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Remotely Delivered Cancer Genetic Testing in the Making Genetic Testing Accessible (MAGENTA) Trial: A Randomized Clinical Trial [Comment]

Swisher, Elizabeth M; Rayes, Nadine; Bowen, Deborah; Peterson, Christine B; Norquist, Barbara M; Coffin, Tara; Gavin, Kathleen; Polinsky, Deborah; Crase, Jamie; Bakkum-Gamez, Jamie N; Blank, Stephanie V; Munsell, Mark F; Nebgen, Denise; Fleming, Gini F; Olopade, Olufunmilayo I; Law, Sherman; Zhou, Alicia; Levine, Douglas A; D'Andrea, Alan; Lu, Karen H
IMPORTANCE/UNASSIGNED:Requiring personalized genetic counseling may introduce barriers to cancer risk assessment, but it is unknown whether omitting counseling could increase distress. OBJECTIVE/UNASSIGNED:To assess whether omitting pretest and/or posttest genetic counseling would increase distress during remote testing. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:Making Genetic Testing Accessible (MAGENTA) was a 4-arm, randomized noninferiority trial testing the effects of individualized pretest and/or posttest genetic counseling on participant distress 3 and 12 months posttest. Participants were recruited via social and traditional media, and enrollment occurred between April 27, 2017, and September 29, 2020. Participants were women aged 30 years or older, English-speaking, US residents, and had access to the internet and a health care professional. Previous cancer genetic testing or counseling was exclusionary. In the family history cohort, participants had a personal or family history of breast or ovarian cancer. In the familial pathogenic variant (PV) cohort, participants reported 1 biological relative with a PV in an actionable cancer susceptibility gene. Data analysis was performed between December 13, 2020, and May 31, 2023. INTERVENTION/UNASSIGNED:Participants completed baseline questionnaires, watched an educational video, and were randomized to 1 of 4 arms: the control arm with pretest and/or posttest genetic counseling, or 1 of 3 study arms without pretest and posttest counseling. Genetic counseling was provided by phone appointments and testing was done using home-delivered saliva kits. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was participant distress measured by the Impact of Event Scale 3 months after receiving the results. Secondary outcomes included completion of testing, anxiety, depression, and decisional regret. RESULTS/UNASSIGNED:A total of 3839 women (median age, 44 years [range 22-91 years]), most of whom were non-Hispanic White and college educated, were randomized, 3125 in the family history and 714 in the familial PV cohorts. In the primary analysis in the family history cohort, all experimental arms were noninferior for distress at 3 months. There were no statistically significant differences in anxiety, depression, or decisional regret at 3 months. The highest completion rates were seen in the 2 arms without pretest counseling. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In the MAGENTA clinical trial, omitting individualized pretest counseling for all participants and posttest counseling for those without PV during remote genetic testing was not inferior with regard to posttest distress, providing an alternative care model for genetic risk assessment. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT02993068.
PMID: 37707822
ISSN: 2374-2445
CID: 5593272

The role of CTNNB1 mutations and matrix metalloproteinases (MMPs) in anti-angiogenesis treatment of endometrial carcinoma

