An analysis of germline DNA in people with advanced cancer finds that inherited mutations may be more common than expected in this group. The findings have implications for genetic counseling and screening.
Memorial Sloan Kettering’s genomic-sequencing test, called MSK-IMPACT™, analyzes tumors for more than 400 genetic mutations known to play a role in cancer. The goal is to match the tumors with targeted therapies. To get to the heart of what makes these tumors genetically unique, a sample of normal tissue is analyzed for comparison.
This testing began in 2014. Experts in MSK’s Clinical Genetics Service quickly realized that sequencing data on normal DNA provided a treasure trove of information about the genetic changes that people with cancer carry in their germlines (the genes that are inherited at birth). This led to the establishment of the Robert and Kate Niehaus Center for Inherited Cancer Genomics, which aims to use hereditary genomic data to develop new approaches for cancer prevention as well as earlier detection and treatment.
One of the first studies resulting from this testing effort has now come out. It has found that about one-half of all people who carry inherited cancer-related gene mutations would not have had those hereditary mutations detected under the current screening guidelines. These findings suggest that doctors should consider taking a closer look at people with cancer to determine who carries mutations. This is especially true for those people with advanced cancer. The results may signify that their family members are at a higher risk of cancer.
“At the time a person is diagnosed with advanced cancer, we have a vital opportunity to conduct comprehensive genetic testing,” says Kenneth Offit, head of the Niehaus Center, Chief of MSK’s Clinical Genetics Service, and co-senior author of the new study, which was published in the Journal of the American Medical Association (JAMA). “By learning about the presence of inherited mutations, we can set the stage for providing genetic counseling to their families. That can, in turn, lead to screening and prevention.
“No other institution is doing this type of testing to the same degree as MSK,” he adds.
MSK molecular pathologist Diana Mandelker, one of the first authors of the paper, says, “We found that tumor-normal sequencing facilitates personalized therapies and prevention by simultaneously detecting inherited markers of cancer risk and identifying tumor-specific targets for treatment.”
Looking at a Broad Range of Cancers
The new study included information from 1,040 people who underwent MSK-IMPACT testing and chose to have the additional analysis to look for inherited mutations. The researchers found that 182 of them (17.5%) carried mutations linked to cancer susceptibility in their germlines. This is significantly higher than the rate that experts expect to see in the general cancer population, which is between 5 and 12%, depending on the type of cancer.
A number of different kinds of cancer were included in the study. The most common ones were breast cancer, colon cancer, rectal cancer, pancreatic cancer, prostate cancer, and renal (kidney) cancer. Several rare cancers were included as well.
“What was surprising about this study was the large number of individuals with inherited mutations who would not have been aware of the risk to their families had we not provided them with this additional testing,” Dr. Offit says. More than one-half of the 182 people (101, or 55%) would not have undergone screening or counseling based on current guidelines, in large part because they did not have a strong family history.Back to top
The Hunt for Inherited Cancer Genes
The MSK-IMPACT test looks for 410 mutations. The germline analysis includes 76 known cancer predisposition genes, some of which, especially BRCA1 and BRCA2, are well known. Many others, however, are not. All of the genes included in the test for hereditary mutations are considered to be clinically actionable. That means testing for them will change recommendations for cancer screening or prevention, or will lead to targeted treatments.
Dr. Offit says that one of the novel findings of the study was that the rate of hereditary cancer gene mutation was higher in those with advanced cancer. “One of the reasons we observed higher rates of inherited mutations was because the majority of people who undergo MSK-IMPACT testing — about 81% in this study — have stage IV [metastatic] disease,” he explains.
He adds that this association builds on prior observations from MSK and other groups. A study published in the New England Journal of Medicine in July 2016 found that inherited DNA-repair mutations are significantly more frequent in men with advanced prostate cancer. In fact, they occur in nearly 12% of those men, compared with less than 5% in men whose cancer has not spread beyond the prostate. (DNA-repair mutations, which include the BRCA genes, correct errors that arise when cells duplicate their DNA before dividing.) This will be an important avenue for future research, according to Dr. Offit.
“Based on our results, we have started a program to provide testing for hereditary DNA-repair mutations to all prostate cancer patients at MSK. This will help them select the most-effective therapies as well as provide information on family risk,” says Mark Robson, Clinic Director of the Clinical Genetics Service and co-senior author of the JAMA report.Back to top
A Challenging Time for Families
Genetic counseling is a significant component of this work. The people who were found to have mutations in hereditary cancer genes were invited to participate in counseling with their families. Family members then had the opportunity to undergo genetic testing as well.
“For these families, it’s a different paradigm than typical genetic counseling because they may not even be expecting to learn they are at risk,” says Yelena Kemel, a genetics counselor at MSK and Niehaus Center Program Manager, who was one of the study’s first authors. “We normally see people referred for genetic testing at all stages of the cancer journey. This includes those who are newly diagnosed and those at risk but not diagnosed.
“Families of patients on our MSK-IMPACT study are already coping with a diagnosis of advanced cancer in a relative. And now they are learning that they may be at risk as well,” she says.
Ms. Kemel adds that for people in the study who didn’t have a family history of cancer, the news of a hereditary mutation may be particularly surprising. “This makes genetic counseling much more challenging to unsuspecting families but also more helpful. This is preventive information they would not otherwise have received,” she says.
Only a small number of patients’ families have received genetic counseling — just 29 at the time of the analysis. Ms. Kemel expects that number to increase over time. “It’s still early, and many family members are just beginning to seek this information to inform screening tests,” she says.Back to top
Findings Will Drive Future Research
The results from this study highlight the need for new methods of screening for cancer, especially early on. Detecting small quantities of cell-free DNA from tumors is an approach that will be tested as part of the MSK Precision Prevention Initiative. The initiative’s aims are to use knowledge of cancer genetics to direct the development of new methods for early detection as well as potentially preventive treatments.
“Based on our experience over the past two decades, we are confident that germline sequencing will improve outcomes for family members,” Dr. Offit comments. “However, more research is needed before universal tumor-normal sequencing becomes more widespread.”
Dr. Robson says that knowledge about certain inherited cancer genes is already changing the way that people are treated. For example, mutations in BRCA1 and BRCA2 can be targeted with drugs called PARP inhibitors. These drugs are already approved for women with ovarian cancer and BRCA mutations. PARP inhibitors are now being studied in other cancers with these mutations, regardless of where the cancer is located in the body. “These drugs can play a very important role in the treatment of these hereditary cancers,” he concludes.
Liying Zhang, Director of MSK’s Diagnostic Molecular Genetics Laboratory, was also a co-first author of the paper.Back to top