kylie-Ann Mallitt, Michael S. Anglesio, Derek S. Chiu, Chi Nam Ignatius Pang, Adelyn Bolithon, Matthew Wakefield, Kylie L. Gorringe, and Nicola S. Meagher

Abstract

Supplementary Tables S1-S11

Published
2023

11. Supplementary Table 1 from Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study

Author

Stan B. Kaye, Alan Ashworth, Christopher J. Lord, Martin E. Gore, Johann S. de Bono, Lina Chen, James Campbell, Ioannis Assiotis, Kerry Fenwick, Iwanka Kozarewa, Louise J. Barber, Ursula Matulonis, Amit M. Oza, Bella Kaufman, Michael L. Friedlander, Lee-May Chen, Susana Banerjee, Shahneen Sandhu, Timothy A. Yap, Tina Atkinson, Jacques De Greve, Vincent Castonguay, Ronnie Shapira-Frommer, Hilda High, C. Bethan Powell, Charlie Gourley, and Joo Ern Ang

Abstract

Supplementary Table 1 - PDF file 57K, Supplementary Table 1. Details of platinum sensitivity and best response to olaparib and post-PARPi chemotherapy of the six patients whose tumor samples were analyzed by massively parallel sequencing. (NE: not evaluable)

Published
2023

12. Data from Long-Term Responders on Olaparib Maintenance in High-Grade Serous Ovarian Cancer: Clinical and Molecular Characterization

Author

Amit M. Oza, Tony W. Ho, J. Carl Barrett, Jonathan Ledermann, Jane D. Robertson, Mark J. O'Connor, C. Blake Gilks, Julia V. Burnier, Katherine Karakasis, Tony Panzarella, Ursula Matulonis, Claire Scott, Elise C. Kohn, David Bowtell, Charlie Gourley, Stan Kaye, Jerry S. Lanchbury, Kirsten M. Timms, Darren R. Hodgson, Sarah Runswick, Brian A. Dougherty, Zhongwu Lai, and Stephanie Lheureux

Abstract

Purpose: Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboring BRCA1/2 mutations. The objective of this study was to characterize long-term (LT) versus short-term (ST) responders to olaparib.Experimental Design: A comparative molecular analysis of Study 19 (NCT00753545), a randomized phase II trial assessing olaparib maintenance after response to platinum-based chemotherapy in HGSOC, was conducted. LT response was defined as response to olaparib/placebo >2 years, ST as BRCA1/2 status, three-biomarker homologous recombination deficiency (HRD) score, BRCA1 methylation, and mutational profiling. Another olaparib maintenance study (Study 41; NCT01081951) was used as an additional cohort.Results: Thirty-seven LT (32 olaparib) and 61 ST (21 olaparib) patients were identified. Treatment was significantly associated with outcome (P < 0.0001), with more LT patients on olaparib (60.4%) than placebo (11.1%). LT sensitivity to olaparib correlated with complete response to chemotherapy (P < 0.05). In the olaparib LT group, 244 genetic alterations were detected, with TP53, BRCA1, and BRCA2 mutations being most common (90%, 25%, and 35%, respectively). BRCA2 mutations were enriched among the LT responders. BRCA methylation was not associated with response duration. High myriad HRD score (>42) and/or BRCA1/2 mutation was associated with LT response to olaparib. Study 41 confirmed the correlation of LT response with olaparib and BRCA1/2 mutation.Conclusions: Findings show that LT response to olaparib may be multifactorial and related to homologous recombination repair deficiency, particularly BRCA1/2 defects. The type of BRCA1/2 mutation warrants further investigation. Clin Cancer Res; 23(15); 4086–94. ©2017 AACR.

Published
2023

13. Table S7 from Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma

Author

Colin A. Semple, Charlie Gourley, Patricia Roxburgh, Andrew V. Biankin, Iain A. McNeish, J. Carl Barrett, Ruth March, Brian Dougherty, Athena Matakidou, Lynn McMahon, Darren Ennis, Brian McDade, Fiona Nussey, Melanie Mackean, Rosalind Glasspool, Suzanne Dowson, Nadeem Siddiqui, Neil McPhail, Trevor McGoldrick, Mairi Lennie, Michelle Ferguson, Ian Croy, Clare Bartos, Tzyvia Rye, C. Simon Herrington, Robert L. Hollis, Graeme R. Grimes, Michael Churchman, Alison Meynert, and Ailith Ewing

Abstract

SV loads in non-BRCA1/2 HR genes per sample by SV type

Published
2023

14. Supplementary Figure S2 from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author

Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang

Abstract

Genetic analyses of BRCA1 mutant cell lines and PDX models.

