Search

Your search keyword '"Birrer, Michael"' showing total 1,893 results
Start Over Author "Birrer, Michael"
1,893 results on '"Birrer, Michael"'

1. Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer.

Author

Chowdhury, Shrabanti, Kennedy, Jacob, Ivey, Richard, Murillo, Oscar, Hosseini, Noshad, Song, Xiaoyu, Petralia, Francesca, Calinawan, Anna, Savage, Sara, Berry, Anna, Reva, Boris, Ozbek, Umut, Krek, Azra, Ma, Weiping, da Veiga Leprevost, Felipe, Ji, Jiayi, Yoo, Seungyeul, Lin, Chenwei, Voytovich, Uliana, Huang, Yajue, Lee, Sun-Hee, Bergan, Lindsay, Lorentzen, Travis, Mesri, Mehdi, Rodriguez, Henry, Hoofnagle, Andrew, Herbert, Zachary, Nesvizhskii, Alexey, Zhang, Bing, Whiteaker, Jeffrey, Fenyo, David, McKerrow, Wilson, Wang, Joshua, Schürer, Stephan, Stathias, Vasileios, Chen, X, Starr, Timothy, Winterhoff, Boris, Nelson, Andrew, Mok, Samuel, Kaufmann, Scott, Drescher, Charles, Cieslik, Marcin, Wang, Pei, Birrer, Michael, Paulovich, Amanda, and Barcellos-Hoff, Mary Helen

Subjects
chemorefractory, high-grade serous ovarian cancer, machine learning, mass spectrometry, multiple reaction monitoring, platinum, precision oncology, predictive biomarker, prognostic biomarker, proteogenomic, Female, Humans, Cystadenocarcinoma, Serous, Ovarian Neoplasms, Proteogenomics
Abstract

To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.

Published
2023

2. Fear of recurrence, emotional well-being and quality of life among long-term advanced ovarian cancer survivors

Author

Osann, Kathryn, Wenzel, Lari, McKinney, Chelsea, Wagner, Lynne, Cella, David, Fulci, Giulia, Scroggins, Mary J, Lankes, Heather A, Wang, Victoria, Nephew, Kenneth P, Maxwell, George L, Mok, Samuel C, Conrads, Thomas P, Miller, Austin, and Birrer, Michael

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Ovarian Cancer, Rare Diseases, Clinical Research, Women's Health, Behavioral and Social Science, 7.1 Individual care needs, Adult, Humans, Female, Quality of Life, Cancer Survivors, Ovarian Neoplasms, Carcinoma, Ovarian Epithelial, Fear, Ovarian cancer, Long-term survival, Fear of recurrence, Quality of life, Emotional well-being, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis, Reproductive medicine
Abstract

ObjectiveAlthough advanced stage epithelial ovarian cancer is widely considered life-threatening, 17% of women with advanced disease will survive long-term. Little is known about the health-related quality of life (QOL) of long-term ovarian cancer survivors, or how fear of recurrence might affect QOL.Methods58 long-term survivors with advanced disease participated in the study. Participants completed standardized questionnaires to capture cancer history, QOL, and fear of recurrent disease (FOR). Statistical analyses included multivariable linear models.ResultsParticipants averaged 52.8 years at diagnosis and had survived >8 years (mean:13.5); 64% had recurrent disease. Mean FACT-G, FACT-O, and FACT-O-TOI (TOI) scores were 90.7 (SD:11.6), 128.6 (SD:14.8), and 85.9 (SD:10.2) respectively. Compared to the U.S. population using T-scores, QOL for participants exceeded that of healthy adults (T-score (FACT-G) = 55.9). Overall QOL was lower in women with recurrent vs. non-recurrent disease though differences did not reach statistical significance (FACT-O = 126.1 vs. 133.3, p = 0.082). Despite good QOL, high FOR was reported in 27%. FOR was inversely associated with emotional well-being (EWB) (p

Published
2023

3. Final survival analysis of topotecan and paclitaxel for first-line treatment of advanced cervical Cancer: A NRG oncology randomized study

Author

Tewari, Krishnansu S, Sill, Michael W, Birrer, Michael J, Penson, Richard T, Huang, Helen, Moore, David H, Ramondetta, Lois M, Landrum, Lisa M, Oaknin, Ana, Reid, Thomas J, Leitao, Mario M, Michael, Helen E, and Monk, Bradley J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Survival Analysis, Topotecan, Paclitaxel, Uterine Cervical Neoplasms, Humans, Female, Cisplatin, Bevacizumab, Young Adult, Adult, Middle Aged, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Cervical Cancer, Platinum, Recurrent, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis, Reproductive medicine
Abstract

ObjectiveTo determine whether a non‑platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma.MethodsGynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m2 plus topotecan 0.75 mg/m2 days 1-3 (n = 223) vs cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2 (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS.ResultsAt the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91-1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82-1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86-1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86-1.38;p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75-1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones.ConclusionsTopotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population. NCT00803062.

Published
2023

6. Overcoming adaptive resistance to anti-VEGF therapy by targeting CD5L

Author

LaFargue, Christopher J., Amero, Paola, Noh, Kyunghee, Mangala, Lingegowda S., Wen, Yunfei, Bayraktar, Emine, Umamaheswaran, Sujanitha, Stur, Elaine, Dasari, Santosh K., Ivan, Cristina, Pradeep, Sunila, Yoo, Wonbeak, Lu, Chunhua, Jennings, Nicholas B., Vathipadiekal, Vinod, Hu, Wei, Chelariu-Raicu, Anca, Ku, Zhiqiang, Deng, Hui, Xiong, Wei, Choi, Hyun-Jin, Hu, Min, Kiyama, Takae, Mao, Chai-An, Ali-Fehmi, Rouba, Birrer, Michael J., Liu, Jinsong, Zhang, Ningyan, Lopez-Berestein, Gabriel, de Franciscis, Vittorio, An, Zhiqiang, and Sood, Anil K.

Published
2023
Full Text
View/download PDF

7. LINE-1 ORF1p as a candidate biomarker in high grade serous ovarian carcinoma

Author

Sato, Sho, Gillette, Michael, de Santiago, Pamela R., Kuhn, Eric, Burgess, Michael, Doucette, Kristen, Feng, Yi, Mendez-Dorantes, Carlos, Ippoliti, Paul J., Hobday, Sara, Mitchell, Marilyn A., Doberstein, Kai, Gysler, Stefan M., Hirsch, Michelle S., Schwartz, Lauren, Birrer, Michael J., Skates, Steven J., Burns, Kathleen H., Carr, Steven A., and Drapkin, Ronny

Published
2023
Full Text
View/download PDF

8. Comprehensive proteogenomic characterization of rare kidney tumors

Author

Lazar, Alexander J., Paulovich, Amanda G., Antczak, Andrzej, Green, Anthony, Ma’ayan, Avi, Pruetz, Barb, Zhang, Bing, Reva, Boris, Druker, Brian J., Goldthwaite, Charles A., Jr., Birger, Chet, Mani, D.R., Chesla, David, Fenyö, David, Schadt, Eric E., Wilson, George, Kołodziejczak, Iga, John, Ivy, Hafron, Jason, Vo, Josh, Zaalishvili, Kakhaber, Ketchum, Karen A., Rodland, Karin D., Nyce, Kristen, Wiznerowicz, Maciej, Domagalski, Marcin J., Anurag, Meenakshi, Borucki, Melissa, Gillette, Michael A., Birrer, Michael J., Edwards, Nathan J., Vatanian, Negin, VanderKolk, Pamela, McGarvey, Peter B., Dhir, Rajiv, Thangudu, Ratna R., Crispen, Reese, Smith, Richard D., Payne, Samuel H., Cottingham, Sandra, Cai, Shuang, Carr, Steven A., Liu, Tao, Le, Toan, Ma, Weiping, Zhang, Xu, Lu, Yin, Shutack, Yvonne, Zhang, Zhen, Li, Ginny Xiaohe, Chen, Lijun, Hsiao, Yi, Mannan, Rahul, Zhang, Yuping, Luo, Jie, Petralia, Francesca, Cho, Hanbyul, Hosseini, Noshad, Leprevost, Felipe da Veiga, Calinawan, Anna, Li, Yize, Anand, Shankara, Dagar, Aniket, Geffen, Yifat, Kumar-Sinha, Chandan, Chugh, Seema, Le, Anne, Ponce, Sean, Guo, Shenghao, Zhang, Cissy, Schnaubelt, Michael, Al Deen, Nataly Naser, Chen, Feng, Caravan, Wagma, Houston, Andrew, Hopkins, Alex, Newton, Chelsea J., Wang, Xiaoming, Polasky, Daniel A., Haynes, Sarah, Yu, Fengchao, Jing, Xiaojun, Chen, Siqi, Robles, Ana I., Mesri, Mehdi, Thiagarajan, Mathangi, An, Eunkyung, Getz, Gad A., Linehan, W. Marston, Hostetter, Galen, Jewell, Scott D., Chan, Daniel W., Wang, Pei, Omenn, Gilbert S., Mehra, Rohit, Ricketts, Christopher J., Ding, Li, Chinnaiyan, Arul M., Cieslik, Marcin P., Dhanasekaran, Saravana M., Zhang, Hui, and Nesvizhskii, Alexey I.

