Molecular subtypes of pancreatic cancer Collisson, Eric A; Bailey, Peter; Chang, David K ...
Nature reviews. Gastroenterology & hepatology,
04/2019, Letnik:
16, Številka:
4
Journal Article
Recenzirano
Cancers that appear morphologically similar often have dramatically different clinical features, respond variably to therapy and have a range of outcomes. Compelling evidence now demonstrates that ...differences in the molecular pathology of otherwise indistinguishable cancers substantially impact the clinical characteristics of the disease. Molecular subtypes now guide preclinical and clinical therapeutic development and treatment in many cancer types. The ability to predict optimal therapeutic strategies ahead of treatment improves overall patient outcomes, minimizing treatment-related morbidity and cost. Although clinical decision making based on histopathological criteria underpinned by robust data is well established in many cancer types, subtypes of pancreatic cancer do not currently inform treatment decisions. However, accumulating molecular data are defining subgroups in pancreatic cancer with distinct biology and potential subtype-specific therapeutic vulnerabilities, providing the opportunity to define a de novo clinically applicable molecular taxonomy. This Review summarizes current knowledge concerning the molecular subtyping of pancreatic cancer and explores future strategies for using a molecular taxonomy to guide therapeutic development and ultimately routine therapy with the overall goal of improving outcomes for this disease.
An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. ...Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine.
The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to ...highly penetrant metastasis (100% metastasis; with >80% liver metastases) in KrasG12D-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.
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•Epithelial NOTCH1 signaling drives metastasis in serrated CRC•Poor-prognosis CRC subtypes CMS4/CRIS-B are controlled by NOTCH1•TGF-β-mediated neutrophil infiltration is critical for NOTCH1-driven metastasis•Neutrophil targeting provides therapeutic opportunity in metastatic CRC
In a genetically engineered mouse model, Jackstadt et al. show that NOTCH1 activation drives metastasis in KRASG12D-driven serrated colorectal cancer (CRC) through TGFβ-dependent neutrophil recruitment. Thus, targeting neutrophil recruitment is a potential therapeutic approach in metastatic CRC.
Pancreatic cancer has become the third leading cause of cancer-related death, with little improvement in outcomes despite decades of research. Surgery remains the only chance of cure, yet only 20% of ...patients will be alive at 5 years after pancreatic resection. Few chemotherapeutics provide any improvement in outcome, and even then, for approved therapies, the survival benefits are marginal. Genomic sequencing studies of pancreatic cancer have revealed a small set of consistent mutations found in most pancreatic cancers and beyond that, a low prevalence for targetable mutations. This may explain the failure of conventional clinical trial designs to show any meaningful survival benefit, except in small and undefined patient subgroups. With the development of next-generation sequencing technology, genomic sequencing and analysis can be performed in a clinically meaningful turnaround time. This can identify therapeutic targets in individual patients and personalize treatment selection. Incorporating preclinical discovery and molecularly guided therapy into clinical trial design has the potential to significantly improve outcomes in this lethal malignancy. In this review, we discuss the findings of recent large-scale genomic sequencing projects in pancreatic cancer and the potential relevance of these data to therapeutic development.
Invasive pancreatic ductal adenocarcinoma is an almost uniformly fatal disease. Several distinct noninvasive precursor lesions can give rise to invasive adenocarcinoma of the pancreas, and the ...prevention, detection, and treatment of these noninvasive lesions offers the potential to cure early pancreatic cancers. Noninvasive precursors of invasive ductal adenocarcinoma of the pancreas include pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Diagnostic criteria, including a distinct ovarian-type stroma, and a consistent nomenclature are well established for mucinous cystic neoplasms. By contrast, consistent nomenclatures and diagnostic criteria have been more difficult to establish for PanINs and IPMNs. Because both PanINs and IPMNs consist of intraductal neoplastic proliferations of columnar, mucin-containing cells with a variable degree of papilla formation, the distinction between these two classes of precursor lesions remains problematic. Thus, considerable ambiguities still exist in the classification of noninvasive neoplasms in the pancreatic ducts. A meeting of international experts on precursor lesions of pancreatic cancer was held at The Johns Hopkins Hospital from August 18 to 19, 2003. The purpose of this meeting was to define an international acceptable set of diagnostic criteria for PanINs and IPMNs and to address a number of ambiguities that exist in the previously reported classification systems for these neoplasms. We present a consensus classification of the precursor lesions in the pancreatic ducts, PanINs and IPMNs.