Published
2023

15. Supplementary Data from Multiomic Characterization of High-Grade Serous Ovarian Carcinoma Enables High-Resolution Patient Stratification

Author

Charlie Gourley, C. Simon Herrington, Richard Kennedy, D. Paul Harkin, Colin A. Semple, Patricia Roxburgh, Athena Matakidou, Ruth March, J. Carl Barrett, Brian Dougherty, Aikou Okamoto, Yasushi Iida, Clare Bartos, Alistair R.W. Williams, W. Glenn McCluggage, Ian Croy, Amelia Hallas-Potts, Michael Churchman, Tzyvia Rye, Caroline O. Michie, Alison M. Meynert, and Robert L. Hollis

Abstract

Supplementary Data from Multiomic Characterization of High-Grade Serous Ovarian Carcinoma Enables High-Resolution Patient Stratification

Published
2023

16. Data from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author

Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang

Abstract

Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo. Furthermore, spliceosome inhibitors reduced BRCA1-Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance. Cancer Res; 76(9); 2778–90. ©2016 AACR.

Published
2023

17. Table S6 from Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma

Author

Colin A. Semple, Charlie Gourley, Patricia Roxburgh, Andrew V. Biankin, Iain A. McNeish, J. Carl Barrett, Ruth March, Brian Dougherty, Athena Matakidou, Lynn McMahon, Darren Ennis, Brian McDade, Fiona Nussey, Melanie Mackean, Rosalind Glasspool, Suzanne Dowson, Nadeem Siddiqui, Neil McPhail, Trevor McGoldrick, Mairi Lennie, Michelle Ferguson, Ian Croy, Clare Bartos, Tzyvia Rye, C. Simon Herrington, Robert L. Hollis, Graeme R. Grimes, Michael Churchman, Alison Meynert, and Ailith Ewing

Abstract

SNVs in non-BRCA1/2 HR genes

Published
2023

18. Table S2 from Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma

Author

Colin A. Semple, Charlie Gourley, Patricia Roxburgh, Andrew V. Biankin, Iain A. McNeish, J. Carl Barrett, Ruth March, Brian Dougherty, Athena Matakidou, Lynn McMahon, Darren Ennis, Brian McDade, Fiona Nussey, Melanie Mackean, Rosalind Glasspool, Suzanne Dowson, Nadeem Siddiqui, Neil McPhail, Trevor McGoldrick, Mairi Lennie, Michelle Ferguson, Ian Croy, Clare Bartos, Tzyvia Rye, C. Simon Herrington, Robert L. Hollis, Graeme R. Grimes, Michael Churchman, Alison Meynert, and Ailith Ewing

Abstract

SVs at BRCA1/2

Published
2023

19. Table S5 from Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma

Author

Colin A. Semple, Charlie Gourley, Patricia Roxburgh, Andrew V. Biankin, Iain A. McNeish, J. Carl Barrett, Ruth March, Brian Dougherty, Athena Matakidou, Lynn McMahon, Darren Ennis, Brian McDade, Fiona Nussey, Melanie Mackean, Rosalind Glasspool, Suzanne Dowson, Nadeem Siddiqui, Neil McPhail, Trevor McGoldrick, Mairi Lennie, Michelle Ferguson, Ian Croy, Clare Bartos, Tzyvia Rye, C. Simon Herrington, Robert L. Hollis, Graeme R. Grimes, Michael Churchman, Alison Meynert, and Ailith Ewing

Abstract

Genes in KEGG HR pathway

Published
2023

20. Supplementary Figure Legends from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author

Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang

Abstract

Legend for Supplementary Figures S1-S6.

Published
2023

21. Supplementary Figure S1 from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author

Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang

Abstract

BRCA1-Delta11q mRNA and protein isoform.

Published
2023

22. Supplementary Figure S5 from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author

Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang

Abstract

Ectopic BRCA1-Deltaq expression promotes resistance in additional cell line backgrounds.

Published
2023

23. Supplementary Figure S4 from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author

Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang

Abstract

CRISPR/Cas9 editing of SUM149PT cells.

Published
2023

24. Supplementary Figure S6 from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author

Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang

Abstract

FOX2 binding motifs are proximal to the BRCA1-11q cryptic slice site.

Published
2023

25. Supplementary Tables S1-S4 from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author

Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang

Abstract

RNA-seq analyses of global exon splicing events (S1); Cell line therapy sensitivities (S2); Hazard ratios for survival of patients with serous ovarian carcinomas associated with BRCA1 mutation, age at diagnosis and stage (S3); Characteristics of studies included in survival analysis from Fig. 5A (S4).

