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Cancer of Unknown Primary in the Molecular Era.

ABSTRACT: Cancer of unknown primary (CUP) is a rare malignancy that presents with metastatic disease and no identifiable site of origin. Most patients have unfavorable features and attempts to treat based on tissue-of-origin identification have not yielded a survival advantage compared with empiric chemotherapy. Next-generation sequencing has revealed genomic alterations that can be targeted in selected cases, suggesting that CUP represents a unique malignancy in which the genomic aberrations may be integral to the diagnosis. Recent trials focusing on tailored combination therapy matched to the genomic alterations in each cancer are providing new avenues of clinical investigation. Here, we discuss recent findings on molecular aberrations in CUP and how the genomic and immune landscape can be leveraged to optimize therapy.

SUBMITTER: Kato S

PROVIDER: S-EPMC8062281 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cancer of unknown primary (CUP) is an umbrella term used to classify a heterogeneous group of metastatic cancers based on the absence of an identifiable primary tumor. Clinically, CUPs are characterized by a set of distinct features comprising early metastatic dissemination in an atypical pattern, an aggressive clinical course, poor response to empiric chemotherapy and, consequently, a short life expectancy. Two opposing strategies to change the dismal prognosis for the better are pursued. On the one hand, following the traditional tissue-gnostic approach, more and more sophisticated tissue-of-origin (TOO) classifier assays are employed to push identification of the putative primary to its limits with the clear intent of allowing tumor-site specific treatment. However, robust evidence supporting its routine clinical use is still lacking, notably with two recent randomized clinical trials failing to show a patient benefit of TOO-prediction based site-specific treatment over empiric chemotherapy in CUP. On the other hand, with regards to a tissue-agnostic strategy, precision medicine approaches targeting actionable genomic alterations have already transformed the treatment for many known tumor types. Yet, an unmet need remains for well-designed clinical trials to scrutinize its potential role in CUP beyond anecdotal case reports. In the absence of practice changing results, we believe that the emphasis on finding the presumed unknown primary tumor at all costs, implicit in the term CUP, has biased recent research in the field. Focusing on the distinct clinical features shared by all CUPs, we advocate adopting the term primary metastatic cancer (PMC) to denominate a distinct cancer entity instead. In our view, PMC should be considered the archetype of metastatic disease and as such, despite accounting for a mere 2-3% of malignancies, unraveling the mechanisms at play goes beyond improving the prognosis of patients with PMC and promises to greatly enhance our understanding of the metastatic process and carcinogenesis across all cancer types.

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Cancer of Unknown Primary in the Molecular Era.

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