Published
2024
Full Text
View/download PDF

9. DAGBagM: learning directed acyclic graphs of mixed variables with an application to identify protein biomarkers for treatment response in ovarian cancer

Author

Chowdhury, Shrabanti, Wang, Ru, Yu, Qing, Huntoon, Catherine J, Karnitz, Larry M, Kaufmann, Scott H, Gygi, Steven P, Birrer, Michael J, Paulovich, Amanda G, Peng, Jie, and Wang, Pei

Subjects
Information and Computing Sciences, Machine Learning, Rare Diseases, Cancer, Ovarian Cancer, Good Health and Well Being, Biomarkers, Causality, Child, Computer Simulation, Confounding Factors, Epidemiologic, Female, Humans, Ovarian Neoplasms, Proteomics, Sensitive and resistant/refractory, Hill climbing, Bootstrap aggregation, Mathematical Sciences, Biological Sciences, Bioinformatics, Biological sciences, Information and computing sciences, Mathematical sciences
Abstract

BackgroundApplying directed acyclic graph (DAG) models to proteogenomic data has been shown effective for detecting causal biomarkers of complex diseases. However, there remain unsolved challenges in DAG learning to jointly model binary clinical outcome variables and continuous biomarker measurements.ResultsIn this paper, we propose a new tool, DAGBagM, to learn DAGs with both continuous and binary nodes. By using appropriate models, DAGBagM allows for either continuous or binary nodes to be parent or child nodes. It employs a bootstrap aggregating strategy to reduce false positives in edge inference. At the same time, the aggregation procedure provides a flexible framework to robustly incorporate prior information on edges.ConclusionsThrough extensive simulation experiments, we demonstrate that DAGBagM has superior performance compared to alternative strategies for modeling mixed types of nodes. In addition, DAGBagM is computationally more efficient than two competing methods. When applying DAGBagM to proteogenomic datasets from ovarian cancer studies, we identify potential protein biomarkers for platinum refractory/resistant response in ovarian cancer. DAGBagM is made available as a github repository at https://github.com/jie108/dagbagM .

Published
2022

10. Quality of Life and Adverse Events: Prognostic Relationships in Long-Term Ovarian Cancer Survival

Author

Wenzel, Lari, Osann, Kathryn, McKinney, Chelsea, Cella, David, Fulci, Giulia, Scroggins, Mary J, Lankes, Heather A, Wang, Victoria, Nephew, Kenneth P, Maxwell, George L, Mok, Samuel C, Conrads, Thomas P, Miller, Austin, Mannel, Robert S, Gray, Heidi J, Hanjani, Parviz, Huh, Warner K, Spirtos, Nick, Leitao, Mario M, Glaser, Gretchen, Sharma, Sudarshan K, Santin, Alessandro D, Sperduto, Paul, Lele, Shashikant B, Burger, Robert A, Monk, Bradley J, and Birrer, Michael

Subjects
Cancer, Rehabilitation, Ovarian Cancer, Clinical Research, Rare Diseases, Management of diseases and conditions, 7.1 Individual care needs, Carcinoma, Ovarian Epithelial, Humans, Ovarian Neoplasms, Prognosis, Quality of Life, Survivors, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundThere is a critical need to identify patient characteristics associated with long-term ovarian cancer survival.MethodsQuality of life (QOL), measured by the Functional Assessment of Cancer Therapy-Ovarian-Trial Outcome Index (FACT-O-TOI), including physical, functional, and ovarian-specific subscales, was compared between long-term survivors (LTS) (8+ years) and short-term survivors (STS) (

Published
2021

11. Pan-cancer proteogenomics characterization of tumor immunity

Author

Abelin, Jennifer, Aguet, François, Akiyama, Yo, An, Eunkyung, Anand, Shankara, Anurag, Meenakshi, Babur, Özgün, Bavarva, Jasmin, Birger, Chet, Birrer, Michael J., Cao, Song, Carr, Steven A., Chan, Daniel W., Chinnaiyan, Arul M., Cho, Hanbyul, Clauser, Karl, Colaprico, Antonio, Zhou, Daniel Cui, da Veiga Leprevost, Felipe, Day, Corbin, Dhanasekaran, Saravana M., Ding, Li, Domagalski, Marcin J., Dou, Yongchao, Druker, Brian J., Edwards, Nathan, Ellis, Matthew J., Foltz, Steven M., Francis, Alicia, Geffen, Yifat, Getz, Gad, Heiman, David I., Hong, Runyu, Hu, Yingwei, Huang, Chen, Jaehnig, Eric J., Jewell, Scott D., Ji, Jiayi, Jiang, Wen, Katsnelson, Lizabeth, Ketchum, Karen A., Kolodziejczak, Iga, Krug, Karsten, Kumar-Sinha, Chandan, Lei, Jonathan T., Liang, Wen-Wei, Liao, Yuxing, Lindgren, Caleb M., Liu, Tao, Liu, Wenke, McDermott, Jason, McKerrow, Wilson, Mesri, Mehdi, Mumphrey, Michael Brodie, Newton, Chelsea J., Oldroyd, Robert, Payne, Samuel H., Pugliese, Pietro, Rodland, Karin D., Rodrigues, Fernanda Martins, Ruggles, Kelly V., Savage, Sara R., Schadt, Eric E., Schnaubelt, Michael, Schraink, Tobias, Schürer, Stephan, Shi, Zhiao, Smith, Richard D., Song, Feng, Song, Yizhe, Stathias, Vasileios, Storrs, Erik P., Tan, Jimin, Terekhanova, Nadezhda V., Thangudu, Ratna R., Thiagarajan, Mathangi, Wang, Liang-Bo, Wen, Bo, Wu, Yige, Wyczalkowski, Matthew A., Yao, Lijun, Li, Qing Kay, Zhang, Hui, Zhang, Qing, Zhang, Xu, Zhang, Zhen, Petralia, Francesca, Ma, Weiping, Yaron, Tomer M., Caruso, Francesca Pia, Tignor, Nicole, Wang, Joshua M., Charytonowicz, Daniel, Johnson, Jared L., Huntsman, Emily M., Marino, Giacomo B., Calinawan, Anna, Evangelista, John Erol, Selvan, Myvizhi Esai, Chowdhury, Shrabanti, Rykunov, Dmitry, Krek, Azra, Song, Xiaoyu, Turhan, Berk, Christianson, Karen E., Lewis, David A., Deng, Eden Z., Clarke, Daniel J.B., Whiteaker, Jeffrey R., Kennedy, Jacob J., Zhao, Lei, Segura, Rossana Lazcano, Batra, Harsh, Raso, Maria Gabriela, Parra, Edwin Roger, Soundararajan, Rama, Tang, Ximing, Li, Yize, Yi, Xinpei, Satpathy, Shankha, Wang, Ying, Wiznerowicz, Maciej, González-Robles, Tania J., Iavarone, Antonio, Gosline, Sara J.C., Reva, Boris, Robles, Ana I., Nesvizhskii, Alexey I., Mani, D.R., Gillette, Michael A., Klein, Robert J., Cieslik, Marcin, Zhang, Bing, Paulovich, Amanda G., Sebra, Robert, Gümüş, Zeynep H., Hostetter, Galen, Fenyö, David, Omenn, Gilbert S., Cantley, Lewis C., Ma'ayan, Avi, Lazar, Alexander J., Ceccarelli, Michele, and Wang, Pei

Published
2024
Full Text
View/download PDF

12. Correlation of imaging and plasma based biomarkers to predict response to bevacizumab in epithelial ovarian cancer (EOC)

Author

Buechel, Megan E, Enserro, Danielle, Burger, Robert A, Brady, Mark F, Wade, Katrina, Secord, Angeles Alvarez, Nixon, Andrew B, Mirniaharikandehei, Seyedehnafiseh, Liu, Hong, Zheng, Bin, O'Malley, David M, Gray, Heidi, Tewari, Krishnansu S, Mannel, Robert S, Birrer, Michael J, and Moore, Kathleen N

Subjects
Cancer, Clinical Trials and Supportive Activities, Rare Diseases, Ovarian Cancer, Clinical Research, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Adiposity, Adult, Aged, Antineoplastic Agents, Immunological, Bevacizumab, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Double-Blind Method, Female, Humans, Intra-Abdominal Fat, Middle Aged, Ovarian Neoplasms, Subcutaneous Fat, Survival Analysis, Tomography, X-Ray Computed, Treatment Outcome, Ovarian cancer, Imaging biomarkers, Plasma biomarkers, Oncology and Carcinogenesis, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis
Abstract

PurposeIncreasing measures of adiposity have been correlated with poor oncologic outcomes and a lack of response to anti-angiogenic therapies. Limited data exists on the impact of subcutaneous fat density (SFD) and visceral fat density (VFD) on oncologic outcomes. This ancillary analysis of GOG-218, evaluates whether imaging markers of adiposity were predictive biomarkers for bevacizumab (bev) use in epithelial ovarian cancer (EOC).Patients and methodsThere were 1249 patients (67%) from GOG-218 with imaging measurements. SFD and VFD were calculated utilizing Hounsfield units (HU). Proportional hazards models were used to assess the association between SFD and VFD with overall survival (OS).ResultsIncreased SFD and VFD showed an increased HR for death (HR per 1-SD increase 1.12, 95% CI:1.05-1.19 p = 0.0009 and 1.13, 95% CI: 1.05-1.20 p = 0.0006 respectively). In the predictive analysis for response to bev, high VFD showed an increased hazard for death in the placebo group (HR per 1-SD increase 1.22, 95% CI: 1.09-1.37; p = 0.025). However, in the bev group there was no effect seen (HR per 1-SD increase: 1.01, 95% CI: 0.90-1.14) Median OS was 45 vs 47 months in the VFD low groups and 36 vs 42 months in the VFD high groups on placebo versus bev, respectively.ConclusionHigh VFD and SFD have a negative prognostic impact on patients with EOC. High VFD appears to be a predictive marker of bev response and patients with high VFD may be more likely to benefit from initial treatment with bev.

Published
2021

13. Molecular determinants of clinical outcomes of pembrolizumab in recurrent ovarian cancer: Exploratory analysis of KEYNOTE-100

Author

Ledermann, Jonathan A., Shapira-Frommer, Ronnie, Santin, Alessandro D., Lisyanskaya, Alla S., Pignata, Sandro, Vergote, Ignace, Raspagliesi, Francesco, Sonke, Gabe S., Birrer, Michael, Provencher, Diane M., Sehouli, Jalid, Colombo, Nicoletta, González-Martín, Antonio, Oaknin, Ana, Ottevanger, P.B., Rudaitis, Vilius, Kobie, Julie, Nebozhyn, Michael, Edmondson, Mackenzie, Sun, Yuan, Cristescu, Razvan, Jelinic, Petar, Keefe, Stephen M., and Matulonis, Ursula A.

