Unknown Primary: Latest Research

Approved by the Cancer.Net Editorial Board, 02/2019

ON THIS PAGE: You will read about the scientific research being done to learn more about this type of cancer and how to treat it. Use the menu to see other pages.

Doctors are working to learn more about CUP, ways to prevent cancer, how to best treat CUP, and how to provide the best care to people diagnosed with this disease. The following areas of research may include new options for patients through clinical trials. Always talk with your doctor about the best diagnostic and treatment options for you. 

  • Using tumor genetics to diagnose the primary site. Different tissues within the body make different proteins, depending on which genes are active. This is called gene expression. For example, some of the genes expressed by healthy lung cells are different from those expressed by healthy colon cells. When cancer develops in these organs, it usually has the same organ-specific pattern of gene expression. It is now possible to analyze a tumor sample from a biopsy to figure out which genes are being expressed. This usually can predict the location where the cancer began.

    As mentioned in the Types of Treatment section, site-specific treatment based on gene expression profiling prediction is replacing empiric chemotherapy as the standard treatment for patients with CUP who do not fit into any of the specific subgroups. Ongoing clinical trials continue to look at the outcomes of assay-directed treatment in order to better define its role in treating CUP.

  • Targeted therapy. As outlined in the Types of Treatment section, targeted therapy is directed at specific molecular abnormalities within the cancer cell or the surrounding tissue environment that contributes to cancer growth and spread. These abnormalities include gene mutations in the tumor and abnormal activity of various signaling proteins within cancer cells. Learn more about the basics of targeted treatments.

    Several targeted therapies are approved by the FDA for specific cancers, either used alone or with chemotherapy. Examples of these targeted treatments include HER2 targeted therapy for HER2-positive breast cancer, BRAF inhibitors for BRAF-mutated melanoma, and EGFR inhibitors for EGFR-mutated non-small cell lung cancer. However, no targeted therapies are currently approved to treat CUP specifically, and the targeted drugs approved for other cancers have not been tested for CUP.

    Since CUP actually covers many tumor types, it is likely that some patients would benefit from the targeted therapies already proven to treat specific tumor types. For example, therapies targeting HER2, which is a molecular abnormality found in about 1 of every 5 breast cancers, have dramatically improved treatment results for these patients.

    Could a patient with CUP who is predicted to have breast cancer by gene expression profiling have an abnormality in HER2? If so, would treatment with a therapy targeting HER2 benefit this patient? The answer to both questions is likely to be “yes.  A few CUP patients who had HER2-positive tumors and responded to HER2-targeted treatment have been reported, but no clinical trials have addressed this issue for HER2 or any other molecular abnormalities. In fact, tumors from patients with CUP are not routinely tested for HER2 abnormalities or for any of the other molecular abnormalities for which targeted treatments exist.

A recent study found that the incidence of potentially treatable molecular abnormalities (using targeted treatments already approved for other cancers) is approximately 25% in CUP. In ongoing clinical trials, people with CUP whose tumors have specific molecular abnormalities are being treated with drugs targeted against the abnormality. It is likely that these clinical trials will identify additional effective treatment options for specific patient groups. 

  • Immunotherapy.  During the last several years, new drugs that induce the immune system to fight cancer (such as anti-PD-1 and anti-PD-L1 drugs) have become standard parts of treatment for several common cancer types including lung, kidney, bladder, head/neck, and certain breast and colon cancers.  Since most of these cancer types are represented in the CUP population. Scientific data shows that it is logical to think that some patients with CUP could also benefit from immune treatments.  Other molecular predictors of response to immunotherapy have recently been recognized.  Patients whose tumors have these predictors (including high MSI [microsatellite instability] or high TMB [tumor mutational burden]) are likely to respond to immunotherapy, regardless of their tumor type.  Both of these molecular abnormalities occur in CUP.  The results of immunotherapy in patients with CUP are unknown, although clinical trials are ongoing.

  • New types of treatment. Many new drugs are being tested for the first time in studies called phase I clinical trials. Usually, these trials are not specifically for patients with CUP, but accept patients of all types of cancer who have already received all standard treatments. The goals of these studies are to identify the side effects and best doses for these new drugs, as well as to learn if they are effective against cancer.

  • Palliative care/supportive care. Clinical trials are underway to find better ways of reducing symptoms and side effects of current cancer treatments to improve comfort and quality of life for patients.

Looking for More About the Latest Research?

If you would like additional information about the latest areas of research regarding CUP, explore these related items that take you outside of this guide: 

The next section in this guide is Coping with Treatment. It offers some guidance in how to cope with the physical, emotional, social, and financial changes that cancer and its treatment can bring. Use the menu to choose a different section to read in this guide.