CDKN1A (p21) Level as a Quantitative Predictor of CDK4/6 Inhibitor Benefit Magnitude in Luminal A Breast Cancer: A Geometry-Derived Biomarker Hypothesis with Proposed Validation in MONARCH, PALOMA, and MONALEESA Trial Datasets

Waddington attractor geometry applied to 19,542 single breast cancer cells (GSE176078) identifies CDKN1A (p21) loss as the primary lock mechanism in Luminal A breast cancer. This document advances a specific, falsifiable hypothesis: that baseline quantitative CDKN1A expression level predicts the magnitude of CDK4/6 inhibitor benefit in Luminal A patients — not merely binary sensitivity/resistance — producing a continuous monotonic gradient across expression quartiles. This is distinguished from the established binary resistance literature (complete CDKN1A loss causes CDK2 bypass) by its focus on the continuous quantitative relationship across the full expression range and its restriction to the PAM50 Luminal A subtype, where the CDK gate is the primary attractor-maintaining mechanism. The hypothesis is testable in existing MONARCH, PALOMA, and MONALEESA trial biobank datasets requiring no new patient recruitment. Predicted: Q4 CDKN1A expression derives largest PFS benefit from CDK4/6i; Q1 derives smallest; gradient is monotonic; and the gradient is steeper in LumA than LumB. Part of the OrganismCore BRCA Cross-Subtype Analysis (Document BRCA-S8h, 2026-03-05), which derived 30 pre-specified findings from attractor geometry before literature review. CS-LIT-14 carries NOVEL verdict — no direct published equivalent for the quantitative continuous-predictor formulation was identified. Verdict locked before literature check.