A Primer on Pancreatic Cancer

  Familial Pancreatic Cancer

In familial pancreatic cancer, there exists a kindred which contains at least a pair of first-degree relatives who were affected with pancreatic adenocarcinoma. Roughly 5-10% of patients suffering from pancreatic adenocarcinoma have this aspect. Half of these with familial pancreatic cancer are male, and the average age at diagnosis of affected members is younger (64-65, in comparison to 71) than the usual. The age at diagnosis also did not appear to be correlated with the increasing number of affected individuals in the kindred, according to the PACGENE study. Additionally, one of the main clinical features of hereditary cancer is that it also promotes the development of multiple cancers; in the case of both the BRCA2 (Breast Cancer gene 2) and the CDKN2A (Cyclin Dependent Kinase Inhibitor 2A), both promote pancreatic cancer and thus are essential to the study.

Genetics of Pancreatic Cancer Germline Mutations


The genetic basis of pancreatic cancer and FPC has been extensively investigated over the past decade. The goals of most studies that would have timely clinical translation have been the identification of high penetrance susceptibility genes and characterization of their deleterious mutations. Increased risk of pancreatic cancer is now known to be associated with several inherited syndromes for which the predisposing genes have been identified, including BRCA1, BRCA2, CDKN2A, mismatch repair genes associated with Lynch syndrome, and hereditary pancreatitis-related genes, PRSS1 and SPINK2. 

Germline mutations have been identified in PALB2 and ATM among FPC (Familial Pancreatic Cancer) probands, thus extending the list of predisposing genes for pancreatic cancer. PALB2 is vital for homologous recombination repair in response to DNA double-strand breaks, and also functions as a tumor suppressor and participates in the maintenance of genome integrity. This makes PALB2 key in preventing cancer, so it becomes dangerous if it is mutated. When mutated, PALB2 is not able to respond to breakage in strands of DNA, so the information may be lost or changed; when this occurs, the cell can respond by turning to apoptosis (cell death) or it may begin to overproliferate cells with the same incorrect instructions, causing cancer. The maintenance of genome integrity is also crucial to preventing cancer because it contributes toward organism survival as well as the inheritance of traits to offspring. Genome instability mostly arises from DNA damage or aberrant DNA replication or uncoordinated cell division, which can lead to gene mutations.

Regarding PALB2 (Partner and Localizer of BRCA2) and ATM, functional roles for identified germline mutations were supported by the loss of heterozygosity of the wild-type allele in the pancreatic tumor of the patients. In the course of complete exome sequencing of unselected pancreatic cancer patients, a germline truncating mutation in PALB2 that co-segregated in an FPC kindred was identified. This led to screening the DNA of 96 more FPC patients specifically for PALB2 mutations. Truncating mutations were detected in three additional patients, but no difference was found in age at diagnosis of these carriers. Additionally, no PALB2 mutations were found in 1,084 normal controls. Similarly to the correlation found in PALB2, mutations in the ataxia telangiectasia mutated (ATM) gene were found to co-segregate with the pancreatic cancer phenotype in two FPC kindreds. After screening the ATM (Ataxia-Telangiectasia Mutated) gene for mutations in DNA of 166 FPC patients, four carriers of deleterious mutations were identified. No similar mutations were seen in 190 controls.

DNA damage and repair pathways. Different factors are responsible for initiating DNA damage such as radiation and reactive oxygen species which cause several types of lesions in the DNA double helix. The repair pathway involved in the process is dependent on the damaging agent and lesion generated. Base excision repair (BER), nucleotide excision repair (NER), non-homologous end joining (NHEJ), reactive oxygen species (ROS) and DNA mismatch repair (MMR). [Source]

As for the ATM gene, it is located on chromosome 11, and helps to control cell growth and repair damaged DNA. It is the fifth DNA repair gene and is associated with more modest risks of breast cancer. The serine/threonine kinase protein that it makes the instructions for is located primarily in the cell nucleus, and here it helps to control the rate at which cells grow and divide. Because of this, ATM is widely considered a major tumor suppressor gene. Women who carry a mutation in the ATM gene have an estimated 20-60% increased risk for breast cancer.

When considering syndromes, the most prominent syndromes are hereditary breast-ovarian cancer syndrome, particularly due to germline mutations in BRCA2, and familial atypical mole and melanoma syndrome, due to mutations in CDKN2A, which encodes the well-known tumorigenic protein, p16. We must pay close attention to the hereditary aspect of this syndrome because if a BRCA mutation is identified, you are more likely to get curtain cancers. There is an increased risk for other cancers, including pancreatic. This may be remedied by undergoing more frequent cancer screenings.

