Liquid biopsy technologies are revolutionizing our ability to detect cancer earlier and more precisely, and are poised to enable more personalized response-adapted cancer treatment. Here we analyzed plasma cell-free DNA … of patients with NF1-associated malignant peripheral nerve sheath tumor (MPNST) vs. its benign precursor lesion (plexiform neurofibroma) via low-pass whole genome sequencing. We performed cell-free DNA fragment size and copy number analysis and determined that patients with MPNST have shorter cell-free DNA fragment sizes and greater copy number alterations than patients with benign plexiform neurofibroma. These properties enabled us to accurately distinguish patients with MPNST from those harboring only the benign precursor lesion. We separately performed urine cell-free DNA analysis from patients with muscle-invasive bladder cancer, and identified molecular residual disease (MRD) after neoadjuvant chemotherapy but before surgery in a subset of patients. These patients had superior survival outcomes, and urine-derived MRD performed favorably compared to gold-standard pathological response assessment of the surgical specimen. The liquid biopsy technologies described herein have the potential to enable more personalized and precise management of patients and improve clinical outcomes through earlier cancer detection.