Published
2023
Full Text
View/download PDF

14. Deep learning integrates histopathology and proteogenomics at a pan-cancer level

Author

Aguet, François, Akiyama, Yo, Anand, Shankara, Anurag, Meenakshi, Babur, Özgün, Bavarva, Jasmin, Birger, Chet, Birrer, Michael J., Cantley, Lewis C., Cao, Song, Carr, Steven A., Ceccarelli, Michele, Chan, Daniel W., Chinnaiyan, Arul M., Cho, Hanbyul, Chowdhury, Shrabanti, Cieslik, Marcin P., Clauser, Karl R., Colaprico, Antonio, Zhou, Daniel Cui, da Veiga Leprevost, Felipe, Day, Corbin, Dhanasekaran, Saravana M., Domagalski, Marcin J., Dou, Yongchao, Druker, Brian J., Edwards, Nathan, Ellis, Matthew J., Selvan, Myvizhi Esai, Foltz, Steven M., Francis, Alicia, Geffen, Yifat, Getz, Gad, Gonzalez Robles, Tania J., Gosline, Sara J.C., Gümüş, Zeynep H., Heiman, David I., Hiltke, Tara, Hostetter, Galen, Hu, Yingwei, Huang, Chen, Huntsman, Emily, Iavarone, Antonio, Jaehnig, Eric J., Jewell, Scott D., Ji, Jiayi, Jiang, Wen, Johnson, Jared L., Katsnelson, Lizabeth, Ketchum, Karen A., Kolodziejczak, Iga, Krug, Karsten, Kumar-Sinha, Chandan, Lei, Jonathan T., Liang, Wen-Wei, Liao, Yuxing, Lindgren, Caleb M., Liu, Tao, Ma, Weiping, Rodrigues, Fernanda Martins, McKerrow, Wilson, Mesri, Mehdi, Nesvizhskii, Alexey I., Newton, Chelsea J., Oldroyd, Robert, Paulovich, Amanda G., Payne, Samuel H., Petralia, Francesca, Pugliese, Pietro, Reva, Boris, Rykunov, Dmitry, Satpathy, Shankha, Savage, Sara R., Schadt, Eric E., Schnaubelt, Michael, Schürer, Stephan, Shi, Zhiao, Smith, Richard D., Song, Xiaoyu, Song, Yizhe, Stathias, Vasileios, Storrs, Erik P., Terekhanova, Nadezhda V., Thangudu, Ratna R., Thiagarajan, Mathangi, Tignor, Nicole, Wang, Liang-Bo, Wang, Pei, Wang, Ying, Wen, Bo, Wiznerowicz, Maciej, Wu, Yige, Wyczalkowski, Matthew A., Yao, Lijun, Yaron, Tomer M., Yi, Xinpei, Zhang, Bing, Zhang, Hui, Zhang, Qing, Zhang, Xu, Zhang, Zhen, Wang, Joshua M., Hong, Runyu, Demicco, Elizabeth G., Tan, Jimin, Lazcano, Rossana, Moreira, Andre L., Li, Yize, Calinawan, Anna, Razavian, Narges, Schraink, Tobias, Gillette, Michael A., Omenn, Gilbert S., An, Eunkyung, Rodriguez, Henry, Tsirigos, Aristotelis, Ruggles, Kelly V., Ding, Li, Robles, Ana I., Mani, D.R., Rodland, Karin D., Lazar, Alexander J., Liu, Wenke, and Fenyö, David

Published
2023
Full Text
View/download PDF

15. Proteogenomic insights suggest druggable pathways in endometrial carcinoma

Author

Antczak, Andrzej, Anurag, Meenakshi, Bauer, Thomas, Birger, Chet, Birrer, Michael J., Borucki, Melissa, Cai, Shuang, Calinawan, Anna, Carr, Steven A., Castro, Patricia, Cerda, Sandra, Chan, Daniel W., Chesla, David, Cieslik, Marcin P., Cottingham, Sandra, Dhir, Rajiv, Domagalski, Marcin J., Druker, Brian J., Duffy, Elizabeth, Edwards, Nathan J., Edwards, Robert, Ellis, Matthew J., Eschbacher, Jennifer, Fam, Mina, Fevrier-Sullivan, Brenda, Francis, Jesse, Freymann, John, Gabriel, Stacey, Getz, Gad, Gillette, Michael A., Godwin, Andrew K., Goldthwaite, Charles A., Grady, Pamela, Hafron, Jason, Hariharan, Pushpa, Hindenach, Barbara, Hoadley, Katherine A., Huang, Jasmine, Ittmann, Michael M., Johnson, Ashlie, Jones, Corbin D., Ketchum, Karen A., Kirby, Justin, Le, Toan, Ma'ayan, Avi, Madan, Rashna, Mareedu, Sailaja, McGarvey, Peter B., Modugno, Francesmary, Montgomery, Rebecca, Nyce, Kristen, Paulovich, Amanda G., Pruetz, Barbara L., Qi, Liqun, Richey, Shannon, Schadt, Eric E., Shutack, Yvonne, Singh, Shilpi, Smith, Michael, Tansil, Darlene, Thangudu, Ratna R., Tobin, Matt, Um, Ki Sung, Vatanian, Negin, Webster, Alex, Wilson, George D., Wright, Jason, Zaalishvili, Kakhaber, Zhang, Zhen, Zhao, Grace, Dou, Yongchao, Katsnelson, Lizabeth, Gritsenko, Marina A., Hu, Yingwei, Reva, Boris, Hong, Runyu, Wang, Yi-Ting, Kolodziejczak, Iga, Lu, Rita Jui-Hsien, Tsai, Chia-Feng, Bu, Wen, Liu, Wenke, Guo, Xiaofang, An, Eunkyung, Arend, Rebecca C., Bavarva, Jasmin, Chen, Lijun, Chu, Rosalie K., Czekański, Andrzej, Davoli, Teresa, Demicco, Elizabeth G., DeLair, Deborah, Devereaux, Kelly, Dhanasekaran, Saravana M., Dottino, Peter, Dover, Bailee, Fillmore, Thomas L., Foxall, McKenzie, Hermann, Catherine E., Hiltke, Tara, Hostetter, Galen, Jędryka, Marcin, Jewell, Scott D., Johnson, Isabelle, Kahn, Andrea G., Ku, Amy T., Kumar-Sinha, Chandan, Kurzawa, Paweł, Lazar, Alexander J., Lazcano, Rossana, Lei, Jonathan T., Li, Yi, Liao, Yuxing, Lih, Tung-Shing M., Lin, Tai-Tu, Martignetti, John A., Masand, Ramya P., Matkowski, Rafał, McKerrow, Wilson, Mesri, Mehdi, Monroe, Matthew E., Moon, Jamie, Moore, Ronald J., Nestor, Michael D., Newton, Chelsea, Omelchenko, Tatiana, Omenn, Gilbert S., Payne, Samuel H., Petyuk, Vladislav A., Robles, Ana I., Rodriguez, Henry, Ruggles, Kelly V., Rykunov, Dmitry, Savage, Sara R., Schepmoes, Athena A., Shi, Tujin, Shi, Zhiao, Tan, Jimin, Taylor, Mason, Thiagarajan, Mathangi, Wang, Joshua M., Weitz, Karl K., Wen, Bo, Williams, C.M., Wu, Yige, Wyczalkowski, Matthew A., Yi, Xinpei, Zhang, Xu, Zhao, Rui, Mutch, David, Chinnaiyan, Arul M., Smith, Richard D., Nesvizhskii, Alexey I., Wang, Pei, Wiznerowicz, Maciej, Ding, Li, Mani, D.R., Zhang, Hui, Anderson, Matthew L., Rodland, Karin D., Zhang, Bing, Liu, Tao, and Fenyö, David

Published
2023
Full Text
View/download PDF

16. Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin

Author

Aguet, François, Akiyama, Yo, An, Eunkyung, Anand, Shankara, Anurag, Meenakshi, Babur, Ozgun, Bavarva, Jasmin, Birger, Chet, Birrer, Michael, Calinawan, Anna, Cantley, Lewis C., Cao, Song, Carr, Steve, Ceccarelli, Michele, Chan, Daniel, Chinnaiyan, Arul, Cho, Hanbyul, Chowdhury, Shrabanti, Cieslik, Marcin, Clauser, Karl, Colaprico, Antonio, Zhou, Daniel Cui, da Veiga Leprevost, Felipe, Day, Corbin, Dhanasekaran, Mohan, Domagalski, Marcin, Dou, Yongchao, Druker, Brian, Edwards, Nathan, Ellis, Matthew, Selvan, Myvizhi Esai, Francis, Alicia, Getz, Gad, Gillette, Michael A., Robles, Tania Gonzalez, Gosline, Sara, Gümüş, Zeynep, Heiman, David, Hiltke, Tara, Hong, Runyu, Hostetter, Galen, Hu, Yingwei, Huang, Chen, Huntsman, Emily, Iavarone, Antonio, Jaehnig, Eric, Jewel, Scott, Ji, Jiayi, Jiang, Wen, Lee Johnson, Jared, Katsnelson, Lizabeth, Ketchum, Karen, Krug, Karsten, Kumar-Sinha, Chandan, Lei, Jonathan, Liao, Yuxing, Lindgren, Caleb, Liu, Tao, Liu, Wenke, Ma, Weiping, Rodrigues, Fernanda Martins, McKerrow, Wilson, Mesri, Mehdi, Nesvizhskii, Alexey I., Newton, Chelsea, Oldroyd, Robert, Omenn, Gilbert, Paulovich, Amanda, Petralia, Francesca, Pugliese, Pietro, Reva, Boris, Ruggles, Kelly, Rykunov, Dmitry, Satpathy, Shankha, Savage, Sara, Schadt, Eric, Schnaubelt, Michael, Schraink, Tobias, Shi, Zhiao, Smith, Dick, Song, Xiaoyu, Stathias, Vasileios, Storrs, Erik, Tan, Jimin, Terekhanova, Nadezhda, Thangudu, Ratna, Thiagarajan, Mathangi, Tignor, Nicole, Wang, Joshua, Wang, Liang-Bo, Wang, Pei, Wang, Ying (Cindy), Wen, Bo, Wu, Yige, Yao, Lijun, Yaron, Tomer M., Yi, Xinpei, Zhang, Bing, Zhang, Hui, Zhang, Qing, Zhang, Xu, Zhang, Zhen, Chan, Daniel W., Dhanasekaran, Saravana M., Schürer, Stephan, Smith, Richard D., Wyczalkowski, Matthew A., Liang, Wen-Wei, Lu, Rita Jui-Hsien, Jayasinghe, Reyka G., Foltz, Steven M., Porta-Pardo, Eduard, Geffen, Yifat, Wendl, Michael C., Lazcano, Rossana, Kolodziejczak, Iga, Song, Yizhe, Govindan, Akshay, Demicco, Elizabeth G., Li, Xiang, Li, Yize, Sethuraman, Sunantha, Payne, Samuel H., Fenyö, David, Rodriguez, Henry, Wiznerowicz, Maciej, Shen, Hui, Mani, D.R., Rodland, Karin D., Lazar, Alexander J., Robles, Ana I., and Ding, Li

