Hepatocellular carcinoma (HCC) remains one of the most challenging malignancies worldwide, ranking as the sixth most common cancer and the third leading cause of cancer-related deaths globally [1]. Despite significant advances in early detection and prevention strategies, particularly in viral hepatitis management, the prognosis for advanced HCC patients continues to be poor [2]. The landscape of systemic therapy for advanced HCC has evolved dramatically over the past decade, with the emergence of molecular targeted agents and immunotherapy. However, the optimal treatment sequence, especially after first-line immunotherapy, remains a critical unresolved question in clinical practice.

In this issue of the journal, Terashima and colleagues present a compelling analysis of comprehensive genomic profiling (CGP) [3,4,5], offering valuable insights into the potential role of precision medicine in treatment selection for advanced HCC patients [6]. Their study of 52 patients from three tertiary hospitals in Japan demonstrates that CGP can identify actionable genetic alterations in a significant proportion of HCC patients. CGP tests have potential implications for identifying the resistance markers for first-line treatment, detecting the acquired mutations during the treatment course, and guiding treatment decisions particularly in the second-line setting.

The findings from this study are particularly noteworthy for several reasons. First, they confirm the previously reported genomic landscape of HCC [7, 8], with frequent alterations in TERT promoter, CTNNB1, TP53, and ARID1A. More importantly, they demonstrate that 87% of patients harbored potentially druggable genetic alterations, with 65% receiving specific treatment recommendations from the molecular tumor board [9]. This high proportion of actionable findings suggests that CGP could play a meaningful role in clinical decision-making for advanced HCC patients. The study identified three patients (6%) with high tumor mutational burden (TMB-high), but no cases of microsatellite instability-high (MSI-H) were observed. These findings highlight the need for further investigation into the potential clinical significance of these biomarkers, particularly in relation to immunotherapy, which could assist in the refinement of treatment strategies.

This study raises several important points for consideration in the evolving field of HCC treatment. The identification of rare but clinically significant alterations, such as the TPM3-NTRK1 fusion and MET amplifications, led to successful targeted therapy in some patients. These cases highlight the potential value of CGP in identifying subset of patients who might benefit from specific molecular targeted approaches, even after progression on standard therapies [10]. However, the study also illuminates several challenges in implementing precision medicine for HCC. Despite the high proportion of patients with potentially actionable alterations, only 10% of patients actually received the recommended targeted therapy. This gap between potential and actual implementation of CGP-guided therapy reflects various barriers, including limited drug availability, health insurance coverage restrictions, and the competing influences of liver function and other clinical factors on treatment decisions [10]. Furthermore, the high cost of CGP may restrict access in low-income settings, potentially worsening health disparities by primarily benefiting wealthier individuals, which represents a significant drawback of precision medicine. Additionally, an overemphasis on genetic factors identified through CGP may result in discrimination or psychologic distress, even among patients responding well to second-line therapies, posing another challenge for precision medicine.

The timing of CGP testing emerges as a crucial consideration from this study. While the authors primarily performed CGP after treatment discontinuation, the findings suggest that earlier testing might provide more therapeutic options for patients, particularly regarding clinical trial enrollment. However, the optimal timing for CGP testing remains unclear, as there is insufficient evidence to justify routine testing before first-line therapy.

Looking ahead, several key questions require attention from the research community:

  1. 1.

    How can we better predict which patients are most likely to benefit from CGP-guided therapy?

  2. 2.

    What is the optimal timing for CGP testing in the treatment course of advanced HCC?

  3. 3.

    How can we overcome the barriers to implementing CGP-guided therapy in clinical practice?

  4. 4.

    What is the role of liquid biopsy-based CGP in patients where tissue sampling is challenging?

The landscape of targeted therapy in HCC is rapidly evolving, with numerous clinical trials evaluating novel agents targeting specific molecular alterations. The CTNNB1 inhibitor trials highlighted in this study represent just one example of how molecular profiling might inform future treatment strategies. As our understanding of HCC biology deepens and more targeted agents become available, the value of CGP is likely to increase.

While their analysis did not clear whether the CGP tests have significance for improving advanced HCC patient’s outcomes, this point deserves further investigation. This study also touches upon an important aspect of modern oncology: the integration of molecular diagnostics with immunotherapy. Understanding the molecular determinants of immunotherapy response could help optimize treatment sequencing and combination strategies [11].

The practical implications of this study extend beyond individual patient care. The findings suggest that healthcare systems need to prepare for the increasing role of precision medicine in HCC management. This includes considerations of cost effectiveness, accessibility of molecular testing, and the development of expertise in interpreting and acting upon molecular findings. It is worth noting that while CGP shows promise, it represents just one tool in the complex landscape of HCC management. The unique challenges of HCC, including the influence of underlying liver disease and the heterogeneity of tumor biology, mean that molecular profiling must be integrated with other clinical factors in treatment decision-making.

In conclusion, the study by Terashima and colleagues provides important evidence supporting the potential utility of CGP in advanced HCC, particularly in the second-line setting. While challenges remain in implementing CGP-guided therapy, the findings suggest that molecular profiling could play an increasingly important role in personalizing treatment strategies for HCC patients. As we move forward, continued research and clinical experience will be crucial in defining the optimal role of CGP in HCC management and in developing more effective precision medicine approaches for this challenging disease.