Published
2023

26. Tables S3 from Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma

Author

Colin A. Semple, Charlie Gourley, Patricia Roxburgh, Andrew V. Biankin, Iain A. McNeish, J. Carl Barrett, Ruth March, Brian Dougherty, Athena Matakidou, Lynn McMahon, Darren Ennis, Brian McDade, Fiona Nussey, Melanie Mackean, Rosalind Glasspool, Suzanne Dowson, Nadeem Siddiqui, Neil McPhail, Trevor McGoldrick, Mairi Lennie, Michelle Ferguson, Ian Croy, Clare Bartos, Tzyvia Rye, C. Simon Herrington, Robert L. Hollis, Graeme R. Grimes, Michael Churchman, Alison Meynert, and Ailith Ewing

Abstract

Supplementary tables 3a and 3b. Germline and somatic SNVs/indels at BRCA1/2.

Published
2023

27. Table S4 from Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma

Author

Colin A. Semple, Charlie Gourley, Patricia Roxburgh, Andrew V. Biankin, Iain A. McNeish, J. Carl Barrett, Ruth March, Brian Dougherty, Athena Matakidou, Lynn McMahon, Darren Ennis, Brian McDade, Fiona Nussey, Melanie Mackean, Rosalind Glasspool, Suzanne Dowson, Nadeem Siddiqui, Neil McPhail, Trevor McGoldrick, Mairi Lennie, Michelle Ferguson, Ian Croy, Clare Bartos, Tzyvia Rye, C. Simon Herrington, Robert L. Hollis, Graeme R. Grimes, Michael Churchman, Alison Meynert, and Ailith Ewing

Abstract

Differentially expressed genes in HR deficiency

Published
2023

28. Suplemmentary Tables 1-6, Suppementary References from Germline Mutation in BRCA1 or BRCA2 and Ten-Year Survival for Women Diagnosed with Epithelial Ovarian Cancer

Author

Paul D.P. Pharoah, David Bowtell, Simon A. Gayther, Georgia Chenevix-Trench, Antonis Antoniou, Douglas F. Easton, Marc Tischkowitz, James D. Brenton, Debra Frost, Steve Ellis, Diether Lambrechts, Amanda E. Toland, Kirsten Moysich, Jennifer T. Loud, Phuong L. Mai, Mark H. Greene, Mary Daly, Robert Nussbaum, Susan Neuhausen, Estrid Høgdall, Allan Jensen, Susanne K. Kjaer, Ava Kwong, Angela Chetrit, Siegal Sadetzki, Elisa Alducci, Marco Montagna, Weiva Sieh, Valerie McGuire, Alice S. Whittemore, Conxi Lazaro, Ignacio Blanco, Gord Glendon, Anna Marie Mulligan, Irene Andrulis, Maria J. Garcia, Javier J. Benitez, Martin Gore, Håkan Olsson, Ilana Cass, Christine Walsh, Jenny Lester, Beth Karlan, Caroline Michie, Charlie Gourley, Kelly L. Bolton, Sian Fereday, Gillian Mitchell, Anna de Fazio, Susan J. Ramus, Patricia Harrington, Ed Dicks, Kathryn Alsop, Melissa C. Larson, Brooke L. Fridley, Julie M. Cunningham, Ellen L. Goode, Honglin Song, and Francisco J. Candido-dos-Reis

Abstract

Supplementary Tables S1-S6, Supplementary References. Supplementary Table S1. Characteristics of included studies; S2. Complete-case analysis of ten years estimated hazard ratios (HR) for all cause death in patients with ovarian cancer. S3. Complete-case analysis of ten years estimated subhazard ratios (SHR) for ovarian cancer death in patients with ovarian cancer. S4. Ten years estimated subhazard ratios (SHR) for ovarian cancer death in patients with ovarian cancer (with multiple imputation for missing grade and stage). S5. Complete-case analysis of ten years estimated hazard ratios (HR) for all cause death in patients with high grade serous ovarian cancer. S6. Ten years estimated hazard ratios (HR) for all cause death in patients with high grade serous ovarian cancer (with multiple imputation for missing stage).

Published
2023

29. Supplementary Figure S3 from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author

Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang

Abstract

BRCA1-minigene analyses.

Published
2023

30. Table S1 from Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma

Author

Colin A. Semple, Charlie Gourley, Patricia Roxburgh, Andrew V. Biankin, Iain A. McNeish, J. Carl Barrett, Ruth March, Brian Dougherty, Athena Matakidou, Lynn McMahon, Darren Ennis, Brian McDade, Fiona Nussey, Melanie Mackean, Rosalind Glasspool, Suzanne Dowson, Nadeem Siddiqui, Neil McPhail, Trevor McGoldrick, Mairi Lennie, Michelle Ferguson, Ian Croy, Clare Bartos, Tzyvia Rye, C. Simon Herrington, Robert L. Hollis, Graeme R. Grimes, Michael Churchman, Alison Meynert, and Ailith Ewing

