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2. Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial

Author

Pujade-Lauraine, Eric, Brown, Jessica, Barnicle, Alan, Wessen, Jonathan, Lao-Sirieix, Pierre, Criscione, Steven W., du Bois, Andreas, Lorusso, Domenica, Romero, Ignacio, Petru, Edgar, Yoshida, Hiroyuki, Vergote, Ignace, Colombo, Nicoletta, Hietanen, Sakari, Provansal, Magali, Schmalfeldt, Barbara, Pignata, Sandro, Martín Lorente, Cristina, Berton, Dominique, Runnebaum, Ingo B., and Ray-Coquard, Isabelle

Published
2023
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3. Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial

Author

Mateo, Joaquin, primary, de Bono, Johann S., additional, Fizazi, Karim, additional, Saad, Fred, additional, Shore, Neal, additional, Sandhu, Shahneen, additional, Chi, Kim N., additional, Agarwal, Neeraj, additional, Olmos, David, additional, Thiery-Vuillemin, Antoine, additional, Özgüroğlu, Mustafa, additional, Mehra, Niven, additional, Matsubara, Nobuaki, additional, Young Joung, Jae, additional, Padua, Charles, additional, Korbenfeld, Ernesto, additional, Kang, Jinyu, additional, Marshall, Helen, additional, Lai, Zhongwu, additional, Barnicle, Alan, additional, Poehlein, Christian, additional, Lukashchuk, Natalia, additional, and Hussain, Maha, additional

Published
2024
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4. Maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer: Outcomes by somatic and germline BRCA and other homologous recombination repair gene mutation status in the ORZORA trial

Author

Pignata, Sandro, Oza, Amit, Hall, Geoff, Pardo, Beatriz, Madry, Radoslaw, Cibula, David, Klat, Jaroslav, Montes Worboys, Ana, Glasspool, Rosalind, Colombo, Nicoletta, Pete, Imre, Herrero Ibáñez, Ana, Romeo Marín, Margarita, Ilieva, Rumyana, Timcheva, Constanta, Maio, Massimo di, Blakeley, Christopher, Taylor, Rosie, Barnicle, Alan, Clamp, Andrew, Pignata, S, Oza, A, Hall, G, Pardo, B, Madry, R, Cibula, D, Klat, J, Montes, A, Glasspool, R, Colombo, N, Pete, I, Herrero Ibáñez, A, Marín, M, Ilieva, R, Timcheva, C, Di Maio, M, Blakeley, C, Taylor, R, Barnicle, A, and Clamp, A

Subjects
Olaparib, Oncology, Maintenance, Ovarian cancer, BRCA mutation, Càncer d'ovari, Genetics, Obstetrics and Gynecology, HRR, Genètica
Abstract

Background: The open-label, single-arm, multicenter ORZORA trial (NCT02476968) evaluated the efficacy and safety of maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSR OC) who had tumor BRCA mutations (BRCAm) of germline (g) or somatic (s) origin or non-BRCA homologous recombination repair mutations (HRRm) and were in response to their most recent platinum-based chemotherapy after ≥2 lines of treatment. Methods: Patients received maintenance olaparib capsules (400mg twice daily) until disease progression. Prospective central testing at screening determined tumor BRCAm status and subsequent testing determined gBRCAm or sBRCAm status. Patients with predefined non-BRCA HRRm were assigned to an exploratory cohort. The co-primary endpoints were investigator-assessed progression-free survival (PFS; modified Response Evaluation Criteria in Solid Tumors v1.1) in BRCAm and sBRCAm cohorts. Secondary endpoints included health-related quality of life (HRQoL) and tolerability. Results: 177 patients received olaparib. At the primary data cut-off (17 April 2020), the median follow-up for PFS in the BRCAm cohort was 22.3months. The median PFS (95% CI) in BRCAm, sBRCAm, gBRCAm and non-BRCA HRRm cohorts was 18.0 (14.3-22.1), 16.6 (12.4-22.2), 19.3 (14.3-27.6) and 16.4 (10.9-19.3) months, respectively. Most patients with BRCAm reported improvements (21.8%) or no change (68.7%) in HRQoL and the safety profile was as expected. Conclusions: Maintenance olaparib had similar clinical activity in PSR OC patients with sBRCAm and those with any BRCAm. Activity was also observed in patients with a non-BRCA HRRm. ORZORA further supports use of maintenance olaparib in all patients with BRCA-mutated, including sBRCA-mutated, PSR OC.

