Evolution of genetic testing for breast cancer spurs questions about best criteria to use
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Genetic testing for breast cancer has evolved substantially since its inception nearly 30 years ago, according to a speaker at Chemotherapy Foundation Symposium.
“Back in the mid-90s, we had certain beliefs about genetic testing — we thought mutations, or pathogenic variants, were rare and that they conferred a virtual certainty for developing either breast cancer or ovarian cancer,” Mark E. Robson, MD, oncologist and associate attending physician of the clinical genetics and breast medicine service in the department of medicine at Memorial Sloan Kettering Cancer Center, said during a presentation. “It is somewhat embarrassing to acknowledge that everything we thought back then is wrong but that’s science — it happens that way sometimes. We did not know that there was a therapeutic benefit to genetic testing and we didn’t even know if preventive interventions would work.”
Resources were also limited when genetic testing began, Robson added.
“There were only so many genetic counselors to go around, and back then there were even fewer tests than there are now — and the tests were expensive,” he said. “We also presumed that we would be able to figure out who had an alteration through clinical criteria and specifically through pedigree analysis.”
Today, much is known about genetic testing but the question of who should be tested remains.
Robson presented three different scenarios for which individuals should be eligible: Only women who meet National Comprehensive Cancer Network criteria, all women with breast cancer or only women aged younger than 65 years.
“Also, should the tests only screen for BRCA1, BRCA2 and PALB2 or should multigene panel testing be used that includes a wider range? What about population testing — should every individual have the chance to be tested? Truthfully, this wouldn’t work for several reasons, but cascade testing — using an effective [patient with breast cancer] as the gateway into a family — could be an efficient strategy to identify all families in the United States who have BRCA alterations,” Robson said.
Genetic testing is also cost-effective under certain assumptions, such as multigene testing for all patients with breast cancer, he added.
“If we test every individual with breast cancer, we will identify more pathogenic variant carriers than if we test by criteria alone. We will identify a few more BRCA and PALB2 carriers who will make more informed decisions about contralateral mastectomy who may be eligible for PARP [poly(ADP-ribose) polymerase] inhibitors in either the metastatic or early-stage disease setting. It will also potentially reduce racial and socioeconomic inequities in genetic testing access,” Robson said.
“Now, should we test all genes?” Robson added. “When thinking about a multigene panel, every testing company has multiple different offerings — some contain 80 to 90 genes]. It is worthwhile to take a step back and think about what might be on the panel.”
On the flip side, genetic testing for all pathogenic variants may cause issues.
“For one, the risks for certain genes are substantially lower than for BRCA1 and BRCA2, and many variants on the testing panels do not have statistically significant associations with breast cancer,” Robson said. “Clinical validity is completely unclear. Even for those with a statistically significant association, risk is often less than that of a woman who has a first-degree relative.”
Another complexity to this is that, unlike BRCA1 and BRCA2 where the risks are not particularly modifiable, the risks for genes such as CHEK2 and ATM are highly modifiable by other factors, including mammographic density, traditional risk factors and polygenic risk, he added.
“The reality is that many of us do perform multigene testing and there is no way to stop this, but we have to keep in mind exactly what that accomplishes,” Robson said.
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Robson ME. Benefits of genetic testing all patients with breast cancer. Presented at: 39th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 3-5, 2021.
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