Stanford Cancer Institute

In the broad field of oncology, pancreatic cancer is one of the toughest cancer types to treat and continues to claim the highest mortality rate across all cancers. Its presence is notoriously difficult to detect, as it grows deep within an individual's body, and any symptoms developed as a result are often broad and unspecified. To make treating this disease an even more complicated endeavor, according to the American Cancer Society, less than 20% of pancreatic cancer cases are detected before they become metastatic. For this reason, early detection is an essential component in the treatment pipeline to successfully approach this elusive form of cancer. 

We caught up with Stanford Cancer Institute members Ash Alizadeh, MD, PhD, and Max Diehn, MD, PhD, who developed several novel techniques for early detection of cancer that rely on blood-based liquid biopsies. 

Liquid biopsies are a relatively new way of detecting cancer by measuring circulating tumor-derived DNA (ct-DNA), a biomarker present in the bloodstream, among other body fluids. This technique allows for repeated measurements throughout the treatment process, helping clinicians monitor the status of the cancer along the way. 

“Currently, most cancer patients only undergo a surgical tumor biopsy to analyze molecular properties of their tumor before treatment,” said Alizadeh. “From then on, repeated sampling is seldomly done. Using liquid biopsy methods, it is now possible to monitor molecular properties of tumors at many points during treatment and surveillance.”

Diehn added, “Using liquid biopsy methods, we are able to monitor how tumors adapt to treatment and can detect resistance mechanisms that cancers use to evade our therapies. Ultimately, we hope to develop ways of reacting to a tumor’s response in order to overcome treatment resistance.”

More frequent sampling provides more surveillance of the cancer’s status, so providers can track the treatment’s progress and the disease’s response. This can give researchers insight into any resistance to treatment and open up new avenues for developing therapeutic strategies mid-course. Currently, liquid biopsies are being utilized in the clinic as a non-invasive method to identify what drug therapy would be an effective treatment in certain subsets of metastatic patients. 

“Particularly in the context of therapies with curative intent; whether you’re doing surgery, radiation or curative chemotherapy, detection of any residual disease can guide treatment adjustments when the burden is very low,” explained Alizadeh. 

Liquid biopsies are conducted in several ways, including two methods developed by the Stanford team: the Phased variant enrichment and detection sequencing (PhasED-Seq) approach or the epigenetic expression inference from cell-free DNA-sequencing (EPIC-seq) approach. 

PhasED-Seq is a novel, ultrasensitive way to track cancer in the human body. As cancer cells die, they release ct-DNA into the bloodstream, which can be obtained via a simple blood draw. The amount of ct-DNA in the blood is usually incredibly small, but Diehn and Alizadeh have developed technologies that can detect even trace amounts of genetic information. “Being able to detect minimal residual cancer (MRD) in the blood could allow catching disease early before it recurs clinically,” said Alizadeh.

Diehn noted, “The ability to identify patients who have minimal residual disease opens opportunities to treat them before their cancer recurs.” 

In current practice, a patient typically is followed without further treatment after completing their course of radiotherapy since it is impossible to tell whether cancer cells are still present. Using the PhasED-Seq approach, microscopic amounts of residual cancer can be detected, creating avenues for further treatment before clinical tumor recurrence.

Alizadeh and Diehn are now looking to push the capabilities of liquid biopsies further by diving deeper into a cancer’s molecular properties. They developed a new method called EPIC-Seq that targets gene promoters and can measure which genes are turned on or off in cancer cells. Being able to infer cancer gene expression from a blood draw can non-invasively identify the type and subtype of cancer and, in some cases, help to identify the most effective treatment method. EPIC-Seq holds promise that future cancer patients may be able to avoid invasive procedures.

“We have already learned that when you profile the tumor, comprehensive profiling using multiple different measurements can give you a more complete picture of the tumor and its behavior,” said Alizadeh. For some specific types of cancer, profiling the tumor’s genetic makeup is essential to developing a viable treatment plan. Indeed, the team is now actively working to apply and further refine these promising liquid biopsy techniques for the detection and monitoring of pancreatic cancers and their adaptations that drive resistance to treatment.

November 2023 by Kai Zheng
Image by Tatiana from Pixabay