Published
2023

5. Efficacy of olaparib (O) plus abiraterone (A) versus placebo (P) plus A in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with single homologous recombination repair gene mutations (HRRm) in the PROpel trial.

Author

Shore, Neal D., Clarke, Noel, Armstrong, Andrew J., Oya, Mototsugu, Procopio, Giuseppe, Guedes, João Daniel Cardoso, Arslan, Cagatay, Mehra, Niven, Brown, Emma, Schlürmann, Friederike, Joung, Jae Young, Sugimoto, Mikio, Vianna, Karina, Hosius, Christian, Barnicle, Alan, Liu, Yu-Zhen, Harrington, Elizabeth, McGuinness, David, del Rosario, Paula Michelle, and Saad, Fred

Published
2024
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7. Table S1 from Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts

Author

Gris-Oliver, Albert, primary, Palafox, Marta, primary, Monserrat, Laia, primary, Brasó-Maristany, Fara, primary, Òdena, Andreu, primary, Sánchez-Guixé, Mònica, primary, Ibrahim, Yasir H., primary, Villacampa, Guillermo, primary, Grueso, Judit, primary, Parés, Mireia, primary, Guzmán, Marta, primary, Rodríguez, Olga, primary, Bruna, Alejandra, primary, Hirst, Caroline S., primary, Barnicle, Alan, primary, de Bruin, Elza C., primary, Reddy, Avinash, primary, Schiavon, Gaia, primary, Arribas, Joaquín, primary, Mills, Gordon B., primary, Caldas, Carlos, primary, Dienstmann, Rodrigo, primary, Prat, Aleix, primary, Nuciforo, Paolo, primary, Razavi, Pedram, primary, Scaltriti, Maurizio, primary, Turner, Nicholas C., primary, Saura, Cristina, primary, Davies, Barry R., primary, Oliveira, Mafalda, primary, and Serra, Violeta, primary

Published
2023
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8. Supplementary Figure 3 from Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer

Author

Smyth, Lillian M., primary, Tamura, Kenji, primary, Oliveira, Mafalda, primary, Ciruelos, Eva M., primary, Mayer, Ingrid A., primary, Sablin, Marie-Paule, primary, Biganzoli, Laura, primary, Ambrose, Helen J., primary, Ashton, Jack, primary, Barnicle, Alan, primary, Cashell, Des D., primary, Corcoran, Claire, primary, de Bruin, Elza C., primary, Foxley, Andrew, primary, Hauser, Joana, primary, Lindemann, Justin P.O., primary, Maudsley, Rhiannon, primary, McEwen, Robert, primary, Moschetta, Michele, primary, Pass, Martin, primary, Rowlands, Vicky, primary, Schiavon, Gaia, primary, Banerji, Udai, primary, Scaltriti, Maurizio, primary, Taylor, Barry S., primary, Chandarlapaty, Sarat, primary, Baselga, José, primary, and Hyman, David M., primary

Published
2023
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9. Figure S1 from Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts

Author

Gris-Oliver, Albert, primary, Palafox, Marta, primary, Monserrat, Laia, primary, Brasó-Maristany, Fara, primary, Òdena, Andreu, primary, Sánchez-Guixé, Mònica, primary, Ibrahim, Yasir H., primary, Villacampa, Guillermo, primary, Grueso, Judit, primary, Parés, Mireia, primary, Guzmán, Marta, primary, Rodríguez, Olga, primary, Bruna, Alejandra, primary, Hirst, Caroline S., primary, Barnicle, Alan, primary, de Bruin, Elza C., primary, Reddy, Avinash, primary, Schiavon, Gaia, primary, Arribas, Joaquín, primary, Mills, Gordon B., primary, Caldas, Carlos, primary, Dienstmann, Rodrigo, primary, Prat, Aleix, primary, Nuciforo, Paolo, primary, Razavi, Pedram, primary, Scaltriti, Maurizio, primary, Turner, Nicholas C., primary, Saura, Cristina, primary, Davies, Barry R., primary, Oliveira, Mafalda, primary, and Serra, Violeta, primary

Published
2023
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10. Supplementary Figure 1 from Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer

Author

Smyth, Lillian M., primary, Tamura, Kenji, primary, Oliveira, Mafalda, primary, Ciruelos, Eva M., primary, Mayer, Ingrid A., primary, Sablin, Marie-Paule, primary, Biganzoli, Laura, primary, Ambrose, Helen J., primary, Ashton, Jack, primary, Barnicle, Alan, primary, Cashell, Des D., primary, Corcoran, Claire, primary, de Bruin, Elza C., primary, Foxley, Andrew, primary, Hauser, Joana, primary, Lindemann, Justin P.O., primary, Maudsley, Rhiannon, primary, McEwen, Robert, primary, Moschetta, Michele, primary, Pass, Martin, primary, Rowlands, Vicky, primary, Schiavon, Gaia, primary, Banerji, Udai, primary, Scaltriti, Maurizio, primary, Taylor, Barry S., primary, Chandarlapaty, Sarat, primary, Baselga, José, primary, and Hyman, David M., primary

Published
2023
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11. Supplementary Figure 2 from Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer

Author

Smyth, Lillian M., primary, Tamura, Kenji, primary, Oliveira, Mafalda, primary, Ciruelos, Eva M., primary, Mayer, Ingrid A., primary, Sablin, Marie-Paule, primary, Biganzoli, Laura, primary, Ambrose, Helen J., primary, Ashton, Jack, primary, Barnicle, Alan, primary, Cashell, Des D., primary, Corcoran, Claire, primary, de Bruin, Elza C., primary, Foxley, Andrew, primary, Hauser, Joana, primary, Lindemann, Justin P.O., primary, Maudsley, Rhiannon, primary, McEwen, Robert, primary, Moschetta, Michele, primary, Pass, Martin, primary, Rowlands, Vicky, primary, Schiavon, Gaia, primary, Banerji, Udai, primary, Scaltriti, Maurizio, primary, Taylor, Barry S., primary, Chandarlapaty, Sarat, primary, Baselga, José, primary, and Hyman, David M., primary

Published
2023
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12. Supplementary Data Legends from Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts

Author

Gris-Oliver, Albert, primary, Palafox, Marta, primary, Monserrat, Laia, primary, Brasó-Maristany, Fara, primary, Òdena, Andreu, primary, Sánchez-Guixé, Mònica, primary, Ibrahim, Yasir H., primary, Villacampa, Guillermo, primary, Grueso, Judit, primary, Parés, Mireia, primary, Guzmán, Marta, primary, Rodríguez, Olga, primary, Bruna, Alejandra, primary, Hirst, Caroline S., primary, Barnicle, Alan, primary, de Bruin, Elza C., primary, Reddy, Avinash, primary, Schiavon, Gaia, primary, Arribas, Joaquín, primary, Mills, Gordon B., primary, Caldas, Carlos, primary, Dienstmann, Rodrigo, primary, Prat, Aleix, primary, Nuciforo, Paolo, primary, Razavi, Pedram, primary, Scaltriti, Maurizio, primary, Turner, Nicholas C., primary, Saura, Cristina, primary, Davies, Barry R., primary, Oliveira, Mafalda, primary, and Serra, Violeta, primary

