Urachal Carcinoma Shares Genomic Alterations with Colorectal Carcinoma and May Respond to Epidermal Growth Factor Inhibition

Abstract

Metastatic urachal carcinoma is a rare, understudied, and aggressive malignancy with limited treatment options. Histologically, urachal carcinomas resemble enteric adenocarcinomas and anecdotally respond to systemic therapies utilized in colorectal cancer. Targeted exome sequencing of archival primary tumor tissue from a patient with metastatic urachal cancer revealed EGFR amplification and wild-type KRAS. The patient was treated with cetuximab, a monoclonal antibody directed against EGFR, as a single agent, and achieved a response lasting more than 8 mo. Subsequent whole-exome sequencing revealed no additional alterations likely to be associated with cetuximab sensitivity. Formalin-fixed, paraffin-embedded tumor specimens from nine additional urachal cancers were subjected to targeted exome sequencing. Mitogen-activated protein kinase (MAPK) pathway mutations were found in four of the nine samples, but no EGFR amplification was detected. Importantly, APC mutations were detected in two of the nine patients. To our knowledge, this is the first report of a response to single-agent cetuximab in a patient with metastatic urachal cancer and of molecular analysis to probe the basis for sensitivity. On the basis of these findings and the histologic, and now genomic, similarities with colorectal cancer, monoclonal antibodies directed at EGFR could be used in the treatment of metastatic urachal cancer. Patient summary Urachal cancers are morphologically and genomically similar to colon adenocarcinomas and may respond to drugs targeting the epidermal growth factor receptor.

Mutations of KRAS, NRAS, BRAF, EGFR, and PIK3CA genes in urachal carcinoma: Occurence and prognostic significance

“…In the present analysis, we found BRAF mutations in 4 of 22 (18%) UrC cases, which frequency seems to be similar to that of in CRC. In contrast, others found no BRAF mutations in UrC [8, 33, 36]. Low case number of that study together with the relative low abundance of BRAF mutation might be the reason for this discrepancy.…”

“…Singh et al identified recurrent mutations in NF1, APC and RNF43 genes suggesting the involvement of MAPK and Wnt/β-catenin pathways in UrC formation [36]. In accordance, a further study found mutations in the MAPK pathway in four of nine cases [8]. …”

“…From the 28, 22 included cases in this study, four showed clinical evidence of response and the one with UrC showed the highest decrease in tumor size of 55%, which was accompanied by a biological response as shown by the decrease of Ki67 proliferation index in the post treatment tumor biopsy [7]. In a recent publication Collazo-Lorduy et al reported cetuximab treatment to be effective for eight months in a patient with metastatic UrC bearing EGFR amplification and wild-type KRAS [8]. These promising data suggest that anti-EGFR therapy might be effective also in UrC.…”

“…Testa et al reported a necrotic involution of the tumor and a significant improvement of abdominal pain in a UrC patient who was treated with second-line multikinase inhibitor (Sunitinib) [6], while Goss et al observed a size regression of a UrC as a response to EGFR-inhibitor therapy with gefitinib (Iressa) [7]. Finally, a recent study reported a patient with lung metastatic UrC who was effectively treated with a monoclonal EGFR-inhibitor (cetuximab) for eight months [8]. …”

The Importance of Biopsy in the Era of Molecular Medicine

“…BRCA mutation carriers with various solid tumors show response to PARP inhibitors. (25) In some cases of rare and understudied tumors, treatment options may be derived from the presence of common mutations (26). Histologically unclassifiable cancers, or those without a known primary site, may be particularly amenable to such a strategy (27).…”