Unknown Primary: Latest Research

Approved by the Cancer.Net Editorial Board, 10/2022

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 cancer of unknown primary (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, genes expressed by healthy lung cells are different than genes expressed by healthy colon cells. When cancer develops somewhere in the body, it usually has the same pattern of gene expression as the place where the cancer started. A tumor sample from a biopsy can be analyzed to figure out which genes are being expressed. This can usually predict where the cancer began.

    As explained in the Types of Treatment section, site-treatment based on gene expression profiling prediction is being used instead of empiric chemotherapy as the standard treatment for people with CUP who do not fit into a specific subgroup. Ongoing clinical trials continue to look at the outcomes of site-specific treatment using gene expression profiling.

  • Targeted therapy. As explained in the Types of Treatment section, targeted therapy directs treatment at specific genes and proteins that are involved in the growth and survival of cancer cells. Learn more about the basics of targeted treatments.

    Several targeted therapies are approved by the FDA for specific cancers. Examples 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 covers many tumor types, it is likely that some of these cancers have molecular abnormalities that have been successfully targeted in other cancer types. Until recently, testing for potential molecular targets (such as HER2, BRAF, and EGFR) had not been performed in CUP. With the availability of comprehensive molecular profiling, recent studies have found that the incidence of potentially treatable molecular abnormalities (using targeted treatments already approved for other cancers) is approximately 25% in CUP.

    The efficacy of targeted treatment aimed at these detected molecular abnormalities has not yet been adequately tested in patients with CUP. However, a few such patients treated outside of clinical trials (with clinically available drugs) have had excellent responses. In ongoing clinical trials, people with CUP whose tumors have specific molecular abnormalities are being treated with drugs targeted against that abnormality. These clinical trials provide a major opportunity to identify additional effective treatment options for specific patient groups.

  • Immunotherapy. Immunotherapy helps the immune system fight cancer. During the last several years, many new immunotherapy drugs have been developed. For example, treatments that target PD-1 and PD-L1 pathways have become standard parts of treatment for several common cancers, including lung, kidney, bladder, head and neck, and certain breast and colon cancers.

    Since people with CUP can have cancer that started in any of these locations, researchers think that some people with CUP could also benefit from immunotherapy. In addition to cancer type, several other predictors of responsiveness to immunotherapy have been identified, including high tumor PD-1 or PD-L1 expression, high microsatellite instability (MSI-H), or high tumor mutational burden (TMB) All of these abnormalities have been detected in CUP, and can be detected with comprehensive molecular profiling. Clinical trials are ongoing to understand the results of immunotherapy treatment in people with CUP. Learn more about the basics of immunotherapy.
  • New types of treatment. Many new drugs are being tested for the first time in studies called phase I clinical trials. Usually, these clinical trials are not specifically for 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 could be 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 more information about the latest areas of research in 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 on 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.