Published
2023
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13. Supplementary Material from Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer

Author

Smyth, Lillian M., primary, Tamura, Kenji, primary, Oliveira, Mafalda, primary, Ciruelos, Eva M., primary, Mayer, Ingrid A., primary, Sablin, Marie-Paule, primary, Biganzoli, Laura, primary, Ambrose, Helen J., primary, Ashton, Jack, primary, Barnicle, Alan, primary, Cashell, Des D., primary, Corcoran, Claire, primary, de Bruin, Elza C., primary, Foxley, Andrew, primary, Hauser, Joana, primary, Lindemann, Justin P.O., primary, Maudsley, Rhiannon, primary, McEwen, Robert, primary, Moschetta, Michele, primary, Pass, Martin, primary, Rowlands, Vicky, primary, Schiavon, Gaia, primary, Banerji, Udai, primary, Scaltriti, Maurizio, primary, Taylor, Barry S., primary, Chandarlapaty, Sarat, primary, Baselga, José, primary, and Hyman, David M., primary

Published
2023
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14. Supplementary Methods from Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts

Author

Gris-Oliver, Albert, primary, Palafox, Marta, primary, Monserrat, Laia, primary, Brasó-Maristany, Fara, primary, Òdena, Andreu, primary, Sánchez-Guixé, Mònica, primary, Ibrahim, Yasir H., primary, Villacampa, Guillermo, primary, Grueso, Judit, primary, Parés, Mireia, primary, Guzmán, Marta, primary, Rodríguez, Olga, primary, Bruna, Alejandra, primary, Hirst, Caroline S., primary, Barnicle, Alan, primary, de Bruin, Elza C., primary, Reddy, Avinash, primary, Schiavon, Gaia, primary, Arribas, Joaquín, primary, Mills, Gordon B., primary, Caldas, Carlos, primary, Dienstmann, Rodrigo, primary, Prat, Aleix, primary, Nuciforo, Paolo, primary, Razavi, Pedram, primary, Scaltriti, Maurizio, primary, Turner, Nicholas C., primary, Saura, Cristina, primary, Davies, Barry R., primary, Oliveira, Mafalda, primary, and Serra, Violeta, primary

Published
2023
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15. EP263/#849 Olaparib treatment in patients with platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: characterization of long-term/short-term treatment duration in light

Author

Liu, Ying, primary, Mathews, Cara, additional, Simpkins, Fiona, additional, Cadoo, Karen, additional, Provencher, Diane, additional, Mccormick, Colleen, additional, Einaggar, Adam, additional, Altman, Alon, additional, Gilbert, Lucy, additional, Black, Destin, additional, Kabil, Nashwa, additional, Taylor, Rosie, additional, Barnicle, Alan, additional, Munley, Jiefen, additional, and Aghajanian, Carol, additional

Published
2022
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16. Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound

Author

Chi, Kim N., primary, Barnicle, Alan, additional, Sibilla, Caroline, additional, Lai, Zhongwu, additional, Corcoran, Claire, additional, Barrett, J. Carl, additional, Adelman, Carrie A., additional, Qiu, Ping, additional, Easter, Ashley, additional, Dearden, Simon, additional, Oxnard, Geoffrey R., additional, Agarwal, Neeraj, additional, Azad, Arun, additional, de Bono, Johann, additional, Mateo, Joaquin, additional, Olmos, David, additional, Thiery-Vuillemin, Antoine, additional, and Harrington, Elizabeth A., additional

Published
2022
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17. Clinical and molecular characteristics of patients with short- and long-term progression-free survival in the phase IIIb OPINION study of maintenance olaparib for patients with non-germline BRCA1/BRCA2-mutated platinum-sensitive relapsed ovarian cancer (306)

Author

Lheureux, Stéphanie, primary, Oaknin, Ana, additional, Sikorska, Magdalena, additional, Ledermann, Jonathan, additional, Blakeley, Chris, additional, Marshall, Helen, additional, Barnicle, Alan, additional, and Poveda, Andrés, additional

Published
2022
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18. Maintenance olaparib in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSROC) by somatic (s) or germline (g) BRCA and other homologous recombination repair (HRR) gene mutation status: Overall survival (OS) results from the ORZORA study.

