Sex

The incidence of PC is lower in women than in men globally. In developed countries, this gap is even more pronounced.³ It may be because the steroid levels are higher in women than in men, which may have a protective effect against PC.⁵ Sadr-Azodi et al. confirmed through a paired cohort study that compared with women who were not administered menopausal hormone therapy (MHT), the prevalence of pancreatic cancer could be reduced by 23% in women who were administered MHT. Further, compared with MHT administration for <1 year, MHT administration for 1-2 years can reduce the prevalence by 35%, and MHT administration for more than 3 years can reduce the prevalence by 60%.⁶

Area

PC incidence varies in different parts of the world. In the United States, the incidence in African Americans is higher than that of Caucasians, while Asian Americans and Pacific Islanders have the lowest incidence.⁷ In China, the health burden of cancer is increasing and the rate of growth in recent years is parallel to that of the world. Possibly due to differences in socioeconomic environment and lifestyle, urban morbidity and mortality in urban areas are higher than those in rural areas.⁸ By 2018, among the people with PC in the world, the highest incidence rate of ASR is in Europe (7.7/10 million) and North America (7.6/10 million, Oceania [6.4/10 million]). The incidence rate in Africa is the lowest, with an estimated incidence rate (2.2 per 100,000 people).⁹

Blood Group

The ABO blood group antigen is present on the entire surface of red blood cells. Recent studies have shown that blood group antigens affect the risk of PC.¹⁰ Among people with diabetes, people with type A, AB, or B blood group have a higher risk of developing PC than those with type O.^7,11 There is some evidence indicating that type A blood group and diabetes will jointly lead to the development of PC.^11,12

The mechanism may involve the regulation of the host inflammatory process related to the ABO blood group, which may be related to the promotion of cancer progression and metastasis. The gene encoding the ABO antigen may be associated with various plasma components, such as soluble intercellular adhesion molecule-1 (sICAM- 1) and tumor necrosis factor (TNF). These proteins are adhesion molecules required for immune cell recruitment, and thus mediate systemic inflammation. These studies indicate that the gene encoding the ABO blood group plays a direct role in tumorigenesis and malignancy, and is involved in tumor cell immune surveillance, cell adhesion, tumor apoptosis, and angiogenesis.¹¹

Genetic Factors

In recent years, studies have found that PC has a clear family basis, and family history of PC greatly increases the risk of disease.^13,14 Mainly caused by genetic and acquired gene mutations, over than 80% of PC are due to sporadic mutations, and a small number of cases are caused by specific genetic mutations. The risk of familial PC increases exponentially with the increase in the number of first-degree relatives^15,16 Currently, chromosomal aberrations at loci13q22.1, 15q14,^17,18 6p25.3, 12p11.21, 7q36.2,¹⁹ 21q21.3, 5p13.1, 21q22.3, 22q13.32 and 10q26.1²⁰ have been discovered by scientists from Japan and China. In the largest genome-wide collection in Europe, 7p12, 1p36.33, 8q21.11, 17q12, and 18q21.32 were identified as new PC susceptibility chromosomal target deletions.²¹ Point mutations^3,7 in K-RAS, CDKN2A (P16), TP53, SMAD4,^22,23 BRCA2, BRCA1, STK11, PRSS1 and MMR^24,25 are the most frequently involved in PC.

In PC stem cells, there are obvious epigenetic changes, mainly manifested in the process of mutations in chromatin regulatory proteins and the control of epithelial-mesenchymal transition (EMT), but these changes do not involve changes in genetic sequence. Only DNA and chromatin structure/chemical changes are involved; thus, these changes ultimately affect the overall phenotypic state of the cell. Based on these ideas, some researchers have begun to investigate whether inhibiting the process of epigenetic regulation contributes to the development of new PC therapies.²⁶

Smoking

Among the factors associated with PC, smoking is the most important modifiable factor. A case-control study demonstrated that smokers had a 74% increased risk of PC.^81,82 The expression of stem cell markers in PDAC cells exposed to CSE and NNN/NNK (Nicotine and Nicotine-derived carcinogens) is significantly enhanced. Studies showed that cigarette smoke and its ingredients could increase the stem cell characteristics of pancreatic cells. The stem cell characteristics enable cancer cells to self-renew and differentiate into other cell types. The specific mechanism may involve CHRNA7 mediates the signal transmission and activates Fosl1 expression through the ERK1/2 pathway, thereby enabling the activation of the promoters of both Fosl1 and PAF1.⁸³

In recent years, e-cigarettes have been proposed as long-term alternatives to traditional smoking or as a means of quitting smoking by heating nicotine; however, there is very little data on their effectiveness and safety. Thus, the relationship between e-cigarettes and pancreatic diseases remains to be elucidated.

