Blood test identifies pancreatic cancers that respond to adjuvant chemotherapy
Pancreatic ductal adenocarcinoma historically has been a challenging cancer to treat, and often is not detected until it has progressed and metastasized. Some subtypes respond well to chemotherapy, whereas others are resistant.
“Pancreatic cancer has an overall survival time that is relatively quite short,” Brian B. Haab, PhD, professor of metabolic and nutritional programming in the Center for Cancer and Cell Biology at Van Andel Institute, said in an interview with Healio. “But previous studies have shown that adjuvant chemotherapy vs. observation conferred a significant survival benefit in about half of patients who had surgery.”
To determine which patients with surgically resected pancreatic cancer might respond best to adjuvant chemotherapy, Haab and colleagues developed and evaluated a blood test that measures concentrations of a glycan called sTRA. This glycan is generated by pancreatic cancers that generally do not respond to chemotherapy.
Haab spoke with Healio about the potential of the test to tailor pancreatic cancer therapy and spare patients from unnecessary treatments and adverse effects.
Question: What did your study seek to determine?
Answer: We conducted our study among patients with resectable disease — clinically organ-confined cases eligible for surgery. It was already known that roughly 50% of patients had significantly longer survival with adjuvant chemotherapy — with median OS of about 2 years — compared with just observation. The other half were fully resistant to any benefit from chemotherapy and relapsed within a year. This was confirmed in several other studies. However, no method was available to distinguish the responders from the nonresponders prior to treatment. We sought to develop a test to determine this.
Q: How did you develop the test and what did the test determine?
A: A 2011 study by Collisson and colleagues using gene-expression profiling first showed that there are very clear pancreatic ductal adenocarcinoma subtypes with differences in response to treatment. These subtypes have been categorized as classical or basal/squamous. The classical subtype overall had longer survival but, in cell culture and other models, was resistant to drugs and did not benefit from adjuvant chemotherapy. In my work, which focused on glycans, we discovered a new glycan biomarker that defines a subgroup of 60% to 65% of patients. This subgroup is distinct from the subgroup detected by CA19-9, a blood biomarker widely used as an FDA-approved serological test. It is used for many gastrointestinal malignancies to confirm diagnosis, to track the status of the disease among patients in whom it is elevated.
In a study published last year in Clinical Cancer Research, we described a test that measured CA19-9 in combination with sTRA. This simple combination test detected almost 70% of pancreatic cancers, with a less than 5% false-positive rate. This was almost 30% more than with CA19-9 alone. We’re getting to the point where we can use a blood test to screen high-risk populations for the presence of cancer vs. no cancer.
Q: What else did you find?
A: As we looked at the tissue that expresses the glycan, it was clear that there was a different cell morphology. Some of the protein expressions were very different from those that didn’t express the glycan. This led to the hypothesis that not only is sTRA a biomarker that increases the ability to detect more cancers, but also that something might be different biologically and clinically in the subgroup that expresses this glycan. As we looked at the cell culture models, we found expression of the glycan generally aligned with the classical subtype, which is more chemotherapy-resistant than the other subtypes. Then, when we looked at blood samples and outcomes, we found that the patients who had high blood levels of this glycan were those who experienced rapid relapse following surgery and chemotherapy. The nice thing about a blood biomarker is that those patients could be identified prior to surgery, because biopsy doesn’t work so well for subtyping.
Q: Could this test be used to determine which patients with pancreatic cancer should receive adjuvant chemotherapy?
A: We envision that patients who are candidates for surgery would be evaluated with this blood test to determine the subtype. If they are negative for this glycan, they would go ahead with surgery and chemotherapy because they would be likely to benefit. If they are positive, they would be spared procedures that have very costly adverse effects and they could be put on alternative treatments. If surgery and chemotherapy are not going to benefit the patient, they are probably just making things worse.
Collisson EA, et al. Nat Med. 2011;doi:10.1038/nm.2344.
Gao C, et al. Clin Cancer Res. 2020;doi:10.1158/1078-0432.CCR-20-2475.
Oettle H, et al. JAMA. 2007;doi:10.1001/jama.297.3.267.
Staal B, et al. Clin Cancer Res. 2019;doi:10.1158/1078-0432.CCR-18-3310.
For more information:
Brian B. Haab, PhD, can be reached at 333 Bostwick Ave. NE, Grand Rapids, MI 49503; email: email@example.com.