Author

Pignata, Sandro, primary, Oza, Amit M., additional, Hall, Geoff, additional, Pardo, Beatriz, additional, Madry, Radoslaw, additional, Cibula, David, additional, Klat, Jaroslav, additional, Montes, Ana, additional, Glasspool, Rosalind, additional, Colombo, Nicoletta, additional, Pete, Imre, additional, Herrero, Ana, additional, Romeo, Marga, additional, Ilieva, Rumyana Nedyalkova, additional, Timcheva, Constanta, additional, Di Maio, Massimo, additional, Barnicle, Alan, additional, Taylor, Rosemary, additional, Bashir, Zahid, additional, and Clamp, Andrew R., additional

Published
2022
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19. Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer

Author

Carr, T. Hedley, primary, Adelman, Carrie, additional, Barnicle, Alan, additional, Kozarewa, Iwanka, additional, Luke, Sally, additional, Lai, Zhongwu, additional, Hollis, Sally, additional, Dougherty, Brian, additional, Harrington, Elizabeth A., additional, Kang, Jinyu, additional, Saad, Fred, additional, Sala, Nuria, additional, Thiery-Vuillemin, Antoine, additional, Clarke, Noel W., additional, Hodgson, Darren, additional, and Barrett, J. Carl, additional

Published
2021
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20. Homologous recombination repair mutation gene panels (excluding BRCA) are not predictive of maintenance olaparib plus bevacizumab efficacy in the first-line PAOLA-1/ENGOT-ov25 trial

Author

Pujade-Lauraine, Eric, primary, Brown, Jessica, additional, Barnicle, Alan, additional, Rowe, Phil, additional, Lao-Sirieix, Pierre, additional, Criscione, Steven, additional, du Bois, Andreas, additional, Lorusso, Domenica, additional, Romero, Ignacio, additional, Petru, Edgar, additional, Yoshida, Hiroyuki, additional, Vergote, Ignace, additional, Colombo, Nicoletta, additional, Hietanen, Sakari, additional, Provansal, Magali, additional, Schmalfeldt, Barbara, additional, Pignata, Sandro, additional, Martin-Lorente, Cristina, additional, Berton, Dominique, additional, Runnebaum, Ingo, additional, and Ray-Coquard, Isabelle, additional

Published
2021
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21. ORZORA: Maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer: outcomes by somatic and germline BRCA and other homologous recombination repair gene mutation status

Author

Pignata, Sandro, primary, Oza, Amit, additional, Hall, Geoff, additional, Pardo, Beatriz, additional, Madry, Radoslaw, additional, Cibula, David, additional, Klat, Jaroslav, additional, Montes, Ana, additional, Glasspool, Rosalind, additional, Colombo, Nicoletta, additional, Pete, Imre, additional, Herrero, Ana, additional, Marin, Margarita Romeo, additional, Ilieva, Rumyana, additional, Timcheva, Constanta, additional, Blakeley, Christopher, additional, Taylor, Rosie, additional, Barnicle, Alan, additional, and Clamp, Andrew, additional

Published
2021
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22. Concordance of BRCA1, BRCA2 (BRCA), and ATM mutations identified in matched tumor tissue and circulating tumor DNA (ctDNA) in men with metastatic castration-resistant prostate cancer (mCRPC) screened in the PROfound study.

