January 16, 2024
In a study of more than 500 people who received standard treatments for advanced colorectal cancer, researchers at the UNC Lineberger Comprehensive Cancer Center found that black patients showed distinctly different patterns of genetic mutations compared to white patients. reported. This finding may reflect environmental exposures common in colorectal cancers that occur in people younger than 50 years. Importantly, some of the mutations are associated with improved overall survival and may serve as predictive and prognostic markers for this disease.
of findings revealed Journal of Clinical Oncology.
Colorectal cancer is the third most common cancer and the second leading cause of cancer death in the United States. The American Cancer Society estimates that in 2024, more than 152,800 people will be newly diagnosed with colorectal cancer in the United States and more than 53,000 people will die from this cancer. According to the National Cancer Institute, black Americans are more likely to be diagnosed with and die from colorectal cancer than white Americans.
In this new study, researchers looked at the results of the large phase III randomized clinical trial CALGB (Alliance)/SWOG 80405, in which two different chemotherapy drugs were tested in 548 patients with metastatic colorectal cancer. We investigated how this affected the mutations. Study participants were randomly assigned to receive either bevacizumab or cetuximab, both targeted therapies plus conventional chemotherapy, or both targeted therapies plus conventional chemotherapy. Trials showed no benefit from any of the three combinations. But by sequencing tumor DNA of more than 400 genes, researchers were able to focus on mutated genes associated with survival and differences in response to treatment.
Dr. Naim Rashid
“Our study identifies DNA mutations that are associated with overall patient survival (prognostic biomarkers) or improved survival with one treatment over the other (predictive biomarkers). ” said the study’s senior author. Dr. Naim U. Rashid, a UNC Lineberger member and associate professor of biostatistics in the UNC Gillings School of Global Public Health. “We also sought to provide insight into racial differences in the molecular characteristics and clinical outcomes of colorectal cancer patients.”
Rashid said analysis of tumor DNA changes and racial differences between black and white patients can predict patient outcomes, inform treatment decisions, and influence clinical trial participation in patients with metastatic colorectal cancer. He said it could provide new tools to improve diversity.
The researchers class and APC The gene was found more frequently in black patients (53% and 85%) than in white patients (27% and 65%, respectively), but BRAF V600E Mutations were less frequent in black patients (5%) than in white patients (14%).They also looked at patients’ overall survival and determined that the mutated virus LRP1B gene (found in 10.7% of patients) was associated with improved overall survival compared to patients with the more common version of the gene. LRP1B.
they again, RNF43 The gene (found in 5.6% of patients) interacted with the drug in different ways: patients who received cetuximab; RNF43 Median overall survival was 11.5 months compared to 30.1 months for patients with the more common form of the gene.Patients treated with bevacizumab, patients with mutations RNF43 Median overall survival was 25.0 months compared to 31.3 months for patients with the more common form of the gene. Collectively, the results provide valuable insight into which genes and treatments may benefit specific patients with this progressive disease.
“Black Americans are routinely underrepresented in clinical trials, and this case is no exception. However, to our knowledge, this is the first time we have used cutting-edge genetic sequencing to identify genetic mutations in this population.” This is the first prospective trial to look at it,” Rashid said. “We hope these discoveries will help many patients and their caregivers manage their disease and achieve better outcomes.”
In an accompanying editorial, Justin Stebbing, Ph.D., of Anglia Ruskin University in Cambridge, UK, and Benjamin L. Schlechter, M.D., Ph.D., of Dana-Farber Cancer Institute in Boston, wrote in an editorial accompanying the paper that previous studies have shown important results; He said: Race- and age-related disparities in both cancer incidence and outcomes. “We now have thought-provoking data on early-onset colorectal cancer and mutational profiles that are common to black people.” [patients]Further prospective studies are needed to validate these findings and identify potential causes of this condition. There are also two new markers to incorporate into clinical trial designs to stratify risk. ”
They said the results of this study demonstrate the need to incorporate next-generation sequencing into clinical practice to identify important biomarkers that influence patient outcomes, enhance prognosis, and inform treatment planning. He added that
Author and disclosure information
The paper’s first author is Federico Innocenti, MD, formerly of UNC-Chapel Hill and now at AbbVie San Mateo in California, and the corresponding author is Heinz-Josef Lenz, MD, of the University of Southern California Norris Comprehensive Cancer Center in Los Angeles. . Angeles. In addition to Rashid, the study’s other authors are Wansen Mu, Ph.D., a biostatistics graduate student at UNC-Chapel Hill; Xueping Qu, PhD, Mayo Clinic, Rochester, Minnesota; Fang-Shu Ou, Ph.D., and Omar Kabbarah, Ph.D., Genentech, San Francisco. Charles David Blanke, MD, Oregon Health & Science University, Portland, Oregon. Alan P. Venuk, MD, University of California, San Francisco;
This research was supported by National Cancer Institute grants U10CA180821, U10CA180882, and U24CA196171 (to the Oncology Clinical Trials Alliance), UG1CA233253, UG1CA233327, UG1CA233373, U10CA180888 (SWOG), and R01CA143237. Funding from Bristol-Myers Squibb (BMS), Genentech, Pfizer, and Sanofi.
Rashid reported that he holds a patent for the PurIST classifier, which is licensed to Gene Centric.a Full disclosure to other authors Reported in online newspapers.
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Please contact the UNC Gillings School of Global Public Health Communications Team. sphcomm@unc.edu.