Researchers Explore Using Tumor Gene Signatures to Determine Lymph Node Involvement Prior to Rectal Cancer Surgery

Moving toward more individualized therapy for patients with rectal cancer, Cleveland Clinic researchers are exploring the use of tumor gene signatures—sets of genes that are consistently and significantly up- or down-regulated depending on lymph node status—to more accurately determine lymph node involvement before surgery.

The research aims to improve treatment decisions by reducing under- and overtreatment that can occur as much as 20 percent of the time using the current clinical staging model that employs pelvic ultrasound or MRI.

The American Cancer Society estimates that almost 40,000 new cases of rectal cancer will be diagnosed in 2015.

While surgery is the primary treatment for rectal cancer, presurgical radiation or chemotherapy may be recommended depending on clinical staging.

Clinical stage currently imperfect

“However, current methods of clinical staging are far from perfect, and staging is proven incorrect about 20 percent of the time once we perform surgery,” says Matthew Kalady, MD, Director of Cleveland Clinic’s Colorectal Cancer Translational Science Laboratory. “As a result, we may overtreat with unnecessary presurgical radiation or chemotherapy, or undertreat by not providing presurgical treatment,” says Dr. Kalady. “If we were able to better predict before resection which patients will have lymph node involvement, it would help us devise more personalized and effective care strategies.”

Individualized therapy based on cancer gene signatures

Over the past few years, Dr. Kalady and colleagues have explored creating a gene test that would more accurately determine patients’ lymph node involvement. They analyze cDNA microarrays from fresh-frozen tumor samples to identify genetic differences between primary rectal cancers with and without lymph node involvement.

“We take a biopsy of the tumor and analyze it for expression pattern of certain genes that are up- or down-regulated, and use that as a predictive marker for lymph node positivity,” Dr. Kalady explains. “Some of the signatures that we’ve worked on are 80 to 90 percent accurate.”

Their 2012 analysis of 77 patients with either stage II (N = 55) or stage III (N = 22) rectal cancer yielded two groups of patients that successfully differentiated between the stages.

The stage III group was characterized by significant differential expression of five key genes Only one patient with significant differential expression of these five genes had stage II cancer. 54 of the 55 patients with stage II rectal cancer clustered in an alternative gene signature profile for that group. This provides promise that a test using only a small number of genes could be developed and implemented to help distinguish patient populations requiring different treatments.

Using public gene expression repositories

While these results are intriguing, the study was relatively small. To further confirm their results, they made use of public gene expression repositories, which are comprised of rapidly growing, publicly available genetic data for various conditions, offering unique opportunities to study human diseases.

In a collaborative study with colleagues from the University of Limerick in Limerick, Ireland, Cleveland Clinic researchers used computer-generated models and showed that analysis of public gene expression repositories can be used to generate gene expression profiles that accurately predict lymph node status in patients with colorectal cancer.

“Using our tumor gene signatures, along with imaging and other current techniques, would improve our ability to identify those who are likely to have lymph node involvement and who could benefit from presurgical therapy,” Dr. Kalady explains.

First validation, then product

The challenge now is to confirm the validity of these genetic markers, a challenge Dr. Kalady and others are working on. “If we can in fact validate the effectiveness of these tumor signatures, this could become the standard of care, where every patient diagnosed with rectal cancer would undergo this testing. This would tremendously improve our decision-making capabilities on behalf of our patients.”

Colorectal surgeon Matthew Kalady, MD, is Co-Director of Cleveland Clinic’s Comprehensive Colorectal Cancer Program, and Director of the Colorectal Cancer Translational Science Laboratory. He has joint appointments in the Department of Stem Cell Biology and Regenerative Medicine, the Cancer Biology Department (Lerner Research Institute) and the Cleveland Clinic Cancer Center.