Blood test identifies hidden cancer origins in patients with unknown primary tumors

Clues in the Blood: Solving the Mystery of Cancer of Unknown Origin

A blood test capable of scanning multiple cancer sites simultaneously is transforming how doctors tackle one of oncology's most lethal diagnostic puzzles: cancers whose starting point cannot be found through conventional imaging and tissue biopsies.

When the Tumor's Origin Remains Hidden

Cancer of Unknown Primary (CUP) confronts clinicians with a paradox, patients present with metastatic tumors, yet standard procedures fail to identify where the cancer originally began. The condition affects 3 to 5 percent of all cancer patients, making it far more prevalent than commonly understood. CUP ranks as the fourth worldwide leading cause of cancer death, with patients facing a median survival of just 8 to 12 months. The prognosis reflects both the aggressive nature of these cancers and the challenge of selecting optimal treatment without knowing the primary site.

Medical imaging and tissue biopsies, the traditional diagnostic workhorses, often prove insufficient in these cases. Doctors find themselves in the position of a detective who discovers clear clues at a crime scene but cannot determine where the crime actually took place.

Blood-Based Genomic Profiling Changes the Equation

Liquid biopsy, comprehensive genomic profiling (CGP) performed on a blood sample, offers a fundamentally different diagnostic pathway. Unlike tissue sampling, which requires invasive procedures and sufficient viable tumor material, blood-based CGP needs only a simple blood draw. The technology detects circulating tumor DNA and analyzes the genetic signatures of cancer cells traveling in the bloodstream.

Speed represents a critical advantage. Blood-based CGP results are often available within two weeks, enabling rapid identification of actionable genetic targets and expanding treatment options. This turnaround time stands in stark contrast to the weeks or months that conventional diagnostic pathways can consume, particularly when initial tissue samples prove inadequate.

The genomic panel examines multiple genes simultaneously, revealing mutations that guide therapy selection. Recent advances have extended CGP by adding RNA analysis, which detects gene fusions, abnormal joining of two genes, that serve as highly specific actionable treatment targets. These fusions appear particularly in lung cancer, some pancreatic cancers, kidney tumors, and sarcomas.

A Mother's Diagnostic Deadlock Broken

Professor El Helali describes a case that demonstrates the clinical impact of this technology. A patient in her 50s with school-age children presented with widespread liver and lymph node involvement. Repeated tissue biopsies showed only differentiated adenocarcinoma (gland cell cancer), and extensive immunohistochemistry, tissue staining and imaging tests, combined with standard imaging failed to identify the primary site. The tumor was metastatic, not a primary liver cancer, and more than two months of diagnostic work had already elapsed.

The patient could not tolerate further tissue sampling, and insufficient tissue remained for additional testing. The medical team decided to perform a liquid biopsy for comprehensive genomic profiling and prioritized the test to avoid further delay.

The expedited blood-based CGP returned in approximately ten days and revealed a BRAF mutation. This genetic clue prompted the molecular tumor board, comprising oncologists, pathologists, biologists, data scientists, pharmacists, and surgeons, to initiate a dual targeted therapy. The genomic panel also identified additional mutations to guide alternative treatment options if the initial therapy failed.

Despite an expected median survival of roughly a few months for CUP, the patient remained alive at one and a half years after diagnosis and had recently gone on holiday abroad. The case illustrates how molecular information from blood can break diagnostic stalemates and enable treatment when conventional approaches reach their limits.

Validating Liquid Biopsy in Lung Cancer

The clinical benefits of liquid genomic profiling extend beyond CUP. Recently, the United Kingdom's National Health Service made headlines by incorporating liquid-based genomic profiling into routine diagnostics to fast-track targeted therapies for patients with non-small cell lung cancer (NSCLC).

In Hong Kong, a territory-wide, multicenter prospective CGP project was conducted across the seven hospital authority clusters for NSCLC, run by the University of Hong Kong and the Hospital Authority and funded by the Innovation and Technology Commission (ITC)-Hong Kong under the Partnership Research Programme scheme. In this local study of 878 patients, CGP in blood and tissue was interchangeable, but only if enough cancer cells were detected in the blood.

The research revealed an additional capability: blood can detect emerging gene changes that could alter how clinicians manage a patient's tumor. This real-time monitoring potential makes liquid biopsy not just a diagnostic tool but a way to track cancer evolution and treatment resistance as it develops.

The Access Challenge

Blood-based CGP is typically self-financed, though some insurers cover genomic testing, especially when professional guidelines support it, such as those issued by the European Society of Medical Oncology. In Hong Kong, public hospitals currently lack the infrastructure for a liquid-first diagnostic approach for CUP. Clinicians often consider patients' financial circumstances before recommending blood-based CGP.

Professor El Helali outlines an ideal diagnostic sequence: many doctors would start with a liquid biopsy because it is minimally invasive and quickly provides broad molecular information; if the blood test finds nothing actionable, the next step would be tissue biopsy for further testing. "Introducing liquid biopsy earlier could allow patients to begin treatment much sooner while diagnostic decisions and discussions continue," Professor El Helali says.

"Early use of liquid biopsy can shorten delays and help initiate therapy without waiting for every conventional test to be completed, which may translate into longer survival and better quality of life," Professor El Helali explains. This liquid-first strategy challenges the traditional diagnostic hierarchy that places tissue biopsy at the center, proposing instead that blood testing should be the initial molecular investigation when clinically appropriate.

The shift toward liquid-first diagnostics requires infrastructure investment, reimbursement policy changes, and clinical guideline updates. Yet the logic is compelling: a test that is faster, less invasive, and capable of providing actionable information without requiring adequate tumor tissue addresses several bottlenecks in the current cancer diagnostic pathway.

Why This Matters Now

CUP patients face a compressed timeline, the median survival of 8 to 12 months means that diagnostic delays directly reduce the window for effective treatment. Blood-based CGP collapses the time from presentation to molecular diagnosis, potentially adding weeks or months of treatment opportunity.

For conditions where the primary site cannot be determined through standard means, liquid biopsy provides a way forward when tissue-based approaches reach their limits. The technology detects the molecular fingerprints of cancer regardless of where the tumor began, shifting the diagnostic question from "where did this start?" to "what mutations drive this cancer and which drugs can target them?".

The approach also addresses practical barriers: patients who cannot tolerate invasive procedures, cases where tissue samples are insufficient or inaccessible, and situations where repeat biopsies would cause unacceptable delays. Blood can be drawn repeatedly without the complications of surgical sampling, enabling both initial diagnosis and ongoing monitoring.

As healthcare systems in the United Kingdom and research initiatives in Hong Kong demonstrate, liquid genomic profiling is moving from niche application to mainstream cancer care. The challenge now is ensuring equitable access so that financial circumstances do not determine which patients can benefit from faster, more precise molecular diagnosis.

The content of this article has been produced by an advertising partner.

Source: South China Morning Post