Use of breast surveillance between women with pathogenic variants and variants of uncertain significance in breast cancer susceptibility genes

Abstract

Background Use of surveillance mammography and magnetic resonance imaging (MRI) has been understudied among women with variant of uncertain significance (VUS) compared to pathogenic and likely pathogenic variants (P/LP). Methods Using data from two cancer settings, we calculated use of risk‐reducing mastectomy (RRM) and surveillance during each 13‐month span after genetic testing up to 6 years afterwards for a cohort of genetically elevated risk women. Results Of 889 women, VUS carriers were less likely to undergo RRM compared to those with P/LP (hazard ratio [HR], 0.17; p = <.001) and high‐risk women were more likely to undergo RRM than average‐risk women (HR, 3.91; p = .005). Longitudinally, surveillance use among unaffected women decreased from 49.8% in the first year to 31.2% in the sixth year after genetic testing. In comparison, a greater proportion of women with a personal history of breast cancer underwent surveillance, which increased from 59.3% in the first year to 63.6% in the sixth year after genetic testing. Mammography rates did not differ between women with P/LP and VUS within the first 13 months after genetic testing and up to 4 years afterward. Over the first 4 years after genetic testing, women with VUS were less likely to undergo annual MRIs compared to P/LP. Conclusion The authors found that VUS, whether in high or moderate penetrance breast cancer susceptibility genes, was associated with lower use of annual breast MRI compared to P/LP variants and equivalent use of annual mammography. These results add important evidence regarding VUS‐related breast surveillance.

Risk management actions following genetic testing in the Cancer Health Assessments Reaching Many (CHARM) Study: A prospective cohort study

“…In contrast to individuals who received a new diagnosis of inherited breast cancer susceptibility, the use of breast MRI was rare among those who did not receive actionable recommendations and the majority of them who had mammograms and/or colonoscopies were over age 40 or 45 years, respectively. These findings are consistent with other work examining patient actions after clinical exome sequencing 19,21,36 and suggest that overtreatment following cancer genetic testing is likely rarer than expected based on prior vignette and case studies 37,38 …”

“…These findings are consistent with other work examining patient actions after clinical exome sequencing 19,21,36 and suggest that overtreatment following cancer genetic testing is likely rarer than expected based on prior vignette and case studies. 37,38 Our findings offer a number of useful lessons for health care systems interested in implementing programs to provide clinically-indicated cancer genetic testing to their patients. First, initiatives to equitably scale-up risk assessment and genetic testing, like CHARM, can facilitate proactive risk management use.…”

“…These findings are consistent with other work examining patient actions after clinical exome sequencing 19 , 21 , 36 and suggest that overtreatment following cancer genetic testing is likely rarer than expected based on prior vignette and case studies. 37 , 38 …”

Protein-Folding Chaperones Predict Structure-Function Relationships and Cancer Risk inBRCA1Mutation Carriers

“…Understanding how changes in genotype transform into phenotypes is paramount to predicting cancer risk and developing efficacious treatments in the clinic. In the era of personalized genomics, the number of variants of uncertain clinical significance (VUS) has grown faster than the rate of variant assignment [1][2][3] . In addition, there exists substantial discordance among leading commercial laboratories that classify variants and provide genetic testing services 4 .…”