Fig. 5: Companion Diagnostic using AACS.
a Cyclin-dependent kinase inhibitors (CDKi) mechanisms of action41,42. Canonically, CDKi’s (including Palbociclib, Ribociclib, Abemaciclib, and assets in development) inhibit cancer cell proliferation through the cell cycle by inhibiting CDK4/6 binding to cyclin D1. This limits phosphorylation of Rb, needed for activation of E2F-associated cell cycle control genes. In addition, CDKi’s have recently been shown to suppress production of Regulatory T cells. These cells create immune tolerance and are associated with decreasing immunosurveillance during cancer metastasis. In this way, CDKi’s increase immunosurveillance. b Clinical characteristics of N = 33 Hormone Receptor positive, HER2 negative metastatic breast cancer patients who were recommended for CDKi’s according to current treatment guidelines. Patients were prescribed CDKi’s as per standard of care, but before starting treatment, their blood sample was collected and analysed using AACS. Their response was evaluated on a 6-month CT scan according to RECIST criteria. Non-responding patients had cancer progression by 6 months. c Pre-treatment AACS measured for CDKi-prescribed patients plotted in N-dimensional space, coloured according to subsequently assessed response at 6 months. 3/5 dimensions shown for visual clarity. The 3 presented features were selected using an ANOVA feature ranking in Supplementary Fig. 13. d A linear SVM classifier was trained and validated using held-back, unseen validation data. True positive rate (sensitivity) and false negative rate (1 - specificity) on the validation data. This metric evaluates what percentage of true responders and non-responders are identified using the classifier. e Positive predictive value, and false discovery rate for the classifier described in (d). This metric evaluates when a prediction is made by the classifier, what percentage of the time is it correct. f Average normalised SHAP values with standard errors for a linear Support Vector Machine (SVM) model trained and validated on the N = 33 datapoints using 5X cross validation. g Among N = 33 CDKi-treated patients, 10 had progressed by the time of writing. Their plasma sample was measured again when progression was identified, and the AACS results compared in N-dimensional space for before the started CDKi treatment versus at the timepoints where their progression was identified.