Alcohol

A cohort study of 2187 patients with PC found that the risk of illness was significantly higher in people who drank more than 30 g per day (RR: 1.22, 95% confidence interval (CI): 1.03–1.45).⁸⁴ There was also a meta-analysis that found that low- and moderate-drinking alcohol was not associated with PC risk, and there was a dose-response relationship between alcohol consumption and risk in high-drinking populations.⁸⁵

Chronic Pancreatitis

There is growing evidence that CP is an independent risk factor for PC.⁸⁶ CP is a progressive inflammatory state of the pancreas that causes pancreatic fibrosis and loss of islet cells.⁸⁷ Frequent seizures of CP can lead to disease progression, as well as pancreatic exocrine and/or endocrine insufficiency, eventually leading to abnormal pancreatic enzymes. CP may also disrupt the endoplasmic reticulum, mitochondria, and lysosomal autophagy systems of pancreatic cells and can lead to cellular DNA damage, chromosomal mutations, and oncogene activation. A large cohort study and case-control study found that the combined relative risk of PC in CP patients was estimated to be 13.3.⁸⁷

Tumor Biomarkers

In recent years, our knowledge of PDAC molecular changes has grown significantly and has helped identify new serum tumor markers. Currently, there are 6 common tumor biomarkers (CA19-9, CA242, carcinoembryonic antigen [CEA], CA125, microRNAs and K-RAS gene mutations) in PC.⁹³ The combination of tumor markers and imaging methods may be the first choice for early screening for PC.⁹⁴ According to reports in the literature, the combination of CA19-9 and CA125 increased sensitivity compared to CA19-9 alone, and the combination of serum CA19-9 and CEA increased specificity by 84%.⁹⁵ Other researchers have shown through meta-analysis that the CA19-9 and CA242 combination, or CA19-9 and K-RAS gene mutation or endoscopic retrograde cholangiopancreatography and EUS may be more diagnostic than separate detection.^96-99 There is also evidence that the combination of microRNAs and CA19-9 is more accurate.^100,101 In recent years, advances in cytology and genomics have been used in conjunction with serum tumor markers for early diagnosis of PC. In the early stages of PC, tumor-associated macrophages (TAM) have been reported to be associated with a decrease in neutrophils and T cells.¹⁰² Among genes related to PC, including KRAS, TP53, CDKN2A, Smad4, PDAC1 and BRCA2.^103,104 CA19-9 is the most commonly used indicator for postoperative detection in PC recurrence and prognosis.^102,105 B7-H4, IL-6, IL-8, and IL-10 are indicators for assessing poor prognosis in PC.^106,107

In recent years, circulating cell-free DNA (CfDNA) and mutation-specific circulating cell-free tumor DNA (CftDNA) have been identified as new potential biomarkers. The current studies show that there is a statistically significant correlation between changes in cfDNA and cftDNA concentrations and treatment response. Therefore, cfDNA and cftDNA may become new biomarkers for evaluating the efficacy of cancer after treatment, and because of their correlation with the tumor volume of metastases, they can also be used as tools to estimate tumor volume.¹⁰⁸

Cooperation With Neoadjuvant Therapy

To achieve better local tumor control and ultimately improve patient survival and quality of life, it has been demonstrated in many clinical trials in the United States, Europe, and Japan that surgical resection is more likely if full-dose chemotherapy is given prior to surgery. Patient survival and quality of life increased significantly. Preoperative chemotherapy/radiation may eliminate potential metastatic lesions, and preoperative treatment may be more effective than postoperative treatment, possibly due to poor drug delivery and low sensitivity after tumor removal.¹¹⁶ Neoadjuvant chemotherapy should be applied to make local tumors easier to surgically remove.

In general, arterial-affected PC is considered unsuitable for resection. In a study of patients with unresectable PC, 76 of the 125 patients (61%) were able to undergo tumor resection after neoadjuvant chemotherapy, with a significant increase in the median survival period.¹¹⁷

Surgical Techniques

PC resection includes total pancreatectomy, distal pancreatectomy plus splenectomy and pancreaticoduodenectomy. However, only 10% of patients are diagnosed with early-onset PC, and standard excision methods can be used. About 60% of patients have metastatic disease or poor performance.