Abstract

Number of samples with BRCA1/2 SVs

Published
2023

31. Data from Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma

Author

Colin A. Semple, Charlie Gourley, Patricia Roxburgh, Andrew V. Biankin, Iain A. McNeish, J. Carl Barrett, Ruth March, Brian Dougherty, Athena Matakidou, Lynn McMahon, Darren Ennis, Brian McDade, Fiona Nussey, Melanie Mackean, Rosalind Glasspool, Suzanne Dowson, Nadeem Siddiqui, Neil McPhail, Trevor McGoldrick, Mairi Lennie, Michelle Ferguson, Ian Croy, Clare Bartos, Tzyvia Rye, C. Simon Herrington, Robert L. Hollis, Graeme R. Grimes, Michael Churchman, Alison Meynert, and Ailith Ewing

Abstract

Purpose:The abundance and effects of structural variation at BRCA1/2 in tumors are not well understood. In particular, the impact of these events on homologous recombination repair deficiency (HRD) has yet to be demonstrated.Experimental Design:Exploiting a large collection of whole-genome sequencing data from high-grade serous ovarian carcinoma (N = 205) together with matched RNA sequencing for the majority of tumors (N = 150), we have comprehensively characterized mutation and expression at BRCA1/2.Results:In addition to the known spectrum of short somatic mutations (SSM), we discovered that multi-megabase structural variants (SV) were a frequent, unappreciated source of BRCA1/2 disruption in these tumors, and we found a genome-wide enrichment for large deletions at the BRCA1/2 loci across the cohort. These SVs independently affected a substantial proportion of patients (16%) in addition to those affected by SSMs (24%), conferring HRD and impacting patient survival. We also detail compound deficiencies involving SSMs and SVs at both loci, demonstrating that the strongest risk of HRD emerges from combined SVs at both BRCA1 and BRCA2 in the absence of SSMs. Furthermore, these SVs are abundant and disruptive in other cancer types.Conclusions:These results extend our understanding of the mutational landscape underlying HRD, increase the number of patients predicted to benefit from therapies exploiting HRD, and suggest there is currently untapped potential in SV detection for patient stratification.

Published
2023

32. Supplementary Information from Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma

Author

Colin A. Semple, Charlie Gourley, Patricia Roxburgh, Andrew V. Biankin, Iain A. McNeish, J. Carl Barrett, Ruth March, Brian Dougherty, Athena Matakidou, Lynn McMahon, Darren Ennis, Brian McDade, Fiona Nussey, Melanie Mackean, Rosalind Glasspool, Suzanne Dowson, Nadeem Siddiqui, Neil McPhail, Trevor McGoldrick, Mairi Lennie, Michelle Ferguson, Ian Croy, Clare Bartos, Tzyvia Rye, C. Simon Herrington, Robert L. Hollis, Graeme R. Grimes, Michael Churchman, Alison Meynert, and Ailith Ewing

Abstract

Supplementary methods and supplementary figures

Published
2023

33. Data from Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study

Author

Stan B. Kaye, Alan Ashworth, Christopher J. Lord, Martin E. Gore, Johann S. de Bono, Lina Chen, James Campbell, Ioannis Assiotis, Kerry Fenwick, Iwanka Kozarewa, Louise J. Barber, Ursula Matulonis, Amit M. Oza, Bella Kaufman, Michael L. Friedlander, Lee-May Chen, Susana Banerjee, Shahneen Sandhu, Timothy A. Yap, Tina Atkinson, Jacques De Greve, Vincent Castonguay, Ronnie Shapira-Frommer, Hilda High, C. Bethan Powell, Charlie Gourley, and Joo Ern Ang

Abstract

Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing.Results: Data were collected from 89 patients who received a median of 3 (range 1–11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13–21] and 34 weeks (95% CI, 26–42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15–29) and OS of 45 weeks (95% CI, 15–75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0–0.375)].Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. Clin Cancer Res; 19(19); 5485–93. ©2013 AACR.

Published
2023

34. Supplementary Methods and References from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author

Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang

Abstract

Description of additional methods and procedures used in the study. Also includes Supplementary References.

Published
2023

35. Supplementary material from Long-Term Responders on Olaparib Maintenance in High-Grade Serous Ovarian Cancer: Clinical and Molecular Characterization

Author

Amit M. Oza, Tony W. Ho, J. Carl Barrett, Jonathan Ledermann, Jane D. Robertson, Mark J. O'Connor, C. Blake Gilks, Julia V. Burnier, Katherine Karakasis, Tony Panzarella, Ursula Matulonis, Claire Scott, Elise C. Kohn, David Bowtell, Charlie Gourley, Stan Kaye, Jerry S. Lanchbury, Kirsten M. Timms, Darren R. Hodgson, Sarah Runswick, Brian A. Dougherty, Zhongwu Lai, and Stephanie Lheureux

Abstract

Supplementary Figure 1. Mutational analysis of TP53 in the olaparib arm. (A) Analysis of TP53 mutation type. (B) BRCA1 and BRCA2 mutation type Supplementary Table 1. Platinum sensitivity and outcome on olaparib maintenance treatment. Supplementary Table 2. Mutational analysis of the FoundationOne® panel from the LT and ST responders in the olaparib arm. Supplementary Table 3. Mutational analysis of PTEN in the olaparib and placebo arms. Supplementary Table 4. Analysis of BRCA1, BRCA2, and TP53 mutation frequency in olaparib patients in the LT and ST responder group.

