Cancer of Unknown Primary Site: A New Era of Practice-Changing Approaches to Diagnosis, Staging, and Precision Therapy

The enigmatic syndrome of metastatic cancer of unknown primary (CUP) site has frustrated physicians and patients for decades. There has been debate whether CUP is a single biologically distinct cancer or a constellation of many different cancers with clinically undetectable anatomic primary sites. For the past 40 years, the diagnosis of a specific cancer type for most patients was indeterminate, and fit patients were usually treated as a single cancer with the same empiric chemotherapy (EC) regimens with poor overall results. The aggregate data from autopsies, clinical observations, specialized standard pathology, molecular testing, and several clinical trials support CUP as a multitude of clinically occult invasive primary tumors requiring different site-specific therapies (SSTs). In the past several years, improved genomic testing has been used, and the addition of molecular-guided therapies (MGTs) and immunotherapy (IO) has been shown to be superior for many different advanced cancers. Two older randomized prospective trials conducted before the advent of IO and most MGT failed to show a better outcome for patients with molecularly diagnosed cancers who received SST (tailored chemotherapy regimens) versus EC, although patients with more responsive tumor types appeared to benefit. Two recently reported randomized trials documented the clinical relevance of molecular diagnosis and comprehensive genomic profiling. The administration of improved precision SST guided by molecular diagnosis and characterization revealed significantly improved outcomes compared with EC. The management of patients with CUP is undergoing rapid change including the diagnosis of the presumed primary tumors, TNM staging for selected patients, molecular profiling, and an expanded improved role of precision therapies highlighting the rapid emergent new era of practice changing standards of care.