Cancer of unknown primary (CUP) remains a complex diagnostic challenge, particularly when conventional pathology and imaging are unable to establish where a tumour originated. Uncertainty around the tissue of origin can complicate treatment selection and may be especially challenging in community oncology settings, where access to specialised diagnostic expertise and multidisciplinary services can vary. Advances in liquid biopsy and circulating cell-free DNA analysis are opening new possibilities for generating additional diagnostic insights from a blood sample.
BillionToOne’s Northstar Origin is designed to predict the tissue of origin in cancers of unknown primary by combining DNA methylation profiling with tissue-specific somatic variant signals. In a validation study, the test identified the correct tissue of origin within its top three predictions in 91 per cent of cases. The company says the test is intended to complement, rather than replace, conventional tissue-based testing, particularly when biopsy material is limited, poor quality or difficult to obtain.
Alongside this development, BillionToOne has expanded its Northstar Select liquid biopsy panel from 84 to 102 genes, adding biomarkers including MTAP deletion to broaden its ability to identify clinically relevant genomic alterations and support therapy selection.
In this interview with MedTech Spectrum, Allen Chen, MD, Vice President of Oncology Clinical Development and Medical Affairs, BillionToOne, discusses the clinical need for tissue-of-origin prediction, the role of Northstar Origin in complementing pathology and imaging, and how methylation and somatic variant signals contribute to its diagnostic performance. He also outlines the significance of the expanded Northstar Select panel and its potential to support oncologists in identifying actionable biomarkers and emerging targeted treatment options.
Northstar Origin is designed to predict tissue of origin for cancers of unknown primary (CUP) using circulating cell-free DNA. What unmet clinical need were you seeking to address with this test, and how does it complement existing pathology and imaging-based approaches?
Northstar Origin is designed to help close the diagnostic gap that can often exist between community oncologists and physicians at academic centers, wherein the former might not have the same access to multi-disciplinary tumor boards, advanced imaging, interventional services, and specialized pathology support.
In fact, up to 15 per cent of cancer diagnoses established within community oncology settings may be plagued by uncertainty. This inability to identify the primary tumor site leads to difficulty personalizing care, which can result in over-treatment or under-treatment, sometimes with adverse consequences. We believe the ability to equip community oncologists with a simple blood test that can further illuminate where the cancer originated from is incredibly valuable. For the patient, this can mean the difference between success and failure from both an efficacy and a quality-of-life standpoint
The validation study reported that Northstar Origin identified the correct tissue of origin in its top three predictions in 91 per cent of cases. What do these results mean for clinical decision-making, particularly in community oncology settings?
We consider these validation study results to be highly significant because, in many cases, identifying the tissue of origin can help dictate the ideal type of treatment for the patient and also provide important prognostic information. Moreover, there is an important emotional benefit for patients and providers to be able to obtain a complete picture of the disease, even if it does not change the particular therapy selection. Finally, Northstar Origin is the only liquid biopsy test that allows clinicians to rule out certain tissue types, potentially saving patients from having to undergo additional diagnostic work.
Could you explain how the combination of methylation profiling and tissue-specific somatic variant signals from Northstar Origin enables tissue-of-origin prediction from a single blood sample? What advantages does this approach offer over tissue-based testing?
The combination of methylation profiling and tissue-specific somatic variant signals is the recipe that allows Northstar Origin to provide such a high level of accuracy. The methylation profiling is the primary driver of the test, and it adds an independent signal obtained from the tissue-specific somatic variants detected by Northstar Select.
It is important to note that Northstar Origin is designed to complement, not replace, tissue-based testing approaches. However, this test enables a prediction when tissue is limited or of poor quality. For patients who have tumors located in anatomical locations that are challenging to access and/or place them at high risk for biopsy-related complications, Northstar Origin offers a highly practical alternative. As such, we believe providing community oncologists with an additional and convenient source of diagnostic information will be a practical benefit to them and to their patients.
The Northstar Select panel has also been expanded from 84 to 102 genes. What impact will this expanded panel have on therapy selection and the ability of oncologists to align patients with emerging targeted treatments?
The panel expansion of 18 new genes is noteworthy, and we are particularly excited at the inclusion of MTAP deletion, an emerging biomarker of increasing clinical relevance. While there are currently no FDA-approved treatments specifically designated for MTAP-deleted cancers, it is likely this will change in the future considering how many drugs are in the pipeline focused on MTAP inhibition. Even with this expansion, it is important to note that the Northstar Select panel was built with intention, focused on genes that matter most for therapy selection- to prioritize practicality and actionability. As demonstrated in our head-to-head study, Northstar Select has higher sensitivity for pathogenic and clinically actionable alterations while also having fewer null reports when compared to other common assays.
