Unfavorable carcinoma of unknown primary with a gastrointestinal profile: a retrospective study

Background: Carcinoma of unknown primary (CUP) with a gastrointestinal profile is categorized by the European Society of Medical Oncology (ESMO) guidelines into favorable and unfavorable subsets. Favorable CUPs benefit from site-specific chemotherapy (CT), while the optimal treatment for unfavorable CUPs is still undefined.

Materials and methods: We conducted a single-center retrospective study to describe outcomes of patients with CUP with a gastrointestinal profile referred to our center from January 2000 to August 2023. Favorable CUPs were defined as CK7-/CK20+/CDX2+ by immunohistochemistry, according to the ESMO definition; all other cases were considered unfavorable. The main endpoint was the progression-free survival (PFS) of first-line CT for advanced disease in all patients and in the unfavorable group.

Results: A total of 56 patients were included, of whom 46 (82%) had unfavorable CUPs. After a median follow-up of 43.9 months, the median overall survival (mOS) was 11.8 months [95% confidence interval (CI) 8.3-15.3 months]. At univariate analysis, the presence of peritoneal metastases and residual tumor after primary surgery were associated with a shorter OS. The median PFS (mPFS) was 6.1 months (95% CI 3.6-8.7 months). In the unfavorable CUP subgroup, the mOS was 12.6 months (95% CI 8.7-16.5 months), the mPFS was 6.1 months (95% CI 3.5-8.9 months) and none of the CT regimens used showed to portend better PFS. The most relevant altered genes included: KRAS (9/29; 31%), BRAF (1/26; 4%), NRAS (1/25; 4%), TP53 (9/23; 39%).

Conclusions: CUPs with a gastrointestinal profile are characterized by poor prognosis and the absence of biomarker for treatment personalization. No CT regimen was superior in terms of PFS in patients with unfavorable CUPs.