AFP-L3 or DCP expression is associated with poor outcomes in unresectable HCC

Yes, the expression of AFP-L3 or DCP is strongly associated with poor outcomes in patients with unresectable hepatocellular carcinoma (HCC), as demonstrated by the study you referenced. Here's a detailed explanation of why these biomarkers are significant and how their expression correlates with prognosis:

### What is AFP-L3 and How is it Different from AFP?

• **AFP (Alpha-fetoprotein):** AFP is a glycoprotein produced primarily by the fetal liver and yolk sac during development. In adults, elevated AFP levels are commonly associated with liver diseases such as hepatitis, cirrhosis, and HCC. However, AFP alone has limitations as a biomarker because up to half of early-stage HCC patients have normal AFP levels, making it insufficient for accurate risk stratification.

• **AFP-L3 (Lens culinaris agglutinin-reactive AFP):** AFP-L3 is a specific isoform of AFP that is bound to a lectin called Lens culinaris agglutinin. Unlike total AFP, AFP-L3 is more specific to malignant hepatocytes and is considered a highly sensitive marker for HCC. It is especially useful in detecting aggressive and invasive tumor phenotypes. Elevated AFP-L3 levels have been associated with poorer prognosis, higher recurrence rates, and greater likelihood of vascular invasion.

### What is DCP (Des-gamma-carboxyprothrombin)?

• **DCP:** DCP, also known as PIVKA-II (Protein Induced by Vitamin K Absence or Antagonist-II), is an abnormal form of prothrombin that arises due to defective post-translational carboxylation in malignant hepatocytes. It is a well-recognized biomarker for HCC and is associated with tumor progression, angiogenesis, and metastasis. DCP is particularly useful in detecting HCC in patients with normal AFP levels and in predicting poor outcomes.

### Why Are AFP-L3 and DCP Helpful for Prognosis in Unresectable HCC?

• **Detection of Aggressive Tumor Biology:** Persistent AFP-L3 and DCP expression after liver-directed therapy (LDT) indicates the presence of viable, aggressive tumor tissue that may not be detectable through imaging. These biomarkers are associated with more invasive and advanced disease phenotypes.

• **Prognostic Value Beyond Imaging:** While imaging techniques like CT or MRI are critical for assessing tumor response, they may not capture microscopic or indeterminate residual disease. Biomarkers like AFP-L3 and DCP provide additional, independent prognostic information about the biological activity of the tumor.

• **Risk Stratification:** Patients with AFP-L3 and/or DCP positivity have a significantly higher risk of disease progression and worse survival outcomes compared to those with negative biomarker profiles. This allows for early identification of high-risk patients who may require more aggressive or alternative treatment strategies.

### Association of AFP-L3/DCP Expression with Poor Outcomes in Unresectable HCC

1. **Incomplete Response to LDT:**

• Patients with persistent AFP-L3 or DCP positivity after LDT (e.g., Yttrium-90 radioembolization, microwave ablation, or chemoembolization) are less likely to achieve a complete radiographic response. Only 29% of biomarker-positive patients achieved a complete response compared to 64% of triple-negative patients (AFP, AFP-L3, and DCP all negative).

2. **Higher Risk of Disease Progression:**

• Persistent AFP-L3/DCP positivity was associated with dramatically increased rates of disease progression:
• 1-year progression rate: 39% in biomarker-positive patients vs. 8% in biomarker-negative patients.
• 2-year progression rate: 66% in biomarker-positive patients vs. 10% in biomarker-negative patients.
• Median time-to-progression (TTP) was only 18 months in biomarker-positive patients, whereas it was not reached in biomarker responders (triple-negative patients).

3. **Poor Overall Survival (OS):**

• Two-year OS was significantly worse in biomarker-positive patients (62%) compared to biomarker-negative patients (81%).
• Patients with AFP-L3+/DCP+ phenotypes had the worst outcomes, with a 10.8-fold higher progression risk compared to triple-negative or AFP-only groups, even after adjusting for competing risks.

4. **Phenotypic Subgroups and Survival:**

• The AFP+ AFP-L3+/DCP+ subgroup had the poorest outcomes, with a 2-year OS of only 36%, which is similar to survival rates seen in advanced HCC (BCLC-C stage), despite their earlier clinical stage (BCLC A–B).
• In contrast, patients with only AFP positivity but negative AFP-L3 and DCP had outcomes comparable to triple-negative patients, highlighting the importance of distinguishing isolated AFP elevation from multi-biomarker positivity.

5. **Shorter Time-to-Progression in Incomplete Responders:**

• Among patients with incomplete radiographic response to LDT, those with AFP-L3+/DCP+ expression had a median TTP of only 9 months, compared to 63 months in patients with AFP-only or triple-negative profiles.

### Biological Interpretation

• Persistent AFP-L3 and/or DCP positivity likely reflects residual tumor activity that is not fully eradicated by LDT. These biomarkers may signify the presence of viable but radiographically indeterminate tumor tissue, which could explain the higher rates of progression and poorer survival outcomes.
• The inferior outcomes associated with AFP-L3/DCP expression were independent of liver function parameters, such as Child–Pugh score, bilirubin, or albumin levels, suggesting that these biomarkers provide prognostic information beyond hepatic reserve or liver dysfunction.

### Clinical Implications

1. **Routine Multi-Biomarker Testing:**

• Incorporating AFP-L3 and DCP testing alongside AFP into routine clinical practice can improve risk stratification, identify high-risk residual disease, and guide treatment decisions after LDT.

2. **Therapeutic Considerations:**

• Patients with persistent AFP-L3+/DCP+ expression may benefit from earlier transition to systemic therapy or combination regimens, such as LDT with immunotherapy, as suggested by ongoing trials like EMERALD-01 and LEAP-012.
• Intensified surveillance and more aggressive retreatment strategies may be warranted for biomarker-positive patients to prevent early progression.

3. **Personalized Treatment:**

• Distinguishing between biomarker profiles (e.g., triple-negative, AFP-only, AFP-L3+/DCP+) can help tailor therapy to individual patient risk, optimizing outcomes and avoiding unnecessary interventions in lower-risk patients.

### Conclusion

The study conclusively demonstrates that persistent AFP-L3 or DCP expression following LDT is a robust predictor of incomplete tumor response, rapid disease progression, and poor survival in unresectable HCC. These biomarkers provide critical prognostic information that complements imaging and liver function tests, offering a powerful tool for early risk stratification and personalized therapy planning.