Author

Chi, Kim N., primary, Barnicle, Alan, additional, Sibilla, Caroline, additional, Lai, Zhongwu, additional, Corcoran, Claire, additional, Williams, J. Andrew, additional, Barrett, J Carl, additional, Adelman, Carrie A., additional, Qiu, Ping, additional, Easter, Ashley, additional, Dearden, Simon, additional, and Harrington, Elizabeth, additional

Published
2021
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23. Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients withAKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer

Author

Smyth, Lillian M., primary, Tamura, Kenji, additional, Oliveira, Mafalda, additional, Ciruelos, Eva M., additional, Mayer, Ingrid A., additional, Sablin, Marie-Paule, additional, Biganzoli, Laura, additional, Ambrose, Helen J., additional, Ashton, Jack, additional, Barnicle, Alan, additional, Cashell, Des D., additional, Corcoran, Claire, additional, de Bruin, Elza C., additional, Foxley, Andrew, additional, Hauser, Joana, additional, Lindemann, Justin P.O., additional, Maudsley, Rhiannon, additional, McEwen, Robert, additional, Moschetta, Michele, additional, Pass, Martin, additional, Rowlands, Vicky, additional, Schiavon, Gaia, additional, Banerji, Udai, additional, Scaltriti, Maurizio, additional, Taylor, Barry S., additional, Chandarlapaty, Sarat, additional, Baselga, José, additional, and Hyman, David M., additional

Published
2020
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24. Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts

Author

Gris-Oliver, Albert, primary, Palafox, Marta, additional, Monserrat, Laia, additional, Brasó-Maristany, Fara, additional, Òdena, Andreu, additional, Sánchez-Guixé, Mònica, additional, Ibrahim, Yasir H., additional, Villacampa, Guillermo, additional, Grueso, Judit, additional, Parés, Mireia, additional, Guzmán, Marta, additional, Rodríguez, Olga, additional, Bruna, Alejandra, additional, Hirst, Caroline S., additional, Barnicle, Alan, additional, de Bruin, Elza C., additional, Reddy, Avinash, additional, Schiavon, Gaia, additional, Arribas, Joaquín, additional, Mills, Gordon B., additional, Caldas, Carlos, additional, Dienstmann, Rodrigo, additional, Prat, Aleix, additional, Nuciforo, Paolo, additional, Razavi, Pedram, additional, Scaltriti, Maurizio, additional, Turner, Nicholas C., additional, Saura, Cristina, additional, Davies, Barry R., additional, Oliveira, Mafalda, additional, and Serra, Violeta, additional

Published
2020
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25. Olaparib maintenance monotherapy for non-germline BRCA1/2-mutated (non-gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase IIIb OPINION interim analysis.

Author

Poveda, Andres, primary, Lheureux, Stephanie, additional, Colombo, Nicoletta, additional, Cibula, David, additional, Lindemann, Kristina, additional, Weberpals, Johanne I, additional, Bjurberg, Maria, additional, Oaknin, Ana, additional, Sikorska, Magdalena, additional, Gonzalez Martin, Antonio, additional, Madry, Radoslaw, additional, Rubio Pérez, Maria Jesus, additional, Davidson, Richard, additional, Blakeley, Christopher, additional, Bennett, James, additional, Barnicle, Alan, additional, and Skof, Erik, additional

Published
2020
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26. Abstract P1-19-05: Capivasertib (AZD5363) in combination with fulvestrant in PTEN-mutant ER+ metastatic breast cancer

Author

Smyth, Lillian M, primary, Batist, Gerald, additional, Meric-Bernstam, Funda, additional, Kabos, Peter, additional, Spanggaard, Iben, additional, Lluch, Ana, additional, Schram, Alison, additional, Varga, Andrea, additional, Wong, Andrea, additional, Ambrose, Helen, additional, Barnicle, Alan, additional, Carr, T. Hedley, additional, de Bruin, Elza C, additional, Salinas-Souza, Carolina, additional, Foxley, Andrew, additional, Hauser, Joana, additional, Lindemann, Justin PO, additional, Maudsley, Rhiannon, additional, McEwen, Robert, additional, Moschetta, Michele, additional, Roudier, Martine, additional, Schiavon, Gaia, additional, Razavi, Pedram, additional, Banerji, Udai, additional, Chandarlapaty, Sarat, additional, Baselga, José, additional, and Hyman, David M, additional

