Genetic Testing Misses Half of Women at Risk for Breast Cancer


Nearly half of patients with breast cancer who, on multigene panel testing, are found to have a pathogenic or likely pathogenic variant for breast cancer do not meet current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing, new research shows.

In a cohort of 959 women who were either currently undergoing treatment or had previously been treated for breast cancer, 49.9% met established 2017 NCCN germline genetic testing guidelines, and 50% did not, lead author Peter Beitsch, MD, Dallas Surgical Group–TME/Breast Care Network, Texas, and colleagues report.

Of those patients who met NCCN guidelines for germline testing, 9.39% had either a pathogenic or a likely pathogenic variant; 7.9% of those who did not meet the guidelines also had a pathogenic or likely pathogenic variant. The difference between the two groups was not statistically significant, the investigators add.

“Our results indicate that nearly half of patients with breast cancer with a P/LP [pathogenic/likely pathogenic] variant with clinically actionable and/or management guidelines in development are missed by current testing guidelines,” the investigators observe.

“We recommend that all patients with a diagnosis of breast cancer undergo expanded panel testing,” they conclude.

The study was published online December 7 in the Journal of Clinical Oncology.

However, in a related editorial, breast cancer experts argue that widespread testing would detect genetic variants of unknown significance for which there are currently no established clinical courses of action.

Study Details

For their study, Beitsch and colleagues set up a multicenter, prospective registry with the help of 20 community and academic sites, all of which were experienced in cancer genetic testing and counseling.

They focussed on 959 patients who had a history of breast cancer but had not undergone prior single-gene or multigene testing.

“All patients underwent germ line genetic testing with a multicancer panel of 80 genes,” the authors explain.

“Overall, 83 (8.65%) of 959 patients had a P/LP variant,” they write.

The investigators then considered findings from only BRCA1 and BRCA2 genetic testing.

In this subgroup analysis, positive BCRA1/2 rates were fourfold higher among those who met current NCCN germline testing guidelines, at 2.51%, compared to those who did not, at 0.63% (P = .020).

However, the authors point out that patients with a clearly identifiable personal and family history consistent with NCCN testing guidelines were likely to have already undergone genetic testing and therefore would have been excluded from the study.

In contrast, rates of variants of “uncertain significance” were virtually identical between those who met current NCCN guidelines for genetic testing and those who did not.

“Carriers of clinically actionable variants in genes other than BRCA1/2 are likely to fall outside of the current guidelines,” Beitsch and colleagues point out.

“Results of our study suggest that a strategy that simply tests all patients with a personal history of breast cancer would almost double the number of patients identified as having a clinically actionable genetic test result,” they reason.

Variants of Unknown Significance

In a related editorial, Kara Milliron, MS, and Jennifer J. Griggs, MD, MPH, both from the University of Michigan Cancer Center in Ann Arbor, argue that widespread uptake of genetic testing would increase the likelihood of identifying pathogenic variants of genes for which there are no established guidelines for reducing cancer risk.

For example, pathogenic variants in ATM are associated with an increased breast cancer risk, “but there is insufficient evidence to support risk-reducing breast surgery or bilateral salpingo-oophorectomy,” they point out.

Furthermore, more widespread testing is likely to increase detection rates of variants of unknown significance, which were common in the study by Beitsch and colleagues.

“These variants present challenges for both patients and medical providers in the management of ambiguity that arises in a patient with a malignancy and family members,” Milliron and Griggs write. This issue is particularly problematic in certain racial and ethnic groups in which such variants are both more common and more poorly characterized, they add.

Of greater concern are barriers to high-quality counseling following genetic testing.

“The shortage of genetic counselors has been well documented,” the editorialists note, and currently, “many patients receive genetic testing without seeing a genetic counselor,” they state.

Lastly, the cost of widespread testing and counseling cannot be overlooked, especially when considering expanding that testing to all patients with breast cancer.

Medicare does cover BCRA1/2 testing, and some states cover genetic testing.

“Thus, costs to patients may be prohibitive in the most vulnerable populations,” the editorialists write.

NCCN guidelines for genetic testing were published about 20 years ago and were designed to identify patients who were most likely to carry BRCA1/2 variants.

This was done to reduce the number needed to test; at that time, the cost of genetic testing was $2000 to $5000 per test.

Now, it is approximately 10 times less costly to conduct germline testing than it was when the guidelines were originally established.

Still, Milliron and Griggs calculate that the call to have all women with breast cancer undergo genetic testing would amount to about $400 million in total costs to insurance companies. They arrive at this estimate by considering the current cost of $1500 per test multiplied by the number of new breast cancer cases diagnosed each year in the United States.

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