Ritu R Singh1, Johanna Goldberg2, Anna M Varghese3, Kenneth H Yu3, Wungki Park3, Eileen M O'Reilly4. 1. Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai St. Luke's and Mount Sinai West, New York, NY 10019, USA. Electronic address: ritu.singh@mountsinai.org. 2. MSK Library, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: goldbejb@mskcc.org. 3. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. 4. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: oreillye@mskcc.org.
Abstract
CONTEXT: Pancreatic cancer (PDAC) is one of the most challenging cancers to treat with modest recent improvements in survival from new systemic therapies. There is growing interest in individualized therapy underpinned by somatic and germline genomic alterations. OBJECTIVE: A systematic review of data on therapies targeting somatic and germline alterations, and their downstream pathways in PDAC. METHOD: A systematic literature search was conducted using PRISMA guidelines to include relevant results published after January 1, 2008. RESULTS: A total of 71 relevant studies were included. We identified 36 studies targeting the KRAS-pathway, the most common being with MEK-inhibitor therapy. Twenty-two studies were identified that evaluated platinum-based chemotherapy and PARP inhibitors in patients with deleterious mutations in DNA damage repair genes and have shown encouraging results. Immunotherapy has demonstrated activity in patients with mismatch repair deficiency/microsatellite instability. CONCLUSION: Evidence from translational and clinical research presents an exciting platform for genomic targeted therapy in PDAC. Validity for targeting BRCA with platinum and PARP inhibitors and microsatellite instability with immune therapy has been established, nonetheless, evidence for targeting the common driver oncogenes is lacking and much work is needed. Of importance is identifying the subgroup of KRAS -wild type PDAC (approximately 5%) where there is enrichment for targetable opportunities.
CONTEXT: Pancreatic cancer (PDAC) is one of the most challenging cancers to treat with modest recent improvements in survival from new systemic therapies. There is growing interest in individualized therapy underpinned by somatic and germline genomic alterations. OBJECTIVE: A systematic review of data on therapies targeting somatic and germline alterations, and their downstream pathways in PDAC. METHOD: A systematic literature search was conducted using PRISMA guidelines to include relevant results published after January 1, 2008. RESULTS: A total of 71 relevant studies were included. We identified 36 studies targeting the KRAS-pathway, the most common being with MEK-inhibitor therapy. Twenty-two studies were identified that evaluated platinum-based chemotherapy and PARP inhibitors in patients with deleterious mutations in DNA damage repair genes and have shown encouraging results. Immunotherapy has demonstrated activity in patients with mismatch repair deficiency/microsatellite instability. CONCLUSION: Evidence from translational and clinical research presents an exciting platform for genomic targeted therapy in PDAC. Validity for targeting BRCA with platinum and PARP inhibitors and microsatellite instability with immune therapy has been established, nonetheless, evidence for targeting the common driver oncogenes is lacking and much work is needed. Of importance is identifying the subgroup of KRAS -wild type PDAC (approximately 5%) where there is enrichment for targetable opportunities.