Published
2023
Full Text
View/download PDF

17. A randomized phase II trial of bevacizumab vs. bevacizumab and erlotinib as first-line consolidation after carboplatin, paclitaxel, and bevacizumab in newly diagnosed patients with mullerian tumors

Author

Campos, Susana, Matulonis, Ursula, Berlin, Suzanne, Horowitz, Neil, Liu, Joyce, Krasner, Carolyn, Hang, Lee, Zarwan, Corrine, Barry, William, Colella, Tina, Whalen, Christen, Shoni, Melina, Lundquist, Christine, Birrer, Michael J., and Penson, Richard

Published
2022
Full Text
View/download PDF

18. Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation

Author

An, Eunkyung, Anurag, Meenakshi, Bavarva, Jasmin, Birrer, Michael J., Babur, Özgün, Cao, Song, Ceccarelli, Michele, Chan, Daniel W., Chinnaiyan, Arul M., Cho, Hanbyul, Chowdhury, Shrabanti, Cieslik, Marcin P., Colaprico, Antonio, Carr, Steven A., da Veiga Leprevost, Felipe, Day, Corbin, Domagalski, Marcin J., Dou, Yongchao, Druker, Brian J., Edwards, Nathan, Ellis, Matthew J., Fenyo, David, Foltz, Steven M., Francis, Alicia, Gonzalez Robles, Tania J., Gosline, Sara J.C., Gümüş, Zeynep H., Hiltke, Tara, Hong, Runyu, Hostetter, Galen, Hu, Yingwei, Huang, Chen, Iavarone, Antonio, Jaehnig, Eric J., Jewel, Scott D., Ji, Jiayi, Jiang, Wen, Katsnelson, Lizabeth, Ketchum, Karen A., Kolodziejczak, Iga, Kumar-Sinha, Chandan, Krug, Karsten, Lei, Jonathan T., Liang, Wen-Wei, Liao, Yuxing, Lindgren, Caleb M., Liu, Tao, Liu, Wenke, Ma, Weiping, McKerrow, Wilson, Mesri, Mehdi, Mani, D.R., Nesvizhskii, Alexey I., Newton, Chelsea, Oldroyd, Robert, Omenn, Gilbert S., Paulovich, Amanda G., Petralia, Francesca, Pugliese, Pietro, Reva, Boris, Rodland, Karin D., Ruggles, Kelly V., Rykunov, Dmitry, Rodrigues, Fernanda Martins, Savage, Sara R., Schadt, Eric E., Schnaubelt, Michael, Schraink, Tobias, Shi, Zhiao, Smith, Richard D., Song, Xiaoyu, Stathias, Vasileios, Storrs, Erik P., Schürer, Stephan, Selvan, Myvizhi Esai, Tan, Jimin, Terekhanova, Nadezhda V., Thangudu, Ratna R., Tignor, Nicole, Thiagarajan, Mathangi, Wang, Joshua M., Wang, Pei, Wang, Ying (Cindy), Wen, Bo, Wiznerowicz, Maciej, Wu, Yige, Wyczalkowski, Matthew A., Yao, Lijun, Yi, Xinpei, Zhang, Bing, Zhang, Hui, Zhang, Xu, Zhang, Zhen, Zhou, Daniel Cui, Geffen, Yifat, Anand, Shankara, Akiyama, Yo, Yaron, Tomer M., Song, Yizhe, Johnson, Jared L., Govindan, Akshay, Li, Yize, Huntsman, Emily, Wang, Liang-Bo, Birger, Chet, Heiman, David I., Zhang, Qing, Miller, Mendy, Maruvka, Yosef E., Haradhvala, Nicholas J., Calinawan, Anna, Belkin, Saveliy, Kerelsky, Alexander, Clauser, Karl R., Satpathy, Shankha, Payne, Samuel H., Gillette, Michael A., Dhanasekaran, Saravana M., Rodriguez, Henry, Robles, Ana I., Lazar, Alexander J., Aguet, François, Cantley, Lewis C., Ding, Li, and Getz, Gad

Published
2023
Full Text
View/download PDF

19. Pan-cancer proteogenomics connects oncogenic drivers to functional states

Author

An, Eunkyung, Anurag, Meenakshi, Bavarva, Jasmin, Birrer, Michael J., Calinawan, Anna, Ceccarelli, Michele, Chan, Daniel W., Chinnaiyan, Arul M., Cho, Hanbyul, Chowdhury, Shrabanti, Cieslik, Marcin P., da Veiga Leprevost, Felipe, Day, Corbin, Domagalski, Marcin J., Dou, Yongchao, Druker, Brian J., Edwards, Nathan, Ellis, Matthew J., Selvan, Myvizhi Esai, Foltz, Steven M., Francis, Alicia, Gonzalez Robles, Tania J., Gosline, Sara J.C., Gümüş, Zeynep H., Hiltke, Tara, Hong, Runyu, Hostetter, Galen, Hu, Yingwei, Huang, Chen, Huntsman, Emily, Jaehnig, Eric J., Jewel, Scott D., Ji, Jiayi, Jiang, Wen, Katsnelson, Lizabeth, Ketchum, Karen A., Kolodziejczak, Iga, Lei, Jonathan T., Liao, Yuxing, Lindgren, Caleb M., Liu, Tao, Ma, Weiping, McKerrow, Wilson, Nesvizhskii, Alexey I., Newton, Chelsea, Oldroyd, Robert, Omenn, Gilbert S., Paulovich, Amanda G., Petralia, Francesca, Reva, Boris, Rodland, Karin D., Ruggles, Kelly V., Rykunov, Dmitry, Savage, Sara R., Schadt, Eric E., Schnaubelt, Michael, Schraink, Tobias, Shi, Zhiao, Smith, Richard D., Song, Xiaoyu, Tan, Jimin, Thangudu, Ratna R., Tignor, Nicole, Wang, Joshua M., Wang, Pei, Wang, Ying (Cindy), Wen, Bo, Wiznerowicz, Maciej, Yi, Xinpei, Zhang, Bing, Zhang, Hui, Zhang, Xu, Zhang, Zhen, Li, Yize, Porta-Pardo, Eduard, Tokheim, Collin, Bailey, Matthew H., Yaron, Tomer M., Stathias, Vasileios, Geffen, Yifat, Imbach, Kathleen J., Cao, Song, Anand, Shankara, Akiyama, Yo, Liu, Wenke, Wyczalkowski, Matthew A., Song, Yizhe, Storrs, Erik P., Wendl, Michael C., Zhang, Wubing, Sibai, Mustafa, Ruiz-Serra, Victoria, Liang, Wen-Wei, Terekhanova, Nadezhda V., Rodrigues, Fernanda Martins, Clauser, Karl R., Heiman, David I., Zhang, Qing, Aguet, Francois, Calinawan, Anna P., Dhanasekaran, Saravana M., Birger, Chet, Satpathy, Shankha, Zhou, Daniel Cui, Wang, Liang-Bo, Baral, Jessika, Johnson, Jared L., Huntsman, Emily M., Pugliese, Pietro, Colaprico, Antonio, Iavarone, Antonio, Chheda, Milan G., Ricketts, Christopher J., Fenyö, David, Payne, Samuel H., Rodriguez, Henry, Robles, Ana I., Gillette, Michael A., Kumar-Sinha, Chandan, Lazar, Alexander J., Cantley, Lewis C., Getz, Gad, and Ding, Li

Published
2023
Full Text
View/download PDF

20. Proteogenomic data and resources for pan-cancer analysis

Author

Lazar, Alexander J., Paulovich, Amanda G., Colaprico, Antonio, Iavarone, Antonio, Chinnaiyan, Arul M., Druker, Brian J., Kumar-Sinha, Chandan, Newton, Chelsea J., Huang, Chen, Mani, D.R., Smith, Richard D., Huntsman, Emily, Schadt, Eric E., An, Eunkyung, Petralia, Francesca, Hostetter, Galen, Omenn, Gilbert S., Cho, Hanbyul, Rodriguez, Henry, Zhang, Hui, Kolodziejczak, Iga, Johnson, Jared L., Bavarva, Jasmin, Tan, Jimin, Rodland, Karin D., Clauser, Karl R., Krug, Karsten, Cantley, Lewis C., Wiznerowicz, Maciej, Ellis, Matthew J., Anurag, Meenakshi, Mesri, Mehdi, Gillette, Michael A., Birrer, Michael J., Ceccarelli, Michele, Dhanasekaran, Saravana M., Edwards, Nathan, Tignor, Nicole, Babur, Özgün, Pugliese, Pietro, Gosline, Sara J.C., Jewell, Scott D., Satpathy, Shankha, Chowdhury, Shrabanti, Schürer, Stephan, Carr, Steven A., Liu, Tao, Hiltke, Tara, Yaron, Tomer M., Stathias, Vasileios, Liu, Wenke, Zhang, Xu, Song, Yizhe, Zhang, Zhen, Li, Yize, Dou, Yongchao, Da Veiga Leprevost, Felipe, Geffen, Yifat, Calinawan, Anna P., Aguet, François, Akiyama, Yo, Anand, Shankara, Birger, Chet, Cao, Song, Chaudhary, Rekha, Chilappagari, Padmini, Cieslik, Marcin, Zhou, Daniel Cui, Day, Corbin, Domagalski, Marcin J., Esai Selvan, Myvizhi, Fenyö, David, Foltz, Steven M., Francis, Alicia, Gonzalez-Robles, Tania, Gümüş, Zeynep H., Heiman, David, Holck, Michael, Hong, Runyu, Hu, Yingwei, Jaehnig, Eric J., Ji, Jiayi, Jiang, Wen, Katsnelson, Lizabeth, Ketchum, Karen A., Klein, Robert J., Lei, Jonathan T., Liang, Wen-Wei, Liao, Yuxing, Lindgren, Caleb M., Ma, Weiping, Ma, Lei, MacCoss, Michael J., Martins Rodrigues, Fernanda, McKerrow, Wilson, Nguyen, Ngoc, Oldroyd, Robert, Pilozzi, Alexander, Reva, Boris, Rudnick, Paul, Ruggles, Kelly V., Rykunov, Dmitry, Savage, Sara R., Schnaubelt, Michael, Schraink, Tobias, Shi, Zhiao, Singhal, Deepak, Song, Xiaoyu, Storrs, Erik, Terekhanova, Nadezhda V., Thangudu, Ratna R., Thiagarajan, Mathangi, Wang, Liang-Bo, Wang, Joshua M., Wang, Ying, Wen, Bo, Wu, Yige, Wyczalkowski, Matthew A., Xin, Yi, Yao, Lijun, Yi, Xinpei, Zhang, Qing, Zuhl, Maya, Getz, Gad, Ding, Li, Nesvizhskii, Alexey I., Wang, Pei, Robles, Ana I., Zhang, Bing, and Payne, Samuel H.

