Citations 2
Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma
Garsed, Dale W. , Pandey, Ahwan , Ariyaratne, Dinuka , Laumont, Céline M. , Hamilton, Phineas T. , Alsop, Jennifer , Antoniou, Antonis C. , Au‐Yeung, George , Beckmann, Matthias W. , González, Amy Berrington de , Bisinotto, Christiani, Blome, Freya , Bodelón, Clara , Boros, Jessica , Brand, Alison H. , Carney, Michael E., Coulson, Penny , Cushing‐Haugen, Kara L. , Cybulski, Cezary, Darcy, Kathleen M. , David, C. W. Mabey, Davidson, Trent , Emons, Julius , Farrell, Rhonda , Gentry-Maharaj, Aleksandra, Harter, Philipp, Hartmann, Arndt, Heikaus, Sebastian, Hettiaratchi, Anusha , Heublein, Sabine , Huntsman, David G. , Jimenez-Linan, Mercedes , Jones, Michael E. , Kang, Eunyoung , Konecny, Gottfried E. , Kruitwagen, Rutgerus, Kwon, Jessica, Lambrechts, Diether , Lester, Jenny, Leung, Samuel , Leung, Yee , Loverix, Liselore , Mateoiu, Constantina , McNeish, Iain A. , Nevins, Nikilyn, Olawaiye, Alexander , Oršulić, Sandra , Osório, Ana , Quinn, Carmel M. , Mohan, Ganendra Raj , Ruebner, Matthias , Salfinger, Stuart , Samra, Spinder , Stewart, Colin J.R. , Talhouk, Aline , Tan, Adeline , Tarney, Christopher M., Aa, Maaike AVan Der, Gorp, Toon Van , Nieuwenhuysen, Els Van, Wagensveld, Lilian van , Wahner-Hendrickson, Andrea E., Walter, Christina B., Welz, Julia , Wentzensen, Nicolas , Winterhoff, Boris , Berchuck, Andrew, Fasching, Peter A. , Gayther, Simon A. , Kelemen, Linda E. , Maxwell, G. Larry , Menon, Usha , Modugno, Francesmary, Schildkraut, Joellen M. , Staebler, Annette , Swedlow, Anthony, Vergote, Ignace , Wu, Anna H. , Pearce, Celeste Leigh, Pike, M. C., Goode, Ellen L. , Bowtell, David D.L. , Lambrechts, Diether , Garsed, Dale W , Fereday, Sian , Pandey, Ahwan , Ariyaratne, Dinuka , Kennedy, Catherine J , Milne, Katy , Berrington de Gonzalez, Amy , Blome, Freya , Bodelon, Clara , Christie, Elizabeth L , Ekici, Arif B , Ghatage, Prafull , Hettiaratchi, Anusha , Jones, Michael E , Kommoss, Felix , Lambrechts, Diether , Lee, Cheng-Han , Leung, Yee , Linder, Anna , McNeish, Iain A , Nelson, Gregg S , Nevins, Nikilyn , Ray-Coquard, Isabelle L. , Roxburgh, Patricia , Van de Vijver, Koen , Wahner-Hendrickson, Andrea, Wang, Chen , Wentzensen, Nicolas , Winham, Stacey J , Anglesio, Michael S , Cohen, Paul , Conrads, Thomas , Fasching, Peter A , Horlings, Hugo , Karlan, Beth Y , Menon, Usha , Neuhausen, Susan L. , Brenton, James D , Pharoah, Paul D P , Goode, Ellen L , Ramus, Susan J , Köbel, Martin , Nelson, Brad H , Fazio, Anna de , Friedlander, Michael , Lambrechts, Diether , Brand, Alison H , Bowtell, David D , Goodman, Marc T , Zwimpfer, Tibor A. , Fereday, Sián , Jayawardana, Madawa , Twomey, Laura , Kennedy, Catherine J. , Bolithon, Adelyn , Meagher, Nicola S. , Milne, Katy , Cazorla, Alicia , Chiu, Derek S , Christie, Elizabeth L. , Chudecka-Glaz, Anita Monika , Ekici, Arif B. , Elishaev, Esther , Engler, Tobias , Fischer, Anna, García‐Closas, Montserrat , Gentry‐Maharaj, Aleksandra , Glasspool, Rosalind , Hartkopf, Andreas D , Hernandez, Brenda Y. , Kaznowska, Ewa B. , Kluz, Tomasz , Kruitwagen, Roy F.P.M. , Kwon, Jessica, Lee, Cheng‐Han , Lester, Jenny, Leung, Samuel, Linder, Anna , Lissowska, Jolanta , Lubiński, Jan , Moubarak, Malak , Nelson, Gregg , Olbrecht, Siel , Rodríguez‐Antona, Cristina , Schoemaker, Minouk J. , Sinn, Hans‐Peter , Sonke, Gabe S. , Steele, Linda, Taylor, Sarah E , Nieuwenhuysen, Els Van , Wang, Chen , Wilkens, Lynne R. , Winham, Stacey J. , Anglesio, Michael S. , Reis, Francisco José Cândido dos , Cohen, Paul A. , Crowe, Philip John , Doherty, Jennifer A. , Fortner, Renée T. , García, María J. , Goodman, Marc T. , Gronwald, Jacek , Harris, Holly R. , Heitz, Florian , Karlan, Beth Y. , Sundfeldt, Karin , Brenton, James D. , Pharoah, Paul D.P. , Ramus, Susan J. , Köbel, Martin , Nelson, Brad H. , DeFazio, Anna , Friedländer, Michael
No container title available | October 3, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.
A Phase I Study of sequences of the CDK4/6 Inhibitor, Ribociclib Combined with Gemcitabine in Patients with Advanced Solid Tumors
Seetharam, Mahesh , Norman, Aurora, Allred, Jacob B., Kong, Jianping , Lou, Yanyan , Dy, Grace K. , Weroha, S. John , Hendrickson, Andrea E. Wahner , Adjei, Alex A. , Allred, Jacob, Weroha, John, Wahner-Hendrickson, Andrea, Opyrchal, Mateusz , Wee, Wen , Mahipal, Amit , Reid, Joel M.
No container title available | April 25, 2024 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Background: Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine is synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods: In this single arm multicohort phase I trial, we evaluated the safety and efficacy of Ribociclib plus Gemcitabine in patients with advanced solid tumors. Patients received Gemcitabine intravenously on days 1 and 8 followed by Ribociclib days 8–14, with treatment repeated every 3 weeks. Results: The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800mg daily and gemcitabine 1000mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease. Conclusions: The addition of Ribociclib to Gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Ribociclib and gemcitabine could have synergistic activity in certain tumor types, and our data provides support for the combination. Clinical Trial Registration: NCT03237390