MOLECULAR EXAMINATIONS
Carcinoma of Unknown Primary (CUP) and Tumor Agnostic Biomarkers
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About Cancer of Unknown Primary and Tumor Agnostic Biomarkers
In about 2% of people diagnosed with cancer, the cancer is found in one area of the body, but routine tests cannot help doctors find where the cancer started (its primary site). This cancer is called Carcinoma of Uncertain Primary Site (CUP).
This may be due to the fact that:
The primary tumor is still very small, so it is difficult to detect.
The person’s body has caused the primary tumor to shrink or disappear.
The primary tumor was removed during a previous surgery for another condition, such as a surgery to remove a woman’s uterus, known as a hysterectomy.
In any case, consult your clinician.
Tumor agnostic biomarkers (or tumor-independent biomarkers or agnostic biomarkers) are molecular alterations in a tumor, such as mutations or other gene disorders, that are used to select targeted therapies, regardless of the origin (organ) or histological type of the cancer. This approach, also known as precision medicine, focuses on finding specific gene mutations in patients’ tumors, allowing the application of therapies that target these alterations, leading to more effective treatments for the appropriate patients. Molecular tests in cancer of unknown primary can also be used as tumor agnostic approaches.
Because CUP can occur anywhere in the body, the first symptoms can vary greatly from person to person. Usually, symptoms are related to the areas of the body where the cancer is located. Common sites of cancer include the liver, lungs, bones, or lymph nodes. Symptoms may include any of the following. Sometimes, people with CUP have no symptoms at all. Or, a symptom may be caused by a different medical condition rather than cancer.
Long-term pain in a specific area of the body
Loss of appetite
Unexplained weight loss
Persistent cough or hoarseness
Obesity, swelling or the presence of a tumor mass in any part of the body
Changes in bowel or bladder habits
Unusual bleeding
Recurrent fever or night sweats
If you are concerned about any changes you may be experiencing, contact your doctor.
When a person is diagnosed with cancer, the signs and symptoms of a person often help the doctor plan effective treatment, even when the primary focus cannot be found.
The relief of symptoms is also an important part of care and treatment of cancer. This can be called palliative care or supportive care. It often begins soon after diagnosis and continues throughout treatment.
CUP is detected, after spreading to another part of the body from where it started, a phenomenon called metastasis. Therefore, doctors use many tests to try and find out where cancer started in the body, which means to find the primary site of cancer origin. Some tests can also determine which treatments may be most effective.
This section describes the CUP diagnostic tests used to find the primary focus. You should know that not all the tests listed below are always selected for each person. Your doctor will consider the following factors when choosing a diagnostic test:
Depending on the type of cancer suspected
Your symptoms
Your age and general health
The results of previous medical examinations
In addition to the physical examination, the following tests can be used to diagnose CUP
Biopsy
It is the removal of a small amount of tissue for examination under a microscope. Only histological examination of a biopsy specimen by a pathologist can make a clear diagnosis. The pathologist is the doctor who specializes in interpreting laboratory tests and evaluating cells, tissues, and organs for the definite diagnosis of diseases. Careful evaluation and control of the tumor tissue removed during a biopsy can sometimes provide information about the location of the primary tumor site.
Evaluation, estimation, and interpretation of the pathologist.
The pathologist makes the diagnosis of cancer by testing the tumor sample which was collected during a biopsy. The pathologist can sometimes predict the primary site of the tumor based on the appearance of cancer cells under the microscope or based on the results of special techniques known as immunohistochemistry (IHC), which are part of a comprehensive histological examination. The results of the histological examination provide important, crucial information about cancer and help clinicians schedule additional tests and trials.
When it is not possible to predict the primary site of cancer, a molecular test can be performed to reveal gene expression profiling. For this test, the Pathologist uses the tissue sample from the specimen collected during the biopsy. The results of this molecular test are often helpful in choosing the most appropriate treatment.
Assessment by an Oncologist
Before CUP is diagnosed; several tests must be performed to find the primary site of the tumor. This is called a clinical evaluation and is usually performed by an oncologist. The oncologist is the doctor who specializes in treating people with cancer.
