Liquid Biopsy Test Predicts Tissue of Origin in Cancer of Unknown Primary

Cancers of unknown primary and other uncertain tumor presentations can complicate therapy selection, especially in community oncology settings where subspecialty pathology resources may be limited. Tissue-based testing may be constrained by sample quantity or quality, while additional procedures or blood draws can delay care. A newly launched blood test now predicts tissue of origin from circulating cell-free DNA in a single draw, supporting clinical decision-making in these challenging cases.

BillionToOne has introduced Northstar Origin, a physician-ordered add-on to the Northstar Select comprehensive genomic profiling liquid biopsy. The assay predicts tissue of origin directly from circulating cell-free DNA (cfDNA) for patients with cancer of unknown primary (CUP) or uncertain cancer diagnosis, reducing the need for additional tissue or separate blood draws. It is ordered concurrently with Northstar Select and is intended to complement, not replace, pathology and the broader clinical picture.

Northstar Origin combines cfDNA methylation profiling with the same single-molecule precision used in Northstar Response and incorporates an independent signal from tissue‑specific somatic variants detected by Northstar Select. A supervised classifier trained on 6,025 blood samples produces ranked tissue‑of‑origin predictions. Because it leverages the same specimen, it functions as an add‑on to the therapy‑selection liquid biopsy.

In an independent validation cohort of 1,578 patients, Northstar Origin identified the correct tissue of origin as the top prediction in 87% of cases and within the top three predictions in 91% of cases. BillionToOne reports that the classifier was developed using 6,025 previously submitted blood samples from patients with advanced cancer. Prospective studies are planned to expand the model to additional tumor types and further evaluate clinical utility.

Northstar Select has also expanded from 84 to 102 genes. The update adds 18 genes, including MTAP deletion, a copy number loss biomarker that is typically difficult for liquid biopsy assays to detect. In a prospective head-to-head study of 182 patients across more than 17 solid tumor types, Northstar Select detected 51% more clinically actionable or pathogenic single nucleotide variant (SNV)/indels and 109% more copy number variants (CNVs) than aggregated comparators, with 45% fewer null reports..

“Community oncologists are often asked to make the same complex diagnostic decisions as physicians at academic centers, without the same access to tumor boards or subspecialty pathology support. Northstar Origin is designed to help close that gap. It is a highly accurate, easy-to-use diagnostic aid that can be added to the liquid biopsy a patient already receives for therapy selection. Northstar Origin can extend more equitable access to care,” said Ethan Dmitrovsky, MD, Chief Medical Officer, Oncology at BillionToOne.