About 90% of people who are diagnosed with pancreatic cancer test positive for the KRAS gene, a mutation that promotes cancer development. While the KRAS gene is also associated with other types of cancer – like colorectal and bile duct cancers, for example – it’s most prevalent in pancreatic cancer.
“Not only is the KRAS mutation associated with the majority of pancreatic cancer tumors, it is also found early on in pancreatic cancer,” says Philip Philip, M.D., Ph. D., a medical oncologist at Henry Ford Health who specializes in gastrointestinal cancers. “In most of our patients with pancreatic cancer, we believe KRAS initiates oncogenesis, or the transformation of a healthy cell into a cancerous cell.”
Here, Dr. Philip answers questions about the KRAS gene and what it means for the future of pancreatic cancer treatment.
Is the KRAS gene genetically inherited?
No. Unlike breast cancer genes BRCA1 and BRAC2, for example, the KRAS gene isn’t inherited. Inherited mutations are called germline mutations. The KRAS mutation is a somatic mutation. This means it’s not passed down from parents or grandparents. It develops spontaneously, likely due to environmental and lifestyle factors (e.g., smoking).
“Our cells are constantly dividing and sometimes mistakes (mutations) are made during DNA replication,” says Dr. Philip. “Fortunately, our bodies have a lot of protective mechanisms. Most of the time, we can eliminate those mistakes in DNA replication. Otherwise, by age 10 we’d have all sorts of cancers.
“But certain individuals either get overwhelmed with outside exposures that cause DNA mutations – like smoking, alcohol or other carcinogens – or for some reason they cannot fix the mutation, and then cells keep on dividing unchecked, and they get cancer. This is why, when patients first come to us, we tell them their cancer didn’t develop within the past few weeks or months. It took a long time – many years, in fact – to develop.”
What drives pancreatic cancer in the 10% of patients who don’t have the KRAS gene?
“This group probably has other DNA mutations that are driving their cancer, which we’re trying to discover and target with treatments,” says Dr. Philip. “It could also be that they have a KRAS mutation we can’t detect yet, as there are many subtypes of KRAS mutations.”
Are there treatments targeting the KRAS gene?
“There has been an explosion of drugs targeting KRAS – it has been a very fertile area for research and development,” says Dr. Philip. “That said, it’s not as simple as simply targeting KRAS. As the tumor grows, it acquires additional gene mutations, which can complicate treatment. So although hitting KRAS with targeted drugs may help, we may need additional drugs that address other gene mutations.
“Not only that, but not every patient has exactly the same KRAS mutation. Some drugs can address a few different KRAS mutations, others address one specific KRAS mutation. There are many treatments in clinical trials working to address this. I suspect we’ll start to see FDA approvals within the next few years, if not earlier.”
Dr. Philip urges anyone with KRAS-positive pancreatic cancer to ask their doctor about enrolling in a clinical trial. “Within the next year, clinical trials will be very prevalent,” he says. “Because there will be so many clinical trials, you won’t have to travel cross country to enroll – they will be accessible in many states. Enrolling in a clinical trial is important because standard-of-care treatments for pancreatic cancer offer a very modest benefit.”
How might KRAS-targeted treatments impact the five-year survival rate for pancreatic cancer?
“When I started as an oncologist in 1995, the five-year survival rate for pancreatic cancer was 3 to 4%,” says Dr. Philip. “Since then it has increased to 13%. So, while it has improved incrementally, we are hoping KRAS-inhibiting drugs will result in a transformative change in the five-year survival rate.”
Along with KRAS-inhibiting drugs, there are other areas of research that will help raise the pancreatic cancer survival rate – from increasing early detection to creating mRNA vaccines to help prevent relapse.
“As recent as ten years ago, pancreatic cancer wasn’t an area of investigation that researchers were attracted to,” says Dr. Philip. “They thought the reward for research in such a tough disease was low, there weren’t good tools or drugs that could be tested, and regulatory agencies had disapproved many treatments that weren’t successful. Sponsorships and grant funding agencies were not as keen on pancreatic cancer as they were on breast or prostate cancer. But since then, this has really changed and there are so many researchers taking on pancreatic cancer. We are also very thankful to advocacy groups such as the Pancreatic Cancer Action Network. It’s really exciting.”
Reviewed by Philip A. Philip, M.D., Ph.D., F.R.C.P., an internationally renowned medical oncologist specializing in gastrointestinal cancers. He is the Chief, Division of Hematology/Oncology in the Department of Internal Medicine at Henry Ford Health. He has led numerous studies in the areas of gastrointestinal tumors. He sees patients at Henry Ford Cancer in Detroit and Henry Ford Medical Center – Columbus.