The following diagnostic tests can be included in an evaluation:
• Check cancerous indexes in blood and urine (e.g. PSA, CEA, etc.)
• x-ray
• CT scan or MRI
• PET scan
• Endoscopy
• Mammography
Consult your oncologist for the best personalization for you.
Most people with CUP have 1 of these 4 types of tumors :
1) Adenocarcinoma
Almost 60% of people with CUP have adenocarcinoma. Adenocarcinoma can develop in the glandular tissue of most internal organs, including the lungs, stomach, pancreas, colon, ovaries, and breast. Because of this, it is extremely difficult for the Pathologist to indicate the primary site of adenocarcinoma.
Additional diagnostic tests on biopsy specimens, called Immunohistochemistry (IHC), can predict the primary site of a tumor in about 30% to 40% of cases.
The gene expression profiling in biopsy specimens may be used to predict the primary site of cancer if by Immunohistochemistry (IHC) this has not been feasible.
2) Low differentiated carcinomas
About 20% to 30% of people with CUP have carcinomas of low differentiation. The Pathologist also performs tests on biopsy specimens of these tumors (Immunohistochemistry IHC), because many such cancers can be treated. Similarly, gene expression profiling may help predict the type of tumor in the primary site, which is useful in selecting treatment scenarios.
If this test shows that the cancer is lymphoma, genital cancer, or neuroendocrine carcinoma, then this often means that effective treatments are available.
3) Squamous cell carcinoma
About 5% to 10% of people with CUP have squamous cell carcinoma. If squamous cell carcinoma is found in the lymph nodes of the neck, the primary site of the cancer is often located in the head and neck area. If it is found in the inguinal lymph nodes in the groin, the primary site is often located in the vulva, vagina, cervix, anus, or bladder.
4) Neuroendocrine carcinoma
About 1% to 5% of people with CUP have neuroendocrine carcinoma. The pathologist makes the diagnosis of this cancer more often with the method of Immunohistochemistry (IHC). Some of these tumors are aggressive and develop rapidly, but combined chemotherapy may be effective. Others are very slow-growing and people sometimes live for several years, even without treatment.
Doctors are working to learn more about CUP, how to prevent cancer, how to better treat CUP, and how to take the best care of people diagnosed with the disease.
Consult your doctor about the best diagnostic and treatment options for you.
By using the tumor’s molecular profile to diagnose the primary site of cancer.
Different tissues in the body create different proteins, depending on the genes that are active. This is called gene expression. For example, genes expressed by healthy lung cells are different from those expressed by healthy colorectal cells. When cancer develops in these organs, it usually shows the same pattern of gene expression as the organ (lung, large intestine).
Today it is possible to analyze a tumor’s specimen from a biopsy to understand which genes are expressed. This can predict the location of cancer, which means to predict its primary site.
Personalized treatment based on the molecular profile of gene expression of the tumor replaces empirical chemotherapy as the standard treatment for patients with CUP, who are not part of any of these subgroups (see CUP Types). Ongoing clinical trials are examining the results of the selected treatment based on the molecular profile of the gene expression of the tumor, in order to better determine its role in the CUP treatment.
Targeted treatment.
Targeted treatment is addressed to specific molecular abnormalities within the cancer cell or surrounding environment and through the tumor. These abnormalities include gene mutations in the tumor and abnormal activity of various signaling proteins in the tumor.
Some targeted therapies are approved by the FDA as specific cancers, either as monotherapy or in combination with chemotherapy. Examples of these targeted therapies include:
the target HER2 therapy for breast cancer with HER2 positivity
the BRAF inhibitor for melanoma with BRAF mutation
the EGFR inhibitors for non-small cell lung cancer that exhibits a mutation at the EGFR gene.
However, no specific targeted therapies have been approved for the treatment of CUP particularly, and targeted drugs approved for other cancers have not been tested for CUP.
Because CUP covers many types of tumors, some patients are more likely to benefit from targeted treatments that have already been shown to be successful in treating specific types of tumors. For example, HER2- targeted therapies, which is a molecular mutation found in about 1 in 5 breast cancers, seem to have dramatically improved treatment outcomes in these patients.
