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Genetic testing guidelines miss nearly 50% of breast cancers with actionable variants

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February 26, 2019

Nearly half of patients whose breast cancer is revealed by expanded genetic testing to have a clinically actionable pathogenic or likely pathogenic variant may be overlooked by current testing guidelines, according to findings published in Journal of Clinical Oncology.

“National Comprehensive Cancer Network guidelines for genetic testing were established approximately 20 years ago to identify patients with the highest likelihood of carrying BRCA1/2 variants to reduce the number needed to test at a time when BRCA1/2 genetic testing cost $2,000 to $5,000 per test and in line with known management implications at the time,” Peter D. Beitsch, MD, surgical oncologist at Dallas Surgical Group/TME Breast Cancer Network, and colleagues wrote. “However, with the landmark Supreme Court case on BRCA1/2 in 2013, which overturned patents on naturally occurring genes, and with next-generation sequencing spurring competition, the availability and cost of testing has dropped. Simultaneously management guidelines are developing rapidly and have been revised multiple times.”

Beitsch and colleagues sought to determine whether there was a difference in actionable variants between patients who met NCCN testing guidelines and those who did not by initiating a multicenter prospective registry with data from 20 community and academic breast practices experienced in cancer genetic testing and counseling. Researchers chose sites with the goal of having ethnic distribution representative of U.S. demographics.

The cohort included 959 patients (age range, 18-90 years) who had been diagnosed with breast cancer (650 within the previous 12 months), were currently undergoing treatment or had received prior treatment, and had not undergone previous single- or multigene germline testing.

Sites enrolled equal numbers of patients who met and did not meet 2017 NCCN guidelines, based on answers to a multipart question created in collaboration with a cancer genetic counselor.

All patients underwent germline genetic testing with a multicancer panel of 80 genes. Eleven of these genes (BRCA1, BRCA2, ATM, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, STK11 and TP53) are cited in NCCN management guidelines and frequently included in breast cancer panels.

Researchers powered the study to identify a four percentage-point difference in the pathogenic/likely pathogenic variant rate between those who met and did not meet the guidelines.

The researchers found that 479 patients (49.95%) met the NCCN germline genetic testing guidelines, whereas 480 (50.05%) did not.

Testing detected pathogenic or likely pathogenic variants in 83 (8.65%) of the patients, including 45 (9.3%) of those who met NCCN testing guidelines and 38 (7.9%) of those who did not. There was no statistically significant difference in positive cases between the two groups.


Overall, testing with only an 11-gene breast cancer panel identified 47 patients (4.9%) with a pathogenic or likely pathogenic variant, and 15 patients (1.56%) when only BRCA1/2 were considered.
In an analysis considering only BRCA1 and BRCA2 test results, the in-guideline group had a positive rate that was four times that of the out-of-guideline group (2.51% vs. 0.63%; P = .0201). The two groups had nearly identical variant of uncertain significance rates.

“Universal genetic testing of patients with breast cancer, including currently underserved populations, with a comprehensive gene panel, has the potential to reveal the full component that genetics play in breast cancer development regardless of the age or family history of the patient,” Beitsch and colleagues wrote. “Expanded panel testing can provide information that may present additional treatment and follow-up options, including clinical trials, for all patients with breast cancer, not just those who meet testing guidelines.”

In a related editorial, Kara J. Milliron, MS, genetic counselor at the breast and ovarian cancer risk evaluation clinic at University of Michigan Cancer Center, and Jennifer J. Griggs, MD, MPH, professor in the departments of health management and policy and internal medicine in the hematology and oncology division at University of Michigan School of Public Health, addressed the question of whether economic barriers should prevent the use of multigene panel testing for breast cancer susceptibility in patients who do not meet NCCN testing guidelines.

Beitsch [and colleagues] suggests that there may be value in such testing, but this must be balanced against the need for ethical allocation of scarce resources,” Milliron and Griggs wrote. “In particular we do have the ethical obligation to address inequities in our communities and globally by informing policy and participating in vigorous debates about health care reform in the public arena.” – by Jennifer Byrne

Disclosures: Beitsch reports stock and other ownership interests in Targeted Medical Education. Please see the study for all other authors’ relevant financial disclosures. Milliron reports stock and other ownership interests in InheRET. Griggs reports no relevant financial disclosures.

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