Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Pancreatic Cancer: Systematic Review and Still-Open Questions

Published on Jun 22, 2021in Cancers6.126
· DOI :10.3390/CANCERS13133119
Rita T. Lawlor31
Estimated H-index: 31
,
Paola Mattiolo3
Estimated H-index: 3
+ 13 AuthorsRoberto Salvia52
Estimated H-index: 52
Sources
Abstract
Tumor mutational burden (TMB) is a numeric index that expresses the number of mutations per megabase (muts/Mb) harbored by tumor cells in a neoplasm. TMB can be determined using different approaches based on next-generation sequencing. In the case of high values, it indicates a potential response to immunotherapy. In this systematic review, we assessed the potential predictive role of high-TMB in pancreatic ductal adenocarcinoma (PDAC), as well as the histo-molecular features of high-TMB PDAC. High-TMB appeared as a rare but not-negligible molecular feature in PDAC, being present in about 1.1% of cases. This genetic condition was closely associated with mucinous/colloid and medullary histology (p < 0.01). PDAC with high-TMB frequently harbored other actionable alterations, with microsatellite instability/defective mismatch repair as the most common. Immunotherapy has shown promising results in high-TMB PDAC, but the sample size of high-TMB PDAC treated so far is quite small. This study highlights interesting peculiarities of PDAC harboring high-TMB and may represent a reliable starting point for the assessment of TMB in the clinical management of patients affected by pancreatic cancer.
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#1James W. Smithy (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 9
Last. Eileen M. O'Reilly (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 73
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Metastatic pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related mortality in 2021. Cytotoxic therapies are the therapeutic mainstay for PDAC. The recent approval of olaparib as maintenance therapy for germline BRCA1/2-mutated PDAC and pembrolizumab for mismatch repair deficient PDAC represent molecularly targeted approaches for this disease. Investigational therapeutic strategies include targeting the stroma, metabolism, tumor microenvironment, and the immune system, and se...
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#1Ryuichiro Kimura (Kyushu University)H-Index: 2
#2Takao Ohtsuka (Kyushu University)H-Index: 37
Last. Masafumi Nakamura (Kyushu University)H-Index: 63
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The aim of this study was to investigate the genetic mutation profiles of Japanese pancreatic ductal adenocarcinoma (PDAC) patients. Next-generation sequencing was performed using FoundationOne® CDx on 17 PDAC patients who were treated by surgical resection at Kyushu University Hospital between February 2016 and January 2019. The tumor mutational burden and microsatellite instability status were also assessed. There were 16 patients (94%) with KRAS mutations, 13 (76%) with TP53 mutations, three ...
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#1John H. Strickler (Duke University)H-Index: 19
#2Brent A. Hanks (Duke University)H-Index: 19
Last. Mustafa Khasraw (Duke University)H-Index: 27
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Immune checkpoint inhibitors, including antibodies that block programmed cell death protein-1 (PD-1) and PD-L1, have transformed the management of many cancers. However, the majority of patients have primary or acquired resistance to these immunotherapies. There is a significant unmet need for predictive biomarkers that can reliably identify patients who derive a clinically meaningful response from PD-1/PD-L1 blockade. High tumor mutational burden (TMB-H) has shown promise as a biomarker in lung...
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#1Talia Golan (TAU: Tel Aviv University)H-Index: 14
#1Talia Golan (Sheba Medical Center)H-Index: 20
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Last. Aldo ScarpaH-Index: 99
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#1Chiara BazzichettoH-Index: 9
#2Claudio LuchiniH-Index: 31
Last. Michele Milella (University of Verona)H-Index: 50
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#1Aurélien Marabelle (Université Paris-Saclay)H-Index: 62
#2Marwan Fakih (City of Hope National Medical Center)H-Index: 53
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Summary Background Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours. Methods In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158...
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#2Robert E. Denroche (OICR: Ontario Institute for Cancer Research)H-Index: 16
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Objective To describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP). Design We identified patients with MMRD and MMRP pancreatic cancer in a clinical cohort (N=1213, 519 with genetic testing, 53 with immunohistochemistry (IHC)) and a genomic cohort (N=288 with whole-genome sequencing (WGS)). Results 12 out of 1213 (1.0%) in the clinical cohort were MMRD by IHC or WGS. Of the 14 patients with Lynch syn...
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Last. Susanne Sebens (CAU: University of Kiel)H-Index: 26
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To date, extensive efforts to harness immunotherapeutic strategies for the treatment of pancreatic ductal adenocarcinoma (PDAC) have yielded disappointing results in clinical trials. These strategies mainly focused on cancer vaccines and immune checkpoint inhibitors alone or in combination with chemotherapeutic or targeted agents. However, the growing preclinical and clinical data sets from these efforts have established valuable insights into the immunological characteristics of PDAC biology. M...
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