Published
2023

36. Supplementary Figure 1 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Author

Hani Gabra, John F. Smyth, Morwenna Muir, David J. Harrison, Szymon Janczar, Mingjun Sun, Jieqing Zhang, Barbara Kuske, Carol Ward, Karen J. Taylor, Adam J.W. Paige, and Charlie Gourley

Abstract

Supplementary Figure 1 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Published
2023

37. Supplementary Figure 5 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Author

Hani Gabra, John F. Smyth, Morwenna Muir, David J. Harrison, Szymon Janczar, Mingjun Sun, Jieqing Zhang, Barbara Kuske, Carol Ward, Karen J. Taylor, Adam J.W. Paige, and Charlie Gourley

Abstract

Supplementary Figure 5 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Published
2023

38. Supplementary Figure 3 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Author

Hani Gabra, John F. Smyth, Morwenna Muir, David J. Harrison, Szymon Janczar, Mingjun Sun, Jieqing Zhang, Barbara Kuske, Carol Ward, Karen J. Taylor, Adam J.W. Paige, and Charlie Gourley

Abstract

Supplementary Figure 3 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Published
2023

39. Supplementary Figure 4 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Author

Hani Gabra, John F. Smyth, Morwenna Muir, David J. Harrison, Szymon Janczar, Mingjun Sun, Jieqing Zhang, Barbara Kuske, Carol Ward, Karen J. Taylor, Adam J.W. Paige, and Charlie Gourley

Abstract

Supplementary Figure 4 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Published
2023

41. Supplementary Figure 2 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Author

Hani Gabra, John F. Smyth, Morwenna Muir, David J. Harrison, Szymon Janczar, Mingjun Sun, Jieqing Zhang, Barbara Kuske, Carol Ward, Karen J. Taylor, Adam J.W. Paige, and Charlie Gourley

Abstract

Supplementary Figure 2 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Published
2023

43. Supplementary Methods, Tables, 2, 3, and 5, Figures 1-10 from HDAC4-Regulated STAT1 Activation Mediates Platinum Resistance in Ovarian Cancer

Author

Hani Gabra, Roberto Dina, Robert Brown, Antonello Mai, Gordon B. Mills, Bryan T. Hennessy, Charlie Gourley, Tankut G. Guney, Roshan Agarwal, James B. Studd, Christoph Datler, Nona Rama, Albandri Alfraidi, and Euan A. Stronach

Abstract

Supplementary Methods, Tables, 2, 3, and 5, Figures 1-10 from HDAC4-Regulated STAT1 Activation Mediates Platinum Resistance in Ovarian Cancer

Published
2023

44. Supplementary Methods, Legends for Figures 1-5 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Author

Hani Gabra, John F. Smyth, Morwenna Muir, David J. Harrison, Szymon Janczar, Mingjun Sun, Jieqing Zhang, Barbara Kuske, Carol Ward, Karen J. Taylor, Adam J.W. Paige, and Charlie Gourley

Abstract

Supplementary Methods, Legends for Figures 1-5 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Published
2023

45. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial

Author

David M Gershenson, Austin Miller, William E Brady, James Paul, Karen Carty, William Rodgers, David Millan, Robert L Coleman, Kathleen N Moore, Susana Banerjee, Kate Connolly, Angeles Alvarez Secord, David M O'Malley, Oliver Dorigo, Stephanie Gaillard, Hani Gabra, Brian Slomovitz, Parviz Hanjani, John Farley, Michael Churchman, Ailith Ewing, Robert L Hollis, C Simon Herrington, Helen Q Huang, Lari Wenzel, and Charlie Gourley

Subjects
Adult, Ovarian Neoplasms, Paclitaxel, Pyridones, MAP Kinase Kinase 1, Administration, Oral, Standard of Care, Pyrimidinones, General Medicine, Carcinoma, Ovarian Epithelial, Middle Aged, Progression-Free Survival, United Kingdom, United States, Treatment Outcome, General & Internal Medicine, Antineoplastic Combined Chemotherapy Protocols, Humans, Female, Neoplasm Grading, Neoplasm Recurrence, Local, 11 Medical and Health Sciences, Aged
Abstract