Published
2023
Full Text
View/download PDF

21. Circulating Tumor Cells In Advanced Cervical Cancer: NRG Oncology—Gynecologic Oncology Group Study 240 (NCT 00803062)

Author

Tewari, Krishnansu S, Sill, Michael W, Monk, Bradley J, Penson, Richard T, Moore, David H, Lankes, Heather A, Ramondetta, Lois M, Landrum, Lisa M, Randall, Leslie M, Oaknin, Ana, Leitao, Mario M, Eisenhauer, Eric L, DiSilvestro, Paul, Van Le, Linda, Pearl, Michael L, Burke, James J, Salani, Ritu, Richardson, Debra L, Michael, Helen E, Kindelberger, David W, and Birrer, Michael J

Subjects
Cervical Cancer, Clinical Research, Cancer, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Disease Management, Female, Humans, Kaplan-Meier Estimate, Middle Aged, Molecular Targeted Therapy, Neoplastic Cells, Circulating, Prognosis, Treatment Outcome, Uterine Cervical Neoplasms, Oncology and Carcinogenesis, Pharmacology and Pharmaceutical Sciences, Oncology & Carcinogenesis
Abstract

To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the antiangiogenesis drug, bevacizumab, in women with recurrent/metastatic cervical cancer. CTCs (defined as anti-cytokeratin+/anti-CD45- cells) were isolated from the buffy coat layer using an anti-EpCAM antibody-conjugated ferrofluid and rare earth magnet, and counted using a semiautomated fluorescence microscope. The median pre-cycle 1 CTC count was 7 CTCs/7.5 mL whole blood (range, 0-18) and, at 36 days posttreatment, was 4 (range, 0-17). The greater the declination in CTCs between time points studied, the lower the risk of death [HR, 0.87; 95% confidence interval (CI), 0.79-0.95)]. Among patients with high (≥ median) pretreatment CTCs, bevacizumab treatment was associated with a reduction in the hazard of death (HR, 0.57; 95% CI, 0.32-1.03) and PFS (HR, 0.59; 95% CI, 0.36-0.96). This effect was not observed with low (< median) CTCs. CTCs can be isolated from women with advanced cervical cancer and may have prognostic significance. A survival benefit conferred by bevacizumab among patients with high pretreatment CTCs may reflect increased tumor neovascularization and concomitant vulnerability to VEGF inhibition. These data support studying CTC capture as a potential predictive biomarker.

Published
2020

22. Predictive Blood-Based Biomarkers in Patients with Epithelial Ovarian Cancer Treated with Carboplatin and Paclitaxel with or without Bevacizumab: Results from GOG-0218.

Author

Alvarez Secord, Angeles, Bell Burdett, Kirsten, Owzar, Kouros, Tritchler, David, Sibley, Alexander, Liu, Yingmiao, Starr, Mark, Brady, J, Lankes, Heather, Hurwitz, Herbert, Mannel, Robert, Tewari, Krishnansu, OMalley, David, Gray, Heidi, Bakkum-Gamez, Jamie, Fujiwara, Keiichi, Boente, Matthew, Deng, Wenbin, Burger, Robert, Birrer, Michael, and Nixon, Andrew

Subjects
Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Biomarkers, Tumor, Carboplatin, Carcinoma, Ovarian Epithelial, Double-Blind Method, Female, Humans, Interleukin-6, Middle Aged, Ovarian Neoplasms, Paclitaxel, Survival Rate
Abstract

PURPOSE: GOG-0218, a double-blind placebo-controlled phase III trial, compared carboplatin and paclitaxel with placebo, bevacizumab followed by placebo, or bevacizumab followed by bevacizumab in advanced epithelial ovarian cancer (EOC). Results demonstrated significantly improved progression-free survival (PFS), but no overall survival (OS) benefit with bevacizumab. Blood samples were collected for biomarker analyses. EXPERIMENTAL DESIGN: Plasma samples were analyzed via multiplex ELISA technology for seven prespecified biomarkers [IL6, Ang-2, osteopontin (OPN), stromal cell-derived factor-1 (SDF-1), VEGF-D, IL6 receptor (IL6R), and GP130]. The predictive value of each biomarker with respect to PFS and OS was assessed using a protein marker by treatment interaction term within the framework of a Cox proportional hazards model. Prognostic markers were identified using Cox models adjusted for baseline covariates. RESULTS: Baseline samples were available from 751 patients. According to our prespecified analysis plan, IL6 was predictive of a therapeutic advantage with bevacizumab for PFS (P = 0.007) and OS (P = 0.003). IL6 and OPN were found to be negative prognostic markers for both PFS and OS (P < 0.001). Patients with high median IL6 levels (dichotomized at the median) treated with bevacizumab had longer PFS (14.2 vs. 8.7 months) and OS (39.6 vs. 33.1 months) compared with placebo. CONCLUSIONS: The inflammatory cytokine IL6 may be predictive of therapeutic benefit from bevacizumab when combined with carboplatin and paclitaxel. Aligning with results observed in patients with renal cancer treated with antiangiogenic therapies, it appears plasma IL6 may also define those patients with EOC more or less likely to benefit from the addition of bevacizumab to standard chemotherapy.

Published
2020

23. Predictive Blood-Based Biomarkers in Patients with Epithelial Ovarian Cancer Treated with Carboplatin and Paclitaxel with or without Bevacizumab: Results from GOG-0218

Author

Secord, Angeles Alvarez, Burdett, Kirsten Bell, Owzar, Kouros, Tritchler, David, Sibley, Alexander B, Liu, Yingmiao, Starr, Mark D, Brady, J Chris, Lankes, Heather A, Hurwitz, Herbert I, Mannel, Robert S, Tewari, Krishnansu S, O'Malley, David M, Gray, Heidi, Bakkum-Gamez, Jamie N, Fujiwara, Keiichi, Boente, Matthew, Deng, Wei, Burger, Robert A, Birrer, Michael J, and Nixon, Andrew B

Subjects
Clinical Trials and Supportive Activities, Ovarian Cancer, Rare Diseases, Clinical Research, Cancer, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Biomarkers, Tumor, Carboplatin, Carcinoma, Ovarian Epithelial, Double-Blind Method, Female, Humans, Interleukin-6, Middle Aged, Ovarian Neoplasms, Paclitaxel, Survival Rate, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeGOG-0218, a double-blind placebo-controlled phase III trial, compared carboplatin and paclitaxel with placebo, bevacizumab followed by placebo, or bevacizumab followed by bevacizumab in advanced epithelial ovarian cancer (EOC). Results demonstrated significantly improved progression-free survival (PFS), but no overall survival (OS) benefit with bevacizumab. Blood samples were collected for biomarker analyses.Experimental designPlasma samples were analyzed via multiplex ELISA technology for seven prespecified biomarkers [IL6, Ang-2, osteopontin (OPN), stromal cell-derived factor-1 (SDF-1), VEGF-D, IL6 receptor (IL6R), and GP130]. The predictive value of each biomarker with respect to PFS and OS was assessed using a protein marker by treatment interaction term within the framework of a Cox proportional hazards model. Prognostic markers were identified using Cox models adjusted for baseline covariates.ResultsBaseline samples were available from 751 patients. According to our prespecified analysis plan, IL6 was predictive of a therapeutic advantage with bevacizumab for PFS (P = 0.007) and OS (P = 0.003). IL6 and OPN were found to be negative prognostic markers for both PFS and OS (P < 0.001). Patients with high median IL6 levels (dichotomized at the median) treated with bevacizumab had longer PFS (14.2 vs. 8.7 months) and OS (39.6 vs. 33.1 months) compared with placebo.ConclusionsThe inflammatory cytokine IL6 may be predictive of therapeutic benefit from bevacizumab when combined with carboplatin and paclitaxel. Aligning with results observed in patients with renal cancer treated with antiangiogenic therapies, it appears plasma IL6 may also define those patients with EOC more or less likely to benefit from the addition of bevacizumab to standard chemotherapy.

