Tothill RW, Li J, Mileshkin L, Doig K, Siganakis T, Cowin P., ... Bowtell DD. Massively-parallel sequencing assists the diagnosis and guided treatment of cancers of unknown primary
Journal of Pathology 231(4):413-23. https://doi.org/10.1002/path.4251
Advanced DNA sequencing techniques can help identify the origin of CUP and guide more targeted treatments. In summary, this research highlights the transformative potential of advanced DNA sequencing in managing CUP, offering patients more personalised and effective treatment options.
Researchers analysed tumour samples from 16 patients with CUP using a method called massively-parallel sequencing, which examines the DNA of 701 genes known to be important in cancer. This approach revealed:
· Identification of Cancer Origin: Sequencing helped determine the likely origin of the cancer in several cases, providing crucial information for treatment planning.
· Potential Treatment Targets: The analysis identified specific genetic alterations that could be targeted with existing or experimental therapies.
· Improved Diagnostic Accuracy: The study highlighted the limitations of traditional diagnostic methods and the added value of advanced sequencing in challenging cases.
For patients with CUP, this study offers several benefits:
· Clearer Diagnosis: Advanced sequencing can provide a more accurate identification of the cancer's origin, leading to more informed treatment decision.
· Personalised Treatment Options: Identifying specific genetic alterations allows for the consideration of targeted therapies, which may be more effective than standard treatments.
· Access to Clinical Trials: Patients may become eligible for clinical trials testing new therapies tailored to their genetic profile.
CUP is a complex condition where the cancer's origin is unknown, making treatment challenging. This study underscores the potential of advanced DNA sequencing to:
· Enhance Diagnostic Accuracy: Providing clearer insights into the cancer's origin can lead to more precise diagnoses.
· Guide Targeted Therapies: Understanding genetic alterations enables the use of treatments tailored to the individual's cancer profile.
· Improve Patient Outcomes: By moving beyond traditional treatments, patients may
experience better responses and outcomes.
Posner A, Prall OWJ, Sivakumaran T, Etemadamoghadam D, Thio N, Pattison A., ...Tothill RW.
A comparison of DNA sequencing and gene-expression profiling to assist tissue of origin diagnosis in cancer of unknown primary Journal of Pathology PMID: 36287571. https://doi.org/10.1002/path.6022
Advanced DNA and RNA tests can help identify the origin of cancers of CUP in about one-third of cases, providing more targeted treatment options.
This study compared two advanced tests - DNA sequencing and gene expression profiling (GEP) - to determine the origin of CUP in215 patients. Key findings include:
Overall, DNA sequencing was more effective than GEP in providing diagnostic clarity.
For patients with CUP, these advanced tests offer:
CUP is challenging to treat due to its unclear origin. This study highlights that:
In summary, advanced DNA and RNA tests play a crucial role in diagnosing and treating CUP, offering patients more precise and effective care options In Brief
Advanced DNA and RNA tests can help identify the origin of cancers of CUP in about one-third of cases, providing more targeted treatment options.
Kato S, Krishnamurthy N, Banks KC, De P, Williams K, Williams C., ... Kurzrock R. Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary
©2017 American Association for Cancer Research. 2017 Aug 15;77(16):4238-4246. https://doi.org/10.1158/0008-5472.can-17-0628
Using a simple blood test called a liquid biopsy,researchers found that most patients with CUP have unique, drug-targetable genetic changes, offering new hope for tailored treatment.
In this study, researchers analysed blood samples (circulating tumour DNA or ctDNA) from 442 people diagnosed with CUP. They used advanced genetic testing to look at 54–70 cancer-related genes. The results showed:
· 80% of patients had detectable ctDNA alterations.
· 66% (290 out of 442) had at least one clear,actionable genetic change (excluding uncertain variants).
· Among those with characterized alterations,nearly 99.7% had at least one genetic change that could, in theory, be targeted with existing or investigational treatments.
This study demonstrates that:
· A non-invasive blood test can detect genetic changes in most people with CUP.
· Almost every patient with such changes - 99.7% -could potentially benefit from a targeted therapy or immunotherapy, based on their specific alterations.
· These findings support the use of liquid biopsies in clinical trials and future treatment pathways tailored to a person’s unique cancer biology.
CUP is traditionally hard to treat because doctors don’t know where the cancer started, so treatment is often limited to standard chemotherapy. This study shows that:
· Most CUP patients have actionable genetic changes that could guide more precise, personalised treatments.
· A simple blood test (liquid biopsy) makes testing easier - especially when tissue samples are limited or hard to obtain.
· Liquid biopsies may open a path toward more effective, targeted care for many patients with CUP.
