Research Improves Accuracy Of Colorectal Cancer Staging
Results of a pioneering study led by researchers at the John Wayne Cancer Institute at Saint John's Health Center show that sensitive molecular diagnostic techniques can effectively upstage early stage colorectal cancer patients believed to be cancer-free according to conventional methods. The findings could lead to more sensitive cancer detection, as well as more consistent ways of identifying patients who would benefit most from adjuvant therapy after surgery for colorectal cancer.
The study, "Prognostic Relevance of Occult Nodal Micrometastases and Circulating Tumor Cells in Colorectal Cancer in a Prospective Multicenter Trial," was published in the November, 2008 edition of the journal Clinical Cancer Research. Participating centers included John Wayne Cancer Institute (California) Century City Hospital (California), University of Colorado Health Science Center, Wake Forest University (North Carolina), and Michigan State University.
Colorectal cancer kills about 50,000 Americans every year. The disease frequently spreads to other areas of the body such as the liver, making it difficult to treat. Even when patients are judged to be cancer-free, the disease can recur, indicating that conventional pathology techniques may miss hidden (occult) metastases.
"Patients with colorectal cancer are at high risk of recurrence, and need to be staged more accurately to determine whether they need additional treatments such as adjuvant therapies that can save lives," says Dave S.B. Hoon, Ph..D., Director of Molecular Oncology at JWCI and senior scientist on the study. "Our goal was to apply highly sensitive detection methods to specimens from early stage colorectal cancer patients, and evaluate whether these advanced methods could help predict which patients are likeliest to recur, so that they could receive more aggressive therapies."
Over a five-year period, researchers analyzed sentinel lymph nodes (SLN) from 67 patients and blood samples from 34 patients enrolled in a prospective multicenter trial of sentinel lymph node mapping for early stage colorectal cancer. Sentinel lymph nodes removed during surgical resection were paraffin-embedded and analyzed for the presence of cancer cells using three methods: routine pathology with hematoxylin and eosin (H&E) staining; cytokeratin immunohistochemistry (IHC); and molecular analysis using quantitative real-time reverse transcriptase-PCR (qRT-PCR), targeting messenger RNA (mRNA) biomarkers.
Although H&E staining is commonly relied upon in pathology laboratories, many variables limit its reliability in detecting microscopic tumors. More sensitive techniques can upstage patients, including the more accurate cytokeratin IHC technique, which has been proven to detect occult micrometastases in SLN classified as tumor-free using H&E staining. Similarly, the highly sensitive qRT-PCR technique has been shown to detect occult metastases in frozen SLN initially classified as tumor-free using routine histopathology.
The study further illustrated the sensitivity of the newer techniques. In patients whose SLN were originally believed to be tumor-free using H&E staining--but whose cancer recurred--30% of samples were found to be positive for cancer cells using cytokeratin IHC, while 60% of the samples were upstaged using qRT-PCR. Using both techniques increased detection rates to 70%. Importantly, the results of SLN mRNA molecular marker analysis had significant prognostic value for disease-free survival: patients whose SLN tested negative for mRNA markers had a mean disease-free survival of 61 months, compared with 37 months for patients who were positive for the biomarkers.
By choosing to work with paraffin-embedded SLN samples, the researchers showed that molecular analysis can be performed with a universally practiced and stable sample preservation method. "This is the first prospective upstaging study of colorectal cancer SLN preserved in paraffin using molecular techniques," says Dr. Hoon. "It clearly shows that you can upstage these SLN samples, and relate the results to disease outcome."
In the blood study, additional prognostic value was demonstrated in overall survival curves: patients whose blood was free of tumor cell markers had a mean overall survival of 50 months, while patients who tested positive for the markers survived for 36 months.
"This is one of the first studies demonstrating the clinical relevance of detecting circulating tumor cells in early stage colon cancer by a sensitive molecular assay," Dr. Hoon adds. "And this was very early stage disease, so if there are already tumor cells in the blood, it indicates the presence of disease spreading in the body."
Results of the new study will support efforts to develop more consistent, automated molecular tests for lymph nodes, as well as a reliable blood test for early stage colorectal cancer. Such tests would be useful in early detection, in monitoring a patient's response to therapy, and in monitoring for cancer recurrence.