Published
2020

25. Contributors

Author

Backes, Floor J., primary, Beffa, Lindsey B., additional, Billingsley, Caroline C., additional, Birrer, Michael J., additional, Bixel, Kristin, additional, Boitano, Teresa K.L., additional, Brewster, Wendy R., additional, Chase, Dana M., additional, Bruce, Shaina, additional, Crown, Angelena, additional, Chu, Christina S., additional, Clarke-Pearson, Daniel L., additional, Ross, Robert A., additional, Crosland, Brian, additional, Cohen, Joshua G., additional, Coleman, Robert L., additional, DiSilvestro, Paul A., additional, Dorigo, Oliver, additional, Duska, Linda R., additional, Eskander, Ramez Nassef, additional, Gemignani, Mary L., additional, Gunderson, Camille Catherine, additional, Hagemann, Andrea R., additional, Herzog, Thomas J., additional, Korenaga, Travis R., additional, Huh, Warner K., additional, Kuroki, Lindsay, additional, Kurnit, Katherine, additional, Mannel, Robert S., additional, Massad, L. Stewart, additional, Mathews, Cara A., additional, Miller, David S., additional, Monk, Bradley J., additional, Mutch, David G., additional, Nikam, Rachita, additional, Pinkerton, JoAnn V., additional, Powell, Matthew, additional, Rash, Dominique L., additional, Landrum, Lisa M., additional, Ring, Kari L., additional, Renz, Malte, additional, Roane, Brandon, additional, Rubin, Stephen C., additional, Salani, Ritu, additional, Satero, Jane, additional, Sood, Anil K., additional, Soper, John T., additional, Stock, Elizabeth Christina, additional, Sung, C. James, additional, Tewari, Krishnansu Sujata, additional, Toboni, Michael D., additional, Tucker, Katherine, additional, Walker, Joan L., additional, Wall, Jaclyn A., additional, Washington, Christina, additional, Wenzel, Lari B., additional, Westin, Shannon N., additional, Yashar, Catheryn M., additional, Creasman, William T., additional, and Zuna, Rosemary E., additional

Published
2023
Full Text
View/download PDF

27. Metabolically active neutrophils represent a permissive niche for Mycobacterium tuberculosis

Author

Tucker Andrews, J., primary, Zhang, Zijing, additional, Krishna Prasad, G.V.R., additional, Huey, Fischer, additional, Nazarova, Evgenia V., additional, Wang, Jocelyn, additional, Ranaraja, Ananya, additional, Weinkopff, Tiffany, additional, Li, Lin-Xi, additional, Mu, Shengyu, additional, Birrer, Michael J., additional, Ching-Cheng Huang, Stanley, additional, Zhang, Nan, additional, Argüello, Rafael J., additional, Philips, Jennifer A., additional, Mattila, Joshua T., additional, and Huang, Lu, additional

Published
2024
Full Text
View/download PDF

28. BLU-222, an investigational, oral, potent, and highly selective CDK2 inhibitor (CDK2i), as monotherapy in patients (pts) with advanced solid tumors and in combination with ribociclib (RIBO) and fulvestrant (FUL) in HR+/HER2− breast cancer (BC).

Author

Juric, Dejan, primary, Patel, Manish R., additional, Duska, Linda R., additional, Jhaveri, Komal L., additional, Henick, Brian S., additional, Matulonis, Ursula A., additional, Munster, Pamela N., additional, Birrer, Michael J., additional, Moore, Kathleen N., additional, Curigliano, Giuseppe, additional, Li, Chia-Cheng, additional, Guo, Jian, additional, He, Kevin, additional, Wu, Rentian, additional, Tamulevich, Sam, additional, Rinne, Mikael, additional, and Yap, Timothy A., additional

Published
2024
Full Text
View/download PDF

30. Final Overall Survival of a Randomized Trial of Bevacizumab for Primary Treatment of Ovarian Cancer.

Author

Tewari, Krishnansu S, Burger, Robert A, Enserro, Danielle, Norquist, Barbara M, Swisher, Elizabeth M, Brady, Mark F, Bookman, Michael A, Fleming, Gini F, Huang, Helen, Homesley, Howard D, Fowler, Jeffrey M, Greer, Benjamin E, Boente, Matthew, Liang, Sharon X, Ye, Chenglin, Bais, Carlos, Randall, Leslie M, Chan, John K, Ferriss, J Stuart, Coleman, Robert L, Aghajanian, Carol, Herzog, Thomas J, DiSaia, Philip J, Copeland, Larry J, Mannel, Robert S, Birrer, Michael J, and Monk, Bradley J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Ovarian Cancer, Clinical Research, Rare Diseases, Genetics, Cancer, Breast Cancer, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Carboplatin, Carcinoma, Ovarian Epithelial, Double-Blind Method, Female, Humans, Kaplan-Meier Estimate, Middle Aged, Ovarian Neoplasms, Paclitaxel, Young Adult, Clinical Sciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

PurposeWe report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma.MethodsA total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m2) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry.ResultsMedian follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non-BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity.ConclusionNo survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

Published
2019

31. GOG 8020/210: Risk stratification of lymph node metastasis, disease progression and survival using single nucleotide polymorphisms in endometrial cancer: An NRG oncology/gynecologic oncology group study

Author

Brooks, Rebecca A, Tritchler, David S, Darcy, Kathleen M, Lankes, Heather A, Salani, Ritu, Sperduto, Paul, Guntupalli, Saketh, DiSilvestro, Paul, Kesterson, Joshua, Olawaiye, Alexander B, Moxley, Katherine, Waggoner, Steven, Santin, Alessandro, Rader, Janet S, Kizer, Nora T, Thaker, Premal H, Powell, Matthew A, Mutch, David G, Birrer, Michael J, and Goodfellow, Paul J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Cancer, Clinical Research, Genetics, Patient Safety, Uterine Cancer, 2.1 Biological and endogenous factors, Aetiology, Aged, Biomarkers, Tumor, Case-Control Studies, Disease Progression, Endometrial Neoplasms, Endometrium, ErbB Receptors, Female, Humans, Lymphatic Metastasis, Middle Aged, NM23 Nucleoside Diphosphate Kinases, Neoplasm Staging, Polymorphism, Single Nucleotide, Prognosis, Progression-Free Survival, Risk Assessment, Endometrial cancer, Risk stratification, SNP association, Node positivity, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis, Reproductive medicine
Abstract

ObjectivesThe ability to stratify a patient's risk of metastasis and survival permits more refined care. A proof of principle study was undertaken to investigate the relationship between single nucleotide polymorphisms (SNPs) in literature based candidate cancer genes and the risk of nodal metastasis and clinical outcome in endometrioid endometrial cancer (EEC) patients.MethodsSurgically-staged EEC patients from the Gynecologic Oncology Group or Washington University School of Medicine with germline DNA available were eligible. Fifty-four genes represented by 384 SNPs, were evaluated by Illumina Custom GoldenGate array. Association with lymph node metastases was the primary outcome. Progression-free survival (PFS) and overall survival (OS) was also evaluated.Results361 SNPs with high quality genotype data were evaluated in 337 patients with outcome data. Five SNPs in CXCR2 had an odds ratio (OR) between 0.68 and 0.70 (p-value ≤ 0.025). The A allele rs946486 in ABL had an OR of 1.5 (p-value = 0.01) for metastasis. The G allele in rs7795743 in EGFR had an OR for metastasis of 0.68 (p-value = 0.02) and hazard ratio (HR) for progression of 0.66 (p-value = 0.004). Importantly, no SNP met genome wide significance after adjusting for multiple test correcting and clinical covariates. The A allele in rs2159359 SNP in NME1 and the G allele in rs13222385 in EGFR were associated with worse OS. Both exhibited genome wide significance; rs13222385 remained significant after adjusting for prognostic clinical variables.ConclusionSNPs in cancer genes including rs2159359 SNP in NME1 and rs13222385 in EGFR may stratify risk in EEC and are prioritized for further investigation.

Published
2019

32. Ovarian Cancer Maintenance: Practice‐Changing Data Calls for Changing Practice

Author

Randall, Leslie M, Birrer, Michael J, and Herzog, Thomas J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Chemotherapy, Adjuvant, Clinical Trials as Topic, Cytoreduction Surgical Procedures, Female, Humans, Maintenance Chemotherapy, Medical Oncology, Neoplasm Recurrence, Local, Ovarian Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Progression-Free Survival, Treatment Outcome, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Staying current on the rapidly evolving therapeutic landscape in oncology is challenging for clinicians. This commentary discusses exciting practice‐changing data specific to ovarian cancer.

Published
2019

34. Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: An NRG Oncology/Gynecologic Oncology Group Study.

Author

Norquist, Barbara, Brady, Mark, Harrell, Maria, Walsh, Tom, Lee, Ming, Gulsuner, Suleyman, Bernards, Sarah, Casadei, Silvia, Burger, Robert, Backes, Floor, Mannel, Robert, Glaser, Gretchen, Bailey, Cheryl, Rubin, Stephen, Soper, John, Lankes, Heather, Ramirez, Nilsa, King, Mary, Birrer, Michael, Swisher, Elizabeth, and Tewari, Krishnansu

Subjects
Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Carboplatin, DNA Copy Number Variations, Female, Humans, Kaplan-Meier Estimate, Middle Aged, Mutation, Outcome Assessment, Health Care, Ovarian Neoplasms, Paclitaxel, Proportional Hazards Models, Recombinational DNA Repair
Abstract

Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab.Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS).Results: Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non-BRCA HRR mutations [HR = 0.73; 95% confidence interval (CI), 0.57-0.94; P = 0.01 for PFS; HR = 0.67; 95% CI, 0.50-0.90; P = 0.007 for OS] and BRCA1 mutations (HR = 0.80; 95% CI, 0.66-0.97; P = 0.02 for PFS; HR = 0.74; 95% CI, 0.59-0.94; P = 0.01 for OS) and were lowest for BRCA2 mutations (HR = 0.52; 95% CI, 0.40-0.67; P < 0.0001 for PFS; HR = 0.36; 95% CI, 0.25-0.53; P < 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations.Conclusions: HRR mutations, including non-BRCA genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status. Clin Cancer Res; 24(4); 777-83. ©2017 AACR.

Published
2018

35. Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer

Author

Huang, Dongqing, Chowdhury, Shrabanti, Wang, Hong, Savage, Sara R., Ivey, Richard G., Kennedy, Jacob J., Whiteaker, Jeffrey R., Lin, Chenwei, Hou, Xiaonan, Oberg, Ann L., Larson, Melissa C., Eskandari, Najmeh, Delisi, Davide A., Gentile, Saverio, Huntoon, Catherine J., Voytovich, Uliana J., Shire, Zahra J., Yu, Qing, Gygi, Steven P., Hoofnagle, Andrew N., Herbert, Zachary T., Lorentzen, Travis D., Calinawan, Anna, Karnitz, Larry M., Weroha, S. John, Kaufmann, Scott H., Zhang, Bing, Wang, Pei, Birrer, Michael J., and Paulovich, Amanda G.

