Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewMolecular classification as prognostic factor and guide for treatment decision of pancreatic cancer
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers [1] with a 5-year survival inferior to 10% and an increasing incidence [2]. Complete surgical removal of the tumor followed by adjuvant chemotherapy is the only curative treatment. However, <20% of patients are candidate to surgery. Recently, adjuvant combination of gemcitabine and capecitabine following pancreatic resection for PDAC (ESPAC-4) showed a median overall survival of 28 months (95% CI 23·5–31·5) for patients who received gemcitabine plus capecitabine compared to 25·5 months (22·7–27·9) for gemcitabine alone [3]. Patients with borderline resectable or locally-advanced tumor are often treated with neoadjuvant chemotherapy (FOLFIRINOX) to obtain a margin-negative resection with a disease-free survival and overall survival better than upfront resected patients (DFS: 29.1 vs 13.7, P < 0.001; OS: 37.7 vs 25.1 months from diagnosis, P = 0.01) [4].
Only few chemotherapy agents (gemcitabine with or without nab-paclitaxel, FOLFIRINOX regimen combining 5-FU, leucovorin, oxaliplatin and irinotecan) and one targeted therapy (erlotinib, a tyrosine kinase inhibitor, notably for the epidermal growth factor receptor (EGFR)) show some degree of efficacy in unselected patients but with a limited clinical impact. Only 31.6%, 23% and <10% of patients respond to FOLFIRINOX, gemcitabine/nab-paclitaxel and gemcitabine, respectively [5,6]. Thus, it is crucial to both develop novel drugs and specifically identify patients most likely to benefit from one or another treatment.
Currently, the AJCC TNM staging is the only prognostic factor used in clinical practice to assess the survival of a resected PDAC and guide treatment decision. However, this clinicopathological factor fails to consistently predict the outcome after pancreatic resection. Characterization of molecular alterations may help develop techniques for early detection, identify new molecular targets and design novel targeted therapies. In breast and lung cancers, targeting drugs to tumor molecular subtypes improves treatment response and outcome [7,8]. Like these tumors, PDAC is a heterogeneous molecular disease. To solve this inter-tumor heterogeneity, high-throughput molecular studies have been applied to PDAC samples. They revealed molecular subtypes associated with different genetic alterations and prognosis, as well as gene expression signatures associated with survival [[9], [10], [11], [12]].
Section snippets
Molecular classification according to genomic alterations
Early studies had shown that the most frequently altered genes in PDACs are KRAS, SMAD4, TP53 and CDKN2A/B. Many genes such as ARID1A, GATA6, SF3B1, and TGFBR2 were later found altered by using comprehensive genomic approaches including array-comparative genomic hybridization [[13], [14], [15], [16]] and large-scale sequencing [[17], [18], [19], [20]]. Since then, many studies have been published and confirmed the high heterogeneity of genomic alterations found in PDAC. In 2012, exome
Molecular classification according to gene expression
The first profiling of PDAC was published in 2011 based on 27 microdissected surgical samples. Three different PDAC subtypes (“classical”, “quasi-mesenchymal”, and “exocrine-like”) with different clinical outcomes and therapeutic responses were defined [10]. These subtypes were validated in three additional public datasets (n = 102 samples). After surgical resection, the classical tumor subtype had a better survival than the quasi-mesenchymal subtype and showed an overexpression of genes
Molecular classification and prognosis
A major challenge is to improve the imperfect current prognostic factors to aid in therapeutic decision-making. Due to variation in survival within AJCC clinical stages and to the large genomic heterogeneity within PDAC tumors, prognostic gene expression signatures may be used to help predict outcome. Indeed, gene expression profiling remains today the most promising and successful high-throughput molecular approach for identifying new prognostic tools in early-stage cancers. Multigene
Molecular classification and treatment
The recently identified molecular PDAC classifications increased our understanding and are important to establish treatment strategies and therapeutic development. Now that genomic and transcriptomic classifications are established, we should move to in vitro and in vivo experiments to validate the best treatment strategy to use in each of the defined subtypes. What treatments could be proposed based on molecular classifications?
Gemcitabine is generally used as the first-line therapy but
Authors' contributions
DJB, EM and DB was involved in the conception and the design of study, analysis and interpretation of data, and draft of the manuscript. PF was involved in the acquisition and analysis of all data. FB was involved in the analysis and interpretation of some data. All authors read critically and approved the final manuscript.
