Combating Colon Cancer Based on Genetic Mutations
Combating Colon Cancer Based on Genetic Mutations
Colorectal cancer is the third most common cancer in the United States and is the second leading cause of cancer deaths. However, the treatment for colorectal cancer may be significantly changing over the next 5 to 10 years as targeted therapies based on genetic mutations become the new standard of care.1
“We are at the beginning of a new era,” said Michael Naughton, MD, who is an assistant professor of medicine in the Division of Oncology at Washington University School of Medicine, St. Louis, MO. “We now understand the biology of the disease.”
Dr. Naughton says the prevention of colorectal cancer, as well as its diagnosis and treatment, now involves specific gene mutations, which are being addressed in clinical practice.
For decades, aspirin has been prescribed for patients with colorectal cancer, although no one could predict which patients would actually benefit from the treatment. New studies are demonstrating that aspirin therapy is only effective in patients with colorectal cancer whose tumors carry a mutation in a key gene; therefore, this method of lowering the risk for colorectal cancer can now be based on this specific gene mutation.
Boston researchers have found that patients who are positive for a mutation in the PIK3CA gene receive a greater survival benefit with aspirin therapy. Investigators analyzed data from 964 patients with either rectal or colon cancer from the Nurses' Health Study and Health Professionals Follow-up Study. They found that the survival benefit from aspirin therapy is limited to the 20% of patients with colorectal cancer who have tumors with the PIK3CA mutation.2
These new findings are based on an investigation that combined the study of disease-related genes and research into large populations of individuals. The study's senior author, Shuji Ogino, MD, PhD, who is a researcher at the Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, said this study is part of a new hybrid field of research that he calls “molecular pathology epidemiology.” According to Dr. Ogino, this field may help bring together two frontiers of cancer research at both the molecular and population levels.
Prevention Efforts Already Paying Off
Currently, the use of colonoscopy for diagnosing and treating colorectal cancer is making a significant difference. A study by researchers at Stanford University has found that the use of colonoscopy may explain the decrease in incidence of upper colon cancer through the identification and removal of precancerous polyps in the last decade.3 The study showed that the overall rate for removing or resecting colorectal cancer dropped from 71.1 to 47.3 per 100,000 persons between 1993 and 2009.
The investigators found that resection rates for lower colorectal cancer gradually decreased (1.2% per year) from 1993 to 1991, and then dropped more steeply (3.8% per years) from 1999 to 2009. However, the resection rate for upper colon cancer remained steady until 2002 before dropping at a rate of 3.1% per year until 2009. Uri Ladabaum, MD, Associate Professor of Gastroenterology and Hepatology at Stanford School of Medicine, Palo Alto, CA, who helped lead this study, said the findings are encouraging. Dr. Ladabaum also said the study results support the idea that the decreasing incidence of colorectal cancer might be associated with “screening in general,” since some patients were already undergoing stool tests and sigmoidoscopy in the early 1990s. However, the reduction in upper colon cancer incidence might be specifically associated with colonoscopy since sigmoidoscopy only extends into the lower part of the colorectum, Dr. Ladabaum commented.
“We have ample evidence that screening is effective. We now have a number of controlled trials that show colonoscopy screening also lowers mortality,” Dr. Ladabaum told ChemotherapyAdvisor.com. “Colon cancer is one of those cancers where the rates are going up and death rates are going down. Some of that is due to screening, but there may be other factors contributing too. In younger patients, the rates are going up, so there may be something in the environment.”
However, the rates are going down in adults age 50 and older Dr. Ladabaun pointed out. Current recommendations indicate that screening for colorectal cancer begins at age 50. However, a new method of screening—through exhaled breath tests—may soon be available for adults of all ages. A study recently published in the British Journal of Surgery4 analyzed volatile organic compounds (VOCs) in breath samples from 37 colorectal cancer patients and 41 healthy controls. The researchers found that the patients with colorectal cancer had a different selective volatile organic compound pattern compared with healthy controls, based on an analysis of 15 of 58 specific compounds in exhaled breath samples. This approach discriminated patients with colorectal cancer with a sensitivity of 86% and a specificity of 83%. “If perfected, it would be a great addition,” said Dr. Ladabaum told ChemotherapyAdvisor.com.
Targeted Therapies Making a Difference
Currently, molecularly targeted therapies are significantly improving the outlook for patients with advanced-stage colorectal cancer. Just 10 years ago, these patients had few treatment options, but three targeted drug therapies— bevacizumab (Avastin®), cetuximab (Erbitux®) and panitumumab (Vectibix®)—are now changing outcomes for patients with advanced disease.
A just-released phase III head-to-head trial evaluating panitumumab versus cetuximab as a single agent for the treatment of chemorefractory metastatic colorectal cancer in patients with wild-type KRAS tumors met its primary endpoint of non-inferiority for overall survival. The study included 1,010 patients and the estimated overall survival hazard ratio was 0.966, favoring panitumumab. These findings were released May 7, 2013 by Amgen Inc., with detailed safety and efficacy data scheduled to be released later this year.
“As more treatment regimens are tailored to KRAS status, the survival rates for colorectal cancer will continue to improve,” Dr. Naughton said. “We are on the cusp of dramatically lowering incidence rates as well as mortality from colorectal cancer as a result of tests and treatments based on molecular pathology.”
1. Colorectal Cancer Prevention (PDQ®). National Cancer Institute. Accessed March 25, 2013. http://www.cancer.gov/cancertopics/pdq/prevention/colorectal/HealthProfessional/page3.
2. Liao X, Lochhead P, Nishihara R et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012 Oct 25;367(17):1596-606.
3. Myer PA, Mannalithara A, Singh G, et al. Proximal and distal colorectal cancer resection rates in the United States since widespread screening by colonoscopy. Gastroenterology. 2012 Nov;143(5):1227-36.
4. Altomare DF, Di Lena M, Porcelli F, et al. Exhaled volatile organic compounds identify patients with colorectal cancer. Br J Surg. 2013 Jan;100(1):144-150.