domingo, 4 de febrero de 2018

Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations. - PubMed - NCBI

2018 Jan 24. pii: clincanres.3099.2017. doi: 10.1158/1078-0432.CCR-17-3099. [Epub ahead of print]

Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations.

Hu ZI1, Shia J2, Stadler ZK3, Varghese AM4, Capanu M5, Salo-Mullen E6, Lowery MA7, Diaz LA8, Mandelker D9, Yu KH1, Zervoudakis A1, Kelsen DP3, Iacobuzio-Donahue CA10, Klimstra DS11, Saltz L1, Sahin IH12, O'Reilly EM13.

Author information

Abstract

PURPOSE:

Immune checkpoint inhibition has been shown to generate profound and durable responses in MMR-D solid tumors and has elicited interest in detection tools and strategies to guide therapeutic decision-making. Herein we address questions on the appropriate screening, detection methods, patient selection, and initiation of therapy for MMR-D PDAC and assess the utility of NGS in providing additional prognostic and predictive information for MMR-D PDAC.

EXPERIMENTAL DESIGN:

Archival and prospectively acquired samples and matched normal DNA from N= 833 PDAC cases were analyzed using a hybridization capture based, NGS assay designed to perform targeted deep sequencing of all exons and selected introns of 341- 468 cancer-associated genes. A computational program using NGS data derived the MSI status from the tumor-normal paired genomesequencing data. Review of available germline testing, IHC, and MSI PCR results were performed to assess and confirm MMR-D and MSI status.

RESULTS:

MMR-D in PDAC is a rare event among PDAC patients (7/833) occurring at a frequency of 0.8%. Loss of MMR protein expression by IHC, high mutational load and elevated MSIsensor scores were correlated with MMR-D PDAC. All 7 MMR-D PDAC patients in the study were found to have Lynch Syndrome. Four (57%) of the MMR-D patients treated with immune checkpoint blockade had treatment benefit (1 complete response; 2 partial responses; 1 stable disease).

CONCLUSIONS:

An integrated approach of germline testing and somatic analyses of tumor tissues in advanced PDAC using NGS may help guide future development of immune and molecularly directed therapies in PDAC patients.