There is evidence that the prognosis is worse in patients with para-aortic lymph node (PALN) metastases, but PALN is insufficient evidence of a grade I contraindication for surgery.¹¹⁸

Laparoscopic surgery has now been performed in large hospitals for the treatment of PC. A retrospective cohort study has shown that laparoscopic PC resection allows patients to return to their diet earlier and reduce hospital stays with less trauma. But this technology is more demanding for doctors.¹¹⁹

In the past few decades, PC surgery has become quite safe and the risk of postoperative mortality has dropped to 3%. However, the risk of postoperative prevalence remains high, and the high invasiveness and metastasis of PC should be an important area of ongoing research. With the development of modern technology, surgical indications have expanded from resectable PC (stages I and II) to locally advanced disease (stage III). Surgical resection will still be the basic means of treatment for patients with PC. For stage IV patients, PC patients with distant metastases are not recommended for tumor reduction surgery, and some patients with distant isolated metastases can undergo surgical evaluation after tumor shrinkage after long-term chemotherapy.¹²⁰

Chemotherapy

Chemotherapy is an important part of the comprehensive treatment of PC. Studies have shown that after radical resection, adjuvant chemotherapy can significantly improve disease-free survival and overall survival of patients with PC. After radical resection, modified leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin (MFOLFIRINOX) are often used for 6 months of adjuvant chemotherapy, or 6 months of gemcitabine and capecitabine. In patients with metastatic PC, the preferred option is the FOLFIRINOX regimen, gemcitabine and NAB-paclitaxel in combination with chemotherapy. If the patient is not suitable for combination chemotherapy, gemcitabine is the first choice. For patients with locally advanced PC, combination therapy with chemotherapy and radiation therapy is the first choice for this type of patient, with gemcitabine (with or without erlotinib) combined with 54 Gy. Currently, researchers are investigating other forms of topical therapy such as radiofrequency ablation, high-intensity focused ultrasound, microwave ablation, irreversible electroporation, and topical anti-KRAS therapy (using siG12D-Loder). In patients with locally advanced unresectable cancer, neoadjuvant therapy combined with chemotherapy and surgical treatment is the only opportunity for secondary surgery in such patients.¹²¹ In the future, specific treatments based on the molecular characteristics of patient organs will become a reality and have considerable prospects.¹²²

Radiotherapy

Radiation therapy uses X-rays to destroy or damage cancer cells, making them unable to proliferate. Radiotherapy is mainly used in patients with locally advanced PC. Multiple studies have shown that in patients with advanced PC, receiving chemotherapy was no better than continuing chemotherapy is better and does not improve patient survival.^123,124 In clinical use, there are 4 main forms of radiotherapy:

1. External beam radiation therapy, which uses external radiation therapy sources that emit X-rays, gamma rays, electrons or heavy particles. However, the surrounding tissue is greatly damaged, and this treatment requires multiple courses of treatment;

2. Brachytherapy, which is mainly used for internal radiotherapy by surgery or laparoscopy in the pancreas or adjacent to the pancreas. It can be administered in the form of single or multiple scores and in combination with external radiation therapy.¹²⁵

Targeted Therapy

Targeted therapy is very successful in many types of cancer. For example, EGFR or VEGF-directed antibodies in colorectal cancer, trastuzumab in HER-2 positive breast cancer, or tyrosine inhibitors in non-small cell lung cancer subpopulations, such as crizotinib. Although the Food and Drug Administration (FDA) has recently approved pembrolizumab as a targeted treatment for PC, to date, all other targeted drugs have failed in PC patients, including affrecept, cetuximab, sorafenib, bevacizumab, and axitinib. The available evidence preliminarily indicates that the efficacy in PDAC patients with HA-high expression depends on PEGPH20 when PARP inhibitors are used in combination with NAB-paclitaxel/gemcitabine.¹²⁶

Recently, 19 patients with metastatic PC were clinically studied. They underwent a molecularly tailored treatment regimen. These patients received dual treatment with gemcitabine and oxaliplatin. The results showed that 55% of patients had tumor markers reduced by >50%. Partially relieved and stable patients were 28% and 50%, respectively. However, 7 (88%) patients still died within 3 months after treatment, and the rest received second-line treatment.¹²⁷ New targets for targeted therapy for PC have recently been identified, such as PEGPH20 and CKAP4.¹²⁸

Because PC tumor cells carry unique genetically driven mutations, this poses a huge challenge for molecular targeted therapy.

