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.

Keywords: cancer of unknown primary; genomic; targeted therapy.

Figure 1.

Proposed Strategy for Patients with CUP. Patients with potential CUP should undergo standard workup (including IHC, imaging, and tissue-of-origin assay) to seek a primary cancer diagnosis. If a primary cancer is identified, patients should seek site-specific therapy. Once a patient is determined to have CUP, we propose obtaining molecular profiling (including NGS from tissue and/or from cell-free DNA) and immune-profiling (including PD-L1, TMB, and MSI testing) to seek actionable targets. If there is no druggable target, the patient may be managed with empiric therapy. However, if there are potentially targetable alterations, the use of a targeted therapy approach based on the underlying molecular features may be considered. Percent indicate the frequency of cognate target among CUP patients. Note: EGFR alterations have been most frequently associated with lung cancer; ERBB2 alterations with breast and gastric cancer; and NTRK alterations, PDL1 expression, and high TMB are tissue agnostic; however, any one of these alterations may occur across a variety of tumor types. Only a few examples of potential genomic alterations are shown. Abbreviations: CUP, Cancer of unknown primary; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; MSI, microsatellite instability; NGS, next-generation sequencing; NTRK, neutropenic tyrosine kinases; PD-L1, programmed death ligand 1; TMB, tumor-mutation burden.

Figure 2.

A 42-Year-Old Woman with Metastatic Adenocarcinoma of Unknown Primary. A 42-year-old woman initially presented with a seizure. Further workup showed multiple brain masses along with lymphadenopathy and bone and liver metastases. Biopsy was consistent with poorly differentiated adenocarcinoma. Immunohistochemistry was positive for CK7 and CDX-2, while CK20 was negative, which was suggestive for upper gastrointestinal primary; however, upper endoscopy was unremarkable without underlying mass. Random biopsy of distal esophagus, stomach, and duodenum were negative for malignancy. Overall, the patient was determined to have cancer of unknown primary and started on carboplatin and paclitaxel. Unfortunately, tumor rapidly progressed on cytotoxic chemotherapies (left to middle). During this time, genomic profiling revealed EGFR amplification and CDKN2A H83Y. Based on the molecular profiling, patient was started on cetuximab (anti-EGFR antibody) and erlotinib (EGFR small molecule inhibitor) (for EGFR amplification) along with palbociclib (CDK4/6 inhibitor) (for CDKN2A H83Y) and initially demonstrated remarkable response (middle to right) [patient consented to profile related evidence determining individualized cancer therapy (PREDICT); NCT02478931]. Unfortunately, after 4 months, the patient progressed and a new alteration, EGFR T790M, a known EGFR resistance mutation, appeared.