A new study from Kenneth Offit, MD, Chief of the Clinical Genetics Service and Robert and Kate Niehaus Chair in Inherited Cancer Genomics at Memorial Sloan Kettering Cancer Center (MSK), finds that more than half of inherited cancer gene mutations in people with advanced cancer are not detected using traditional methods based on family history. These findings suggest that in select populations of people with advanced cancer, universal tumor-normal sequencing (the simultaneous sequencing of tumor DNA and normal tissue for a broad panel of cancer-related genes) may detect more potentially clinically significant heritable mutations than a targeted approach based on current clinical guidelines. Knowledge of these additional mutations sets the stage for precision prevention for patients’ families and can help guide therapy as well as preventive interventions among family members, although whether these interventions would improve outcomes is currently under active investigation.
MSK scientists analyzed DNA samples from 1,040 patients and found that 182 (17.5 percent) had mutations indicating cancer susceptibility. Of these 182 patients, 101 (55 percent) would not have had these mutations detected using traditional guidelines based on family history, age, and tumor type. The clinical actionability of pathogenic variants was defined by evidence of their utility in cancer prevention or their potential utility as therapeutic targets. The frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients and predictive testing in the families of 13, including six for whom genetic evaluation would not have been initiated by guideline-based testing.
Proving that the current guidelines for genetic testing based on family history may not detect all clinically actionable genetic mutations, this study demonstrates that universal sequencing can create a vital opportunity for precision prevention to preemptively treat cancer in the next generation through increased surveillance or risk-reducing surgical procedures.
It was also discovered that there was a significantly greater overall prevalence of germline mutations observed in patients with metastatic disease. Further molecular profiling and prospective studies of treatment response may provide an explanation of this instance.
“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 tumor-normal sequencing at time of their treatment evaluation,” commented Dr. Offit. “At the time of a diagnosis of advanced cancer we have a vital opportunity, through comprehensive genetic testing, to set the stage for precision prevention for patients’ families. The major message for patients is that out of the challenges of a cancer diagnosis can come the opportunity for prevention in the family.”
“As the field of precision medicine continues to expand, genetic testing of tumors has led to major advances in the molecular targeting of therapies,” said pathologist Diana Mandelker, MD, PhD. “We found that tumor-normal sequencing facilitated personalized therapies and prevention by simultaneously detecting inherited markers of cancer risk and identifying tumor-specific genetic targets for treatments.”
“Unlike most other studies, we reported results of inherited mutations directly to families who wished to know,” commented medical oncologist Mark Robson, MD, Clinic Director of the Clinical Genetics Service. “Working with a team of experienced genetic counselors, we were able to provide predictive testing and counseling in a supportive and educational environment to families who would not have received counseling based on published decision rules.”
From January 2014 until May 2016, 10,336 patients at MSK consented to tumor DNA sequencing through MSK-IMPACT™ (Integrated Mutation Profiling of Actionable Cancer Targets). MSK-IMPACT detects gene mutations and other critical genetic aberrations in rare and common cancers, then tests both inherited DNA and tumor DNA. Since May 2015, 1,040 of these patients with advanced cancer additionally consented to germline analysis of 76 cancer predisposition genes. MSK is one of the only centers in the world that is communicating at such scale to patients about inherited risk by using a DNA test as part of normal testing. This study marks one of the first large-scale efforts to return germline findings in the context of tumor-normal sequencing to patients.
The cohort comprised MSK patients with advanced cancer who were undergoing tumor and normal DNA sequencing using MSK-IMPACT, a 410-gene panel. Germline analysis included the 76 genes on the MSK-IMPACT panel that are associated with hereditary cancer predisposition, including all of the cancer-predisposing genes identified in the American College of Medical Genetics and Genomics guidelines. Of 1,040 patients, the median age was 58, 65.3 percent were male, and 81.3 percent had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses.
This study was supported through the Robert and Kate Niehaus Center for Inherited Cancer Genomics at MSK. MSK researchers at the Niehaus Center use the latest in gene-sequencing technologies to discover the inherited causes of cancer in their aim to develop new approaches for early detection and treatment.
This study has several limitations, including physician discretion for referrals to tumor sequencing, unique demographic characteristics, and more. These factors will limit the generalizability of the findings to a community practice environment.
“Mutation Detection in Patients with Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing” appears in the September 5, 2017, issue of the Journal of the American Medical Association.
The leader of the MSK study team was Kenneth Offit, MD, Chief of the Clinical Genetics Service and Robert and Kate Niehaus Chair in Inherited Cancer Genomics. Pathologist Diana Mandelker, MD, PhD, molecular geneticist Liying Zhang, MD, PhD, and genetics counselor Yelena Kemel, MS, were co-primary authors of the report. Medical oncologist Mark Robson, MD, Clinic Director of the Clinical Genetics Service, served as co-senior author.