Berger, Amnon A; Kawaler, Emily A; Dao, Fanny; Misirlioglu, Selim; Fernandez, Ernesto Arostegui; Olvera, Narciso; Van Oudenhove, Elke; DeLair, Deborah; Levine, Douglas A
OBJECTIVE:Treatment options and associated biomarkers for advanced and recurrent disease are limited. Endometrial cancers (ECs) with CTNNB1 exon 3 mutations appear to have preferential response to bevacizumab, an anti-angiogenesis treatment, though the mechanism of action is unknown. We aim to identify mediators of bevacizumab-responsive endometrial cancers. METHODS:We analyzed RNA expression from TCGA and protein expression from CPTAC to identify likely targets for β-catenin overactivity. We then transiently and stably overexpressed β-catenin in EC cells to confirm the results suggested by our in silico analysis. We performed corroborative experiments by silencing CTNNB1 in mutated cell lines to demonstrate functional specificity. We implanted transduced cells into xenograft models to study microvessel density. RESULTS:CTNNB1-mutated ECs were associated with increased β-catenin and MMP7 protein abundance (P < 0.001), but not VEGF-A protein abundance. Overexpressing β-catenin in EC cells did not increase VEGF-A abundance but did increase expression and secretion of MMP7 (P < 0.03). Silencing CTNNB1 in CTNNB1-mutated cells decreased MMP7 gene expression in EC (P < 0.0001). Microvessel density was not increased. CONCLUSIONS:These data provide a mechanistic understanding for bevacizumab-response in CTNNB1-mutated ECs demonstrated in GOG-86P. We hypothesize that overexpressed and secreted MMP7 potentially digests VEGFR-1, releasing VEGF-A, and increasing its availability. These activities may drive the formation of permeable vessels, which contributes to tumor progression, metastasis, and immune suppression. This mechanism is unique to EC and advocates for further clinical trials evaluating this treatment-related biomarker.
PMID: 36150916
ISSN: 1095-6859
CID: 5335802

An Accessible Communication System for Population-Based Genetic Testing: Development and Usability Study

Coffin, Tara; Bowen, Deborah; Swisher, Elizabeth; Lu, Karen; Rayes, Nadine; Norquist, Barbara; Blank, Stephanie; Levine, Douglas; Bakkum-Gamez, Jamie; Fleming, Gini; Olopade, Olufunmilayo; D'Andrea, Alan; Nebgen, Denise; Peterson, Christine; Munsell, Mark; Gavin, Kathleen; Lechner, Rebecca; Crase, Jamie; Polinsky, Deborah; Romero, Iris
BACKGROUND:Genetic testing uptake is low, despite the well-established connection between pathogenic variants in certain cancer-linked susceptibility genes and ovarian cancer risk. Given that most major insurers cover genetic testing for those with a family history suggestive of hereditary cancer, the issue may lie in access to genetic testing. Remotely accessible web-based communication systems may improve awareness, and uptake, of genetic testing services. OBJECTIVE:This study aims to present the development and formative evaluation of the multistep web-based communication system required to support the implementation of, and access to, genetic testing. METHODS:While designing the multistep web-based communication system, we considered various barriers and facilitators to genetic testing, guided by dimensions of accessibility. In addition to conducting usability testing, we performed ongoing assessments focusing on the function of the web-based system and participant response rates, with the goal of continuing to make modifications to the web-based communication system as it is in use. RESULTS:The combined approach of usability testing and expert user experience consultation resulted in several modifications to the multistep web-based communication system, including changes that related to imagery and content, web accessibility, and general organization of the web-based system. All recommendations were made with the goal of improving the overall accessibility of the web-based communication system. CONCLUSIONS:A multistep web-based communication system appears to be an effective way to address many potential barriers to access, which may otherwise make genetic testing difficult for at-risk individuals to participate in. Importantly, some dimensions of access were easy to assess before study recruitment, but other aspects of the communication system required ongoing assessment during the implementation process of the Making Genetic Testing Accessible study.
PMCID:9623457
PMID: 36251350
ISSN: 2561-326x
CID: 5360232

Using Social Media to Facilitate Communication About Women's Testing: Tool Validation Study

