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Introduction <p>PTEN hamartoma tumor syndrome (PHTS) is a rare genetic disorder caused by germline pathogenic variants in the PTEN tumor suppressor gene. Everolimus, an oral mTORC1 inhibitor, is approved for the treatment of tuberous sclerosis complex-related tumors; however, evidence for its efficacy in PHTS remains limited. A recent randomized controlled trial (RCT) reported safety and efficacy findings, but the composite primary efficacy endpoint did not reach statistical significance.</p> Methods <p>We conducted a sensitivity analysis of this RCT to further evaluate the efficacy of everolimus in PHTS. Five statistical approaches were applied: analysis of covariance and four linear mixed-effects models. Outcomes included the composite neurocognitive score as a primary endpoint and multiple secondary neurocognitive and behavioral measures.</p> Results <p>Across all analysis approaches, everolimus did not significantly improve the composite neurocognitive score compared with placebo. However, several secondary outcomes showed consistent benefits. Fine motor function assessed by the Purdue Pegboard Test (left hand) demonstrated sustained improvement over placebo across models. Social functioning, assessed by the total score (higher values indicating better functioning) of the reverse-coded Social Responsiveness Scale, second edition, improved over time, with significant differences observed at 6&#xa0;months in the everolimus group. Several additional secondary endpoints showed consistent trends favoring everolimus.</p> Conclusion <p>Although the composite primary endpoint did not demonstrate significant improvement, sensitivity analyses identified potential benefits of everolimus in motor and social domains in individuals with PHTS. These results are consistent with the original trial findings and provide further support for investigating everolimus as a therapeutic option in this population.</p>

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Sensitivity Analysis of the Efficacy of Everolimus for Neurocognitive Symptoms in PTEN Hamartoma Tumor Syndrome

  • 期刊论文

  • 发表日期：

    2025年12月22日

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  • Yiran Liu,
  • Runqiu Wang,
  • Siddharth Srivastava,
  • Booil Jo,
  • Thomas Frazier,
  • Rajna Filip-Dhima,
  • Charis Eng,
  • Rabi Hanna,
  • Mustafa Sahin,
  • Antonio Y. Hardan,
  • Bo Zhang

摘要

Introduction

PTEN hamartoma tumor syndrome (PHTS) is a rare genetic disorder caused by germline pathogenic variants in the PTEN tumor suppressor gene. Everolimus, an oral mTORC1 inhibitor, is approved for the treatment of tuberous sclerosis complex-related tumors; however, evidence for its efficacy in PHTS remains limited. A recent randomized controlled trial (RCT) reported safety and efficacy findings, but the composite primary efficacy endpoint did not reach statistical significance.

Methods

We conducted a sensitivity analysis of this RCT to further evaluate the efficacy of everolimus in PHTS. Five statistical approaches were applied: analysis of covariance and four linear mixed-effects models. Outcomes included the composite neurocognitive score as a primary endpoint and multiple secondary neurocognitive and behavioral measures.

Results

Across all analysis approaches, everolimus did not significantly improve the composite neurocognitive score compared with placebo. However, several secondary outcomes showed consistent benefits. Fine motor function assessed by the Purdue Pegboard Test (left hand) demonstrated sustained improvement over placebo across models. Social functioning, assessed by the total score (higher values indicating better functioning) of the reverse-coded Social Responsiveness Scale, second edition, improved over time, with significant differences observed at 6 months in the everolimus group. Several additional secondary endpoints showed consistent trends favoring everolimus.

Conclusion

Although the composite primary endpoint did not demonstrate significant improvement, sensitivity analyses identified potential benefits of everolimus in motor and social domains in individuals with PHTS. These results are consistent with the original trial findings and provide further support for investigating everolimus as a therapeutic option in this population.