BRCA mutations cause more cancers because they make cells more likely to divide and change rapidly, which can lead to cancer. Because one of cancer’s main hallmarks is its sustaining of proliferative signaling, BRCA encourages cells to maintain this cancerous aspect, thus promoting cancer to occur in the body. The BRCA genes typically protect you from getting certain cancers; however, once mutated, the protection is removed.

In the case of the BRCA1 gene, its main function is to provide instructions for making tumor suppressor proteins. This protein is also involved in repairing damaged DNA. However, once the protein is mutated, it is not able to repair the damaged DNA and is also unable to suppress uncontrolled cell proliferation. If there is DNA damage, the instructions may become unclear for the cell and it will begin to divide rapidly as a “malfunction” rather than referring to apoptosis. By making unlimited copies of cells with these damaged instructions that ultimately harm the body, cancer can occur as these cells carry out the wrong instructions and proliferate without anything to keep them in check.

In the case of the BRCA2 gene, its main function is to also provide instructions for making tumor suppressor proteins, as well as repairing damaged DNA. Overall, it carries many of the same characteristics as the BRCA1 gene, and so the consequences are just as lethal if it becomes mutated. The consequences of the mutated BRCA genes are similar to the mutated ATM because they are all shown to be involved in breast cancer predisposition; in fact, they are also involved with TP53 and CHEK2 for the same reason. BRCA1, BRCA2, and TP53 are usually more associated with high risks of breast cancer, while ATM and CHEK2 are associated with more modest risks, as previously stated.


Genetics of Familial Pancreatic Cancer (Results of the PACGENE Consortium study)


The most comprehensive analysis to characterize the genetic variation in FPC patients tested across four genes was found through the PACGENE Consortium study, germline DNA of 727 unrelated probands with positive family history (521 met criteria for FPC) were tested for mutations in BRCA1, BRCA2, PALB2, and CDKN2A, and prevalence estimated. 

Among FPC probands, prevalences were: BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. BRCA2 and CDKN2A account for the majority of mutations in FPC (6%).  As for CDKN2A, this is also a highly dangerous mutation as individuals with this mutation have been found to develop melanoma at an earlier age than those without a mutation in the gene; other cancers also tend to be developed, particularly lung or pancreatic cancers . The full name of the gene is CDKN2A-p16-Leiden, and carriers of its mutation have a substantial risk of developing pancreatic ductal adenocarcinoma (PDAC). This is because the CDKN2A gene provides instructions for making several proteins, such as the p16(INK4A) and the p14(ARF) proteins. These proteins both function as tumor suppressor genes, meaning that they stop cells from growing or dividing too rapidly in an uncontrolled way, thus suppressing the onslaught of cell over-proliferation.

Figure 1: Erroneous signaling pathways of pancreatic cancer. This most prominently illustrates the over-expression of the protein GPC1, an over-expression common in pancreatic cancer cases. GPC1 promotes growth and migration in cancer cells by regulating the TGF-beta1/SMAD2 signaling pathway; GPC1 causes FGF-2 to become relentlessly secreted, preventing cells from undergoing apoptosis and simultaneously boosting cell proliferation and angiogenesis (construction of blood vessels).

Somatic Mutations in PC


There are at least 12 genes associated with the increased risk of developing pancreatic cancer, most notably BRCA2 and CDK2NA. In the mutations of known cancer predisposition genes, next-generation sequencing has revealed extensive heterogeneity; this means that the cancer is, genetically, more variable and diverse, and more susceptible to mutation, which increases its survival rate as it can adapt to and resist new medication. Precise oncology has opened the possibility of incidental germline mutations that may have implications for family members; however, evidence-based recommendations are more concrete and therefore reliable.

Ultimately, pancreatic cancer is a disease caused by damage to the DNA, mutating it. These mutations can either be inherited, caused by chance, or caused by harmful behaviors such as smoking. Cigarette smoke contains a diverse array of carcinogens, most importantly PAH, N-nitrosamines, aromatic amines, 1,3-butadiene, benzene, aldehydes, and ethylene oxide for their carcinogenic potency and high levels in cigarette smoke, and thus damages a key cancer-associated gene in a cell in the pancreas—this may then cause the cell to grow into a cancer.

Figure 2: This diagram illustrates different gene mutations linked to pancreatic cancer. Those in red (KRAS, CDKN2A, TP53, SMAD4) have been found to cause the most tumors, while those in blue follow. The pie chart demonstrates the structural genome variants in the different categories of tumors. Locally rearranged tumors, in which chromosomes have complex structures, were shown to have large numbers of structural variants.