Coffin, Tara; Bowen, Deborah; Lu, Karen; Swisher, Elizabeth M; Rayes, Nadine; Norquist, Barbara; Blank, Stephanie V; Levine, Douglas A; Bakkum-Gamez, Jamie Nadine; Fleming, Gini F; I Olopade, Olufunmilayo; Romero, Iris; D'Andrea, Alan; Nebgen, Denise R; Peterson, Christine; Munsell, Mark F; Gavin, Kathleen; Crase, Jamie; Polinsky, Deborah; Lechner, Rebecca
BACKGROUND:Strong participant recruitment practices are critical to public health research but are difficult to achieve. Traditional recruitment practices are often time consuming, costly, and fail to adequately target difficult-to-reach populations. Social media platforms such as Facebook are well-positioned to address this area of need, enabling researchers to leverage existing social networks and deliver targeted information. The MAGENTA (Making Genetic Testing Accessible) study aimed to improve the availability of genetic testing for hereditary cancer susceptibility in at-risk individuals through the use of a web-based communication system along with social media advertisements to improve reach. OBJECTIVE:This paper is aimed to evaluate the effectiveness of Facebook as an outreach tool for targeting women aged ≥30 years for recruitment in the MAGENTA study. METHODS:We designed and implemented paid and unpaid social media posts with ongoing assessment as a primary means of research participant recruitment in collaboration with patient advocates. Facebook analytics were used to assess the effectiveness of paid and unpaid outreach efforts. RESULTS:Over the course of the reported recruitment period, Facebook materials had a reach of 407,769 people and 57,248 (14.04%) instances of engagement, indicating that approximately 14.04% of people who saw information about the study on Facebook engaged with the content. Paid advertisements had a total reach of 373,682. Among those reached, just <15% (54,117/373,682, 14.48%) engaged with the page content. Unpaid posts published on the MAGENTA Facebook page resulted in a total of 34,087 reach and 3131 instances of engagement, indicating that around 9.19% (3131/34,087) of people who saw unpaid posts engaged. Women aged ≥65 years reported the best response rate, with approximately 43.95% (15,124/34,410) of reaches translating to engagement. Among the participants who completed the eligibility questionnaire, 27.44% (3837/13,983) had heard about the study through social media or another webpage. CONCLUSIONS:Facebook is a useful way of enhancing clinical trial recruitment of women aged ≥30 years who have a potentially increased risk for ovarian cancer by promoting news stories over social media, collaborating with patient advocacy groups, and running paid and unpaid campaigns. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT02993068; https://clinicaltrials.gov/ct2/show/NCT02993068.
PMID: 36155347
ISSN: 2561-326x
CID: 5333922

Impact of Homologous Recombination Status and Responses with Veliparib Combined with First-Line Chemotherapy in Ovarian Cancer in the Phase 3 VELIA/GOG-3005 Study

Swisher, Elizabeth M.; Aghajanian, Carol; O'Malley, David M.; Fleming, Gini F.; Kaufmann, Scott H.; Levine, Douglas A.; Birrer, Michael J.; Moore, Kathleen N.; Spirtos, Nick M.; Shahin, Mark S.; Reid, Thomas J.; Friedlander, Michael; Steffensen, Karina Dahl; Okamoto, Aikou; Sehgal, Vasudha; Ansell, Peter J.; Dinh, Minh H.; Bookman, Michael A.; Coleman, Robert L.
SCOPUS:85130778239
ISSN: 0021-9355
CID: 5314382

Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Dareng, Eileen O; Tyrer, Jonathan P; Barnes, Daniel R; Jones, Michelle R; Yang, Xin; Aben, Katja K H; Adank, Muriel A; Agata, Simona; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Aravantinos, Gerasimos; Arun, Banu K; Augustinsson, Annelie; Balmaña, Judith; Bandera, Elisa V; Barkardottir, Rosa B; Barrowdale, Daniel; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Bernardini, Marcus Q; Bjorge, Line; Black, Amanda; Bogdanova, Natalia V; Bonanni, Bernardo; Borg, Ake; Brenton, James D; Budzilowska, Agnieszka; Butzow, Ralf; Buys, Saundra S; Cai, Hui; Caligo, Maria A; Campbell, Ian; Cannioto, Rikki; Cassingham, Hayley; Chang-Claude, Jenny; Chanock, Stephen J; Chen, Kexin; Chiew, Yoke-Eng; Chung, Wendy K; Claes, Kathleen B M; Colonna, Sarah; Cook, Linda S; Couch, Fergus J; Daly, Mary B; Dao, Fanny; Davies, Eleanor; de la Hoya, Miguel; de Putter, Robin; Dennis, Joe; DePersia, Allison; Devilee, Peter; Diez, Orland; Ding, Yuan Chun; Doherty, Jennifer A; Domchek, Susan M; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana M; Eliassen, Heather A; Engel, Christoph; Evans, Gareth D; Fasching, Peter A; Flanagan, James M; Fortner, Renée T; Machackova, Eva; Friedman, Eitan; Ganz, Patricia A; Garber, Judy; Gensini, Francesca; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goodman, Marc T; Greene, Mark H; Gronwald, Jacek; Hahnen, Eric; Haiman, Christopher A; HÃ¥kansson, Niclas; Hamann, Ute; Hansen, Thomas V O; Harris, Holly R; Hartman, Mikael; Heitz, Florian; Hildebrandt, Michelle A T; Høgdall, Estrid; Høgdall, Claus K; Hopper, John L; Huang, Ruea-Yea; Huff, Chad; Hulick, Peter J; Huntsman, David G; Imyanitov, Evgeny N; Isaacs, Claudine; Jakubowska, Anna; James, Paul A; Janavicius, Ramunas; Jensen, Allan; Johannsson, Oskar Th; John, Esther M; Jones, Michael E; Kang, Daehee; Karlan, Beth Y; Karnezis, Anthony; Kelemen, Linda E; Khusnutdinova, Elza; Kiemeney, Lambertus A; Kim, Byoung-Gie; Kjaer, Susanne K; Komenaka, Ian; Kupryjanczyk, Jolanta; Kurian, Allison W; Kwong, Ava; Lambrechts, Diether; Larson, Melissa C; Lazaro, Conxi; Le, Nhu D; Leslie, Goska; Lester, Jenny; Lesueur, Fabienne; Levine, Douglas A; Li, Lian; Li, Jingmei; Loud, Jennifer T; Lu, Karen H; LubiÅ„ski, Jan; Mai, Phuong L; Manoukian, Siranoush; Marks, Jeffrey R; Matsuno, Rayna Kim; Matsuo, Keitaro; May, Taymaa; McGuffog, Lesley; McLaughlin, John R; McNeish, Iain A; Mebirouk, Noura; Menon, Usha; Miller, Austin; Milne, Roger L; Minlikeeva, Albina; Modugno, Francesmary; Montagna, Marco; Moysich, Kirsten B; Munro, Elizabeth; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Yie, Joanne Ngeow Yuen; Nielsen, Henriette Roed; Nielsen, Finn C; Nikitina-Zake, Liene; Odunsi, Kunle; Offit, Kenneth; Olah, Edith; Olbrecht, Siel; Olopade, Olufunmilayo I; Olson, Sara H; Olsson, HÃ¥kan; Osorio, Ana; Papi, Laura; Park, Sue K; Parsons, Michael T; Pathak, Harsha; Pedersen, Inge Sokilde; Peixoto, Ana; Pejovic, Tanja; Perez-Segura, Pedro; Permuth, Jennifer B; Peshkin, Beth; Peterlongo, Paolo; Piskorz, Anna; Prokofyeva, Darya; Radice, Paolo; Rantala, Johanna; Riggan, Marjorie J; Risch, Harvey A; Rodriguez-Antona, Cristina; Ross, Eric; Rossing, Mary Anne; Runnebaum, Ingo; Sandler, Dale P; Santamariña, Marta; Soucy, Penny; Schmutzler, Rita K; Setiawan, V Wendy; Shan, Kang; Sieh, Weiva; Simard, Jacques; Singer, Christian F; Sokolenko, Anna P; Song, Honglin; Southey, Melissa C; Steed, Helen; Stoppa-Lyonnet, Dominique; Sutphen, Rebecca; Swerdlow, Anthony J; Tan, Yen Yen; Teixeira, Manuel R; Teo, Soo Hwang; Terry, Kathryn L; Terry, Mary Beth; Thomassen, Mads; Thompson, Pamela J; Thomsen, Liv Cecilie Vestrheim; Thull, Darcy L; Tischkowitz, Marc; Titus, Linda; Toland, Amanda E; Torres, Diana; Trabert, Britton; Travis, Ruth; Tung, Nadine; Tworoger, Shelley S; Valen, Ellen; van Altena, Anne M; van der Hout, Annemieke H; Van Nieuwenhuysen, Els; van Rensburg, Elizabeth J; Vega, Ana; Edwards, Digna Velez; Vierkant, Robert A; Wang, Frances; Wappenschmidt, Barbara; Webb, Penelope M; Weinberg, Clarice R; Weitzel, Jeffrey N; Wentzensen, Nicolas; White, Emily; Whittemore, Alice S; Winham, Stacey J; Wolk, Alicja; Woo, Yin-Ling; Wu, Anna H; Yan, Li; Yannoukakos, Drakoulis; Zavaglia, Katia M; Zheng, Wei; Ziogas, Argyrios; Zorn, Kristin K; Kleibl, Zdenek; Easton, Douglas; Lawrenson, Kate; DeFazio, Anna; Sellers, Thomas A; Ramus, Susan J; Pearce, Celeste L; Monteiro, Alvaro N; Cunningham, Julie; Goode, Ellen L; Schildkraut, Joellen M; Berchuck, Andrew; Chenevix-Trench, Georgia; Gayther, Simon A; Antoniou, Antonis C; Pharoah, Paul D P
PMID: 35314806
ISSN: 1476-5438
CID: 5206612

Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Dareng, Eileen O; Tyrer, Jonathan P; Barnes, Daniel R; Jones, Michelle R; Yang, Xin; Aben, Katja K H; Adank, Muriel A; Agata, Simona; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Aravantinos, Gerasimos; Arun, Banu K; Augustinsson, Annelie; Balmaña, Judith; Bandera, Elisa V; Barkardottir, Rosa B; Barrowdale, Daniel; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Bernardini, Marcus Q; Bjorge, Line; Black, Amanda; Bogdanova, Natalia V; Bonanni, Bernardo; Borg, Ake; Brenton, James D; Budzilowska, Agnieszka; Butzow, Ralf; Buys, Saundra S; Cai, Hui; Caligo, Maria A; Campbell, Ian; Cannioto, Rikki; Cassingham, Hayley; Chang-Claude, Jenny; Chanock, Stephen J; Chen, Kexin; Chiew, Yoke-Eng; Chung, Wendy K; Claes, Kathleen B M; Colonna, Sarah; Cook, Linda S; Couch, Fergus J; Daly, Mary B; Dao, Fanny; Davies, Eleanor; de la Hoya, Miguel; de Putter, Robin; Dennis, Joe; DePersia, Allison; Devilee, Peter; Diez, Orland; Ding, Yuan Chun; Doherty, Jennifer A; Domchek, Susan M; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana M; Eliassen, Heather A; Engel, Christoph; Evans, Gareth D; Fasching, Peter A; Flanagan, James M; Fortner, Renée T; Machackova, Eva; Friedman, Eitan; Ganz, Patricia A; Garber, Judy; Gensini, Francesca; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goodman, Marc T; Greene, Mark H; Gronwald, Jacek; Hahnen, Eric; Haiman, Christopher A; HÃ¥kansson, Niclas; Hamann, Ute; Hansen, Thomas V O; Harris, Holly R; Hartman, Mikael; Heitz, Florian; Hildebrandt, Michelle A T; Høgdall, Estrid; Høgdall, Claus K; Hopper, John L; Huang, Ruea-Yea; Huff, Chad; Hulick, Peter J; Huntsman, David G; Imyanitov, Evgeny N; Isaacs, Claudine; Jakubowska, Anna; James, Paul A; Janavicius, Ramunas; Jensen, Allan; Johannsson, Oskar Th; John, Esther M; Jones, Michael E; Kang, Daehee; Karlan, Beth Y; Karnezis, Anthony; Kelemen, Linda E; Khusnutdinova, Elza; Kiemeney, Lambertus A; Kim, Byoung-Gie; Kjaer, Susanne K; Komenaka, Ian; Kupryjanczyk, Jolanta; Kurian, Allison W; Kwong, Ava; Lambrechts, Diether; Larson, Melissa C; Lazaro, Conxi; Le, Nhu D; Leslie, Goska; Lester, Jenny; Lesueur, Fabienne; Levine, Douglas A; Li, Lian; Li, Jingmei; Loud, Jennifer T; Lu, Karen H; LubiÅ„ski, Jan; Mai, Phuong L; Manoukian, Siranoush; Marks, Jeffrey R; Matsuno, Rayna