BACKGROUND: Low-grade serous carcinoma of the ovary or peritoneum is characterised by MAPK pathway aberrations and its reduced sensitivity to chemotherapy relative to high-grade serous carcinoma. We compared the MEK inhibitor trametinib to physician's choice standard of care in patients with recurrent low-grade serous carcinoma. METHODS: This international, randomised, open-label, multicentre, phase 2/3 trial was done at 84 hospitals in the USA and UK. Eligible patients were aged 18 years or older with recurrent low-grade serous carcinoma and measurable disease, as defined by Response Evaluation Criteria In Solid Tumors version 1.1, had received at least one platinum-based regimen, but not all five standard-of-care drugs, and had received an unlimited number of previous regimens. Patients with serous borderline tumours or tumours containing low-grade serous and high-grade serous carcinoma were excluded. Eligible patients were randomly assigned (1:1) to receive either oral trametinib 2 mg once daily (trametinib group) or one of five standard-of-care treatment options (standard-of-care group): intravenous paclitaxel 80 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin 40-50 mg/m2 by body surface area once every 4 weeks; intravenous topotecan 4 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole 2·5 mg once daily; or oral tamoxifen 20 mg twice daily. Randomisation was stratified by geographical region (USA or UK), number of previous regimens (1, 2, or ≥3), performance status (0 or 1), and planned standard-of-care regimen. The primary endpoint was investigator-assessed progression-free survival while receiving randomised therapy, as assessed by imaging at baseline, once every 8 weeks for 15 months, and then once every 3 months thereafter, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02101788, and is active but not recruiting. FINDINGS: Between Feb 27, 2014, and April 10, 2018, 260 patients were enrolled and randomly assigned to the trametinib group (n=130) or the standard-of-care group (n=130). At the primary analysis, there were 217 progression-free survival events (101 [78%] in the trametinib group and 116 [89%] in the standard-of-care group). Median progression-free survival in the trametinib group was 13·0 months (95% CI 9·9-15·0) compared with 7·2 months (5·6-9·9) in the standard-of-care group (hazard ratio 0·48 [95% CI 0·36-0·64]; p

Published
2022

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

Author

Ignace Vergote, Antonio Gonzalez-Martin, Domenica Lorusso, Charlie Gourley, Mansoor Raza Mirza, Jean-Emmanuel Kurtz, Aikou Okamoto, Kathleen Moore, Frédéric Kridelka, Iain McNeish, Alexander Reuss, Bénédicte Votan, Andreas du Bois, Sven Mahner, Isabelle Ray-Coquard, Elise C Kohn, Jonathan S Berek, David S P Tan, Nicoletta Colombo, Rongyu Zang, Nicole Concin, Dearbhaile O'Donnell, Alejandro Rauh-Hain, C Simon Herrington, Christian Marth, Andres Poveda, Keiichi Fujiwara, Gavin C E Stuart, Amit M Oza, Michael A Bookman, Christoph Grimm, Regina Berger, Ting-Chang Chang, Kazunori Ochiai, Val Gebski, Alison Davis, Philip Beale, Hannelore Denys, Vincent Vandecaveye, Francisco Jose Candido dos Reis, Maria Del Pilar Estevez Diz, Gavin Stuart, Helen MacKay, Mark Carey, David Cibula, Pavel Dundr (path), Oliver Dorigo, Jonathan Berek, Abu Saadeh, Ingrid Boere, Christianne Lok, Pluvio Coronado, Nelleke Ottevanger, David SP Tan, Joseph Ng, Antonio Gonzalez Martin, Ana Oaknin, Alejandro Perez Fidalgo, Karen Lu, Carlos López-Zavala, Eva María Gómez-García, Xavier Paoletti, Florence Joly, Michael Bookman, Rebecca Arend, Hiroyuki Fujiwara, Kosei Hasegawa, Ilan Bruchim, Dalia Tsoref, Katsutoshi Oda, Takayuki Enomoto, Dayana Michel, Hee-Seung Kim, Jung-Yun Lee, Asima Mukhopadhyay, Dionyssios Katsaros, Sandro Pignata, Giovanni Scambia, Elise Kohn, Jung-Min Lee, Shibani Nicum, Laura Farrelly, Jalid Sehouli, Maren Keller, Elena Braicu, Line Bjørge, Annika Auranen, Stephen Welch, Viola Heinzelmann, Patricia Roxburgh, Ros Glasspool, Jianqing Zhu, 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, and Bookman, M

Subjects
Ovarian Neoplasms, Consensus, Oncology, SDG 3 - Good Health and Well-being, Humans, Consensu, Female, Carcinoma, Ovarian Epithelial, Forecasting, Human, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17]
Abstract

Contains fulltext : 283536.pdf (Publisher’s version ) (Closed access) 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

47. Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial

Author

Gabe S. Sonke, Cara Mathews, Carol Aghajanian, Nicoletta Colombo, Alexandra Leary, Ana Oaknin, Joyce F. Liu, Giovanni Scambia, William H. Bradley, Elizabeth S. Lowe, Jae Weon Kim, Alla Lisyanskaya, Antonio González-Martín, Anne Floquet, Michael Friedlander, Kathleen N. Moore, Ralph Bloomfield, Amit M. Oza, Charlie Gourley, Susana Banerjee, Paul DiSilvestro, Colombo, N, Moore, K, Scambia, G, Oaknin, A, Friedlander, M, Lisyanskaya, A, Floquet, A, Leary, A, Sonke, G, Gourley, C, Banerjee, S, Oza, A, Gonzalez-Martin, A, Aghajanian, C, Bradley, W, Kim, J, Mathews, C, Liu, J, Lowe, E, Bloomfield, R, Disilvestro, P, Institut Català de la Salut, [Colombo N] University of Milan-Bicocca and IEO European Institute of Oncology IRCCS, Milan, Italy. [Moore K] Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, OK, United States. [Scambia G] Fondazione Policlinico Universitario A. Gemelli IRCCS Università Cattolica, Rome, Italy. [Oaknin A] Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Friedlander M] University of New South Wales Clinical School, Prince of Wales Hospital, Randwick, Australia. [Lisyanskaya A] St Petersburg City Oncology Dispensary, St Petersburg, Russia, and Vall d'Hebron Barcelona Hospital Campus

Subjects
medicine.medical_specialty, Nausea, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas [ENFERMEDADES], Neutropenia, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Piperazines, Olaparib, chemistry.chemical_compound, Double-Blind Method, Ovarian cancer, Internal medicine, Humans, Medicine, Adverse effect, BRCA2 Protein, Ovarian Neoplasms, BRCA1 Protein, business.industry, Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms [DISEASES], BRCA mutation, Obstetrics and Gynecology, Ovaris - Càncer - Tractament, Middle Aged, Tolerability, medicine.disease, Newly diagnosed, Discontinuation, Oncology, chemistry, Mutation, Avaluació de resultats (Assistència sanitària), Vomiting, Phthalazines, Female, Safety, medicine.symptom, business
Abstract

Olaparib; Ovarian cancer; Tolerability Olaparib; Cáncer de ovarios; Tolerabilidad Olaparib; Càncer d'ovaris; Tolerabilitat Objectives In the phase III SOLO1 trial (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation who were in response after platinum-based chemotherapy. We analyzed the timing, duration and grade of the most common hematologic and non-hematologic adverse events in SOLO1. Methods Eligible patients were randomized to olaparib tablets 300 mg twice daily (N = 260) or placebo (N = 131), with a 2-year treatment cap in most patients. Safety outcomes were analyzed in detail in randomized patients who received at least one dose of study drug (olaparib, n = 260; placebo, n = 130). Results Median time to first onset of the most common hematologic (anemia, neutropenia, thrombocytopenia) and non-hematologic (nausea, fatigue/asthenia, vomiting) adverse events was

Published
2021

48. A phase 2 study of anastrozole in patients with oestrogen receptor and/progesterone receptor positive recurrent/metastatic granulosa cell tumours/sex-cord stromal tumours of the ovary: The PARAGON/ANZGOG 0903 trial

Author

Vinod Menon Mullassery, Andrew R Clamp, Marcia Hall, Monica Tang, Peter Grant, Richard J. Edmondson, Karen Carty, David Millan, Jeffrey C. Goh, N. Bradshaw, Orla McNally, Laura Alexander, Susana Banerjee, Michael Friedlander, Laura Divers, S Nottley, Katrin Marie Sjoquist, Tony Bonaventura, Charlie Gourley, Peter Sykes, Rosemary Lord, Caroline Kelly, and Rachel O'Connell

Subjects
Adult, Oncology, medicine.medical_specialty, Granulosa cell, Anastrozole, Phases of clinical research, Ovary, Internal medicine, Clinical endpoint, Humans, Sex Cord-Gonadal Stromal Tumors, Medicine, Adverse effect, Aged, Granulosa Cell Tumor, Ovarian Neoplasms, business.industry, Obstetrics and Gynecology, Retrospective cohort study, Middle Aged, medicine.anatomical_structure, Receptors, Estrogen, Quality of Life, Hormonal therapy, Female, Neoplasm Recurrence, Local, Receptors, Progesterone, business, medicine.drug
Abstract

