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We include here some brief notes on possible tests that an oncologist may ask you to have if the initial tests have failed to identify your cancer. For CUP you may have a large number of tests to allow the specialists to gain as much detail as possible from different perspectives. The oncologist will judge which tests are likely to be most useful based on the site(s) of the cancer spread and which are most appropriate on clinical grounds. Tests are likely to involve a blood sample to identify tumour markers and probably a biopsy where this is practical. (Throughout your treatment there will be regular blood samples to help monitor progress.) If possible, the doctors are likely to need an ‘adequate’ tissue sample – a biopsy- from a cancerous tumour; a Fine Needle Aspiration (FNA) will probably not be adequate. Biopsies are discussed on this page. A more detailed clinical description of the likely tests is shown here: Investigations likely for the MUO/CUP patient.
Shown below is an explanation of some of the tests that may be used. Do be careful to follow any special instructions you are given about fasting, for example, before tests to ensure accurate results.
Mammogram. A mammogram is an X-ray of the breasts.
Ultrasound. An Ultrasound uses sound waves to build up a picture of the inside of the body. They are completely painless. The ultrasound scanner has a microphone which gives off sound waves. The sound waves bounce off the organs inside your body, and are picked up again by the microphone as they bounce back. The microphone is linked to a computer. This turns the reflected sound waves into a picture.
Endoscopy. An endoscopy is a test that looks inside the hollow organs of the body such as the stomach using a long flexible tube that you swallow. It has a camera and light inside it which allows a specialist to see if there are any growths or other abnormal looking areas and to take samples (biopsies) if necessary. Most people are given a choice between having the test while they are awake with a numbing spray, or being sedated.
Colonoscopy. A flexible tube, as Endoscopy above, that allows exploration of the colon and rectum.
PSA – Prostate Specific Antigen- test. PSA is a protein produced by both normal and cancerous prostate cells. A high level of PSA can be a sign of cancer.
MRI – Magnetic Resonance Imaging. A powerful magnet is combined with a computer to produce images that can be interpreted by a radiologist. Sometimes a dye is used. There are no known side effects but the downside is that a patient may be in an enclosed scanner for some time (not suitable either for those with pacemakers). This may not be used if you have a pacemaker or other implants. The scanner can see down to about 2 millimetres.
CT / CAT– Computerised Axial Tomography. This uses low level x-rays with a computer to produce pictures of layers of the human body (like looking at a slice of bread without actually cutting into the loaf). Sometimes a drink or injection of dye is necessary as a contrast agent to allow the radiologist to see the images clearly. CT scans have been shown to be more useful than PET scans for CUP patients although some oncologists may want to combine the information from the CT Scan with a PET Scan.
PET – Positron Emission Tomography. This scan can show how body tissues are working, as well as what they look like. With a PET scan you first have an injection of a very small amount of a radioactive tracer. The amount of radiation is no more than you have during a normal X-ray and it only stays in the body for a few hours. The radioactive substance will travel to particular parts of your body. The most common substance is a radioactive version of glucose which shows-up cancers because they use glucose in a different way from normal tissue. It has not proved particularly useful in trying to identify a CUP primary.
Nuclear medicine. May be used for bone scans to identify cancer spread and the resulting images can be overlaid on CT or PET-CT or MRI. Radioactive isotopes are injected into the patient and their take-up (radioactive decay) is measured by a Gamma camera.
There are genomic tests available, which are becoming increasingly used, to try and identify the source of the cancer or the genetic mutations, in someone with metastatic cancer. Where appropriate, gene expression profiling, sometimes called molecular profiling, of cancerous tissue of unknown origin can sometimes be useful when integrated with the results of conventional pathology techniques (immunohistochemistry). There are different techniques employed by different companies, but in essence, this approach aims to identify the primary tumour by ‘profiling’ the genetic signature from a tissue sample (see biopsy in the section on Hospital diagnosis) and matching them to a database of known primaries. Targeted therapies based on identifying the treatable genetic mutations of a person’s cancer is another approach which is being trialed but the research evidence for CUP patients is presently  limited. This Roche factsheet on Cancer of Unknown Primary gives an idea of the personalised approach to diagnosis. If you want to have a better understanding of Genomics in general, here is an excellent, short, background presentation about Genomics in cancer from Roche.