Could a patient with CUP who is predicted to have breast cancer have a molecular profile of gene expression with a mutation in HER2? If so, could the treatment targeting HER2 mutation benefit this patient? The answer to both questions is likely to be affirmative.
A recent study found that the incidence of potentially treatable molecular abnormalities (using targeted therapies that have already been approved for other cancers) is about 25% in CUP. In ongoing clinical trials, people with CUP whose tumors have specific molecular abnormalities are treated with drugs that target the abnormality. It is likely that these clinical trials will identify additional effective treatment options for specific groups of patients.
Immunotherapy.
In recent years, new drugs that activate the immune system to fight cancer (such as anti-PD-1 and anti-PD-L1 receptor drugs) have been used to treat various types of cancer, such as lung cancer, kidney cancer, head/neck cancer, and some breast and colon cancers.
Since most of these cancers are represented in the population as cancers of unknown primary site (CUP), scientific evidence suggests that it makes sense to believe that some patients with CUP could also benefit from immunotherapy.
Recently, other molecular prognostic factors for response to immunotherapy have been identified. Patients whose tumors have these prognostic factors (including high microsatellite instability MSI or high mutational tumor’s load – TMB) are likely to respond to immunotherapy, regardless of their tumor type. Both of these molecular abnormalities occur in CUP.
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Frequently Asked Questions (FAQ)
In any case of cancer of unknown primary focus, the findings of a molecular test will help in choosing the most appropriate therapeutic alternative. Possible discovery of gene mutations (determination of the molecular profile of the tumor) will help the Oncologist choose the best possible treatment (targeted therapy or immunotherapy versus chemotherapy, or combinations of the above).
The tests are performed on the surgical specimen (paraffin cubes) or the biopsy material (paraffin cube) from which your histological examination was performed or on the aspiration material (FNAB, EBUS) from which your cytological examination was performed. In our fully integrated Laboratory, the pathologist selects the most appropriate & representative paraffin cube, ensuring that the most appropriate sample will be used for the tests. Qualitative and quantitative parameters are checked.
In case your sample is not already at Microdiagnostics archive, please contact us immediately so that we can arrange for its safe and rapid transport to our laboratory. You will also need to quickly and easily complete the Consent Form.
In this case, and once sample enrichment manipulations have been exhausted, we contact your clinician to discuss alternative approaches in order to obtain the desired information to select the optimal treatment for you. Some examples:
- Performing an alternative test (e.g. Immunohistochemistry instead of PCR, or choosing Next Generation Sequencing (NGS))
- Performing Immunohistochemistry instead of FISH (Fluorescent In Situ Hybridization) and tubulin
- Possible blood sampling instead of tissue testing (liquid biopsy)
- Possible option to take a new biopsy or puncture
- When the tumor is inaccessible
- When available tissue is minimal or exhausted (paraffin cube)
- When the patient cannot support a repeat biopsy
- When repeat biopsy is not recommended
- When the patient does not respond to treatment and there is a need for reassessment
LI.B.E.R.O. & LI.B.E.R.O. PLUS detects gene alterations of major clinical significance, which are then used by your Oncologist to personalize your treatment regimen.
A small amount of blood (~20 ml) is taken, as in a routine hematology test. In case the blood collection is not done at Microdiagnostics facilities, the blood should be collected in 2 Streck 10ml vials (please contact us to supply them to you).
Transport conditions: The blood vials are kept at room temperature. Please note that the blood should not be refrigerated, exposed to ice packs, or frozen. After collection, it is recommended that it be transported at Microdiagnostics facilities as soon as possible.
Contact us at 2310 23 22 72 and we will immediately assist you in quickly transporting the sample to our laboratory.
By cash, bank card, bank deposit, or Online interbank deposit.
One of the primary concerns at Microdiagnostics is the protection of your personal data as well as the strict observance of the conditions for the protection of your genetic material and medical results.
In full compliance with the General Data Protection Regulation (GDPR), we ensure that any examination conducted is done with your knowledge and consent and we do not communicate results over the phone.