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

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3119
Author(s):  
Rita T. Lawlor ◽  
Paola Mattiolo ◽  
Andrea Mafficini ◽  
Seung-Mo Hong ◽  
Maria L. Piredda ◽  
...  
Keyword(s):  
Systematic Review ◽  
Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Molecular Feature ◽  
Molecular Features ◽  
Mutational Burden ◽  
Open Questions ◽  
Potential Biomarker ◽  
Starting Point ◽  
Tumor Mutational Burden

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.

Association of BRCA-mutant pancreatic cancer with high tumor mutational burden (TMB) and higher PD-L1 expression.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4133-4133 ◽  
Author(s):  
Andreas Seeber ◽  
Alberto Puccini ◽  
Joanne Xiu ◽  
Richard M. Goldberg ◽  
Axel Grothey ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Pancreatic Adenocarcinoma ◽  
Brca Mutation ◽  
Ductal Adenocarcinoma ◽  
Familial Pancreatic Cancer ◽  
Brca Mutations ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Brca2 Mutations

4133 Background: In the U.S. 56,000 Americans are expected to be diagnosed with pancreatic cancer in 2019. Prognosis in pancreatic cancer is poor. Therefore, new treatment strategies are urgently needed to improve survival. BRCA1 and BRCA2 mutations have been described to be the most common genetic mutations involved in familial pancreatic cancer. The optimal treatment regimen to use in BRCA-mutant pancreatic cancer has still to be established. Moreover, no data are available on association of BRCA mutation with immune-associated markerssuch as tumor mutational burden (TMB), microsatellite instability (MSI) or PD-L1 expression. Methods: Tumor samples of 2824 patients with pancreatic ductal adenocarcinoma were analyzed for BRCA mutation by NGS and for other genes (MiSeq on 47 genes, NextSeq on 592 genes) at Caris Life Sciences, Phoenix, AZ. TMB was calculated based on somatic nonsynonymous missense mutations, and MSI was evaluated by NGS of known MSI loci. PD-L1 expression was evaluated using immunohistochemistry. Results: In 4.4% (N = 124) of all pancreatic adenocarcinoma samples BRCA mutations were detected. BRCA2 mutations were more common: 3.1% (N = 89) vs 1.1% BRCA1 mutations (N = 35). BRCA mutations were associated with younger age ( BRCA1: 61 yrs for mutated vs. 64 for wild-type, p = 0.07; BRCA2: 61 yrs vs. 64, p = 0.002; both: p < 0.001). BRCA mutations were associated with higher MSI-H frequency (4.8% vs. 1.2%, p = 0.002), elevated PD-L1 expression (22% vs. 11%, p < 0.001) and higher TMB (mean 8.7 mut/MB vs. 6.5, p < 0.001); the differences remain significant in MSS tumors (p < 0.05). BRCA-mutant pancreatic carcinomas showed a significantly lower mutation frequencies in TP53 (59% vs 73%, p = 0.001), CKDN2A (13% vs 25%, p = 0.006), but higher frequencies in APC (6.5% vs 2.2%), KMT2A (1.9% vs 0.2%), AMER1 (1.9 vs 0.5%) and SETD2 (3.7% vs 0.4%) mutations (p < 0.05 for all comparisons). Conclusions: BRCA mutations are found in a significant subgroup of pancreatic ductal adenocarcinoma and these carcinomas are associated with an immunogenic tumor profile. These data suggest evaluating PARP inhibitors in combination with immunotherapy in patients with BRCA-mutant pancreatic adenocarcinoma especially in tumors that are MSS.

scholarly journals Exercise efficacy and prescription during treatment for pancreatic ductal adenocarcinoma: a systematic review

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dominic O’Connor ◽  
Malcolm Brown ◽  
Martin Eatock ◽  
Richard C. Turkington ◽  
Gillian Prue
Keyword(s):  
Quality Of Life ◽  
Systematic Review ◽  
Pancreatic Cancer ◽  
Adjuvant Therapy ◽  
Physical Function ◽  
Meta Analysis ◽  
Ductal Adenocarcinoma ◽  
Key Stakeholders ◽  
The Impact

