Germline Testing Could Help More Patients

Combining secondary germline analyses with tumor sequencing might uncover additional mutations that are clinically useful, a recent study reveals (JAMA 2017;318:825–35).

Using tumor sequencing to tailor treatments has become part of individualized cancer care, but doctors usually offer germline DNA sequencing for cancer risk only in certain circumstances. Different sets of guidelines weigh factors such as family history of cancer, age, and tumor characteristics. For example, guidelines issued in 2015 by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors recommend germline sequencing in cases of renal cell cancer with clear cell histology only if the patient is younger than 50 at diagnosis, has bilateral or multifocal tumors, or has one or more close relatives with the same tumor type.

Kenneth Offit, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, and colleagues suspected that applying an agnostic approach—concurrent germline and somatic analyses for all consenting patients—would pinpoint more individuals who might qualify for targeted treatments or whose relatives might benefit from preventive measures. The researchers therefore sequenced 410 genes in normal and tumor tissue from 1,040 patients, most of whom had stage III or IV cancers, including bladder, colon, ovarian, breast, and prostate tumors. They checked for germline mutations of 76 genes associated with hereditary cancer predisposition, including BRCA1, BRCA2, ATM, CHEK2, and RAD51D.

The scientists found that 182 patients carried cancer-predisposing germline mutations that were clinically actionable. For example, 44 of 62 cases of prostate cancer had clinically actionable inherited mutations that would not have been detected under existing guidelines, including 12 in highly penetrant genes like BRCA1 and MSH. Overall, the actionable hereditary mutations found in 55.5% of these patients would not have been predicted otherwise by their family history or disease phenotype.

Certain ethnic backgrounds have increased rates of specific germline mutations, and adding ancestry as a criterion for screening increases the number of actionable mutations detected. For example, Offit and colleagues calculated that screening for mutations common in people of Northern European or Ashkenazi ancestry, such as alterations in APC, MUTYH, and CHEK2, would have identified an additional 44 patients in the cohort who have actionable mutations.

Offit notes that his team's strategy influenced treatment in some cases. Of the 182 patients with actionable findings, 132 had mutations in DNA repair genes. As a result, 11 patients began receiving PARP inhibitors, platinum-based chemotherapy, or both. These therapies were discussed with or are planned for another 27 patients. Germline screening results also spurred the researchers to offer genetic testing to the families of 29 patients. Had they followed current guidelines, they wouldn't have identified 13 of these families.

“Our agnostic sequencing clearly detected actionable mutations that would have been missed,” says Offit. However, he cautions, it's too early to start rewriting the guidelines for germline testing “until there's been further validation of this approach.”

“It's a pretty exciting paper,” says Heather Hampel, MS, a licensed genetic counselor at The Ohio State University in Columbus who helped write the 2015 genetic testing recommendations. “It's difficult to know how many people we are missing” with current guidelines, she says. Given the declining costs for germline testing, guidelines may one day no longer be necessary, she adds. “It may be the beginning of an era in which all cancer patients get tested for hereditary cancer mutations when they are diagnosed.” –Mitch Leslie

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.