Exploring the efficacy of somatostatin analogs in treating pancreatic neuroendocrine tumors with Ki-67 index ≥10% based on recent clinical evidence.
Imagine receiving a diagnosis of a pancreatic neuroendocrine tumor (PanNET)—a rare, often slow-growing cancer—only to learn that a specific marker in your tumor cells suggests it might be more aggressive. This marker, called the Ki-67 index, helps doctors gauge how quickly cancer cells are multiplying. When this index climbs to 10% or higher, it creates a critical gray zone for treatment decisions. For years, the primary first-line therapy for advanced PanNETs has been a class of drugs called somatostatin analogs (SSAs), which are known for their effectiveness in low-grade tumors. But this leaves patients and doctors with a pressing question: Do these targeted therapies still work when the Ki-67 is 10% or more? 1 9
Recent groundbreaking research is now providing answers, offering new hope and clarity for this specific group of patients. This article delves into the science behind these treatments and explores the real-world evidence that is shaping modern cancer care.
Pancreatic neuroendocrine tumors (PanNETs) are a rare type of cancer that originates from the hormone-producing cells of the pancreas. They account for only 1-2% of all pancreatic neoplasms. 3
The Ki-67 index is a crucial pathological measurement that acts like a "speedometer" for a tumor, indicating the percentage of cancer cells that are actively dividing and growing. 3
| Grade | Ki-67 Index | Description |
|---|---|---|
| Grade 1 (G1) | Ki-67 < 3% | Low-grade, slow-growing tumors |
| Grade 2 (G2) | Ki-67 3-20% | Intermediate-grade tumors |
| Grade 3 (G3) | Ki-67 > 20% | High-grade, aggressive tumors |
The threshold of 10% within the G2 category has emerged as a critical cutoff, effectively separating "low-G2" from "high-G2" tumors with distinct prognoses and potential responses to therapy. 4
While earlier clinical trials established SSAs as the first-line treatment for well-differentiated PanNETs, their efficacy specifically in tumors with a Ki-67 ≥10% remained uncertain. To fill this knowledge gap, a multicenter consortium of expert centers designed a retrospective, real-world study. 1 9
Researchers identified 73 patients from 10 expert centers worldwide who had been diagnosed with advanced, nonfunctioning, well-differentiated PanNETs with a Ki-67 index ≥10%. The vast majority (68 patients) had G2 tumors, while 5 had well-differentiated G3 tumors. 9
All patients had received a first-line long-acting SSA (either octreotide LAR or lanreotide) between 2014 and 2018. Their medical records were thoroughly analyzed, with researchers tracking their progress for a median of over three years. 1 9
The study's primary goals were to determine:
The results, published in The Oncologist in 2021, provided robust and encouraging answers: 1 9
The median overall survival was an impressive 86 months (over 7 years), underscoring the relatively indolent nature of well-differentiated PanNETs even with a higher Ki-67. 9
| Outcome Measure | Median Duration (Months) | 95% Confidence Interval |
|---|---|---|
| Progression-Free Survival (PFS) | 11.9 months | 8.6 - 14.1 months |
| Time to Next Treatment (TNT) | 14.2 months | 11.6 - 16.2 months |
| Overall Survival (OS) | 86 months | 56.8 - 86 months |
| Predictive Factor | Better Response Group | Hazard Ratio (HR) for Progression | Impact on PFS |
|---|---|---|---|
| Tumor Grade | Grade 2 (G2) | HR: 4.4 (for G3 vs. G2) | G3 tumors had a 4.4x higher risk of progression |
| Liver Tumor Load | ≤ 25% | HR: 2.0 (for >25% vs. ≤25%) | High tumor load doubled the risk of progression |
| Reagent / Tool | Function in Research | Relevance to SSAs |
|---|---|---|
| Ki-67 (MIB1 antibody) | Labels proliferating cells in tumor tissue to calculate the Ki-67 index. | Used to classify tumor grade and select patients for studies on SSA efficacy. |
| SSTR2 Antibodies | Detects the presence and density of somatostatin receptor 2 on tumor cells. | Predicts whether a tumor is likely to respond to SSA therapy. High SSTR2 expression is a positive marker. |
| Radiolabeled SSAs (e.g., ⁶⁸Ga-DOTATATE) | Used in PET imaging to visualize SSTR-positive tumors throughout the body. | Critical for patient selection for SSA treatment and for monitoring response. |
| Long-Acting SSAs (Octreotide LAR, Lanreotide Autogel) | The therapeutic agents themselves, formulated for slow release. | The direct intervention being studied for its antiproliferative effect. |
The confirmation that SSAs have antiproliferative activity even in PanNETs with a Ki-67 ≥10% solidifies their role as a safe and effective first-line option, particularly for patients with G2 tumors and low disease burden. 1 2 9
The treatment landscape is rapidly evolving. For patients with higher-grade, SSTR-positive tumors, Peptide Receptor Radionuclide Therapy (PRRT) is emerging as a powerful option. This treatment involves attaching a radioactive isotope to an SSA, creating a "therapeutic missile" that delivers radiation directly to the cancer cells.
The recent NETTER-2 trial showed that PRRT can be effective even as a first-line treatment for higher-grade G2 and G3 GEP-NETs, opening new avenues for sequencing these targeted therapies. 6 8
A recent 2025 publication in Scientific Reports provided strong validation for using the 10% Ki-67 cut-off. Through sophisticated genomic and molecular analysis, researchers confirmed that G2 PanNETs with a Ki-67 ≥10% have distinct genetic profiles and more aggressive behaviors, similar to G3 tumors, further justifying tailored treatment approaches. 4
The question posed at the beginning—"Any benefit when Ki-67 is ≥10%?"—can now be answered with a cautious but definitive "yes." Real-world evidence has illuminated a path forward, demonstrating that somatostatin analogs retain significant antiproliferative power for a well-defined subset of patients with more aggressive-looking PanNETs.
This knowledge empowers oncologists to make more personalized treatment decisions, optimizing outcomes for patients navigating this complex diagnosis. As research continues to refine our understanding of tumor biology and develop novel targeted therapies, the future for patients with pancreatic neuroendocrine tumors grows brighter.