Ross JS, Sokol ES, Moch H, Mileshkin L, Baciarello G, Losa F., ...Krämer A. Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Origin: Retrospective Molecular Classification Considering the CUPISCO Study Design. Oncologist. 26(3) https://doi.org/10.1002/onco.13597
In a recent study reviewing genomic data from people with CUP, one-third of patients would have been eligible for personalized treatment in the ongoing CUPISCO trial - highlighting how genetic profiling may open new therapeutic avenues.
CUP is traditionally treated with broad chemotherapy due to unclear tumor origins and limited treatment options. This study demonstrates that genomic profiling can meaningfully broaden access to targeted therapies or immunotherapy, offering hope for more effective care in a significant subset of patients. It supports the growing move towards personalised cancer treatment even when the primary site isn't identified.
Arielle van Mourik, Gina Tonkin-Hill, John O'Farrell, Shohei Waller, Lavinia Tan, Richard W Tothill., ... Linda Mileshkin. Six-year experience of Australia’s first dedicated CUP clinic British Journal of Cancer 129:301–308. https://doi.org/10.1038/s41416-023-02254-6
Australia’s first dedicated Cancer of Unknown Primary (CUP) clinic is helping patients by providing clearer diagnoses, better access to DNA testing, and more personalised treatments. The study shows that patients seen in the clinic had improved options, including targeted therapies and clinical trials, leading to better outcomes and greater hope.
This study looked at the first six years of Australia’s CUP clinic at Peter MacCallum Cancer Centre. CUP is a rare diagnosis where cancer has spread, but doctors cannot find where it started. This makes treatment decisions more difficult.
The clinic supported patients by:
· Confirming whether they truly had CUP, another cancer, or a non-cancer condition.
· Completing important tests, including DNA (genomic) testing.
· Linking patients to clinical trials and newer treatments.
Patients benefited through:
· Clearer diagnosis, avoiding unnecessary or incorrect treatments.
· Better access to DNA testing, giving treatment clues in about one-third of patients.
· More personalised treatment, such as targeted therapies or immunotherapy, which were linked to longer survival compared to standard chemotherapy.
· Access to clinical trials, offering promising treatments not otherwise available.
For people with CUP, having a dedicated clinic means care is more focused, personalised, and hopeful. By combining thorough diagnosis, modern DNA testing, and access to new treatments, the CUP clinic improves the chances of finding effective therapies and supporting patients through a challenging diagnosis.
Richard J. Rebello, Atara Posner, Ruining Dong, Owen W. J. Prall, Tharani Sivakumaran, Camilla B.Mitchell., ... Richard W. Tothill. Whole Genome Sequencing to improve the tissue of origin diagnosis and treatment options for patients with Cancer of Unknown Primary
Nature Communications, 16, Article 4422 . https://doi.org/10.1038/s41467-025-59661-x
A new study shows that whole-genome and transcriptome sequencing (WGTS) can give people with CUP clearer answers about where their cancer began and open up more treatment options, including access to clinical trials. This advanced testing offers new hope by replacing uncertainty with more personalised choices.
Researchers studied 72 CUP patients, comparing WGTS with standard genetic panel tests. They found WGTS:
· Detected all the same changes as panel tests plus more, adding useful information.
· Predicted where the cancer started in 71% of patients (vs. 34% with panel tests).
· Identified potential treatment targets in 74% of patients, increasing therapy and trial options.
WGTS can:
· Provide clearer answers about the cancer’s origin.
· Guide more personalised treatments such as targeted therapy or immunotherapy.
· Improve access to clinical trials.
· Sometimes use a blood test when tissue samples are limited.
CUP is challenging because treatment is less precise without knowing where the cancer began. WGTS offers a powerful new tool that:
· Improves diagnostic certainty
· Expands treatment options
· Brings greater hope to people facing CUP.
Discover how whole genome sequencing on diagnostic biopsies and cell-free DNA improves diagnosis when it comes to cancers of unknown primary (CUP). Clinical background to case studies and curated findings of the case vignettes will be presented. Case vignettes will be presented to demonstrate insights gained from employing these techniques, while also describing challenges in significantly influencing patient outcomes.
Precision Oncology Forum: Genomics to solve cancers of unknown primary
When: 21 Feb 2025, 2.45–4.00PM
Where: Lecture Theatre C, Level 7, VCCC Building Peter MacCallum Cancer Centre, 305 Grattan Street, Parkville (also via Microsoft Teams)
More VCCC Upcoming events here
Here are the links to other clinician resources. You may also use the quick links on the right side of the page to navigate.
Most people are diagnosed with cancer of unknown primary (CUP) after they have symptoms or become unwell. Some people may be diagnosed during tests for another health condition. When cancer is suspected, you might be referred for tests or to a specialist.
The treatment you have depends on a number of things, including where the cancer is and your general health. A team of doctors and other professionals discuss the best treatment and care for you. The main treatment for Cancer of Unknown Primary is cancer drugs, most commonly chemotherapy. You may also have radiotherapy to help to control your symptoms and hormone therapy.
