乌鸦传媒

More than one-third of pathogenic germline variants (PGVs) identified using a universal testing strategy would have been missed by a guideline-based approach, suggesting a role for expanding germline testing, a study showed.

Several initiatives recommend expanding germline testing for adolescents and young adults with cancer and those with advanced cancer. This approach may also be relevant for patients with endometrial, gastrointestinal, breast, and colorectal cancers.

The American College of Medical Genomics and Genetics (ACMG) has identified medically actionable genes -- primarily associated with cancer and cardiovascular diseases -- called secondary findings. The ACMG recommends that clinical laboratories report PGVs incidentally discovered during clinical whole-genome and whole-exome sequencing.These recommendations, however, do not apply to genetic findings found during research sequencing.

In the study, published in , Jill Kolesar, PharmD, director of the Precision Medicine Clinic at the University of Kentucky Markey Cancer Center in Lexington, and colleagues aimed to evaluate the feasibility of reporting secondary PGVs identified in research sequencing using the institutional molecular tumor board and the patient's treating oncology physician. Secondary aims included tabulating germline findings potentially missed using National Comprehensive Cancer Network germline genetic testing guidelines and comparison with an independent population with cancer.

In the following interview, Kolesar describes the feasibility of reporting secondary finding PGVs using the molecular tumor board and clinical team, and discusses how this strategy would identify more patients with PGVs than the guideline-directed approach.

What does the study add to the literature?

Kolesar: This is the first report of returning results to patients undergoing research germline testing. We conducted a prospective, interventional cohort study, enrolling Total Cancer Care [a multi-institutional, prospective, observational cohort study led by the Oncology Research Information Exchange Network ()] participants with any cancer diagnosis.

The 781 enrolled patients underwent research-grade germline whole-exome sequencing, with bioinformatic analysis to verify pathogenic/likely PGVs in any genes. The molecular tumor board reported PGVs to treating oncology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing.

Many patients are sequenced and data are stored in large databases and never returned to patients. We found that about 4% of patients have an actionable hereditary predisposition gene for cancer, including 3.1% who were heterozygous carriers of an autosomal recessive cancer predisposition syndrome and 1.8% who had other hereditary disease PGVs. Guideline-directed testing would have missed 37.5% of the inherited cancer predisposition PGVs, which included BRCA1, BRCA2, MSH6, SDHAF2, SDHB, and TP53 variants.

We developed a process to review research data for mutations, alert treating physicians and refer patients to genetic counselors. It was feasible to return these research results.

Almost half the participants (315) consented to reporting results, and results for all living patients were reported to the clinical team, with half referred to a licensed genetic counselor. There was concordance between all research variants identified in nine patients who underwent clinical confirmatory sequencing.

What are the implications specifically for ovarian and endometrial cancer patients?

Kolesar: Women with ovarian or endometrial cancer are the most likely to have cancer predisposition PGVs, and current recommendations are to assess all patients for their presence. It is crucial to identify predisposition PGVs. Knowing about a cancer predisposition gene can change a patient's therapy and alert family members to be tested before a cancer diagnosis, when prevention strategies are effective.

How can the role of genetic counselors be expanded?

Kolesar: Genetic counselors could perform routine review of research sequencing. Patients with non–cancer-related hereditary disease predisposition variants were frequently not referred by the treating oncology physician or declined testing, suggesting our strategy of reporting non–cancer-related gene variants by the molecular tumor board to our oncology physicians is an unreliable way to return these results. This may be related to the lack of a clear clinical process for referrals to licensed genetic counselors for noncancer genes or a perceived lack of importance of these noncancer genes by oncology physicians or individuals with cancers.

What is your main message for practicing oncologists?

Kolesar: Research-grade germline sequencing with clinical confirmation is feasible and may affect patients with cancer and their relatives who undergo cascade testing.

Hereditary cancer predisposition genes are not rare and, given the number of patients undergoing research sequencing, there is a need to assess research sequencing and return these results to patients.

Read the study here.