The findings from such tests add additional information to the conventional pathology work-up. The results may help reduce a patient’s anxiety and may assist the cancer doctor to select an improved treatment plan. Such tests are not available on the NHS in the UK unless used on a CUP trial (but they can sometimes be covered by private health insurance although this will require a case to be made by an oncologist). We show information below about different companies and their products to help patients when discussing the options with their doctors.
Oncofocus® from Oncologica UK Ltd is a test that is performed on your initial tissue biopsy held in the hospital pathology department and enables your tumour to be linked to over 480 targeted therapies. No additional biopsies or blood tests are required. The test is entirely evidence-based and targeted therapies for patients with Cancer of Unknown Primary can be identified in at least 85% of cases (http://www.oncologica.com/report/). The linkages to targeted therapies are based on clinical evidence and not research data and arise out of the US NCI-MATCH initiative, the world’s largest precision oncology programme ever undertaken. The test can be requested by your oncologist, primary practitioner or by the patient themselves. Oncofocus® can be used early or at an advanced stage of the disease even if previous treatments such as chemotherapy have been prescribed. Oncofocus® is a dynamic test updated every 12 weeks so any new targeted therapies entering clinical trials are included and recent changes in drug approval status reported. The test performed by Oncologica UK Ltd (http://www.oncologica.com/) costs £1500 and includes the transfer and return of your sample by courier from the hospital and associated logistics. [information correct at Feb 17]
CancerType ID®. This test has been developed by bioTheranostics (part of the French bioMerieux group). It is priced at $US 3,600 and is purchased from bioTheranostics in the USA . This test, now in its second generation, measures the activity levels of 92 genes in a tumour and identifies 54 types of cancer – the company claims the broadest coverage so far among all molecular diagnostic tests for cancer of unknown or uncertain primary. A small amount of tumour tissue, usually from a previously taken biopsy is sent by your oncologist or pathologist to bioTheranostics’ laboratory in San Diego, California (US). The test result is sent back to your oncologist and pathologist usually within 15 days from receipt of the sample. The report contains the prediction of the most likely primary origin of the tumour and the “rule-outs”. (The company’s first generation technology was marketed by Agendia in Europe as CupPrint®). [updated 3/17]
The Rosetta Cancer Origin Test™ (formerly miRview®mets2) developed by Rosetta Genomicsis a tool which may help assist in accurately identifying the primary origin in difficult and challenging cases using microRNA technologies. The Cancer Origin Test is priced at $US 4,356. The test uses 64 microRNA biomarkers to identify 42 tumor origins. It aims to identify about 95% of all cancer origins with 90% sensitivity. Once the tissue sample has been tested in the CAP accredited, CLIA certified laboratory, a report is generated that may help the physician in determining the primary origin of your cancer to better guide treatment. In the majority of cases, the Cancer Origin Test returns a single tissue prediction. The ordering process is shown on the Rosetta Genomics website (which gives more information about the assay). [information correct at Feb 14]
Tissue of Origin ® from Cancer Genetics. The Test is based on microarray technology and assesses the expression profile of 2000-gene to aid in determining the primary site of metastatic cancer in FFPE samples. TOO® is Medicare-reimbursed and priced at USD 3250.00 and is the only tumour molecular diagnostics of its kind to be cleared by the United States Food and Drug Administration. It categorizes tumours into 15 of the most common tumour types (breast, non-small cell lung, pancreas, gastric, colorectal, liver, bladder, kidney, thyroid, non-Hodgkin’s lymphoma, melanoma, ovarian, sarcoma, testicular germ cell, and prostate). The categories on the Test Panel cover approximately 90% of all solid tumours. The Test has undergone extensive analytical and clinical validation, performance: 89% positive percent agreement (akin to sensitivity) and 99% negative percent agreement (akin to specificity). A recent study showed TOO® had a statistically significant improvement in accuracy of tumour classification over immunohistochemistry (IHC), especially in poorly differentiated carcinomas where TOO was 91% accurate versus 71% for IHC. A TOO® report with the most likely tissue or origin and the “ruled out” categories is provided two weeks from the date the sample is received in the laboratory. [Information correct at Apr 16]