Competing interests
The authors declare that they have no conflict of interest.
Funding
Our work was supported by Institut Paoli-Calmettes, Institut National de la Santé et de la Recherche Médicale, Institut National du Cancer, and Site de Recherche Intégrée sur le Cancer Marseille (INCa-DGOS-Inserm 6038 grant). None of them had any role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Transparency document
Acknowledgments
Not applicable.
References (73)
- et al.
Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial
Lancet
(2017 Mar 11) After neoadjuvant therapy, imaging no longer provides a clear answer
Int. J. Radiat. Oncol. Biol. Phys.
(2017 Oct 1)- et al.
Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes
Cell
(1988 May 20) - et al.
A gene expression signature of epithelial tubulogenesis and a role for ASPM in pancreatic tumor progression
Gastroenterology
(2013 Nov) - et al.
Transcriptomic analysis predicts survival and sensitivity to anticancer drugs of patients with a pancreatic adenocarcinoma
Am. J. Pathol.
(2015 Apr) - et al.
Immunotherapy in pancreatic ductal adenocarcinoma: an emerging entity?
Ann. Oncol.
(2017 Dec 1) - et al.
Tumour-stroma interactions in pancreatic ductal adenocarcinoma: rationale and current evidence for new therapeutic strategies
Cancer Treat. Rev.
(2014 Feb) - et al.
Anticancer agent CHS-828 inhibits cellular synthesis of NAD
Biochem. Biophys. Res. Commun.
(2008 Mar 21) Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia
Cancer Cell
(2014 Nov 10)- et al.
Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012
Int. J. Cancer
(2015 Mar 1)
Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States
Cancer Res.
Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial
J. Clin. Oncol.
Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine
N. Engl. J. Med.
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib
N. Engl. J. Med.
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2
N. Engl. J. Med.
Genomic analyses identify molecular subtypes of pancreatic cancer
Nature
Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy
Nat. Med.
Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma
Nat. Genet.
Whole genomes redefine the mutational landscape of pancreatic cancer
Nature
Genome profiling of pancreatic adenocarcinoma
Genes Chromosom. Cancer
Endometriosis-associated ovarian carcinomas
N. Engl. J. Med.
Interglandular cytogenetic heterogeneity detected by comparative genomic hybridization in pancreatic cancer
Cancer Res.
Evaluation of the reliability of chromosomal imbalances detected by combined use of universal DNA amplification and comparative genomic hybridization
Jpn. J. Cancer Res.
DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1
Science
Core signaling pathways in human pancreatic cancers revealed by global genomic analyses
Science
Genomic profiling identifies GATA6 as a candidate oncogene amplified in pancreatobiliary cancer
PLoS Genet.
Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
Nature
Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets
Nat. Commun.
Signatures of mutational processes in human cancer
Nature
Hypermutation in pancreatic cancer
Gastroenterology
GATA4 and GATA6 control mouse pancreas organogenesis
J. Clin. Invest.
Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis
J. Clin. Invest.
Prognostic relevance of molecular subtypes and master regulators in pancreatic ductal adenocarcinoma
BMC Cancer
Pancreatic cancer
Annu. Rev. Pathol.
Stratification of pancreatic ductal adenocarcinoma: combinatorial genetic, stromal, and immunologic markers
Clin. Cancer Res.
Prognostic value of PDL1 expression in pancreatic cancer
Oncotarget
Cited by (25)
The dynamic interactions between the stroma, pancreatic stellate cells and pancreatic tumor development: Novel therapeutic targets
2019, Cytokine and Growth Factor ReviewsCitation Excerpt :The classical subtype displayed better survival rates and was characterized by the upregulation of adhesion and epithelial genes and GATA6, which codes for a TF mediating pancreatic development [22]. In contrast, quasi-mesenchymal tumors correlated with the poorest survival rates of all three classes and exhibited increased levels of mesenchymal genes, including CAV1, HK2 and TWIST1 [6,7]. Finally, the exocrine-like tumors were characterized by the overexpression of genes coding for digestive enzymes and linked to exocrine pancreas function [6,7].
Nowadays pancreatic cancer prognosis
2019, Medicina ClinicaLong non-coding RNA HULC promotes proliferation, migration and invasion of pancreatic cancer cells by down-regulating microRNA-15a
2019, International Journal of Biological Macromolecules