History, Survival Rates, and Obstacles


Pancreatic cancer, among the major cancers, has the lowest survival rate of all cancers (one-year: 20%, five-year: 9%, ten-year: 5%). This survival rate depends on whether the cancer is localized or has become regional or distant. If the cancer remains in the pancreas, a patient has a 42% survival rate for five years; if regional, 14%; if distant, 3%; and if these stages are combined, there will be an 11% chance of survival. The number of deaths has been increasing steadily since 2004, as several “baby-boomers” are now reaching the risk window of ages older than 45—at diagnosis, the median range is 71. In the United States in 2022, there will be about 62,210 people diagnosed with pancreatic cancer, with 49,380 of them dying of it; six years ago in 2016, there was an estimated 53,070 cases and 41,780 deaths. While a slightly higher percentage of people appear to be surviving (~21% in 2022 compared to ~20.8% in 2016), there have been more and more cases. Granted, with a positive outlook, this could mean that more people are having their cancer treated, rather than undiagnosed cancer deaths occurring. However, by 2030, pancreatic cancer will most likely become the second most common cause of cancer mortality (after lung cancer).

From personal experience, I would like to add that my grandmother died of stage-four pancreatic cancer in 2016 at the age of 69, roughly two months before her 70th birthday. She was diagnosed in 2013. Though I believe she had no history of smoking, she may have been exposed to it either during her childhood and adulthood, as she lived in the Philippines until her early adult years. She was treated with chemotherapy, and lived out the rest of her days in hospice as the cancer had grown for surgery or proton therapy.

Pancreatic cancer has also historically been the least studied, most likely due to its inconvenient position in the body. Greek anatomist and philosopher Herophilus was apparently first to discover the pancreas, but its main duct and significance were only demonstrated in the 17th century. It was the same century that pancreatic cancer was first identified, in 1761. The pancreas is located at the intersection of major blood vessels deep within the body, which makes surgery difficult as well as makes it easy for the cancer to metastasize throughout the body. Because the pancreas is located so unsuitably, the early tumors cannot be seen or felt by healthcare providers during routine physical exams, and symptoms are not typically noticed until it has become very severe. Pancreatic tumors may be diagnosed by ultrasound, computerized tomography (CT) scans, magnetic resonance imaging (MRI), and, sometimes, positron emission tomography (PET) scans. With insurance and in California, an ultrasound may cost between $150-$1514, a CT may cost anywhere between $220-$9000, an MRI may cost between $39-$7695, and a PET scan may cost between $1250-$9225. Additionally, screening is not altogether covered by insurance for all cancers yet, and people typically have to pay out of pocket for these things. Due to the cost of the scans required to locate the hypothetical cancer, people feel discouraged to do a checkup on their pancreas, as they may spend so much money only to find nothing out of the ordinary.

Syndromes and genes associated with hereditary predisposition to pancreatic adenocarcinoma, relative and lifetime risk [Source]

HP: Hereditary pancreatitis; 

FAP: Familial adenomatous polyposis; 

PC: Pancreatic adenocarcinoma; 

FDR: First-degree relative; 

PJS: Peutz-Jeghers syndrome; 

MPCS: Melanoma pancreatic-cancer syndrome; 

FAMMM: Familial atypical multiple mole melanoma; 

HBOC: Hereditary breast-ovarian cancer; 

LS: Lynch syndrome; 

FPC: Familial 

PC; CF: Cystic fibrosis; 

HP: Hereditary pancreatitis.

Tumor Microenvironment

Tumorigenesis, the formation of cancerous cells that become tumors, arises when malignant cells form lumps of tissue as a result of not performing apoptosis. To continue cancerous proliferation, the tumor is able to steal sustenance from the rest of the body in order to support its cells. The malignant cells do this by bridging blood vessels to grow towards tumors, which supply the tumor with oxygen and nutrients while also providing a pathway for tumor waste removal. This is known as a tumor microenvironment, as the tumor is able to create its own support system to thrive both inside and apart from the body.

Cancerous cells are able to keep the tumor alive by either evading detection by the immune system or convincing the immune system to assist the tumor. They can evade attacks by restricting the immune cells’ ability to recognize cancerous antigens, inhibiting the immune system, and inducing T-cell exhaustion, in which the T-cells (immune cells) lose their ability to destroy certain cells, such as cancer cells. T-cell exhaustion is a frequent symptom that occurs if a body’s immune system is forced by a disease or infection to stay active for an extended period of time. Malignant cells are also able to convince the immune system that it is nothing more than another part of the body, inducing immune cells to protect the tumor rather than the rest of the body.