Recently, there has been an increasing interest in the development and characterization of patient-derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal ...histologic and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biologic studies, and personalized medicine strategies. This article summarizes the current state of the art in this field, including methodologic issues, available collections, practical applications, challenges and shortcomings, and future directions, and introduces a European consortium of PDX models.
PDX models are increasingly used in translational cancer research. These models are useful for drug screening, biomarker development, and the preclinical evaluation of personalized medicine strategies. This review provides a timely overview of the key characteristics of PDX models and a detailed discussion of future directions in the field.
International experts met to discuss recent advances and to revise the 2004 recommendations for assessing and reporting precursor lesions to invasive carcinomas of the pancreas, including pancreatic ...intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm, and other lesions. Consensus recommendations include the following: (1) To improve concordance and to align with practical consequences, a 2-tiered system (low vs. high grade) is proposed for all precursor lesions, with the provision that the current PanIN-2 and neoplasms with intermediate-grade dysplasia now be categorized as low grade. Thus, "high-grade dysplasia" is to be reserved for only the uppermost end of the spectrum ("carcinoma in situ"-type lesions). (2) Current data indicate that PanIN of any grade at a margin of a resected pancreas with invasive carcinoma does not have prognostic implications; the clinical significance of dysplasia at a margin in a resected pancreas with IPMN lacking invasive carcinoma remains to be determined. (3) Intraductal lesions 0.5 to 1 cm can be either large PanINs or small IPMNs. The term "incipient IPMN" should be reserved for lesions in this size with intestinal or oncocytic papillae or GNAS mutations. (4) Measurement of the distance between an IPMN and invasive carcinoma and sampling of intervening tissue are recommended to assess concomitant versus associated status. Conceptually, concomitant invasive carcinoma (in contrast with the "associated" group) ought to be genetically distinct from an IPMN elsewhere in the gland. (5) "Intraductal spread of invasive carcinoma" (aka, "colonization") is recommended to describe lesions of invasive carcinoma invading back into and extending along the ductal system, which may morphologically mimic high-grade PanIN or even IPMN. (6) "Simple mucinous cyst" is recommended to describe cysts >1 cm having gastric-type flat mucinous lining at most minimal atypia without ovarian-type stroma to distinguish them from IPMN. (7) Human lesions resembling the acinar to ductal metaplasia and atypical flat lesions of genetically engineered mouse models exist and may reflect an alternate pathway of carcinogenesis; however, their biological significance requires further study. These revised recommendations are expected to improve our management and understanding of precursor lesions in the pancreas.
MYC is implicated in the development and progression of pancreatic cancer, yet the precise level of MYC deregulation required to contribute to tumor development has been difficult to define. We used ...modestly elevated expression of human MYC, driven from the
locus, to investigate the pancreatic phenotypes arising in mice from an approximation of
trisomy. We show that this level of MYC alone suffices to drive pancreatic neuroendocrine tumors, and to accelerate progression of KRAS-initiated precursor lesions to metastatic pancreatic ductal adenocarcinoma (PDAC). Our phenotype exposed suppression of the type I interferon (IFN) pathway by the combined actions of MYC and KRAS, and we present evidence of repressive MYC-MIZ1 complexes binding directly to the promoters of the genes encodiing the type I IFN regulators IRF5, IRF7, STAT1, and STAT2. Derepression of IFN regulator genes allows pancreatic tumor infiltration by B and natural killer (NK) cells, resulting in increased survival. SIGNIFICANCE: We define herein a novel mechanism of evasion of NK cell-mediated immunity through the combined actions of endogenously expressed mutant KRAS and modestly deregulated expression of MYC, via suppression of the type I IFN pathway. Restoration of IFN signaling may improve outcomes for patients with PDAC.
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Background
Pancreatic cancer (PC) is a highly lethal disease with few effective treatment options. Over the past few decades, many anti‐cancer therapies have been tested in the locally advanced and ...metastatic setting, with mixed results. This review attempts to synthesise all the randomised data available to help better inform patient and clinician decision‐making when dealing with this difficult disease.
Objectives
To assess the effect of chemotherapy, radiotherapy or both for first‐line treatment of advanced pancreatic cancer. Our primary outcome was overall survival, while secondary outcomes include progression‐free survival, grade 3/4 adverse events, therapy response and quality of life.
Search methods
We searched for published and unpublished studies in CENTRAL (searched 14 June 2017), Embase (1980 to 14 June 2017), MEDLINE (1946 to 14 June 2017) and CANCERLIT (1999 to 2002) databases. We also handsearched all relevant conference s published up until 14 June 2017.