Abstract Background Surgical resection remains the only curative treatment for pancreatic cancer and is associated with significant post-operative morbidity and mortality. Patients eligible for surgery, increasingly receive neo-adjuvant therapy before surgery or adjuvant therapy afterward, inherently exposing them to toxicity. As such, optimizing physical function through exercise during treatment remains imperative to optimize quality of life either before surgery or during rehabilitation. However, current exercise efficacy and prescription in pancreatic cancer is unknown. Therefore, this study aims to summarise the published literature on exercise studies conducted in patients with pancreatic cancer undergoing treatment with a focus on determining the current prescription and progression patterns being used in this population. Methods A systematic review of four databases identified studies evaluating the effects of exercise on aerobic fitness, muscle strength, physical function, body composition, fatigue and quality of life in participants with pancreatic cancer undergoing treatment, published up to 24 July 2020. Two reviewers independently reviewed and appraised the methodological quality of each study. Results Twelve studies with a total of 300 participants were included. Heterogeneity of the literature prevented meta-analysis. Exercise was associated with improvements in outcomes; however, study quality was variable with the majority of studies receiving a weak rating. Conclusions High quality evidence regarding the efficacy and prescription of exercise in pancreatic cancer is lacking. Well-designed trials, which have received feedback and input from key stakeholders prior to implementation, are required to examine the impact of exercise in pancreatic cancer on key cancer related health outcomes.

scholarly journals Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications

Gut ◽  
2020 ◽  
Vol 70 (1) ◽  
pp. 148-156 ◽  
Author(s):  
Claudio Luchini ◽  
Lodewijk A A Brosens ◽  
Laura D Wood ◽  
Deyali Chatterjee ◽  
Jae Il Shin ◽  
...  
Keyword(s):  
Systematic Review ◽  
Microsatellite Instability ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Data ◽  
The Cancer Genome Atlas ◽  
Research Network ◽  
Ductal Adenocarcinoma ◽  
Precision Oncology ◽  
Dna Mismatch ◽  
Molecular Features

ObjectiveRecently, tumours with microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) have gained considerable interest due to the success of immunotherapy in this molecular setting. Here, we aim to clarify clinical-pathological and/or molecular features of this tumour subgroup through a systematic review coupled with a comparative analysis with existing databases, also providing indications for a correct approach to the clinical identification of MSI/dMMR pancreatic ductal adenocarcinoma (PDAC).DesignPubMed, SCOPUS and Embase were searched for studies reporting data on MSI/dMMR in PDAC up to 30 November 2019. Histological and molecular data of MSI/dMMR PDAC were compared with non-MSI/dMMR PDAC and with PDAC reference cohorts (including SEER database and The Cancer Genome Atlas Research Network - TCGA project).ResultsOverall, 34 studies with 8323 patients with PDAC were included in the systematic review. MSI/dMMR demonstrated a very low prevalence in PDAC (around 1%–2%). Compared with conventional PDAC, MSI/dMMR PDAC resulted strongly associated with medullary and mucinous/colloid histology (p<0.01) and with a KRAS/TP53 wild-type molecular background (p<0.01), with more common JAK genes mutations. Data on survival are still unclear.ConclusionPDAC showing typical medullary or mucinous/colloid histology should be routinely examined for MSI/dMMR status using specific tests (immunohistochemistry, followed by MSI-PCR in cases with doubtful results). Next-generation sequencing (NGS) should be adopted either where there is limited tissue or as part of NGS tumour profiling in the context of precision oncology, acknowledging that conventional histology of PDAC may rarely harbour MSI/dMMR.

scholarly journals In-house Implementation of Tumor Mutational Burden Testing to Predict Durable Clinical Benefit in Non-small Cell Lung Cancer and Melanoma Patients

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1271 ◽  
Author(s):  
Heeke ◽  
Benzaquen ◽  
Long-Mira ◽  
Audelan ◽  
Lespinet ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Clinical Benefit ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Potential Biomarker ◽  
Tumor Mutational Burden ◽  
Melanoma Patients

Tumor mutational burden (TMB) has emerged as an important potential biomarker for prediction of response to immune-checkpoint inhibitors (ICIs), notably in non-small cell lung cancer (NSCLC). However, its in-house assessment in routine clinical practice is currently challenging and validation is urgently needed. We have analyzed sixty NSCLC and thirty-six melanoma patients with ICI treatment, using the FoundationOne test (FO) in addition to in-house testing using the Oncomine TML (OTML) panel and evaluated the durable clinical benefit (DCB), defined by >6 months without progressive disease. Comparison of TMB values obtained by both tests demonstrated a high correlation in NSCLC (R2 = 0.73) and melanoma (R2 = 0.94). The association of TMB with DCB was comparable between OTML (area-under the curve (AUC) = 0.67) and FO (AUC = 0.71) in NSCLC. Median TMB was higher in the DCB cohort and progression-free survival (PFS) was prolonged in patients with high TMB (OTML HR = 0.35; FO HR = 0.45). In contrast, we detected no differences in PFS and median TMB in our melanoma cohort. Combining TMB with PD-L1 and CD8-expression by immunohistochemistry improved the predictive value. We conclude that in our cohort both approaches are equally able to assess TMB and to predict DCB in NSCLC.

