Stage Shift as an Endpoint in Cancer Screening Trials: Implications for Evaluating Multicancer Early Detection Tests

Area of Science:

• Oncology
• Biostatistics
• Cancer Screening Research

Background:

• Disease-specific mortality is a key endpoint in cancer screening trials.
• Multi-cancer early detection (MCED) tests necessitate faster trial processes.
• Stage shift is a proposed surrogate endpoint, but its predictive validity for mortality reduction is uncertain across various cancers.

Purpose of the Study:

• To develop a mathematical model linking stage shift to disease-specific mortality reduction.
• To evaluate the reliability of stage shift as a surrogate endpoint for MCED tests.
• To compare predicted mortality reduction with observed outcomes in existing cancer screening trials.

Main Methods:

• Mathematical formulation of stage shift's impact on mortality.
• Analysis of cancer- and stage-specific survival distributions.
• Comparison of model predictions with published data from breast, lung, ovarian, and prostate cancer screening trials.

Main Results:

• Expected mortality reduction varies significantly based on cancer type and survival distributions.
• Substantial stage shifts may yield minimal mortality improvement for certain cancers.
• The model's predictions did not consistently align with observed mortality reductions in published trials.

Conclusions:

• Stage shift is an unreliable predictor of mortality reduction across cancers targeted by MCED tests.
• The impact of stage shift on mortality benefit is highly cancer-dependent.
• Relying on stage shift for MCED test evaluation may be misleading due to inter-cancer variability.