Immunotherapy

Immune checkpoint blockade (ICB) therapy is now approved for various types of cancer, such as melanoma, lung cancer, renal cell carcinoma, and head and neck squamous cell carcinoma.¹²⁹ However, PC is considered to be a less immunogenic cancer. The microenvironment of PC tumors is thought to create an immunosuppressive environment. Therefore, there is currently no immunotherapy approved for patients with PC. Monotherapy of CTLA-4 or PD1 inhibitors is essentially ineffective in PC, and many clinical studies have tested immunotherapy in combination with chemotherapy, chemoradiotherapy, vaccines, and cytokine antagonism.¹³⁰ In theory, clinically relevant drug chemotherapy should reduce the immune response, but clinical studies have shown that the patient’s immune status does not change.^131,132 Radiation therapy can cause tumor macrophages to obtain an immunosuppressive phenotype and to disable T cell-mediated anti-tumor responses, thereby inhibiting cellular immune function. Nonetheless, the FDA approved the use of pembrolizumab in the treatment of microsatellite unstable cancers unrelated to the type of cancer, which is contrary to the conclusion that radiotherapy reduces cellular immune function. This milestone study is ongoing.¹³³

However, certain tumors develop resistance and relapse during ICB treatment. Some intrinsic factors of immune cells and tumor cells may affect the patient’s response to ICB, including T cell infiltration; T cell and innate immune cells activate differentiation and antigen presentation to MHC-1 molecule.¹³⁴ Recently, a study from the United States made a breakthrough in immunotherapy, and the results showed that interferon (IFNs) is a double-edged sword in the tumor immune response. IFNs activate dendritic cells at the initial stage to promote cross-activation of tumor-specific CD8+ T cells, but sustained IFNs can produce negative feedback, causing T cell failure to produce immunosuppression.¹³⁵ Another study on enhancing the efficacy of tumor immunotherapy has made breakthroughs. It has shown that inhibiting IFNG signaling pathway in tumor cells can enhance the body’s ability to adapt to tumor cells or innate immune killing, and improve the efficacy of immunotherapy.¹³⁶

Microbial Therapy

There is now strong evidence that the human microbiota plays a key role in regulating cancer development and response to cancer treatment. It affects the response of intestinal and parenteral tissues to cancer treatment.³⁰ In one study, the researchers transplanted intestinal bacterial extracts from PC hosts into a mouse model and found that macrophages in the bacterial extract of patients prevented the activation of CD4+ and CD8+ T cells. Decreased ability to present antigenic macrophage antigens induces higher activation of different pattern recognition receptors (PRRs) in tumor macrophages. In contrast, PCs that grow in antibiotic ablation hosts show significantly opposite results.¹³⁷

To date, the results of intestinal microflora forming systemic immunity and tumor-specific immunity in PC have been confirmed, but the mechanism remains to be studied. For example, it is unclear whether gut microbes only regulate tumors affecting immune cells in distant intestinal/intestinal-associated lymphoid tissue barriers or whether microbes need to affect local antigen presentation in tumor and tumor-draining lymph nodes.¹³⁸ In addition, differential effects of microbial-derived metabolites have been reported to regulate PDAC immunity. This poses a challenge for clinically targeted tumor-targeted synthetic bacteria and probiotics. At the same time, the role of microbial-derived metabolites and microbial-matrix interactions in metastatic disease remains unclear.¹³⁹ Several studies have shown that human microbes and gut bacteria are important components of the PC tumor microenvironment, and microbial conditioning such as fecal transplantation is a strong candidate for future clinical trials.¹⁴⁰

In the future, how microflora contributes to the establishment and maintenance of immune tolerance is the focus of research in the attempt to find novel treatment strategies. A detailed analysis of the PC-associated microflora can be used to identify specific communities that play a positive or negative role in the development and progression of PC, thereby allowing more selective methods to modulate responses.

Palliative Care

Because PC patients need palliative care at some point, palliative care is as important as other treatments. Percutaneous bile duct drainage, surgical gastrojejunostomy, and endoscopic duodenal stents are the 3 main approaches form management of patients with gastric outlet obstruction.⁹⁵

I would like to thank everyone who helped me during the writing of this paper.