Kim; Matsuo, Keitaro; May, Taymaa; McGuffog, Lesley; McLaughlin, John R; McNeish, Iain A; Mebirouk, Noura; Menon, Usha; Miller, Austin; Milne, Roger L; Minlikeeva, Albina; Modugno, Francesmary; Montagna, Marco; Moysich, Kirsten B; Munro, Elizabeth; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Yie, Joanne Ngeow Yuen; Nielsen, Henriette Roed; Nielsen, Finn C; Nikitina-Zake, Liene; Odunsi, Kunle; Offit, Kenneth; Olah, Edith; Olbrecht, Siel; Olopade, Olufunmilayo I; Olson, Sara H; Olsson, HÃ¥kan; Osorio, Ana; Papi, Laura; Park, Sue K; Parsons, Michael T; Pathak, Harsha; Pedersen, Inge Sokilde; Peixoto, Ana; Pejovic, Tanja; Perez-Segura, Pedro; Permuth, Jennifer B; Peshkin, Beth; Peterlongo, Paolo; Piskorz, Anna; Prokofyeva, Darya; Radice, Paolo; Rantala, Johanna; Riggan, Marjorie J; Risch, Harvey A; Rodriguez-Antona, Cristina; Ross, Eric; Rossing, Mary Anne; Runnebaum, Ingo; Sandler, Dale P; Santamariña, Marta; Soucy, Penny; Schmutzler, Rita K; Setiawan, V Wendy; Shan, Kang; Sieh, Weiva; Simard, Jacques; Singer, Christian F; Sokolenko, Anna P; Song, Honglin; Southey, Melissa C; Steed, Helen; Stoppa-Lyonnet, Dominique; Sutphen, Rebecca; Swerdlow, Anthony J; Tan, Yen Yen; Teixeira, Manuel R; Teo, Soo Hwang; Terry, Kathryn L; Terry, Mary Beth; Thomassen, Mads; Thompson, Pamela J; Thomsen, Liv Cecilie Vestrheim; Thull, Darcy L; Tischkowitz, Marc; Titus, Linda; Toland, Amanda E; Torres, Diana; Trabert, Britton; Travis, Ruth; Tung, Nadine; Tworoger, Shelley S; Valen, Ellen; van Altena, Anne M; van der Hout, Annemieke H; Van Nieuwenhuysen, Els; van Rensburg, Elizabeth J; Vega, Ana; Edwards, Digna Velez; Vierkant, Robert A; Wang, Frances; Wappenschmidt, Barbara; Webb, Penelope M; Weinberg, Clarice R; Weitzel, Jeffrey N; Wentzensen, Nicolas; White, Emily; Whittemore, Alice S; Winham, Stacey J; Wolk, Alicja; Woo, Yin-Ling; Wu, Anna H; Yan, Li; Yannoukakos, Drakoulis; Zavaglia, Katia M; Zheng, Wei; Ziogas, Argyrios; Zorn, Kristin K; Kleibl, Zdenek; Easton, Douglas; Lawrenson, Kate; DeFazio, Anna; Sellers, Thomas A; Ramus, Susan J; Pearce, Celeste L; Monteiro, Alvaro N; Cunningham, Julie; Goode, Ellen L; Schildkraut, Joellen M; Berchuck, Andrew; Chenevix-Trench, Georgia; Gayther, Simon A; Antoniou, Antonis C; Pharoah, Paul D P
Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
PMID: 35027648
ISSN: 1476-5438
CID: 5119062

