Classification is one of the core problems in Computer-Aided Diagnosis (CAD), targeting for early cancer detection using 3D medical imaging interpretation. High detection sensitivity with desirably low false positive (FP) rate is critical for a CAD system to be accepted as a valuable or even indispensable tool in radiologists' workflow. Given various spurious imagery noises which cause observation uncertainties, this remains a very challenging task. In this paper, we propose a novel, two-tiered coarse-to-fine (CTF) classification cascade framework to tackle this problem. We first obtain classification-critical data samples (e.g., samples on the decision boundary) extracted from the holistic data distributions using a robust parametric model (e.g., \cite{Raykar08}); then we build a graph-embedding based nonparametric classifier on sampled data, which can more accurately preserve or formulate the complex classification boundary. These two steps can also be considered as effective "sample pruning" and "feature pursuing + $k$NN/template matching", respectively. Our approach is validated comprehensively in colorectal polyp detection and lung nodule detection CAD systems, as the top two deadly cancers, using hospital scale, multi-site clinical datasets. The results show that our method achieves overall better classification/detection performance than existing state-of-the-art algorithms using single-layer classifiers, such as the support vector machine variants \cite{Wang08}, boosting \cite{Slabaugh10}, logistic regression \cite{Ravesteijn10}, relevance vector machine \cite{Raykar08}, $k$-nearest neighbor \cite{Murphy09} or spectral projections on graph \cite{Cai08}.