Gene expression analysis points metastatic CRC patient to successful irbesartan therapy

By Lynda Williams, Senior medwireNews Reporter

A patient with recurrent metastatic colorectal cancer has been successfully treated with the angiotensin receptor blocker irbesartan, researchers report.

The case study, published in the Annals of Oncology, details the management of a woman who was initially diagnosed in 2010 with stage III colon adenocarcinoma at the age of 67 years and underwent hemicolectomy. Her adjuvant capecitabine and oxaliplatin chemotherapy was limited to four cycles because of severe neuropathy.

She experienced recurrent disease to her right psoas muscle in 2012 and this was excised leaving a positive retroperitoneal resection margin. The patient was also treated with concurrent radiotherapy and capecitabine, the dose of which again was reduced because of neuropathy.

In 2013, the patient received stereotactic radiotherapy for recurrent disease in the L3 spinous process but relapsed at the same site in 2014 and underwent palliative surgery, say Howard Lim, from British Columbia Cancer Agency in Vancouver, Canada, and co-authors.

Genomic analysis at time of the initial recurrence revealed abnormal mismatch repair profile with loss of MLH1 protein but no evidence of a BRAF V600E mutation.

And analysis of the L3 spinous process showed overexpression of FOS and JUN genes that encode the AP-1 transcriptional complex, with c-JUN protein expression confirmed by immunohistochemistry.

"This indicated that mitigation of upstream factors leading to activation of this complex might provide a therapeutic advantage", explain the researchers, noting that the renin-angiotensin system is one pathway that signals through this complex.

The patient was started on irbesartan 150 mg/day in December 2014; her carcinoembryonic antigen (CEA) level fell from 18.0 before treatment to 3.1 after 5 weeks of treatment, below the upper limit of normal of 5.

Moreover, positron emission tomography/computed tomography imaging taken at baseline and again after 5 weeks and 3 months of irbesartan treatment revealed "complete functional radiological resolution".

This finding has been maintained after 10 months, with a CEA of 1.4, the researchers add.

"This case highlights the use of whole genome analysis, including transcriptome data, to identify new candidate therapeutic targets", Lim et al write, noting that combining integrative profiling and bioinformatics can bring "excellent, and perhaps unexpected, results".

They conclude: "As genomic technology linked to clinical implementation advances, further therapeutic options with the possibility of repurposing medications will be realized for more oncology patients."

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