Number of mutations in a tumor varies by age and type of cancer
WASHINGTON (May 17, 2017) — A team of investigators led by researchers at Georgetown Lombardi Comprehensive Cancer Center has found that the tumor mutation load, or TML, in a patient's cancer biopsy varied by age and the type of cancer, along with several other factors.
Researchers say the findings are some of the most comprehensive analyses of TML to date as they include 14 types of solid tumors. Over 8,000 tissue samples were included in the study making this one of the larger collections of tumors examined for TML. The abstract describing the work was released today. Additional details will be presented at the American Society of Clinical Oncology annual meeting next month in Chicago.
TML is a measurement of the number of mutations in DNA. Mutated DNA can be subsequently translated to harmful changes in proteins. Mutated proteins often appear foreign to the immune system and can therefore activate a robust immune response that can be boosted by immunotherapeutic agents.
"One of our more interesting findings was the fact that mutation load increased with age in many cancers," says the study's principal investigator, Mohamed E. Salem, M.D., assistant professor of medicine at Georgetown Lombardi. "Older age correlated closely with TML in most of the cancers we examined, but in some cancers, such as bladder cancer, there was no correlation by age, which also makes for an important observation in a difficult to treat type of cancer."
Looking for high levels of mutations in tumor may seem to be a contrary way of looking for what therapies might be most effective to fight cancer. Because immunotherapies work by taking the brakes off the immune system, and hence allowing immune-fighting cells to go after cancer cells, the more mutations a cancer cell has may make it appear more alien to the immune-fighting cells and therefore, a more focused object of attack. If a cell's TML is high, an immunotherapy could be more effective and hence Salem's interest in quantifying TML. Tumor mutation load also could be used as a marker to determine which types of cancer and which patients, or subsets of patients, could most benefit from immunotherapy.
"We found that, as expected, melanoma had the highest TML as we know clinically that this type of cancer responds best to immunotherapy," says Salem, also a member of Georgetown Lombardi's Ruesch Center for the Cure of GI Cancer. "Indeed, the mean TML for melanoma was nearly double that of the next highest mean, non-small cell lung cancer. In addition, we see that high TML often occurs in tumors lacking well-known cancer-related genes, like BRAF or NRAS genes in melanoma and EGFR or ALK genes in non-small cell lung cancer. This suggests that immune checkpoint inhibitors may be particularly effective in patients who are not candidates for common targeted therapies in these types of cancer."
"Our next step is to validate and correlate TML levels with outcomes in patients who have received immunotherapy. We'll look to see if patients had high TML levels before they started therapy and then determine if those with the highest levels had the best clinical outcome, which is what we might expect," he says.
"If validation studies prove helpful, they could be very useful in designing clinical trials for many types of cancer," Salem concludes.
Co-authors include John Marshall, Michael Atkins, Jimmy J. Hwang, Geoffrey Thomas Gibney, Georgetown Lombardi; Joanne Xiu, Zoran Gatalica, and Nianqing Xiao, Caris Life Sciences; Heinz-Josef Lenz, USC Norris Comprehensive Cancer Center; Philip Agop Philip, Karmanos Cancer Center: Antoinette R. Tan and Derek Raghavan, Levine Cancer Institute; Wafik S. El-Deiry, Fox Chase Cancer Center; and Edward S. Kim and Anthony Frank Shields, Wayne State University.
The work was supported by the Ruesch Center for the Cure of GI Cancers. CARIS provided analysis of the tumor samples. Salem and the other co-authors report having no personal financial interests related to the study.
About Georgetown Lombardi Comprehensive Cancer Center
Georgetown Lombardi Comprehensive Cancer Center is designated by the National Cancer Institute as a comprehensive cancer center — the only cancer center of its kind in the Washington, DC area. A part of Georgetown University Medical Center and MedStar Georgetown University Hospital, Georgetown Lombardi seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Connect with Georgetown Lombardi on Facebook (Facebook.com/GeorgetownLombardi) and Twitter (@LombardiCancer).
About Georgetown University Medical Center
Georgetown University Medical Center (GUMC is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC's mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis — or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health. Connect with GUMC onFacebook (Facebook.com/GUMCUpdate), Twitter (@gumedcenter) and Instagram (@gumedcenter).