Testing for pathogenic variants (PVs) in breast cancer genes and clinical/genetic risk models identify different subsets of high-risk women and are not interchangeable for determining risk-based breast cancer screening strategies, according to research presented May 31 at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.
In the recently completed WISDOM risk-based breast cancer screening trial, most carriers of PVs who were screened with MRI alternating with mammography every six months would not have been recommended for high-risk screening based on clinical risk models and polygenic risk scores alone.
“Versions of risk-based screening that omit PV testing are likely to miss a substantial portion of women eligible for high-risk screening,” said presenter and first author Yiwey Shieh, MD, of the University of California, San Francisco.
The new research was motivated by the currently restricted role of germline testing for PVs to women with a strong personal or family history of breast or ovarian cancer, Shieh said.
In the WISDOM trial, unrestricted PV testing was performed on a population level, however. Screening recommendations in that study were based on panel-based testing for PVs in nine breast cancer genes, as well as a five-year risk score based on the Breast Cancer Surveillance Consortium (BCSC) clinical risk model plus a polygenic risk score including common genetic variants.
Incremental impact?
As a number of risk-based screening studies underway are currently omitting PV testing, the researchers wanted to explore its incremental impact. They used data from the WISDOM study to make hypothetical screening assignments based only on a risk model and compare them to the actual assignment based on PV status.
The hypothetical assignment based on the risk model would categorize women as high-risk if they had a five-year risk of ±6%. Annual mammography would be recommended for annual mammography if they had a five-year risk in the top 2.5th percentile for age or were between the ages of 40 and 50 and had extremely dense breasts.
Biennial mammography would recommended for women ±50 or ages 40 to 49 and a five-year risk of ≥1.3%. No screening would be recommended at this time for women ages 40 to 49 with a five-year risk of <1.3%.
In the actual assignment in WISDOM based on PV status, women were assigned to high-risk screening with MRI and mammography alternating every six months if they had PV in a high-penetrance gene or PV in a moderate-penetrance gene with a family history of breast cancer. Women who had PV in a moderate-penetrance gene without a family history of breast cancer were assigned to annual mammography.
The researchers cross-tabulated actual versus hypothetical screening assignments for the 712 PV carriers in the WISDOM trial who had received a screening assignment. Of the 712 women, 232 (32%) had a PV in at least one high-penetrance gene (BRCA2, BRCA1, PALB2, TP53, CDH1, STK11), 30% had a PV in a moderate-penetrance gene (CHEK2, ATM), and 202 were CHEK2 low penetrance.
Minimal overlap
The most important finding was that 100% of high-risk penetrance PV carriers received a high-risk screening recommendation, but only 1% of those women would have been recommended for the same high-risk screening assignments based on the clinical risk score and polygenic risk score.
Instead, 29% would have been asked to wait on screening until age 50, 59% would have been recommended for biennial mammography, and 10% would have been recommended for annual mammography, he said.
Shieh acknowledged the limitations of the research, which was descriptive in nature and does not directly address the impact of PV testing on screening outcomes. Additionally, the BCBC + PRS risk score strategy is not intended for use in PV carriers and is shown for hypothetical purposes only.
However, he also highlighted lessons learned from unrestricted PV testing in the WISDOM trial.
“We know that in WISDOM of the group assigned high-risk screening, there was evidence of downstaging, as this group had the highest overall breast cancer incidence, but no advanced cancers,” he said. No stage IIB+ cancers were found in this patient group.
The researchers concluded that germline testing for PVs and clinical/genetic risk models “are both critical cornerstones of risk-based screening.”
“Versions of risk-based screening that omit PV testing are likely to miss a substantial portion of women eligible for high-risk screening,” he said.
In risk-based screening strategies that omit PV testing, “these women would potentially miss on the benefits of downstaging seen with high-risk screening in WISDOM,” Shieh said. “This analysis and the WISDOM results highlight the importance of unrestricted germline genetic testing to assess breast cancer risk.”
