Pancreatic neuroendocrine tumors (PanNETs) can have a variety of behaviors. Some stay slow-growing for years, while others take a sudden, aggressive turn, even when they’re small and seem low-risk. That unpredictability has made it hard for doctors and patients to decide on the best course of action: to monitor or to treat aggressively?
A new breakthrough, collaborative study led by Christopher Heaphy, PhD, and Aatur Singhi, MD, PhD and funded in part by NETRF, may help bring clarity. This work was recently published in the journal Modern Pathology. Drs. Heaphy and Singhi have developed a more accessible and clinically practical test that identifies a key genetic trait in PanNETs, alternative lengthening of telomeres (ALT), that flags tumors with a higher risk of coming back after surgery.
“Determining the status of ALT in PanNETs provides prognostic information since ALT positivity is associated with increased risk of developing distant metastases, even in small tumors, says Dr. Christopher Heaphy. Therefore, the presence of ALT represents a critical biomarker for risk stratification and helps to guide clinical decision-making. Our newly developed ALT-CISH assay utilizes commercially available reagents and standard laboratory equipment, and thus can easily be implemented in most clinical pathology laboratories. Along with Dr. Singhi, we are actively working with several academic hospitals to integrate the ALT-CISH assay into routine clinical workflows with the ultimate goal of widespread clinical use and potential incorporation of the ALT biomarker into future clinical trials.”
Why ALT Matters in PanNETs
Telomeres are the protective caps on the ends of our chromosomes. In many cancers, they’re kept long by an enzyme called telomerase, but some cancers, such as PanNETs, use a telomerase-independent process called ALT. ALT-positive tumors have a higher chance of spreading and returning after surgery.
Until now, detecting ALT relied on a complex, expensive test called FISH (fluorescence in situ hybridization). While reliable, it’s not widely available in clinical labs and needs specialized equipment and training.
Enter: ALT–CISH, A Simpler Solution
This study introduced a new test for ALT, called CISH. It works similarly to FISH but with one major difference: it can be run using standard lab equipment already found in most pathology labs.
When researchers validated this method on 360 PanNET samples, they found that:
- About 1 in 3 primary PanNETs were ALT-positive.
- ALT-positive tumors were more likely to be larger, higher-grade, and to have already spread to lymph nodes or distant sites.
- Patients with ALT-positive tumors had shorter relapse-free survival—only 35% were disease-free after 5 years, compared to 94% of ALT-negative patients.
Most importantly, ALT–CISH was 100% accurate when compared with the gold standard FISH test.
Why This Matters for Patients
For patients with PanNETs, especially small or early-stage ones, the decision to operate or monitor can be tough. Until now, doctors have relied heavily on size and grade, which don’t always tell the full story.
ALT–CISH offers a new, reliable biomarker to better predict which tumors are likely to behave aggressively. That means more personalized treatment plans, potentially sparing some patients from overtreatment while catching high-risk cases early.
A Step Toward Targeted Therapies
The presence of ALT isn’t just about prognosis; it’s also a potential therapeutic target. ALT-positive cells experience unique DNA stress that specific drugs could exploit. Clinical trials are already exploring ATM and ATR inhibitors that seem potentially effective against ALT-positive tumors.
That makes the ability to test for ALT not just a tool for forecasting, but potentially a gateway to better treatments.
Looking Ahead
“This study underscores the clinical utility of detecting ALT through chromogenic in situ hybridization, offering a practical and cost-effective biomarker for prognosticating pancreatic neuroendocrine tumors and other neoplasms,” says Dr. Aatur Singhi. ”The development and validation of this assay were the result of a collaborative effort between the University of Pittsburgh (Dr. Singhi) and Boston University (Dr. Heaphy), made possible by generous funding support from NETRF. Importantly, this assay is available today for patient care, paving the way for its integration into routine pathology practice to enhance clinical decision-making and improve patient outcomes.”
At NETRF, we believe in bringing the latest science to the clinic. ALT–CISH could help patients and clinicians make more confident decisions, and move us one step closer to precision care in PanNETs and beyond.