Caris Molecular Intelligence is an evidence-guided oncology tumour profiling service developed by Caris Life Scienceswhich costs approximately £3,480. It builds a unique molecular “fingerprint” of your tumour by testing a biopsy sample for important cell components, often called ‘biomarkers’, which have been shown in clinical research to indicate whether specific cancer treatments are likely to be effective or not. This personalised “fingerprint” can help your doctor to identify which therapies have the best chance of working specifically for you and which should be avoided as they are less likely to work. It can also help to find therapies which may not have been thought of previously. Caris Molecular Intelligence is most commonly used in people with metastatic cancer who have already gone through all of the standard treatments for their cancer and those with paricularly fast growing or rare cancers such as CUP. Even if you have already received treatment for your cancer, you can still have the service performed. Caris Molecular Intelligence can only be ordered by your oncologist using the process shown on theCaris Life Sciences EU website. [information correct at Feb 14]
The FoundationOne test from Roche Foundation Medicine (RFM)is a comprehensive genomic profiling service that allows clinicians to match the genetic DNA make-up of cancer with the treatments or trials that could potentially provide the best outcome for a patient. The FoundationOne test – priced at £3000 – is designed to provide clinicians and patients with clinically relevant information which will help support treatment decisions and potentially identify opportunities for patients to enter a clinical trial. The test is validated to detect all classes of genomic alterations in more than 300 cancer related genes. In a retrospective study of 200 cancer of unknown primary patients, the RFM service was shown to identify clinically relevant genomic alterations in 85 percent of patients . For further information and the ordering process see www.foundationmedicine.co.uk [information correct @ Jan 2018]
Guardant360 was developed by Guardant Health. From a blood test, Guardant360 captures the DNA that is shed from a patient’s tumor. This provides a comprehensive overview of the cancer genomics from both the primary tumor and any metastatic sites. The Guardant360 report shows the patient’s cancer’s genomic alterations detected in the blood. Associated approved therapies and drugs still in clinical trials are listed where available. The patient’s physician will interpret the results to identify the best treatment option. Guardant360 examines 70+ clinically-relevant genes to identify genomic alterations within the cancer’s DNA while avoiding the complications and delays of a tissue biopsy. Some of these genomic alterations may respond well to specific drugs. Others make the cancer resistant to treatment. Knowing which alterations are within the cancer helps the patient’s doctor choose the best treatment. Guardant360 costs £2,490. For more information about Guardant360, please visit http://www.guardant360.com/ To get in touch with Guardant Health, please contact Client Services at [email protected] [information correct @ June 2019]
CUP Guide in Australia, New Zealand, Malaysia and Singapore offered by Healthscope/ Circadian Technologies Ltd. See Guide Fact Sheet for further details.
Canhelp®-Origin Assay is a molecular diagnostic assay developed by Canhelp Genomics Co., Ltd, a biomarker company in China focused on molecular diagnostics & personalized medicine in the field of oncology. The test is based on quantitative polymerase chain reaction (qPCR) technology and is validated with an overall accuracy of 90% for identifying the primary site of metastatic tumor, especially in poorly differentiated carcinoma. Their aim is to improve patient care by providing supporting evidence that would help to resolve diagnostic uncertainty which increases opportunity to more actionable plans. The qPCR assay measures the expression pattern of 90 specific markers of tissue samples and classifies 21 major tumor types origin from adrenal gland, brain, breast, cervix, colorectum, endometrium, gastro-esophagus, head and neck, kidney, liver, lung, lymphatic tissues, skin, mesothelial tissues, neuroendocrine tissues, ovary, pancreas, prostate, connective tissue, testis, thyroid, and urinary tract, covering more than 95% of solid tumor by incidence. Recent studies showed Canhelp®-Origin Assay an excellent accuracy (up to 95%), for classifying metastatic triple-negative breast cancer and identifying primary site of metastatic brain tumors. A Phase III study (ClinicalTrials.gov Identifier: NCT03278600) is ongoing to evaluate the clinical utility of Canhelp®-Origin Assay in predicting primary site and directing therapy in patients with cancer of unknown primary. The requirement is for FFPE tissue sections which for ease of long-term preservation and shipping. Generally, your physician will receive the report within five working days from the date we receive your specimen in our laboratory. A Canhelp®-Origin report is automatically generated with one single prediction of the most likely primary site of the tumor and the “rule-out” tumor types. For more information and the ordering process see http://canhelpdx.com/products. [Information correct @ Jul 2018]