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).

Risk factors

PDA is most often seen in the elderly population, because it results from acquired genetic defects over many years. The median age of onset is 71 years, and 75% of patients are diagnosed between the ages of 55 and 84 years. The age-adjusted incidence rate is 12 out of 100,00 in the United States, and the lifetime risk of developing PDA is 1.5%, or 1 in 67 people. Of note, African Americans have a slightly increased risk compared with Caucasians.

The greatest risk factor for developing PDA is having a strong family history. As mentioned, 10% to 15% of all pancreatic cancers are considered familial, which is defined as at least 2 affected first-degree relatives (FDRs, eg, parents, offspring, siblings). The lifetime risk for patients with 3 or more FDRs is 40%, 10% for 2 FDRs, and 6% for 1 FDR (a 4.6-fold increase compared with the general population).

In addition to genetic risk factors, the Pancreatic Cancer Case Control Consortium (PanC4, http://panc4.org/index.html ) has evaluated many environmental risk factors through rigorous metaanalyses. Smoking is the best characterized and validated environmental risk factor for PDA. Active smokers have an increased relative risk of 1.74, and the number of daily cigarettes directly correlates to the risk of developing PDA. Interestingly, cigars are associated with an increased risk, whereas smokeless tobacco is not. Individuals with a family history and who smoke carry twice the risk compared with those high-risk patients who do not smoke. The risk of developing PDA decreases in former smokers, and has the potential to return to baseline after 20 years of smoking cessation. Other risk factors are described in Table 3 . Enhanced risk associated with recent pancreatitis or diabetes (compared with chronic disease) is most likely attributable to the respective diagnoses doubling as presenting symptoms of PDA, as opposed to true causal risk factors.

Early detection

There are no validated early detection strategies for PDA, even for high-risk patients. Nevertheless, options are available and have been reported. Whole-body computed tomography (CT) screening for healthy patients has been described, and is offered commercially at selected imaging centers, yet data are lacking to support usefulness of this practice for routine cancer screening. Downsides include high cost, radiation exposure, and an high incidence of false-positive or low-consequence findings. High-risk populations, such as individuals with a family history, may benefit from surveillance using endoscopic ultrasonography, CT, or MRI. The Cancer of the Pancreas Screening Project (CAPS study) is an ongoing prospective study to better evaluate screening strategies in such high-risk patients. Unfortunately, available data indicate that the sensitivity of screening programs even in high-risk groups remains low, and the most commonly identified lesions are cysts, as opposed to conventional PDA. Recently, a 49-member multidisciplinary panel at the International CAPS Consortium summit generated screening recommendations for high-risk patients best on available data and expert opinion. Screening by endoscopic ultrasonography and MRI is recommended for patients with at least 2 FDRs, Peutz-Jeghers syndrome, hereditary nonpolyposis colon cancer mutation with 1 FDR, or individuals with germline mutations in p16 ( CDKN2A ) or BRCA2 . Surveillance should be performed annually and begin around 50 years of age. Any suspicious mass should be further evaluated by CT. Among their recommendations, the panel also made a point to discuss the possibility and potential dangers of false positives and the implications of these findings.

Conceptually speaking, early detection remains a holy grail for PDA management. Patients who present with “early” disease in fact typically have occult micrometastatic disease that becomes clinically relevant within the first 2 years after resection. A recent study of small invasive intraductal papillary mucinous neoplasms (<2 cm invasive component) reveals that a large proportion of small or early PDAs recur after resection, even in the absence of lymph node metastases. Moreover, owing to limitations in modern imaging, conventional PDA (not associated with a cystic component) rarely presents at the T1 or even T2 stage. Ideally, PDA would be detected and treated at the PanIN 3 stage (carcinoma in situ); this would maximize cures and at the same time minimize any unnecessary treatment or overtreatment that would inevitably follow treatment of earlier PanIN lesions. Autopsy studies reveal that the incidence of PanIN 3 is similar to PDA, suggesting that most of these premalignant cases progress to PDA in patients’ lifetimes. Yachida and colleagues measured passenger mutations in PDAs, and determined mathematically that the disease develops over roughly 20 years. These data provide a glimmer of hope that early detection remains a possibility.