scholarly journals Organotypic Culture of Acinar Cells for the Study of Pancreatic Cancer Initiation

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2606
Author(s):  
Carlotta Paoli ◽  
Alessandro Carrer
Keyword(s):  
Pancreatic Cancer ◽  
Ex Vivo ◽  
Acinar Cells ◽  
Lineage Tracing ◽  
Metabolic Reprogramming ◽  
Pancreatic Acinar Cells ◽  
Ductal Adenocarcinoma ◽  
Molecular Features ◽  
The Impact

The carcinogenesis of pancreatic ductal adenocarcinoma (PDA) progresses according to multi-step evolution, whereby the disease acquires increasingly aggressive pathological features. On the other hand, disease inception is poorly investigated. Decoding the cascade of events that leads to oncogenic transformation is crucial to design strategies for early diagnosis as well as to tackle tumor onset. Lineage-tracing experiments demonstrated that pancreatic cancerous lesions originate from acinar cells, a highly specialized cell type in the pancreatic epithelium. Primary acinar cells can survive in vitro as organoid-like 3D spheroids, which can transdifferentiate into cells with a clear ductal morphology in response to different cell- and non-cell-autonomous stimuli. This event, termed acinar-to-ductal metaplasia, recapitulates the histological and molecular features of disease initiation. Here, we will discuss the isolation and culture of primary pancreatic acinar cells, providing a historical and technical perspective. The impact of pancreatic cancer research will also be debated. In particular, we will dissect the roles of transcriptional, epigenetic, and metabolic reprogramming for tumor initiation and we will show how that can be modeled using ex vivo acinar cell cultures. Finally, mechanisms of PDA initiation described using organotypical cultures will be reviewed.

Tumor mutational burden as a potential biomarker for PD1/PD-L1 therapy in colorectal cancer.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 3587-3587 ◽  
Author(s):  
Thomas J. George ◽  
Garrett Michael Frampton ◽  
James Sun ◽  
Kyle Gowen ◽  
Mark Kennedy ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mutational Burden ◽  
Potential Biomarker ◽  
Tumor Mutational Burden

Thromboembolic events in advanced pancreatic cancer: A systematic review.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 461-461
Author(s):  
Mann Muhsin ◽  
Omar Dabbous ◽  
Blake Morrison ◽  
Piet Vervaet ◽  
Dimitrios Chondros
Keyword(s):  
Systematic Review ◽  
Pancreatic Cancer ◽  
Clinical Trials ◽  
Literature Review ◽  
Observational Studies ◽  
Randomized Clinical Trials ◽  
Advanced Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Thromboembolic Events ◽  
Ambulatory Patient

461 Background: Pancreatic ductal adenocarcinoma (PDA) is highly associated with thromboembolic events (TEs). There is no consensus for prophylaxis of TEs across thromboprophylactic guidelines in ambulatory patient settings. Published ASCO (2014) and ESMO (2011) guidelines recommend use of primary thromboprophylaxis in pancreatic cancer outpatients at high risk of TEs. This systematic review investigated TE rates and prophylaxis among advanced PDA patients. Methods: A literature review identified clinical trials and observational studies reporting TE rates with and without thromboprophylaxis in PDA patients undergoing chemotherapy. A search was conducted using electronic databases including Medline, Medline In-Process, and Embase; limited to English language and publication between 1990 and April 2017. Retrieved articles were cross-referenced and scrutinized to identify additional publications. Results: Seven studies were identified; 2 randomized clinical trials (RCTs) and 5 observational/retrospective studies met the stated criteria. The TE rate in PDA in the 5 observational studies without prophylaxis ranged from 9.6% to 36.0%. Thromboprophylaxis was used in the 2 RCTs and was associated with lower TE rates. Conclusions: This comprehensive literature review shows that PDA patients face a substantial risk of TE after chemotherapy. The high rates of TEs in PDA, and the effectiveness of thromboprophylaxis in patients with PDA, highlight the importance of having consensus for prophylaxis of TEs across thromboprophylactic guidelines in ambulatory patient settings as a critical early preventive measure during the treatment of patients with advanced PDA. [Table: see text]

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