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Finding More Clues about Circulating Tumor DNA

pancreatic cancer researcher Dr. Gehan Botrus
Pancreatic cancer is one tough disease. Fortunately, researchers are looking at novel ways to diagnose it earlier.

They are also looking at ways to quickly determine how well patients may be responding to a particular treatment approach so it can be modified if necessary. And they want to find the best way to choose a particular course of treatment based on a molecular profile specific to that patient’s tumor.

It’s a tall order, but tiny fragments of DNA called circulating tumor DNA are showing some promise in detecting gene alterations and what those gene alterations mean in terms of prognosis and how well a tumor is responding to treatment. “One of the tough things in pancreatic cancer is it’s difficult to get a good biopsy,” explains oncologist Gehan Botrus, M.B., Ch.B., Ph.D., who led a study on the viability of using circulating tumor DNA as a prognostic tool in advanced pancreatic cancer. The abstract that looked at 104 patients was presented at the ASCO GI Cancers Symposium 2021. It also received the 2021 ASCO Annual Meeting Merit Award.

The problem with a traditional pancreas biopsy is that too often the “tumor is not represented well,” since the organ’s location at the back of the abdomen, as well as the fact that it is surrounded by other organs, makes it sometimes difficult to get a good sample, explains Botrus, who was a hematology–oncology fellow at the Mayo Clinic in Phoenix, Arizona, when she led the study.

“It [a traditional biopsy] can also be very tough for patients since it is an invasive procedure, and that always comes with risk, like infection, bleeding, and perforation of other vital organs.” Comparatively, the collection of circulating tumor DNA is relatively noninvasive, requiring only a blood draw. After the circulating tumor DNA is extracted from the blood, it can be analyzed for important genetic information.

A Precision Medicine Approach

Circulating tumor DNA is DNA that is found in the bloodstream. Its origin is cancerous cells and tumors, which shed dead cells. These dead cells break down, and their components, like DNA, can then be found in the blood. Cell-free DNA comprises all of the DNA in the bloodstream. That means it includes germline DNA (DNA we inherit) as well as tumor DNA.

Researchers are looking at how circulating tumor DNA may be used to help personalize pancreatic cancer treatment. “Monitoring treatment response, helping to better guide us on issues related to resistance, guiding treatment strategies to overcome resistance, and identifying the molecular drivers that influence treatment are all ways that it can potentially help us better treat pancreatic cancer patients,” says Botrus, who received a scholarship to take on the role of assistant professor for drug development and to design phase I clinical trials with TGen and HonorHealth, both in Phoenix. She will be studying early onset in gastrointestinal cancers, with a special focus on patients of color.

About the Abstract

The retrospective study included 104 patients with advanced pancreatic cancer. Circulating tumor DNA was collected at the time of diagnosis. The mean age of participants was 70.5 years. Nearly 40 percent had locally advanced disease, and slightly more than 60 percent had metastatic disease. The researchers found somatic alterations (DNA alterations occurring after conception) in more than 80 percent of patients. No genetic alterations were found in slightly more than 15 percent of patients. Absence of genetic alterations was associated with locally advanced disease more often than with metastatic disease. More than 60 percent of the participants had more than two genetic alterations identified. First-line treatment for participants included FOLFIRINOX (nearly 30 percent) or gemcitabine plus nab-paclitaxel (nearly 60 percent).

In a head-to-head comparison, patients with any detectable genomic alterations had a worse progression-free survival average of 6.2 months compared to patients with no detectable variant who had a progression-free survival of 15.3 months. Patients with more than two detectable genomic alterations had a worse median progression-free survival of 5.6 months versus 11 months and worse median overall survival of 11.5 months versus 24.2 months.

Not surprisingly, KRAS, one of the biggest drivers of pancreatic as well as other solid tumors, was found in more than 60 percent of the patients and was associated with poor outcomes. The presence of TP53 (detected in 60 percent of patients) and CCND2 (detected in 14 percent of patients) genes was also associated with poor outcomes.

In the larger study cohort of advanced and metastatic pancreatic cancer patients, published in the journal The Oncologist in February 2021, the research team looked at 357 samples collected from 282 patients, including the 104 patients presented in the ASCO abstract. The researchers found therapeutically relevant alterations in 170 (48 percent) of the total 357 samples. These alterations included KRAS G12C, which is a single type of KRAS mutation accounting for about 44 percent of all KRAS mutations. Other alterations included EGFR, ATM, BRCA, PIK3CA, and BRAF mutations, which can be targeted with new medications.

Potential Implications for Patient Care

This study was not only the largest sample size, but it also used the largest gene panel for investigation to date for pancreatic cancer, says Botrus. “A significant finding from the study that needs further investigation but, nonetheless, excited the team relates to KRAS and TP53. The researchers found that in 23 patients, who had serial testing with each cycle of chemotherapy, patients with clearance of TP53 and/or KRAS at any time point achieved improved progression-free survival and overall survival, especially those with TP53 clearance.

“This could be a huge prognostic indicator,” Botrus says.

Doctors currently check the tumor marker CA 19-9 to see how well systemic treatment may be working, but it is somewhat limited. “There are many limitations to CA 19-9 serum level evaluation in pancreatic cancer, including poor sensitivity, false negative results, and increased false positivity in the presence of obstructive jaundice,” she notes.

Although all findings from this work need to be confirmed in larger studies, Botrus is hopeful that further circulating tumor cell DNA research will improve the lives of pancreatic cancer patients.

“I am very passionate about pancreatic cancer,” she says. “We have inched forward in terms of mortality, which is 10 percent survival at five years now, but that is far too low. The problem is the mortality rate is pretty much equal to incidence rate. That is unacceptable.

“All the research being done in better understanding the genetics and circulating tumor cells will make a difference. We are very hopeful that difference will be sooner rather than later. The patients need more precise treatments.”


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