Current technologies, however, offer little promise for successful early detection, using PanIN 3 as the desired target lesion. PDA is difficult to image with present-day capabilities. Pancreatic masses are difficult to appreciate, and often are only implied based on the appearance of dilated or obstructed ducts, or atrophic pancreata (all findings consistent with long-standing disease). Indeed, invasive lesions (let alone PanIN 3) are rarely apparent when they are less than 2 cm. It must be emphasized that an effective screening test for PDA, with applicability for the general population, must be extraordinarily accurate owing to low disease prevalence. A test with 99% accuracy would still result in a 1% false-positive rate, which is unacceptably high, because treatment of suspected lesions requires an invasive operation. Moreover, this rate actually approaches the mortality rate of pancreatectomy in high-volume centers. There are significant efforts to determine if blood-based analytes (ie, liquid biopsies) can be used as a minimally invasive and inexpensive screening option. For example, investigators at the M.D. Anderson Cancer Center recently published an analysis of exosomes in the serum, which can protect circulating nucleic acids and, therefore, may be informative. This line of research, however, is somewhat fraught with unfulfilled promise, because circulating markers of PDA are likely evidence that the disease is already beyond curable. Successful studies of liquid biopsies often show that that the test can detect PDA that is already clinically evident and, therefore, do not show any advantage over standard diagnostic strategies (like CT and serum CA 19–9). Thus, this line of research is better suited to measure burden of disease and response to therapy in patients with clinically measurable disease, as opposed to early, premalignant and curable disease.

Diagnostic evaluation

Evaluation of the patient with pancreatic cancer involves a detailed history and physical examination, laboratory tests, and appropriate imaging. The patient history should include questions about risk factors for pancreatic cancer and common presenting symptoms. The initial presentation of a patient is related to the location of the tumor. In patients with a mass in the right side of the pancreas (ie, head, neck, or uncinate process), jaundice (75%) often occurs from obstruction of the common bile duct; other symptoms include weight loss (50%), abdominal pain (40%), new-onset diabetes (10%), and nausea (10%). Pancreatic duct obstruction is often associated with acute pancreatitis and steatorrhea from exocrine insufficiency. Left-sided lesions (the body or tail) frequently present with abdominal pain, back pain, diabetes, or nausea. Laboratory testing should include a complete blood count (principally to evaluate for anemia) and a complete metabolic panel (to evaluate for abnormal liver transaminases and function). A coagulation profile should be drawn, because biliary obstruction can lead to vitamin K deficiency. The physical examination should be focused on key findings such as scleral icterus, jaundice, and lymphadenopathy.

Cross-sectional imaging evaluation is necessary for a pancreatic or periampullary mass and proper staging of the patient. Additional evaluation and treatment recommendations are contingent on the perceived stage (1 and 2 is resectable or borderline, 3 is locally advanced, and 4 is metastatic, Table 4 provides the American Joint Committee on Cancer TNM staging schema for exocrine pancreatic cancer). The preferred imaging modality is a triphasic CT scan, with an early arterial phase, late arterial phase (parenchymal), and portal venous phase. The study is performed with thin slices (2.5–5 mm), 3-dimensional reconstruction, and uses water as an oral contrast agent. Chest imaging (radiograph or CT) is performed in search for pulmonary metastases. PET/CT imaging adds little additional value beyond these studies. Endoscopic ultrasonography is performed for unresectable disease to obtain a definitive tissue-based diagnosis before chemotherapy. The test is not necessary for many resectable lesions when a high degree of suspicion for PDA is present because these individuals are managed with resection; however, the test has value in selected cases where alternative diagnoses are likely (eg, pancreatitis).

Table 4

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