Systemic review of Adenocarcinoma of Pancreas: Molecular mechanisms & Immuno-therapeutic options
Adenocarcinoma of pancreas is the fourth leading cause of cancer-related deaths in the world and will soon progress to number two by 2021 unless a significant development is accomplished. The presence of dense stroma along with strong variations makes it notoriously resistant to chemotherapy and potent inhibitors such as paclitaxelin used in combination with gemcitabine.
Epidemiological reports suggests that individuals between the ages 60–80 are more prone to this form of rare cancer. Among these age groups, the number of cases reported were more in men than women along with higher incidence in developed countries than developing countries. In 2018, of 2.5% cases reported globally, only 0.15% cases managed to survive. With a very faint chance of early detection, surgical dissection can offer a median survival of approximately 8.5%.
Data suggests that around 90% of the pancreatic cancers are sporadic while in 7% and 3% cases can be attributed to familial and genetic aggregation. Mutations in tumour suppressor genes such as BRCA2 increases the risk of pancreatic cancer by 17% among individuals. Germline defect in the STK11/LKB1 gene in patients with Peutz-Jeghers syndrome increases the risk of pancreatic cancer development by 132-fold when compared with general population. Furthermore, defects in DNA mismatch repair genes such as Ataxia-telangiectasia mutated (ATM), predisposes to pancreatic cancer development.
Non-genetic factors such as cigarette smoking, obesity, lack of physical activity, increased alcohol intake along with diabetes mellitus demonstrated an increased risk of pancreatic cancer. Although the association between pancreatic cancer and blood group is unknown, data suggests that the presence of non-O blood group accounts for 20% of pancreatic cancer patients.
Since the tumor fails to restrict itself to the organ, it spreads to other regions often causing jaundice. Some vague indication of cancer includes yellowing of eyes & skin, dramatic weight loss and abdominal pain. Currently there is no reliable screening technique available for the early detection of pancreatic cancer among the general population. CT scan, ultrasound, endoscopy and biopsy are most commonly used and valid techniques employed for detection of cancer in their late stages. Serum blood biomarkers CA-19-A, SPAN-1, CA-50 and DUPAN-2 are investigated to aid early detection of pancreatic cancer.
Due to lack of early screening techniques, a clear understanding of the etiology and risk factors is vital for progression of this disease. Since risk factors associated with age, gender, race, and family history cannot be modified, lifestyle modification might lower pancreatic cancer risk.
The strategies involved in the treatment and management of pancreatic cancer solely depend on the stage of cancer. Currently patients are advised to undergo surgery along with chemotherapy and radiation to ensure long-term survival and cure. Gemcitabine and fluorouracil are primary neoadjuvant based chemotherapeutic agents employed to increase disease free survival upto 13.4 months. Efforts are underway to design an efficient delivery mechanism ensuring better resection and reducing the risk of tumor recurrence. In patients administered with gemcitabine along with albumin conjugated paclitaxel has significant improvement with prolonged survival rates were observed when compared to patients administered gemcitabine alone. FOLFIRINOX has become an option for patients with metastatic disease but causes but has been associated with increased toxicity compared with gemcitabine in patients with advanced disease.
Immunotherapeutic approach has shown an effective way to mount antigen specific anti-cancer immune response. In Japan, Masato Okamoto et.al developed a standardised dendritic cell vaccine ‘Vaccell’ to elicit anti-tumour effects. Recently Linda M of UCLA and her colleagues designed a patient specific immunotherapy for pancreatic cancer. The data suggested that in clinical trials, dendritic cell vaccine improved the life expectancy of these cancer patients and was safe and easy to use unlike other therapies.
Although poor prognosis is associated with this disease, continuous scientific attempts are constantly employed in understanding the disease biology to promote progress in finding effective treatments. Research on identification of effective antigens, biomarkers and use of combination therapies using cancer vaccine + checkpoint inhibitors may help in significant tumor mass reduction and increasing survival rates.