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Tumor, Germline Testing of Cancer Patients Can Give Discordant Results

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NEW YORK — Genetic testing of tumor and germline samples of cancer patients can give discordant results, according to a new analysis presented at this year's virtual annual meeting of the National Society of Genetic Counselors.

Genetic testing of tumor tissue is increasingly performed as part of personalized cancer care to search for alterations that indicate a tumor may be susceptible to targeted therapy. But while tumor testing can also reveal germline alterations that may inform therapy choices, results from tumor and germline testing are not always the same.

Kristen Hanson, a genetic counselor at Aurora Healthcare, and her colleagues sought to explore how often and why discordant results occured in patients who underwent both kinds of testing at their facility. Nearly a quarter of the patients had discordant results, they found, a portion of which involved pathogenic or likely pathogenic variants.

"Tumor testing is not a replacement for germline testing for patients at risk for hereditary cancer syndromes," Hanson said during a talk at the meeting.

She and her colleagues initially identified 822 tumor tests conducted in 2019 in patients with a range of cancers, with gastrointestinal, gynecological, and lung cancer the most common types. Most patients undergoing testing had stage IV or metastatic disease. After reviewing tests from 632 of the patients, they found 202, or about a third, who had had both tumor and germline testing. 

Nearly a quarter of these had discordant results between their tumor and germline tests, meaning they had either a germline finding — a pathogenic variant, likely pathogenic variant, or variant of uncertain significance — that was not reported by tumor testing or a somatic finding that was suspected to be of germline origin but was not confirmed by germline testing.

For 14 of these patients, the discordant result was due to the gene of interest not being analyzed by both tests. Most often, Hanson said, this was a germline finding in a gene that was not included in the tumor test.

But for 26 patients, the germline finding was not identified by the tumor test, despite the gene being included, and for 15 patients, a somatic finding suspected of being germline in origin was not confirmed by germline testing.

While some of these findings were variants of uncertain significance, 14 of the discordant results represented pathogenic or likely pathogenic variants. In particular, five were found in genes not analyzed by both tests and nine in the germline tests that were not identified by the tumor test. About 30 percent of the variants were in BRCA1 or BRCA2, 30 percent in CHEK2, and the other 40 percent in other genes. 

Those genes, Hanson noted, were largely well studied. "It's not as if we were mainly uncovering low-to-moderate risk alleles or patients who were carriers of a recessive disorder," she added.

The variants were most often deletions or duplications, but some were intron alterations or mosaic findings. 

For patients, these discordant results could affect care. For instance, Hanson described a 48-year-old woman with stage IIIC high-grade, serous ovarian adenocarcinoma who underwent surgery and chemotherapy. She was lost to follow-up for two years but then presented again with a recurrence of her cancer. Somatic testing of her tumor uncovered no actionable alterations, but germline panel testing — which was pursued due to her diagnosis and family history — uncovered a pathogenic duplication in the BRCA2 gene that was not detected by the tumor testing.

This finding, Hanson added, not only affected the patient's care, in particular, her eligibility for PARP inhibitor therapy, but is informative for screening and preventive strategies for her family members, particularly her adult children.

Hanson and her colleagues further estimated that 7 percent of the patients in their cohort had a germline pathogenic or likely pathogenic variant that would have been missed by tumor testing alone. "As genetic counselors, we are in a position to understand the limitations of various forms of genetic testing and to help educate providers and patients about the value of both tumor and germline genetic testing," she said.