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Literature DB >> 32444418

Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection.

Wungki Park^1,2,3,4, Jiapeng Chen^1,5,6, Nadeem Riaz^1,5,6, Eileen M O'Reilly^7,2,3, Joanne F Chou^1,8, Anna M Varghese^1,2,3, Kenneth H Yu^1,2,3, Winston Wong¹, Marinela Capanu^1,8, Vinod Balachandran^1,3,4,9, Caitlin A McIntyre^1,9, Imane El Dika^1,2, Danny N Khalil^1,2,4, James J Harding^1,2, Nima Ghalehsari¹, Zoe McKinnell¹, Sree B Chalasani^1,2, Vladimir Makarov^1,6, Pier Selenica^1,10, Xin Pei^1,6, Nicolas Lecomte^1,3,10, David P Kelsen^1,2,3, Ghassan K Abou-Alfa^1,2, Mark E Robson^1,11, Liying Zhang^1,2,10, Michael F Berger^1,12, Nikolaus Schultz^1,12, Timothy A Chan^1,5,6, Simon N Powell^1,5, Jorge S Reis-Filho^1,10, Christine A Iacobuzio-Donahue^1,3,10.

Abstract

PURPOSE: Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response-targeted therapies like platinum in pancreatic ductal adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome. EXPERIMENTAL
DESIGN: We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advanced-stage PDAC, who had both germline- and somatic-targeted gene sequencing. Homologous recombination gene mutations (HRm) were evaluated: BRCA1, BRCA2, PALB2, ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1 HRm status was grouped as: (i) germline versus somatic; (ii) core (BRCAs and PALB2) versus non-core (other HRm); and (iii) monoallelic versus biallelic. Genomic instability was compared using large-scale state transition, signature 3, and tumor mutation burden.
RESULTS: Among 262 patients, 50 (19%) had HRD (15% germline and 4% somatic). Both groups were analyzed together due to lack of difference in their genomic instability and outcome. Median [95% confidence interval (CI)] follow-up was 21.9 (1.4-57.0) months. Median OS and PFS were 15.5 (14.6-19) and 7 (6.1-8.1) months, respectively. Patients with HRD had improved PFS compared with no HRD when treated with first-line (1L) platinum [HR, 0.44 (95% CI: 0.29-0.67); P < 0.01], but not with 1L-non-platinum. Multivariate analysis showed HRD patients had improved OS regardless of their first-line treatment, but most had platinum exposure during their course. Biallelic HRm (11%) and core HRm (12%) had higher genomic instability, which translated to improved PFS on first-line platinum (1L-platinum) versus 1L-non-platinum.
CONCLUSIONS: Pathogenic HRm identifies HRD in patients with PDAC with the best outcome when treated with 1L-platinum. Biallelic HRm and core HRm further enriched benefit from 1L-platinum from HRD. ©2020 American Association for Cancer Research.

Entities: Chemical Disease Gene Mutation Species

Year: 2020 PMID： 32444418 PMCID： PMC7380542 DOI： 10.1158/1078-0432.CCR-20-0418

Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531

38 in total

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Authors: Peter Bailey; David K Chang; Katia Nones; Amber L Johns; Ann-Marie Patch; Marie-Claude Gingras; David K Miller; Angelika N Christ; Tim J C Bruxner; Michael C Quinn; Craig Nourse; L Charles Murtaugh; Ivon Harliwong; Senel Idrisoglu; Suzanne Manning; Ehsan Nourbakhsh; Shivangi Wani; Lynn Fink; Oliver Holmes; Venessa Chin; Matthew J Anderson; Stephen Kazakoff; Conrad Leonard; Felicity Newell; Nick Waddell; Scott Wood; Qinying Xu; Peter J Wilson; Nicole Cloonan; Karin S Kassahn; Darrin Taylor; Kelly Quek; Alan Robertson; Lorena Pantano; Laura Mincarelli; Luis N Sanchez; Lisa Evers; Jianmin Wu; Mark Pinese; Mark J Cowley; Marc D Jones; Emily K Colvin; Adnan M Nagrial; Emily S Humphrey; Lorraine A Chantrill; Amanda Mawson; Jeremy Humphris; Angela Chou; Marina Pajic; Christopher J Scarlett; Andreia V Pinho; Marc Giry-Laterriere; Ilse Rooman; Jaswinder S Samra; James G Kench; Jessica A Lovell; Neil D Merrett; Christopher W Toon; Krishna Epari; Nam Q Nguyen; Andrew Barbour; Nikolajs Zeps; Kim Moran-Jones; Nigel B Jamieson; Janet S Graham; Fraser Duthie; Karin Oien; Jane Hair; Robert Grützmann; Anirban Maitra; Christine A Iacobuzio-Donahue; Christopher L Wolfgang; Richard A Morgan; Rita T Lawlor; Vincenzo Corbo; Claudio Bassi; Borislav Rusev; Paola Capelli; Roberto Salvia; Giampaolo Tortora; Debabrata Mukhopadhyay; Gloria M Petersen; Donna M Munzy; William E Fisher; Saadia A Karim; James R Eshleman; Ralph H Hruban; Christian Pilarsky; Jennifer P Morton; Owen J Sansom; Aldo Scarpa; Elizabeth A Musgrove; Ulla-Maja Hagbo Bailey; Oliver Hofmann; Robert L Sutherland; David A Wheeler; Anthony J Gill; Richard A Gibbs; John V Pearson; Nicola Waddell; Andrew V Biankin; Sean M Grimmond
Journal: Nature Date: 2016-02-24 Impact factor: 49.962

2. FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing.

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Journal: Nucleic Acids Res Date: 2016-06-07 Impact factor: 16.971

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Journal: J Clin Oncol Date: 2011-06-27 Impact factor: 44.544

5. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms.

Authors: Maeve A Lowery; Winston Wong; Emmet J Jordan; Jonathan W Lee; Yelena Kemel; Joseph Vijai; Diana Mandelker; Ahmet Zehir; Marinela Capanu; Erin Salo-Mullen; Angela G Arnold; Kenneth H Yu; Anna M Varghese; David P Kelsen; Robin Brenner; Erica Kaufmann; Vignesh Ravichandran; Semanti Mukherjee; Michael F Berger; David M Hyman; David S Klimstra; Ghassan K Abou-Alfa; Catherine Tjan; Christina Covington; Hannah Maynard; Peter J Allen; Gokce Askan; Steven D Leach; Christine A Iacobuzio-Donahue; Mark E Robson; Kenneth Offit; Zsofia K Stadler; Eileen M O'Reilly
Journal: J Natl Cancer Inst Date: 2018-10-01 Impact factor: 13.506

6. Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma.

Authors: Eileen M O'Reilly; Jonathan W Lee; Maeve A Lowery; Marinela Capanu; Zsofia K Stadler; Malcolm J Moore; Neesha Dhani; Hedy L Kindler; Hayley Estrella; Hannah Maynard; Talia Golan; Amiel Segal; Erin E Salo-Mullen; Kenneth H Yu; Andrew S Epstein; Michal Segal; Robin Brenner; Richard K Do; Alice P Chen; Laura H Tang; David P Kelsen
Journal: Cancer Date: 2018-01-16 Impact factor: 6.860

7. Rucaparib Monotherapy in Patients With Pancreatic Cancer and a Known Deleterious BRCA Mutation.

Authors: Rachna T Shroff; Andrew Hendifar; Robert R McWilliams; Ravit Geva; Ron Epelbaum; Lindsey Rolfe; Sandra Goble; Kevin K Lin; Andrew V Biankin; Heidi Giordano; Robert H Vonderheide; Susan M Domchek
Journal: JCO Precis Oncol Date: 2018-05-16

8. Resistance to therapy caused by intragenic deletion in BRCA2.

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9. Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.

Authors: Matthew T Chang; Saurabh Asthana; Sizhi Paul Gao; Byron H Lee; Jocelyn S Chapman; Cyriac Kandoth; JianJiong Gao; Nicholas D Socci; David B Solit; Adam B Olshen; Nikolaus Schultz; Barry S Taylor
Journal: Nat Biotechnol Date: 2015-11-30 Impact factor: 54.908

10. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma.

Authors: Richard A Moffitt; Raoud Marayati; Elizabeth L Flate; Keith E Volmar; S Gabriela Herrera Loeza; Katherine A Hoadley; Naim U Rashid; Lindsay A Williams; Samuel C Eaton; Alexander H Chung; Jadwiga K Smyla; Judy M Anderson; Hong Jin Kim; David J Bentrem; Mark S Talamonti; Christine A Iacobuzio-Donahue; Michael A Hollingsworth; Jen Jen Yeh
Journal: Nat Genet Date: 2015-09-07 Impact factor: 38.330

44 in total

1. Durable clinical benefit from PARP inhibition in a platinum-sensitive, BRCA2-mutated pancreatic cancer patient after earlier progression on placebo treatment on the POLO trial: a case report.

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Journal: J Gastrointest Oncol Date: 2021-12

Review 2. Pancreas cancer: Therapeutic trials in metastatic disease.

Authors: James W Smithy; Eileen M O'Reilly
Journal: J Surg Oncol Date: 2021-05 Impact factor: 3.454

3. Pancreatic ductal adenocarcinoma in the era of precision medicine.

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4. Circulating Tumor DNA-Based Testing and Actionable Findings in Patients with Advanced and Metastatic Pancreatic Adenocarcinoma.

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5. Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer.

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6. Comprehensive analysis of DNA damage repair genes reveals pathogenic variants beyond BRCA and suggests the need for extensive genetic testing in pancreatic cancer.

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7. Beyond the Front Line: Emerging Data for Maintenance Therapy in Pancreatic Cancer.

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