Published
2020
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27. Analysis and interpretation of epigenomic patterns in colonic epithelia

Author

Barnicle, Alan, Egan, Laurence, Seoighe, Cathal, and Irish Research Council

Subjects
DNA methylation, Ulcerative colitis, Bioinformatics, Science, School of Mathematics, Statistics & Applied Mathematics, Intestinal epithelium
Abstract

The methylation of cytosine nucleotides at the 5' position of DNA is a crucial epigenetic mechanism for the control of gene expression. Epigenome-wide associated studies have demonstrated that specific methylome patterns exist in certain disease states, that methylome signatures can predict cancer susceptibility and that methylation patterns are capable of characterizing epigenomic events that stimulate the survival of cancer cells. Little is known about the effect of chronic inflammation on DNA methylation. In this work, we analysed the effect of chronic inflammation on DNA methylation patterns in ulcerative colitis (UC), a condition that predisposes to colon cancer. Due to the cell type specific nature of DNA methylation patterns, this PhD initially focussed on designing an epithelial cell isolation method that was capable of enriching a purified epithelial population both in diseased and non-diseased states. Secondly, we wished to test the hypothesis that distinct colonic regions have specific methylation signatures, while also comparing DNA methylation patterns in isolated epithelial cells and in whole colonic mucosal biopsies. Finally, using the chronic inflammatory condition of ulcerative colitis (UC) as a pathogenic phenotype, this PhD aimed to identify potential epigenomic and genomic dysregulation that occurs in intestinal epithelial cells in inflamed areas of the colon. Isolation of epithelial cells from mucosal biopsies resulted in purified populations of crypts consisting of ~90% pure epithelium. Using these fractions isolated at 4°C to minimize degradation of nucleic acids, it was demonstrated that stable and integral mRNA and gDNA could successfully be extracted in both diseased and non-diseased states. Using genome-wide technology, specific DNA methylation signatures in the proximal and distal colon in samples from healthy colon were identified. Computational deconvolution was also used to characterize accurate epithelial cell estimates from whole colonic biopsies, while also highlighting the increased DNA methylation variability caused by samples comprised of a mixture of cell lineages. Results from this study identified region-specific epigenomic patterns of HOX genes (specifically HOXB and HOXC families). These patterns represent a valuable tool for interpreting experimental data on diseases that exhibit region-specific expression in the colon such as inflammatory bowel disease and colorectal cancer. By performing genome-wide DNA methylation and transcriptome profiling of purified intestinal epithelial cells, it was demonstrated that significant DNA methylation and gene expression variation occurs in UC. Genes showing inverse correlation between DNA methylation and gene expression levels were also identified, most notably promoter hypermethylation and down regulation of RARB. This gene was previously identified as a tumour suppressor in colorectal adenocarcinoma as well as in breast, lung and prostate cancer. However this is the first finding of RARB potentially playing a functional role in UC. This integrative epigenomic dataset will enhance our understanding of UC pathophysiology, potentially adding to our knowledge of the links between chronic inflammation and carcinogenesis. 2017-06-18

Published
2015

30. Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound.

