Uncertainty Remains Regarding Moderate-Penetrance Breast Cancer-Predisposing Genes in Treatment

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Since the advent of commercially available next-generation sequencing, women have been identified as carrying moderate-penetrance gene mutations.
Since the advent of commercially available next-generation sequencing, women have been identified as carrying moderate-penetrance gene mutations.

SAN ANTONIO—Since the advent of commercially available next-generation sequencing, hundreds—and perhaps thousands—of women have been identified as carrying moderate-penetrance gene mutations that predispose them to breast cancer.1

But how best to put all of this information to clinical use is unclear, cautioned Mark Robson, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, speaking at the 2015 San Antonio Breast Cancer Symposium.

“What is actionable? What actions do we take,” he asked. “And when? At what age to we start surveillance, and how often do we do surveillance?”

With the proliferation of gene panels, “we've all been living with these complexities over the past year or 18 months,” he said.

Tests should be actionable, meaning they should allow reasonable changes in patient management based on their results, he said. “Clinical utility is a higher bar,” because it requires using a test to direct care to improve measurable outcomes, he noted.

“The appropriate management of these predispositions remains unclear, as guidelines developed for those with high-penetrance mutations are not appropriate for most of those with more moderate risks,” Dr Robson said.

 Moderate-penetrance mutations can best be thought of as risk factors, “which interact with other genetic (eg, family history) and nongenetic factors to influence an individual's breast or ovarian cancer risk,” Dr Robson suggested. “This is different from the situation with high-penetrance mutations, where the mutation is causative in isolation. Management should be directed by this concept, tailored to the family history.”

“Mutations in a number of moderate-penetrance genes have been found that confer average relative risks of 2 to 3, with even higher risks in the setting of a family history,” Dr Robson said. “These genes include CHEK2ATMPALB2, and possibly others such as NBN.”

“But clinical actionability requires clinical validity,” Dr Robson emphasized. ATM, CHECK2, PALB2, and NBN have been clinically validated for breast cancer risk, with odds ratios (ORs) of 2.8, 3.0, 5.3 and 2.7, he noted.

Other genes, including BARD1 and MRE11A, may also confer moderate-penetrance breast cancer predisposition, but to date, “evidence of clinical validity is lacking,” Dr Robson cautioned.  

Dr. Robson said that the effectiveness and cost-effectiveness of incremental MRI screening for women at moderate risk of breast cancer is also unclear, “although the lifetime risks associated with several moderate-penetrance mutations cross the 20% threshold proposed by the American Cancer Society and American College of Radiology.”

“There is no consensus, however, as to the age at which to begin this screening,” Dr Robson noted.

There are also problems with the concept of “cumulative lifetime risk,” he was quick to add—including the fact that no consensus exists on how to calculate it (what age calculations should extend to include). “It's nearly impossible to do calibration studies,” he said. “And cumulative lifetime risk is not helpful when deciding when to initiate surveillance.”

RELATED: Clarity, Timing Are Important Factors in the Use of Genetic Testing

“It's good for classification of risk from a gene,” he noted. “It's not so good for individual decision making.”

He recommends calculating gene-associated risks for shorter time horizons, which makes calibration studies more feasible and offers “more clinically meaningful” information.  

Making moderate-penetrance gene tests clinically actionable will ultimately depend on the availability of age-specific risks and incidence, models that incorporate family history and nongenetic risk factors, and consensus about thresholds for action “other than lifetime risk,” Dr Robson said.

Reference

  1. Robson M. Management of non-BRCA breast cancer predisposition. Oral presentation at: San Antonio Breast Cancer Symposium 2015; December 8, 2015; San Antonio, TX.

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