185P - Multi-omics profiling and clinical characterization of colon-like cancer of unknown primary (CUP)

Background

Colon-like cancer of unknown primary (CUP) is defined as a metastatic malignancy with an immunohistochemical profile resembling colorectal cancer (CRC; CK7-, CK20+, CDX2+), where the primary tumor remains elusive despite comprehensive diagnostic workup including negative colonoscopy. Although only very limited data is available, colon-like CUP is managed according to treatment protocols for metastatic CRC. No molecular profiles of this entity and their relation to CRC have been reported yet.

Methods

52 patients with colon-like CUP according to the current ESMO clinical practice guidelines were analyzed regarding demographic, clinical and molecular data using broad panel or whole exome and RNA sequencing of tumor samples. Clinicomolecular data were correlated with progression-free (PFS) and overall survival (OS), and compared to CRC.

Results

Histology mainly included adenocarcinomas (50%), mucinous adenocarcinomas (38.5%) and signet ring cell carcinomas (11.5%). Peritoneal metastases (66.7%) were substantially more frequent than in CRC (15-20%). Whereas 96% of CRCs harbor WNT, including 79% APC alterations, only 19/32 (59.4%) of colon-like CUP samples showed WNT mutations, of which 8/32 (25%) affected APC. 6/32 (18.8%) samples, all belonging to patients with peritoneal metastases, exhibited GNAS mutations, which are commonly present in appendiceal adenocarcinoma, indicating an origin within the appendix. 78.8% of patients were treated with 5-FU-based regimens, which led to a median PFS and OS of 6.8 (95% CI 4.9-12) and 19 (95% CI 14-37) months, respectively, being superior to the median survival of patients with unfavorable CUP treated with platinum-based chemotherapy. Histology, the presence of peritoneal carcinomatosis or molecular profiles did not affect OS.

Conclusions

Colon-like CUP constitutes a heterogeneous malignancy comprising cases that resemble CRC, cases with similarities to appendiceal carcinoma, and cases unrelated to both entities. Treatment according to CRC protocols appears to prolong survival compared to platinum-based unfavorable CUP chemotherapy. Updated data including RNA sequencing and pathway analysis will be available upon presentation.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

German Cancer Aid Foundation.

Disclosure

A. Stenzinger: Financial Interests, Personal, Advisory Board: Aignostics, AstraZeneca, Janssen, Bayer, Seattle Genetics, Pfizer, MSD, Eli Lilly, Illumina, Thermo Fisher, Amgen, Astellas, Agilent, Qlucore, QuiP, Sanofi; Financial Interests, Institutional, Advisory Board: BMS, Takeda, Novartis; Financial Interests, Personal, Invited Speaker: Roche, Incyte, Servier; Financial Interests, Institutional, Research Grant: Bayer, Chugai, BMS, Incyte, MSD. All other authors have declared no conflicts of interest.