Published
2021
Full Text
View/download PDF

39. Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100): an open-label, randomised, phase 3 trial

Author

Monk, Bradley J, Colombo, Nicoletta, Oza, Amit M, Fujiwara, Keiichi, Birrer, Michael J, Randall, Leslie, Poddubskaya, Elena V, Scambia, Giovanni, Shparyk, Yaroslav V, Lim, Myong Cheol, Bhoola, Snehalkumar M, Sohn, Joohyuk, Yonemori, Kan, Stewart, Ross A, Zhang, Xiaoxi, Perkins Smith, Julia, Linn, Carlos, and Ledermann, Jonathan A

Published
2021
Full Text
View/download PDF

41. Genome-wide association study evaluating single-nucleotide polymorphisms and outcomes in patients with advanced stage serous ovarian or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study.

Author

Moore, Kathleen, Tritchler, David, Kaufman, Kenneth, Lankes, Heather, Quinn, Michael, Van Le, Linda, Berchuck, Andrew, Backes, Floor, Lee, Roger, Kesterson, Joshua, Wenham, Robert, Armstrong, Deborah, Krivak, Thomas, Bookman, Michael, Birrer, Michael, and Tewari, Krishnansu

Subjects
Advanced stage serous ovarian, Genome-wide association, Primary peritoneal cancer, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Cystadenocarcinoma, Serous, Female, Genome-Wide Association Study, Humans, Middle Aged, Neoplasm Staging, Ovarian Neoplasms, Peritoneal Neoplasms, Polymorphism, Single Nucleotide, Prognosis, Randomized Controlled Trials as Topic
Abstract

OBJECTIVE: This study evaluated single nucleotide polymorphisms (SNPs) associated with progression free (PFS) and overall survival (OS) in patients with advanced stage serous EOC. METHODS: Patients enrolled in GOG-172 and 182 who provided specimens for translational research and consent were included. Germline DNA was evaluated with the Illuminas HumanOMNI1-Quad beadchips and scanned using Illuminas iScan optical imaging system. SNPs with allele frequency>0.05 and genotyping rate>0.98 were included. Analysis of SNPs for PFS and OS was done using Cox regression. Statistical significance was determined using Bonferroni corrected p-values with genomic control adjustment. RESULTS: The initial GWAS analysis included 1,124,677 markers in 396 patients. To obtain the final data set, quality control checks were performed and limited to serous tumors and self-identified Caucasian race. In total 636,555 SNPs and 289 patients passed all the filters. The pre-specified statistical level of significance was 7.855e-08. No SNPs met this criteria for PFS or OS, however, two SNPs were close to significance (rs10899426 p-2.144e-08) (rs6256 p-9.774e-07) for PFS and 2 different SNPs were identified (rs295315 p-7.536e-07; rs17693104 p-7.734e-07) which were close to significance for OS. CONCLUSIONS: Using the pre-specified level of significance of 1×10-08, we did not identify any SNPs of statistical significance for OS or PFS, however several were close. The SNPs identified in this GWAS study will require validation and these preliminary findings may lead to identification of novel pathways and biomarkers.

Published
2017

42. An evaluation of progression free survival and overall survival of ovarian cancer patients with clear cell carcinoma versus serous carcinoma treated with platinum therapy: An NRG Oncology/Gynecologic Oncology Group experience

Author

Oliver, Kate E, Brady, William E, Birrer, Michael, Gershenson, David M, Fleming, Gini, Copeland, Larry J, Tewari, Krishnansu, Argenta, Peter A, Mannel, Robert S, Secord, Angeles Alvarez, Stephan, Jean-Marie, Mutch, David G, Stehman, Frederick B, Muggia, Franco M, Rose, Peter G, Armstrong, Deborah K, Bookman, Michael A, Burger, Robert A, and Farley, John H

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Clinical Research, Ovarian Cancer, Rare Diseases, Adenocarcinoma, Clear Cell, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Carboplatin, Cystadenocarcinoma, Serous, Disease-Free Survival, Female, Humans, Middle Aged, Neoplasm Staging, Ovarian Neoplasms, Paclitaxel, Prognosis, Proportional Hazards Models, Randomized Controlled Trials as Topic, Survival Rate, Clear cell, Histology, Ovarian, Survival, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis, Reproductive medicine
Abstract

PurposeWe examined disparities in prognosis between patients with ovarian clear cell carcinoma (OCCC) and serous epithelial ovarian cancer (SOC).MethodsWe reviewed data from FIGO stage I-IV epithelial ovarian cancer patients who participated in 12 prospective randomized GOG protocols. Proportional hazards models were used to compare progression-free survival (PFS) and overall survival (OS) by cell type (clear cell versus serous).ResultsThere were 10,803 patients enrolled, 9531 were eligible, evaluable and treated with platinum, of whom 544 (6%) had OCCC, 7054 (74%) had SOC, and 1933 (20%) had other histologies and are not included further. In early stage (I-II) patients, PFS was significantly better in OCCC than in SOC patients. For late stage (III, IV) patients, OCCC had worse PFS and OS compared to SOC, OS HR=1.66 (1.43, 1.91; p

Published
2017

43. Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Author

Network, The Cancer Genome Atlas Research, Abeshouse, Adam, Adebamowo, Clement, Adebamowo, Sally N, Akbani, Rehan, Akeredolu, Teniola, Ally, Adrian, Anderson, Matthew L, Anur, Pavana, Appelbaum, Elizabeth L, Armenia, Joshua, Auman, J Todd, Bailey, Matthew H, Baker, Laurence, Balasundaram, Miruna, Balu, Saianand, Barthel, Floris P, Bartlett, John, Baylin, Stephen B, Behera, Madhusmita, Belyaev, Dmitry, Bennett, Joesph, Benz, Christopher, Beroukhim, Rameen, Birrer, Michael, Bocklage, Thèrése, Bodenheimer, Tom, Boice, Lori, Bootwalla, Moiz S, Bowen, Jay, Bowlby, Reanne, Boyd, Jeff, Brohl, Andrew S, Brooks, Denise, Byers, Lauren, Carlsen, Rebecca, Castro, Patricia, Chen, Hsiao-Wei, Cherniack, Andrew D, Chibon, Fréderic, Chin, Lynda, Cho, Juok, Chuah, Eric, Chudamani, Sudha, Cibulskis, Carrie, Cooper, Lee AD, Cope, Leslie, Cordes, Matthew G, Crain, Daniel, Curley, Erin, Danilova, Ludmila, Dao, Fanny, Davis, Ian J, Davis, Lara E, Defreitas, Timothy, Delman, Keith, Demchok, John A, Demetri, George D, Demicco, Elizabeth G, Dhalla, Noreen, Diao, Lixia, Ding, Li, DiSaia, Phil, Dottino, Peter, Doyle, Leona A, Drill, Esther, Dubina, Michael, Eschbacher, Jennifer, Fedosenko, Konstantin, Felau, Ina, Ferguson, Martin L, Frazer, Scott, Fronick, Catrina C, Fulidou, Victoria, Fulton, Lucinda A, Fulton, Robert S, Gabriel, Stacey B, Gao, Jianjiong, Gao, Qingsong, Gardner, Johanna, Gastier-Foster, Julie M, Gay, Carl M, Gehlenborg, Nils, Gerken, Mark, Getz, Gad, Godwin, Andrew K, Godwin, Eryn M, Gordienko, Elena, Grilley-Olson, Juneko E, Gutman, David A, Gutmann, David H, Hayes, D Neil, Hegde, Apurva M, Heiman, David I, Heins, Zachary, Helsel, Carmen, Hepperla, Austin J, Higgins, Kelly, Hoadley, Katherine A, and Hobensack, Shital

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Cancer, Human Genome, Digestive Diseases, Rare Diseases, Adult, Aged, Aged, 80 and over, Cluster Analysis, DNA Copy Number Variations, Epigenomics, Genome, Human, Genome-Wide Association Study, Humans, Middle Aged, Mutation, Sarcoma, Young Adult, Cancer Genome Atlas Research Network. Electronic address: elizabeth.demicco@sinaihealthsystem.ca, Cancer Genome Atlas Research Network, DNA methylation, The Cancer Genome Atlas, dedifferentiated liposarcoma, genomics, immune infiltration, leiomyosarcoma, molecular subtype, myxofibrosarcoma, pleomorphism, undifferentiated pleomorphic sarcoma, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.

Published
2017

44. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240)

Author

Tewari, Krishnansu S, Sill, Michael W, Penson, Richard T, Huang, Helen, Ramondetta, Lois M, Landrum, Lisa M, Oaknin, Ana, Reid, Thomas J, Leitao, Mario M, Michael, Helen E, DiSaia, Philip J, Copeland, Larry J, Creasman, William T, Stehman, Frederick B, Brady, Mark F, Burger, Robert A, Thigpen, J Tate, Birrer, Michael J, Waggoner, Steven E, Moore, David H, Look, Katherine Y, Koh, Wui-Jin, and Monk, Bradley J

Subjects
Cancer, Clinical Research, Patient Safety, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adult, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Cisplatin, Disease Progression, Disease-Free Survival, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Middle Aged, Paclitaxel, Topotecan, Uterine Cervical Neoplasms, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundOn Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events.MethodsIn this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062.FindingsBetween April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (

Published
2017

45. High stathmin expression is a marker for poor clinical outcome in endometrial cancer: An NRG oncology group/gynecologic oncology group study

Author

Reyes, Henry D, Miecznikowski, Jeffrey, Gonzalez-Bosquet, Jesus, Devor, Eric J, Zhang, Yuping, Thiel, Kristina W, Samuelson, Megan I, McDonald, Megan, Stephan, Jean-Marie, Hanjani, Parviz, Guntupalli, Saketh, Tewari, Krishnansu S, Backes, Floor, Ramirez, Nilsa, Fleming, Gini F, Filiaci, Virginia, Birrer, Michael J, and Leslie, Kimberly K

Subjects
Uterine Cancer, Cancer, Aged, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Carcinoma, Endometrioid, Chemotherapy, Adjuvant, Cisplatin, Disease-Free Survival, Doxorubicin, Endometrial Neoplasms, Female, Humans, Hysterectomy, Immunohistochemistry, Middle Aged, Neoplasm Staging, Paclitaxel, Piperidines, Prognosis, Retrospective Studies, Stathmin, Survival Rate, Endometrial cancer, Oncology and Carcinogenesis, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis
Abstract

ObjectiveGynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin.MethodsWe analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer.ResultsWe first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin.ConclusionsOur findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases.

