Key points

Introduction and public health concerns

Pancreatic ductal adenocarcinoma (PDA) is the 12th most common cancer in the United States. As of January 7, 2016, the American Cancer Society reported that pancreatic cancer had surpassed breast cancer as the third leading cause of cancer related death in the United States. Within the next decade, annual PDA deaths will likely surpass colorectal cancer as well. There were 53,070 new cases of PDA in 2015, and 41,780 deaths in the United States alone. Although the death rates for the most common cancers have declined in recent decades, the death rate for PDA is actually flat to slightly increased, in large part related to the aging demographic. Over the past 4 decades, disease-specific survival has only improved marginally, with 5-year survival rates increasing from 4% to 7%. The lack of clinical progress, in comparison with other cancers, is attributable to a failure to develop novel and effective therapies. Standard treatment still consists of relatively old cytotoxic therapies. The only advance has been improved experience and success administering combinations of drugs, which confer a small survival advantage over single agent therapy. Mutation targeted and immunologic therapies that have shown efficacy or promise for other cancer types have not yet achieved comparable benefits for pancreatic cancer. Herein, we review the molecular and clinical aspects of pancreatic cancer, and highlight the most critical challenges facing the management of this disease.

Introduction and public health concerns

Pancreatic ductal adenocarcinoma (PDA) is the 12th most common cancer in the United States. As of January 7, 2016, the American Cancer Society reported that pancreatic cancer had surpassed breast cancer as the third leading cause of cancer related death in the United States. Within the next decade, annual PDA deaths will likely surpass colorectal cancer as well. There were 53,070 new cases of PDA in 2015, and 41,780 deaths in the United States alone. Although the death rates for the most common cancers have declined in recent decades, the death rate for PDA is actually flat to slightly increased, in large part related to the aging demographic. Over the past 4 decades, disease-specific survival has only improved marginally, with 5-year survival rates increasing from 4% to 7%. The lack of clinical progress, in comparison with other cancers, is attributable to a failure to develop novel and effective therapies. Standard treatment still consists of relatively old cytotoxic therapies. The only advance has been improved experience and success administering combinations of drugs, which confer a small survival advantage over single agent therapy. Mutation targeted and immunologic therapies that have shown efficacy or promise for other cancer types have not yet achieved comparable benefits for pancreatic cancer. Herein, we review the molecular and clinical aspects of pancreatic cancer, and highlight the most critical challenges facing the management of this disease.

Molecular pathways/genetics

Unlike other common cancers, there are currently no well-established and evidence based treatment strategies based on molecular profiling for PDA. Similarly, there are no molecular signatures to improve staging or prognostication. However, numerous studies have been performed that have elucidated common genetic abnormalities in PDA, which highlight potential molecular targets and reveal signaling pathways that are important for disease development. Whole-exome sequencing was performed in 24 PDA genomes, and more than 1300 different genes were mutated in these tumors. The only high-frequency, “actionable” oncogene was KRAS , which is genetically activated in more than 95% of PDAs. Unfortunately, targeted therapy against this gene has proved elusive. In light of this disappointing finding, various alternative approaches to personalized therapy have been proposed. Jones and colleagues have grouped the common genetic abnormalities in PDA into 12 core signaling pathways (eg, apoptosis, DNA damage, and others), with the hope that biologic pathways may be more modifiable than specific gene targets. Biankin and colleagues identified axon guidance genes as a novel molecular pathway with frequent gene mutations in PDA. Perhaps most compelling, there is evidence that a high proportion PDAs harbor functional defects in DNA damage pathways (approximately 25%), which may render these tumors more susceptible to certain agents that target the DNA repair process. Many of the genes are Fanconi anemia pathway genes ( BRCA2 , PALB2 , FANCC , FANCG ), and clinical and preclinical data suggest that affected tumors are particularly sensitive to poly adenosine diphosphate ribose polymerase inhibitors or platinum drugs. Although phase II and III trials examining poly adenosine diphosphate ribose polymerase inhibitors in PDA are ongoing, completed studies in other cancer types (eg, ovarian) give hope that a personalized treatment approach is on the horizon ( Table 1 ).

Oncogenic KRAS remains the best characterized oncogene in PDA. The genetic event occurs early in tumorigenesis, before the development of invasive disease. Activated KRAS activates multiple signaling pathways including BRAF/MAP-K to affect cell proliferation, PI3K/mammalian target of rapamycin to promote cell growth and survival, and phospholipase C/PKC/Ca ⁺⁺ to induce calcium and second messenger signaling. KRAS mutations form the foundation of the most commonly used transgenic mouse model of PDA. The mutation is combined typically with an abnormal tumor suppressor gene in these models, such as TP53.

Other high-frequency mutation genes are classified as tumor suppressor genes ( CDKN2A , TP53 , and SMAD4 ). These genes are often inactivated through a mutation in 1 allele, combined with genetic loss (ie, loss of heterozygosity) in the corresponding chromosome region of the second allele as a result of chromosomal instability. Areas where genetic loss most frequently occurs are nonrandom in the PDA genome, because they typically occur at loci containing the abovementioned tumor suppressor genes: CDKN2A (9p), TP53 (19p), and SMAD4 (18q). The most common gene mutations in PDA are provided in Table 2 .

Pathologic and genetic studies reveal that PDA develops over many years, and follows an adenoma-to-carcinoma sequence, as has been described for other cancer types. Histologic atypia progresses over time through pancreatic intraepithelial neoplasia (PanIN) stages (1–3), and ultimately into invasive disease. In the tumorigenesis timeline, KRAS activation and telomere shortening are among the first events to occur in tumorigenesis, followed by p16 loss in the PanIN-2 stage, and TP53, SMAD4, and BRCA2 inactivation in the PanIN-3 stage. E-cadherin loss is a late event, and leads to epithelial-to-mesenchymal transition and a highly lethal phenotype in very advanced stages. Recent molecular analyses of pancreatic precursor lesions and PDA have determined that this process occurs over 10 to 20 years.

Genetic sequencing studies reveal significant intratumoral heterogeneity in PDA with respect to genetic abnormalities. For instance, Iacobuzio-Donahue and colleagues demonstrated that founder mutations (mutations that arise early in tumorigenesis) are present throughout a tumor, yet progressor mutations (found in subclonal population of cells) are typically present in geospatial niches in the primary tumor and only in a subset of metastatic deposits. This has implications for therapy: targeted therapies designed against progressor mutations may only affect a subset of cancer clones.

Although most genetic mutations in PDA are somatic, germline variants have been described that predispose individuals to the development of PDA. Overall, 10% of PDAs are familial, and only 10% of those have been assigned to a previously defined genetic syndrome. Hereditary breast and ovarian cancer is the most common familial syndrome, and Peutz-Jeghers syndrome holds the greatest lifetime risk for the development of pancreatic cancer (approximately 30%). Other familial disorders linked to PDA include familial atypical multiple-mole melanoma and hereditary nonpolyposis colorectal cancer. Many of the familial syndromes are secondary to germline mutations in the Fanconi anemia DNA repair pathway or alternative DNA repair genes, like ATM , BRCA2 , FANCC , FANCG , and PALB2 .

Aside from genetic abnormalities, other molecular changes have also been shown to be critical in PDA development, such as epigenetic abnormalities (methylation and histone modification), transcriptional regulation, and posttranscriptional regulation (microRNAs and RNA-binding proteins).