Pancreatic cancer is a form of cancer that starts within pancreas tissue cells. The pancreas is a vital organ that aids the body in digesting food. It is also responsible for making hormones that regulate the body’s blood sugar levels. Because of the organ’s important role in healthy body functions, pancreatic cancer is one of the most fatal cancers.
As with most other oncology malignancies, the key to pancreatic cancer survival is early detection. This can be difficult for patients who do not know they have pancreatic cancer. The disease often does not show symptoms until the late stages of the disease manifestation.
Up to 80% of pancreatic cancer cases are diagnosed in its late stages. The average survival rate is around 3.5 years for those patients.
Historically, there has been no early detection test for pancreatic cancer. Next-generation sequencing (NGS) technologies like liquid biopsy are being used in trial studies for early detection of pancreatic cancer. Oncologists are also using liquid biopsies to understand patient reactions to cancer treatment. Often, a genetic factor contributes to why some patients respond well to treatment and others do not.
This article walks through different stages of pancreatic cancer treatment, and discusses how NGS is changing outcomes for patients.
Use of Next-Generation Sequencing in Pancreatic Cancer Treatment
Next-generation sequencing technology allows the entirety of the human genome to be sequenced. Genetic variations can be used to detect the potential for disease before it manifests. They can also provide clues to diseases patients may already have.
NGS is an important tool in pancreatic cancer management. It is useful for risk factor identification, early diagnosis, therapeutic targeting, and long-term recurrence predictions.
Understanding genetic changes
Genetic changes happen when a particular gene develops a mutation. Gene variants are permanent changes to DNA. Not all mutations are cause for concern. However, understanding how genetic changes occur is crucial to interpreting the manifestation of diseases, especially pertaining to cancer.
There are two types of genetic variants:
- Hereditary variants: These variants are passed down to an individual from a parent. These are also called germline mutations.
- Somatic variants: These variants develop during an individual’s life within their somatic cells. These variants won’t be expressed in every cell of the body. There is also no chance of passing these mutations down to offspring. These variants are typically caused by environmental factors.
In terms of pancreatic cancer, only about 10% of cases are hereditary. When a person has inherited pancreatic cancer, the genetic culprit is usually the BRCA1 or BRCA2 mutations. These are the same genes commonly associated with breast cancer and ovarian cancers.
The other 90% of mutations that cause pancreatic cancer are somatic. The most common mutation responsible for pancreatic cancer is the KRAS gene. KRAS mutations are responsible for almost all of these non-hereditary pancreatic cancer cases. However, other genes can also cause pancreatic cancer, like MADH4, CDKN2A, ARMET, and TP53.
KRAS belongs to a class of genes called oncogenes. Oncogenes are genes that have the potential to develop cancer when mutated. These mutations can occur for a variety of reasons. Some common mutation causes include a history of smoking, type 2 diabetes, and poor diet.
Next-generation sequencing can be used to detect these genetic variants. In fact, patients who know they have genetic mutations related to pancreatic cancer are sometimes able to get frequent screenings. Movements like the Penn Medicine Pancreatic Cancer Risk Management Program work to provide these screenings to at-risk patients. Using NGS insights in this way makes use of genetic information to promote early detection.
Early detection and diagnostics
Pancreatic cancer continues to be one of the most fatal cancers. It is a smaller vital organ, making it easier for the disease to spread quickly. For many people, the disease lacks symptoms until the late stages of disease manifestation. Few early detection options are available.
With next-generation sequencing, patients have hope for a better prognosis than ever before. In a study published in October of 2021, researchers used liquid-based cytology and next-generation sequencing to “improve the diagnostic accuracy of pancreatic lesions.” In this same study, researchers successfully identified pancreatic cancer mutations in 44 out of 52 cases.
By integrating next-generation sequencing in pancreatic cancer diagnostics, oncologists may be able to detect the disease earlier. This will improve the odds of patient survival.
Recent research has uncovered several therapeutic targets that will improve prognosis for pancreatic cancer patients. Two of these show promise within the oncological community.
MicroRNAs (miRNAs) are non-coding RNA that help regulate gene expression. They were first discovered by Harvard University researchers in 1993. Since then, further research has shown that MicroRNAs are useful for pancreatic cancer diagnostics. Because they play a role in tumor suppression, unusual miRNA levels could indicate malignancies.
MicroRNAs have also been identified as a potential therapeutic target. This is because they regulate about 60% of the body's protein coding genes. Studies have shown that miRNA could act as a carrier of viral vectors to suppress tumor growth. In combination with other therapies, this treatment has been effective in mice.
The G alpha 13 protein has been shown to stimulate tumor growth and advancement. Pancreatic cancer studies have revealed that there is increased mTOR signaling in tumors caused by the G alpha 13 protein. By targeting the mTOR pathway that signals the protein, oncologists can treat tumor growth. As technology advances, these proteins can be monitored before the disease symptoms begin.
Next-generation sequencing provides a way to monitor the genome in its entirety. By focusing on miRNA and specific proteins, oncologists can identify therapeutic targets specific to pancreatic cancer.
Long term recurrence risk
Recurrence risk for pancreatic cancer is nearly 80% after the first two years of remission. In 2017, the five year survival rate for pancreatic cancer was about 30%. This is an improvement over historic figures, but it is still low when compared to other cancers.
Predicting recurrence often employs a multiomics approach. In a 2020 Scientific Reports study, researchers used whole exome sequencing, RNA sequencing, and DNA methylation analysis to predict patient survival.
Researchers identified five genes that indicated drastically different survival rates for patients with pancreatic adenocarcinoma. They then used an autoencoder to group those patients into two subgroups with varying survival rates. These developments will enable oncologists to identify patients with the highest risk of recurrence and poor outcomes. With more information, doctors and their patients can make more personalized treatment decisions.
Liquid biopsy has also been an effective tool in predicting recurrence risk. A 2020 study analyzed blood samples from 104 patients with pancreatic cancer and liver metastasis. 50% of patients with advanced pancreatic cancer had detectable circulating tumor DNA (ctDNA).
These patients had notably worse survival rates than ctDNA-negative patients. Detectable ctDNA was also identified as a biomarker for recurrence. This study proves that NGS-based blood tests could be effective tools for recurrence prediction and prognosis.
Next-generation sequencing can help oncologists understand the genetic causes of pancreatic cancer. It can also find new ways to identify targeted therapies for pancreatic cancer patients. More research is still needed, but the technology is promising for better prognoses in the future of pancreatic cancer treatment.
Psomagen thanks Dr. Stacy Matthews Branch for her contributions to the research and writing of the original version of this article. Dr. Branch is a biomedical consultant, medical writer, and veterinary medical doctor. She owns Djehuty Biomed Consulting and has published research articles and book chapters in the areas of molecular, developmental, reproductive, forensic, and clinical toxicology. Dr. Matthews Branch received her DVM from Tuskegee University and her Ph.D. from North Carolina State University.
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