Selection criteria
All randomised studies assessing overall survival outcomes in patients with advanced pancreatic ductal adenocarcinoma. Chemotherapy and radiotherapy, alone or in combination, were the eligible treatments.
Data collection and analysis
Two review authors independently analysed studies, and a third settled any disputes. We extracted data on overall survival (OS), progression‐free survival (PFS), response rates, adverse events (AEs) and quality of life (QoL), and we assessed risk of bias for each study.
Main results
We included 42 studies addressing chemotherapy in 9463 patients with advanced pancreatic cancer. We did not identify any eligible studies on radiotherapy.
We did not find any benefit for chemotherapy over best supportive care. However, two identified studies did not have sufficient data to be included in the analysis, and many of the chemotherapy regimens studied were outdated.
Compared to gemcitabine alone, participants receiving 5FU had worse OS (HR 1.69, 95% CI 1.26 to 2.27, moderate‐quality evidence), PFS (HR 1.47, 95% CI 1.12 to 1.92) and QoL. On the other hand, two studies showed FOLFIRINOX was better than gemcitabine for OS (HR 0.51 95% CI 0.43 to 0.60, moderate‐quality evidence), PFS (HR 0.46, 95% CI 0.38 to 0.57) and response rates (RR 3.38, 95% CI 2.01 to 5.65), but it increased the rate of side effects. The studies evaluating CO‐101, ZD9331 and exatecan did not show benefit or harm when compared with gemcitabine alone.
Giving gemcitabine at a fixed dose rate improved OS (HR 0.79, 95% CI 0.66 to 0.94, high‐quality evidence) but increased the rate of side effects when compared with bolus dosing.
When comparing gemcitabine combinations to gemcitabine alone, gemcitabine plus platinum improved PFS (HR 0.80, 95% CI 0.68 to 0.95) and response rates (RR 1.48, 95% CI 1.11 to 1.98) but not OS (HR 0.94, 95% CI 0.81 to 1.08, low‐quality evidence). The rate of side effects increased. Gemcitabine plus fluoropyrimidine improved OS (HR 0.88, 95% CI 0.81 to 0.95), PFS (HR 0.79, 95% CI 0.72 to 0.87) and response rates (RR 1.78, 95% CI 1.29 to 2.47, high‐quality evidence), but it also increased side effects. Gemcitabine plus topoisomerase inhibitor did not improve survival outcomes but did increase toxicity. One study demonstrated that gemcitabine plus nab‐paclitaxel improved OS (HR 0.72, 95% CI 0.62 to 0.84, high‐quality evidence), PFS (HR 0.69, 95% CI 0.58 to 0.82) and response rates (RR 3.29, 95% CI 2.24 to 4.84) but increased side effects. Gemcitabine‐containing multi‐drug combinations (GEMOXEL or cisplatin/epirubicin/5FU/gemcitabine) improved OS (HR 0.55, 95% CI 0.39 to 0.79, low‐quality evidence), PFS (HR 0.43, 95% CI 0.30 to 0.62) and QOL.
We did not find any survival advantages when comparing 5FU combinations to 5FU alone.
Authors' conclusions
Combination chemotherapy has recently overtaken the long‐standing gemcitabine as the standard of care. FOLFIRINOX and gemcitabine plus nab‐paclitaxel are highly efficacious, but our analysis shows that other combination regimens also offer a benefit. Selection of the most appropriate chemotherapy for individual patients still remains difficult, with clinicopathological stratification remaining elusive. Biomarker development is essential to help rationalise treatment selection for patients.
Missense mutations in the p53 tumor suppressor inactivate its antiproliferative properties but can also promote metastasis through a gain-of-function activity. We show that sustained expression of ...mutant p53 is required to maintain the prometastatic phenotype of a murine model of pancreatic cancer, a highly metastatic disease that frequently displays p53 mutations. Transcriptional profiling and functional screening identified the platelet-derived growth factor receptor b (PDGFRb) as both necessary and sufficient to mediate these effects. Mutant p53 induced PDGFRb through a cell-autonomous mechanism involving inhibition of a p73/NF-Y complex that represses PDGFRb expression in p53-deficient, noninvasive cells. Blocking PDGFRb signaling by RNA interference or by small molecule inhibitors prevented pancreatic cancer cell invasion in vitro and metastasis formation in vivo. Finally, high PDGFRb expression correlates with poor disease-free survival in pancreatic, colon, and ovarian cancer patients, implicating PDGFRb as a prognostic marker and possible target for attenuating metastasis in p53 mutant tumors.
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