Background Hormonal therapies are commonly prescribed to patients with metastatic granulosa cell tumours (GCT), based on high response rates in small retrospective studies. Aromatase inhibitors (AIs) are reported to have high response rates and an accepted treatment option. We report the results of a phase 2 trial of an AI in recurrent/metastatic GCTs. Methods 41 patients with recurrent ER/PR + ve GCT received anastrozole 1 mg daily until progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) at 12 weeks, evaluated by RECIST1.1 criteria. Secondary endpoints included progression-free survival (PFS), CBR duration, quality of life and toxicity. Results The CBR at 12 weeks in 38 evaluable patients was 78.9%, which included one (2.6%; 95% CI: 0.5–13.5%) partial response and 76.3% stable disease. Two additional patients without measurable disease were stable, based on inhibin. Median PFS was 8.6 m (95% CI 5.5–13.5 m). There were delayed responses observed after 12 weeks with a total of 4 pts. (10.5%; 95% CI 4.2%–24.1%) with a RECIST partial response; 23 (59%) patients were progression-free at 6 months. The adverse effects were predominantly low grade. Conclusions This is the first prospective trial of hormonal therapy in GCTs. Although there was a high CBR, the objective response rate to anastrozole was much lower than the pooled response rates of >70% to AIs reported in most retrospective series and case reports. PARAGON demonstrates the importance of prospective trials in rare cancers and the need to reconsider the role of AIs as single agents in GCTs.

Published
2021

49. Prognostic nomogram for progression-free survival in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer on maintenance olaparib therapy following response to chemotherapy

Author

Jonathan A. Ledermann, Rebecca Asher, Michael Friedlander, Ilan Bruchim, Sarah J. Lord, Eric Pujade-Lauraine, Ronnie Shapira-Frommer, Clare L. Scott, Ursula A. Matulonis, Amit M. Oza, Philipp Harter, Charlie Gourley, Tomasz Huzarski, Val Gebski, Angelina Tjokrowidjaja, Chee Khoon Lee, Ignace Vergote, Manuel Rodrigues, Werner Meier, and Tsveta Milenkova

Subjects
Adult, Oncology, Cancer Research, medicine.medical_specialty, Genes, BRCA2, Genes, BRCA1, Piperazines, Olaparib, chemistry.chemical_compound, Maintenance therapy, Internal medicine, medicine, Humans, Progression-free survival, Aged, Aged, 80 and over, Ovarian Neoplasms, Proportional hazards model, business.industry, BRCA mutation, Middle Aged, Nomogram, Prognosis, medicine.disease, Progression-Free Survival, Nomograms, chemistry, Mutation, Cohort, Phthalazines, Female, Neoplasm Recurrence, Local, Ovarian cancer, business
Abstract

Background The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients. Methods The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib. Results The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3–11.3), 5.4 (4.8–5.8) and 2.9 (2.8–4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1–22.4) and 8.3 (7.1–10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot). Conclusions This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies.

Published
2021

50. A multi‐ethnic analysis of immune‐related gene expression signatures in patients with ovarian clear cell carcinoma

Author

Yasushi Iida, Mitsutake Yano, Natalie Yl Ngoi, David S.P. Tan, C. Simon Herrington, Aikou Okamoto, Maiko Miwa, Diana Lim, Sb Justin Wong, Valerie Heong, Jieru Ye, Charlie Gourley, Masanori Yasuda, Tuan Zea Tan, Ruby Yj Huang, and Kosei Hasegawa

Subjects
Oncology, medicine.medical_specialty, chemical and pharmacologic phenomena, immune micoenvironment, Biology, White People, Pathology and Forensic Medicine, Immune system, Asian People, Ovarian cancer, Internal medicine, immune subtypes, Tumor Microenvironment, medicine, Humans, clear cell cancer, Gene, Pathological, Aged, Ovarian Neoplasms, Microsatellite instability, Middle Aged, medicine.disease, RNA expression and ethnicity, gene expression signatures, Clear cell carcinoma, mismatch repair protein, Immunohistochemistry, microsatellite instability, Female, DNA mismatch repair, Transcriptome, Adenocarcinoma, Clear Cell
Abstract

Little is known about the immune environment of ovarian clear cell carcinoma (OCCC) and its impact on various ethnic backgrounds. The aim of this OCCC immune-related gene expression signatures (irGES) study was to address the interaction between tumour and immune environment of ethnically-diverse Asian and Caucasian populations and to identify relevant molecular subsets of biological and clinical importance. Our study included 264 women from three different countries (Singapore, Japan, and the UK) and identified four novel immune subtypes (PD1-high, CTLA4-high, antigen-presentation, and pro-angiogenic subtype) with differentially expressed pathways, and gene ontologies using the NanoString nCounter PanCancer Immune Profiling Panel. The PD1-high and CTLA4-high subtypes demonstrated significantly higher PD1, PDL1, and CTLA4 expression, and were associated with poorer clinical outcomes. Mismatch repair (MMR) protein expression, assessed by immunohistochemistry, revealed that about 5% of OCCCs had deficient MMR expression. The prevalence was similar across the three countries and appeared to cluster in the CTLA4-high subtype. Our results suggest that OCCC from women of Asian and Caucasian descent shares significant clinical and molecular similarities. To our knowledge, our study is the first study to include both Asian and Caucasian women with OCCC and helps to shine light on the impact of ethnic differences on the immune microenvironment of OCCC. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Published
2021

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