One of the most fatal forms of pancreatic cancer is ductal adenocarcinoma because of its poor response to current treatments. Researchers recently found new information about DNA damage repair in relation to sporadic and germline mutations. Germline mutations such as BRCA1, BRCA2, ATM and several others are commonly reported in pancreatic cancer patients. The BRCA mutations were the most prevalent. New research using targeted therapies has shown success for people with the BRCA mutations who had cancer of the breasts or ovaries. Similar treatments are currently being tested on people with pancreatic cancer. Although the results are incomplete, they look favorable so far.
What Is Pancreatic Ductal Adenocarcinoma?
PDAC is considered the deadliest human malignancy. In the United States, the overall five-year survival rate is 7.7 percent. For patients who have surgery followed by chemotherapy to treat PDAC, the five-year survival rate is 28.8 percent. In metastatic PDAC patients who received the current top chemotherapy combination, the median survival period was barely over 11 months. In another clinical trial using a different combination of drugs, the median survival period was 8.5 months. Researchers said that recent improvements may show hints of developing benefits in new targeted therapies. Past clinical trials did not show significant benefits.Pancreatic cancer is one of the top five culprits of cancer deaths in the United States. It is expected to move up the list to number two by 2030. Unfortunately, the disease is not usually discovered until it has progressed, and it often progresses fast. Screening can be difficult since PDAC is more positively related to sporadic genetic mutations rather than family history. Researchers said that only up to 10 percent of PDAC patients have a family history of pancreatic cancer.There are several diseases and syndromes that have been identified with a greater risk of developing pancreatic cancer. They include the following:
- Hereditary breast and ovarian cancer
- Familial atypical multiple mole melanoma
- Hereditary pancreatitis
- Peutz-Jeghers syndrome
- Familial adenomatous polyposis
- Hereditary nonpolyposis colorectal carcinoma
In addition to the BRCA1 and BRCA2 gene mutations, PALB2, ATM, CDKN2A, TP53, MSH6, MSH2 and MSH1 are the most common germline mutations associated with PDAC development risk. Germline mutations result in a deoxyribonucleic acid damage repair deficiency because of homologous recombination breaks. Deoxyribonucleic acid repair allows cancer cells to alter and survive the damages of genotoxic stress. The BRCA1 gene’s job is to signal DNA damage repair, and the BRCA2 gene is supposed to regulate RAD51 for homologous recombination. When used with chemotherapy agents, ADP-ribose and PARP inhibitors have helped induce damage repair when the DNA repair mechanism is impaired. The treatments were used in breast and ovarian cancer patients who had the BRCA1 or BRCA2 gene mutations.
Testing Targeted Therapies
The researchers referenced two previous studies using the targeted inhibitors with chemotherapy. In one study with 306 random consecutive pancreatic cancer patients, Ontario researchers did not find a significant relationship between family history of pancreatic cancer and either of the two BRCA gene mutations. Also, they did not find a positive relationship between family history of BRCA gene mutations in relation to family history of ovarian or breast cancer. None of the patients who carried BRCA gene mutations met the Ontario Ministry of Health’s requirements for familial PDAC risk, which meant that they would not have qualified for genetic testing prior to diagnosis.
In another study, researchers tried to improve their estimation abilities for detecting BRCA mutations. To do this, they chose patients whose family members had been diagnosed with pancreatic, ovarian or breast cancer. Patients also reported any other cancer diagnoses in their families. Researchers found that the strongest connection was between people who had PDAC and had a family member who was diagnosed with breast cancer. They also found that several PDAC patients had family members with colorectal cancer. However, they did not find a significant amount of PDAC patients with family members who were diagnosed with pancreatic cancer. Only about 20 percent of the patients who had PDAC in that group would have qualified for genetic testing.
In a separate study of 159 random patients who sought genetic testing on their own, there were 24 reported pathogenic mutations related to a higher risk of developing PDAC. According to several past studies, researchers have determined that the most dangerous genetic mutations are most common among people with Jewish heritage. They said that previous studies reveal the need for more extensive testing among pancreatic cancer patients. Testing could help lead to the development of more targeted therapies. As they noted in their referenced studies, combination therapies that target the BRCA gene mutations are improving. Although family history is not always a positive indicator and most pancreatic cancer cases are sporadic, researchers said that improved recruitment and screening of individuals whose family members have been diagnosed with PDAC is needed for improving future research.
Oncotarget was founded in 2010. It is an online medical journal that publishes peer-reviewed research papers and reviews. The publication is one of the few open-access journals online. It is published by Impact Journals and edited by Mikhail Blagosklonny and Andrei Gudkov. When Dr. Gudkov lived in Russia, he earned two doctoral degrees. He worked with the National Cancer Institute, the Cleveland Clinic Foundation and several other health organizations after coming to the United States. Dr. Gudkov currently serves as a chairman for Roswell Park Cancer Institute in New York. Dr. Blagosklonny also earned two doctoral degrees and serves as an oncology professor at Roswell Park Cancer Institute. He specializes in aging and cancer, and his background includes teaching at other medical facilities. Genetic discovery and targeted therapies are two areas of interest for Dr. Blagosklonny and Dr. Gudkov.When Oncotarget first started, there were weekly publications. Since the journal became so popular, Dr. Gudkov and Dr. Blagosklonny decided to issue two publications per week. The new issues are released on the Oncotarget site every Tuesday and Friday. The journal currently holds a 5.168 impact factor, which is large enough to greatly improve the reach of any cited study or review included in a publication.