Authors: Synne Wedén; Marianne Klemp; Ivar P Gladhaug; Mona Møller; Jon Amund Eriksen; Gustav Gaudernack; Trond Buanes Journal: Int J Cancer Date: 2011-03-01 Impact factor: 7.396
Authors: Thierry Conroy; Françoise Desseigne; Marc Ychou; Olivier Bouché; Rosine Guimbaud; Yves Bécouarn; Antoine Adenis; Jean-Luc Raoul; Sophie Gourgou-Bourgade; Christelle de la Fouchardière; Jaafar Bennouna; Jean-Baptiste Bachet; Faiza Khemissa-Akouz; Denis Péré-Vergé; Catherine Delbaldo; Eric Assenat; Bruno Chauffert; Pierre Michel; Christine Montoto-Grillot; Michel Ducreux Journal: N Engl J Med Date: 2011-05-12 Impact factor: 91.245
Authors: Christopher H Crane; Gauri R Varadhachary; John S Yordy; Gregg A Staerkel; Milind M Javle; Howard Safran; Waqar Haque; Bridgett D Hobbs; Sunil Krishnan; Jason B Fleming; Prajnan Das; Jeffrey E Lee; James L Abbruzzese; Robert A Wolff Journal: J Clin Oncol Date: 2011-06-27 Impact factor: 44.544
Authors: Román Pérez-Soler; Jean Pierre Delord; Allan Halpern; Karen Kelly; James Krueger; Bartomeu Massutí Sureda; Joachim von Pawel; Jennifer Temel; Salvatore Siena; Denis Soulières; Leonard Saltz; James Leyden Journal: Oncologist Date: 2005-05
Authors: Philip A Philip; Jacqueline Benedetti; Christopher L Corless; Ralph Wong; Eileen M O'Reilly; Patrick J Flynn; Kendrith M Rowland; James N Atkins; Barry C Mirtsching; Saul E Rivkin; Alok A Khorana; Bryan Goldman; Cecilia M Fenoglio-Preiser; James L Abbruzzese; Charles D Blanke Journal: J Clin Oncol Date: 2010-07-06 Impact factor: 44.544
Authors: György Bodoky; Constanta Timcheva; David Robert Spigel; Phillip Joseph La Stella; Tudor Eliade Ciuleanu; G Pover; N C Tebbutt Journal: Invest New Drugs Date: 2011-05-19 Impact factor: 3.850
Authors: E Van Cutsem; H van de Velde; P Karasek; H Oettle; W L Vervenne; A Szawlowski; P Schoffski; S Post; C Verslype; H Neumann; H Safran; Y Humblet; J Perez Ruixo; Y Ma; D Von Hoff Journal: J Clin Oncol Date: 2004-04-15 Impact factor: 44.544
Authors: Malcolm J Moore; David Goldstein; John Hamm; Arie Figer; Joel R Hecht; Steven Gallinger; Heather J Au; Pawel Murawa; David Walde; Robert A Wolff; Daniel Campos; Robert Lim; Keyue Ding; Gary Clark; Theodora Voskoglou-Nomikos; Mieke Ptasynski; Wendy Parulekar Journal: J Clin Oncol Date: 2007-04-23 Impact factor: 44.544
Authors: George Fountzilas; Mattheos Bobos; Anna Kalogera-Fountzila; Nikolaos Xiros; Samuel Murray; Helena Linardou; Georgia Karayannopoulou; Angelos K Koutras; Dimitrios Bafaloukos; Epaminondas Samantas; Christos Christodoulou; Theofanis Economopoulos; Konstantine T Kalogeras; Paris Kosmidis Journal: Cancer Invest Date: 2008-10 Impact factor: 2.176
Authors: Caitlin A McIntyre; Sharon A Lawrence; Allison L Richards; Joanne F Chou; Winston Wong; Marinela Capanu; Michael F Berger; Mark T A Donoghue; Kenneth H Yu; Anna M Varghese; David P Kelsen; Wungki Park; Vinod P Balachandran; T Peter Kingham; Michael I D'Angelica; Jeffrey A Drebin; William R Jarnagin; Christine A Iacobuzio-Donahue; Peter J Allen; Eileen M O'Reilly Journal: Cancer Date: 2020-06-23 Impact factor: 6.860
Authors: Eileen M O'Reilly; Jonathan W Lee; Mark Zalupski; Marinela Capanu; Jennifer Park; Talia Golan; Esther Tahover; Maeve A Lowery; Joanne F Chou; Vaibhav Sahai; Robin Brenner; Hedy L Kindler; Kenneth H Yu; Alice Zervoudakis; Shreya Vemuri; Zsofia K Stadler; Richard K G Do; Neesha Dhani; Alice P Chen; David P Kelsen Journal: J Clin Oncol Date: 2020-01-24 Impact factor: 44.544
Authors: Sona Ciernikova; Julie Earl; María Laura García Bermejo; Viola Stevurkova; Alfredo Carrato; Bozena Smolkova Journal: Int J Mol Sci Date: 2020-06-08 Impact factor: 5.923
Authors: Candice Martino; Deep Pandya; Ronald Lee; Gillian Levy; Tammy Lo; Sandra Lobo; Richard C Frank Journal: Pancreas Date: 2020-01 Impact factor: 3.327