Published
2017

46. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Author

Phelan, Catherine M, Kuchenbaecker, Karoline B, Tyrer, Jonathan P, Kar, Siddhartha P, Lawrenson, Kate, Winham, Stacey J, Dennis, Joe, Pirie, Ailith, Riggan, Marjorie J, Chornokur, Ganna, Earp, Madalene A, Lyra, Paulo C, Lee, Janet M, Coetzee, Simon, Beesley, Jonathan, McGuffog, Lesley, Soucy, Penny, Dicks, Ed, Lee, Andrew, Barrowdale, Daniel, Lecarpentier, Julie, Leslie, Goska, Aalfs, Cora M, Aben, Katja KH, Adams, Marcia, Adlard, Julian, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia, AOCS study group, Aravantinos, Gerasimos, Arnold, Norbert, Arun, Banu K, Arver, Brita, Azzollini, Jacopo, Balmaña, Judith, Banerjee, Susana N, Barjhoux, Laure, Barkardottir, Rosa B, Bean, Yukie, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Birrer, Michael J, Bjorge, Line, Black, Amanda, Blankstein, Kenneth, Blok, Marinus J, Bodelon, Clara, Bogdanova, Natalia, Bojesen, Anders, Bonanni, Bernardo, Borg, Åke, Bradbury, Angela R, Brenton, James D, Brewer, Carole, Brinton, Louise, Broberg, Per, Brooks-Wilson, Angela, Bruinsma, Fiona, Brunet, Joan, Buecher, Bruno, Butzow, Ralf, Buys, Saundra S, Caldes, Trinidad, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Carney, Michael E, Cescon, Terence, Chan, Salina B, Chang-Claude, Jenny, Chanock, Stephen, Chen, Xiao Qing, Chiew, Yoke-Eng, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen BM, Conner, Thomas, Cook, Linda S, Cook, Jackie, Cramer, Daniel W, Cunningham, Julie M, D'Aloisio, Aimee A, Daly, Mary B, Damiola, Francesca, Damirovna, Sakaeva Dina, Dansonka-Mieszkowska, Agnieszka, Dao, Fanny, Davidson, Rosemarie, DeFazio, Anna, Delnatte, Capucine, Doheny, Kimberly F, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer Anne, Domchek, Susan M, and Dorfling, Cecilia M

Subjects
AOCS study group, EMBRACE Study, GEMO Study Collaborators, HEBON Study, KConFab Investigators, OPAL study group, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Telomere-Binding Proteins, BRCA1 Protein, BRCA2 Protein, Risk Factors, Genotype, Mutation, Polymorphism, Single Nucleotide, Alleles, Female, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, Carcinoma, Ovarian Epithelial, Genetics, Cancer, Human Genome, Rare Diseases, Prevention, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Published
2017

47. Integrated genomic and molecular characterization of cervical cancer

Author

Burk, Robert D, Chen, Zigui, Saller, Charles, Tarvin, Katherine, Carvalho, Andre L, Scapulatempo-Neto, Cristovam, Silveira, Henrique C, Fregnani, José H, Creighton, Chad J, Anderson, Matthew L, Castro, Patricia, Wang, Sophia S, Yau, Christina, Benz, Christopher, Robertson, A Gordon, Mungall, Karen, Lim, Lynette, Bowlby, Reanne, Sadeghi, Sara, Brooks, Denise, Sipahimalani, Payal, Mar, Richard, Ally, Adrian, Clarke, Amanda, Mungall, Andrew J, Tam, Angela, Lee, Darlene, Chuah, Eric, Schein, Jacqueline E, Tse, Kane, Kasaian, Katayoon, Ma, Yussanne, Marra, Marco A, Mayo, Michael, Balasundaram, Miruna, Thiessen, Nina, Dhalla, Noreen, Carlsen, Rebecca, Moore, Richard A, Holt, Robert A, Jones, Steven JM, Wong, Tina, Pantazi, Angeliki, Parfenov, Michael, Kucherlapati, Raju, Hadjipanayis, Angela, Seidman, Jonathan, Kucherlapati, Melanie, Ren, Xiaojia, Xu, Andrew W, Yang, Lixing, Park, Peter J, Lee, Semin, Rabeno, Brenda, Huelsenbeck-Dill, Lori, Borowsky, Mark, Cadungog, Mark, Iacocca, Mary, Petrelli, Nicholas, Swanson, Patricia, Ojesina, Akinyemi I, Le, Xuan, Sandusky, George, Adebamowo, Sally N, Akeredolu, Teniola, Adebamowo, Clement, Reynolds, Sheila M, Shmulevich, Ilya, Shelton, Candace, Crain, Daniel, Mallery, David, Curley, Erin, Gardner, Johanna, Penny, Robert, Morris, Scott, Shelton, Troy, Liu, Jia, Lolla, Laxmi, Chudamani, Sudha, Wu, Ye, Birrer, Michael, McLellan, Michael D, Bailey, Matthew H, Miller, Christopher A, Wyczalkowski, Matthew A, Fulton, Robert S, Fronick, Catrina C, Lu, Charles, Mardis, Elaine R, Appelbaum, Elizabeth L, Schmidt, Heather K, Fulton, Lucinda A, Cordes, Matthew G, Li, Tiandao, Ding, Li, Wilson, Richard K, Rader, Janet S, Behmaram, Behnaz, Uyar, Denise, and Bradley, William

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cervical Cancer, Cancer, Clinical Research, Human Genome, Sexually Transmitted Infections, Biotechnology, Genetics, 2.1 Biological and endogenous factors, Aetiology, APOBEC-1 Deaminase, Adenocarcinoma, B7-H1 Antigen, Carcinoma, Squamous Cell, Caspase 8, DNA-Binding Proteins, Female, Genomics, HLA-A Antigens, Human papillomavirus 16, Humans, Keratins, Mitogen-Activated Protein Kinase Kinases, Molecular Targeted Therapy, Mutation, Nuclear Proteins, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Programmed Cell Death 1 Ligand 2 Protein, Protein Serine-Threonine Kinases, Proteomics, Proto-Oncogene Proteins p21(ras), RNA, Long Noncoding, Receptor, ErbB-3, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Transcription Factors, Uterine Cervical Neoplasms, Virus Integration, Cancer Genome Atlas Research Network, Albert Einstein College of Medicine, Analytical Biological Services, Barretos Cancer Hospital, Baylor College of Medicine, Beckman Research Institute of City of Hope, Buck Institute for Research on Aging, Canada's Michael Smith Genome Sciences Centre, Harvard Medical School, Helen F. Graham Cancer Center &Research Institute at Christiana Care Health Services, HudsonAlpha Institute for Biotechnology, ILSbio, LLC, Indiana University School of Medicine, Institute of Human Virology, Institute for Systems Biology, International Genomics Consortium, Leidos Biomedical, Massachusetts General Hospital, McDonnell Genome Institute at Washington University, Medical College of Wisconsin, Medical University of South Carolina, Memorial Sloan Kettering Cancer Center, Montefiore Medical Center, NantOmics, National Cancer Institute, National Hospital, Abuja, Nigeria, National Human Genome Research Institute, National Institute of Environmental Health Sciences, National Institute on Deafness &Other Communication Disorders, Ontario Tumour Bank, London Health Sciences Centre, Ontario Tumour Bank, Ontario Institute for Cancer Research, Ontario Tumour Bank, The Ottawa Hospital, Oregon Health &Science University, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, SRA International, St Joseph's Candler Health System, Eli &Edythe L. Broad Institute of Massachusetts Institute of Technology &Harvard University, Research Institute at Nationwide Children's Hospital, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, University of Bergen, University of Texas MD Anderson Cancer Center, University of Abuja Teaching Hospital, University of Alabama at Birmingham, University of California, Irvine, University of California Santa Cruz, University of Kansas Medical Center, University of Lausanne, University of New Mexico Health Sciences Center, University of North Carolina at Chapel Hill, University of Oklahoma Health Sciences Center, University of Pittsburgh, University of São Paulo, Ribeir ão Preto Medical School, University of Southern California, University of Washington, University of Wisconsin School of Medicine &Public Health, Van Andel Research Institute, Washington University in St Louis, Receptor, erbB-3, General Science & Technology
Abstract

Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.

Published
2017

48. ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells

Author

Yazinski, Stephanie A, Comaills, Valentine, Buisson, Rémi, Genois, Marie-Michelle, Nguyen, Hai Dang, Ho, Chu Kwen, Kwan, Tanya Todorova, Morris, Robert, Lauffer, Sam, Nussenzweig, André, Ramaswamy, Sridhar, Benes, Cyril H, Haber, Daniel A, Maheswaran, Shyamala, Birrer, Michael J, and Zou, Lee

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Cancer, Rare Diseases, Ovarian Cancer, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Good Health and Well Being, Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, DNA Repair, DNA, Neoplasm, Drug Resistance, Neoplasm, Female, Homologous Recombination, Humans, Ovarian Neoplasms, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerase Inhibitors, Tumor Cells, Cultured, ATR, BRCA-deficient cancer, PARP inhibitor, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination (HR) and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance. Compared with BRCA1-proficient cells, PARPi-resistant BRCA1-deficient cells are increasingly dependent on ATR for survival. ATR inhibitors (ATRis) disrupt BRCA1-independent RAD51 loading to DSBs and stalled forks in PARPi-resistant BRCA1-deficient cells, overcoming both resistance mechanisms. In tumor cells derived from patients, ATRis also overcome the bypass of BRCA1/2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers.

Published
2017

49. Final results of BrUOG 354: A randomized phase II trial of nivolumab alone or in combination with ipilimumab for people with ovarian and other extra-renal clear cell carcinomas.

Author

Dizon, Don S., Mathews, Cara Amanda, David, Shannon MacLaughlan, Machan, Jason T, Hadfield, Matthew James, Marks, Eric I, Bansal, Rani, McGinn, Christine, Hassinger, Faith, Luppe, Denise, Grigelevich, Janine, Mitchell, Kelly A, Braga, Adam, Sturtevant, Ashlee, Wood, Roxanne, Matulonis, Ursula A., Wright, Alexi A., Campos, Susana M., and Birrer, Michael J.

Published
2024
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results