Impact of homologous recombination status and responses with veliparib combined with first-line chemotherapy in ovarian cancer in the Phase 3 VELIA/GOG-3005 study

Swisher, Elizabeth M; Aghajanian, Carol; O'Malley, David M; Fleming, Gini F; Kaufmann, Scott H; Levine, Douglas A; Birrer, Michael J; Moore, Kathleen N; Spirtos, Nick M; Shahin, Mark S; Reid, Thomas J; Friedlander, Michael; Steffensen, Karina Dahl; Okamoto, Aikou; Sehgal, Vasudha; Ansell, Peter J; Dinh, Minh H; Bookman, Michael A; Coleman, Robert L
OBJECTIVE:In the Phase 3 VELIA trial (NCT02470585), PARP inhibitor (PARPi) veliparib was combined with first-line chemotherapy and continued as maintenance for patients with ovarian carcinoma enrolled regardless of chemotherapy response or biomarker status. Here, we report exploratory analyses of the impact of homologous recombination deficient (HRD) or proficient (HRP) status on progression-free survival (PFS) and objective response rates during chemotherapy. METHODS:Women with Stage III-IV ovarian carcinoma were randomized to veliparib-throughout, veliparib-combination-only, or placebo. Stratification factors included timing of surgery and germline BRCA mutation status. HRD status was dichotomized at genomic instability score 33. During combination therapy, CA-125 levels were measured at baseline and each cycle; radiographic responses were assessed every 9 weeks. RESULTS:Of 1140 patients randomized, 742 had BRCA wild type (BRCAwt) tumors (HRP, n = 373; HRD/BRCAwt, n = 329). PFS hazard ratios between veliparib-throughout versus control were similar in both BRCAwt populations (HRD/BRCAwt: 22.9 vs 19.8 months; hazard ratio 0.76; 95% confidence interval [CI] 0.53-1.09; HRP: 15.0 vs 11.5 months; hazard ratio 0.765; 95% CI 0.56-1.04). By Cycle 3, the proportion with ≥90% CA-125 reduction from baseline was higher in those receiving veliparib (pooled arms) versus control (34% vs 23%; P = 0.0004); particularly in BRCAwt and HRP subgroups. Complete response rates among patients with measurable disease after surgery were 24% with veliparib (pooled arms) and 18% with control. CONCLUSIONS:These results potentially broaden opportunities for PARPi utilization among patients who would not qualify for frontline PARPi maintenance based on other trials.
PMID: 34906376
ISSN: 1095-6859
CID: 5109692

The congressionally directed medical research programs' Ovarian Cancer Academy: a new approach to training in biomedical research

Wyatt, Tasha R; Stepleman, Lara; Coleman, Taylor; Robinson, Leslie; Wylie, Karen; Levine, Douglas A; Maihle, Nita J
Introduction/UNASSIGNED:Researchers have begun to change their approach to training in the biomedical sciences through the development of communities of practice (CoPs). CoPs share knowledge across clinical and laboratory contexts to promote the progress of clinical and translational science. The Congressionally Directed Medical Research Programs' (CDMRP) Ovarian Cancer Academy (OCA) was designed as a virtual CoP to promote interactions among early career investigators (ECIs) and their mentors with the goal of eliminating ovarian cancer. Methods/UNASSIGNED:-tests for Time 1 and Time 2. Qualitative data were analyzed for themes to discern which aspects of the program were useful and where more attention is needed. Results/UNASSIGNED:Preliminary analyses reveal several trends, including the importance of training in grant writing to the ECI's productivity, as well as the value of peer mentorship. Conclusion/UNASSIGNED:The results show that the OCA was an innovative and effective way to create a CoP with broad implications for the field of ovarian cancer research, as well as for the future of biomedical research training.
PMCID:9305081
PMID: 35949654
ISSN: 2059-8661
CID: 5287012

Endometrial cancer

Makker, Vicky; MacKay, Helen; Ray-Coquard, Isabelle; Levine, Douglas A; Westin, Shannon N; Aoki, Daisuke; Oaknin, Ana
Although endometrial cancer management remains challenging, a deeper understanding of the genetic diversity as well as the drivers of the various pathogenic states of this disease has led to development of divergent management approaches in an effort to improve therapeutic precision in this complex malignancy. This comprehensive review provides an update on the epidemiology, pathophysiology, diagnosis and molecular classification, recent advancements in disease management, as well as important patient quality-of-life considerations and emerging developments in the rapidly evolving therapeutic landscape of endometrial cancers.
PMID: 34887451
ISSN: 2056-676x
CID: 5110422