Author

Chi KN, Barnicle A, Sibilla C, Lai Z, Corcoran C, Barrett JC, Adelman CA, Qiu P, Easter A, Dearden S, Oxnard GR, Agarwal N, Azad A, de Bono J, Mateo J, Olmos D, Thiery-Vuillemin A, and Harrington EA

Subjects
Humans, Male, Ataxia Telangiectasia Mutated Proteins genetics, Biomarkers, Tumor genetics, Biomarkers, Tumor therapeutic use, BRCA1 Protein genetics, BRCA2 Protein genetics, Mutation, Retrospective Studies, Clinical Trials, Phase III as Topic, Antineoplastic Agents therapeutic use, Circulating Tumor DNA genetics, Prostatic Neoplasms, Castration-Resistant drug therapy
Abstract

Purpose: Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of difficulties within the testing procedure. Optimization of screening techniques may reduce failure rates; however, a need remains for additional testing methods to detect cancers with alterations in homologous recombination repair genes. We evaluated the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying deleterious BRCA1, BRCA2 (BRCA), and ATM alterations in screened patients with mCRPC from the phase III PROfound study., Patients and Methods: Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an investigational next-generation sequencing (NGS) assay based on FoundationOne®CDx to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investigational assay based on FoundationOne®Liquid CDx., Results: 81% (503/619) of ctDNA samples yielded an NGS result, of which 491 had a tumor tissue result. BRCA and ATM status in tissue compared with ctDNA showed 81% positive percentage agreement and 92% negative percentage agreement, using tissue as reference. At variant-subtype level, using tissue as reference, concordance was high for nonsense (93%), splice (87%), and frameshift (86%) alterations but lower for large rearrangements (63%) and homozygous deletions (27%), with low ctDNA fraction being a limiting factor., Conclusions: We demonstrate that ctDNA can greatly complement tissue testing in identifying patients with mCRPC and BRCA or ATM alterations who are potentially suitable for receiving targeted PARP inhibitor treatments, particularly patients with no or insufficient tissue for genomic analyses., (©2022 The Authors; Published by the American Association for Cancer Research.)

Published
2023
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31. Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1 E17K -Mutant, ER-Positive Metastatic Breast Cancer.

Author

Smyth LM, Tamura K, Oliveira M, Ciruelos EM, Mayer IA, Sablin MP, Biganzoli L, Ambrose HJ, Ashton J, Barnicle A, Cashell DD, Corcoran C, de Bruin EC, Foxley A, Hauser J, Lindemann JPO, Maudsley R, McEwen R, Moschetta M, Pass M, Rowlands V, Schiavon G, Banerji U, Scaltriti M, Taylor BS, Chandarlapaty S, Baselga J, and Hyman DM

Subjects
Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast pathology, Breast surgery, Breast Neoplasms genetics, Breast Neoplasms mortality, Breast Neoplasms pathology, Chemotherapy, Adjuvant adverse effects, Chemotherapy, Adjuvant methods, Female, Fulvestrant adverse effects, Humans, Mastectomy, Middle Aged, Mutation, Progression-Free Survival, Proto-Oncogene Proteins c-akt genetics, Pyrimidines adverse effects, Pyrroles adverse effects, Receptors, Estrogen analysis, Receptors, Estrogen metabolism, Response Evaluation Criteria in Solid Tumors, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Breast Neoplasms therapy, Fulvestrant administration & dosage, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Pyrimidines administration & dosage, Pyrroles administration & dosage
Abstract

Purpose: The activating mutation AKT1 E17K occurs in approximately 7% of estrogen receptor-positive (ER + ) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with AKT1 E17K -mutant ER + MBC., Patients and Methods: Patients with an AKT1 E17K mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), and clinical benefit rate at 24 weeks (CBR 24 ). Biomarker analyses were conducted in the combination cohort., Results: From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although the latter group may have had more aggressive disease at baseline. AKT1 E17K mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (76%, 31/41). A ≥50% decrease in AKT1 E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy [most frequent grade ≥3 adverse events: rash (9% vs. 20%), hyperglycemia (5% vs. 30%), diarrhea (5% vs. 10%)]., Conclusions: Capivasertib demonstrated clinically meaningful activity in heavily pretreated patients with AKT1 E17K -mutant ER + MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination., (©2020 American Association for Cancer Research.)

Published
2020
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