Figure 3: This diagram illustrates the pancreatic stellate cells of pancreatic cancer; these are cells that are bale to interact with cancer cells as well as other cells that may be linked to the cancer's growth. These interactions promote cancer proliferation. As shown in the diagram, they are able to control islets, neurons, endothelial cells, cancer cells, t-cells, and immune cells. Through these processes, they are able to decrease the islets' insulin production (causing the body to lose blood sugar) by killing them; they can force neurons to exacerbate cancer migration; they can cause endothelial cells to partake in cancerous angiogenesis; they can increase the growth and migration of cancer cells while lowering cancer cell death rates; they can force t-cells to become inhibited, causing the body's immune response to dwindle; they can cause mast cells to activate in order to widen blood vessels via the release of histamine, which allows cancer cells to obtain nutrients at a higher rate; and, lastly, they can cause myeloid-derived suppressor cells to inhibit immune response, which then allows cancer to proliferate further.

Therapies for Pancreatic Cancer

In the 1970s and early 1980s, the Gastrointestinal Tumor Study Group (GITSG) performed a randomized trial testing the effectiveness of adjuvant chemoradiotherapy with 5-fluorouracil for patients with resected (cut out/removed tissue) pancreatic cancer. Adjuvant therapy is additional cancer treatment given after the primary treatment in an attempt to lower the risk of the cancer’s relapse. 

To give clarity on cancer relapse, cancer recurrences can occur because some cells from the original cancer remain even after treatment. These are much more difficult to combat because these cells have adapted to the original treatment that was meant to kill them and now resist those antibiotics. These may grow and stay in their original location, or they might be found in other parts of the body, either by metastasizing from the original cancer or by metastasizing after the original cancer was thought to be defeated.

On the topic of 5-fluorouracil (or 5-FU), it is a drug used in chemotherapy that primarily inhibits the enzyme thymidylate synthase blocking the thymidine formation that is required for DNA synthesis. This trial demonstrated a significant survival benefit for patients that received this chemoradiotherapy, as the median overall survival was raised to 20 months versus the 11-month survival rate of the control group that was simply observed. The National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) both recommend 6 months of adjuvant systemic therapy for patients with resected cancer who have not completed preoperative therapy. Modern treatments include modified FOLFIRINOX (a combination of cancer drugs composed of folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin for advanced pancreatic cancer that destroy quickly dividing cancerous cells), gemcitabine (an antimetabolite chemotherapy drug that interferes with DNA and RNA synthesis by acting as false metabolites, thus preventing DNA synthesis) and capecitabine (an antineoplastic chemotherapy drug that targets and kills rapidly dividing cancerous and healthy dividing cells, and single-agent gemcitabine (single-agent meaning it is given alone rather than as part of a combination) or fluorouracil. 

In Asian countries including Japan, S-1 (an oral 5-fluorouracil prodrug) is now the standard adjuvant treatment option following the JASPAC 01 trial. A phase III trial in Japanese patients with stage I-III pancreatic cancer showed promising results for the S-1 drug compared to the original standard drug, gemcitabine. Previous studies had indicated that S-1 has more harmful side effects in Caucasian patients, but is most effective in Asian patients. This is because there are metabolic differences between Asian and Caucasian ethnic groups, so the gastrointestinal side effects of S-1 are more severe among Caucasian patients. In the present study conducted in Japan, investigators randomly assigned 385 patients to postoperative treatment with gemcitabine or S-1, and analysis of trial data found that patients who received S-1 had a 44 percent lower risk of death than patients who received gemcitabine. In two years, the survival rates were 70% for those receiving S-1, and 53% for those who received gemcitabine. S-1-receiving patients were also shown to relapse less, with 49% of S-1 patients not relapsing compared to the 29% of gemcitabine patients. S-1 was also tolerated well, as over 70% of patients were able to complete the therapy.

In 2018, a western trial known as the PRODIGE-24 trial randomized 493 patients with resected pancreatic cancer to receive modified-FOLFIRINOX versus gemcitabine and demonstrated significant improvement in median disease-free survival. At the median follow-up of 33.6 months, those who had received modified-FOLFIRINOX had a median disease-free survival of 21.6 months, while those who had received gemcitabine only had a median of 12.8 months. In 3 years, this rate was 39.7% for those who had received modified-FOLFIRINOX and 21.5% for those with gemcitabine. In terms of overall survival rate in 3 years, modified-FOLFIRINOX patients had an overall survival of 63.4% (54.4 months) while gemcitabine patients had an overall survival of 48.6% (35.0 months). However, it was shown that there were higher events of toxic effects in patients that took modified-FOLFIRINOX; these adverse events of grade 3 or 4 in severity (life-threatening) appeared in 75.9% of modified-FOLFIRINOX patients, while only occurring in 52.9% of gemcitabine patients. One gemcitabine patient died of toxic effects; interstitial pneumonitis caused by long-term exposure to an unknown source.


References