Abstract P6-02-04: Use of breast surveillance between women with pathogenic variants and variants of uncertain significance in breast cancer susceptibility genes
Authors: Makhnoon Sukh , Chen Minxing , Levin Brooke , Ensinger Megan , Mattie Kristin , Grana Generosa , Shete Sanjay , Arun Banu K. , Peterson Susan K. 
Published: March 2023

Background: Surveillance is a fundamental tool in the early detection and secondary prevention of many cancers. For women at increased genetic risk of breast cancer, mammography and breast magnetic resonance imaging (MRI) serve as the standard screening modalities. Use of surveillance mammography and MRI has been understudied among women with variant of uncertain significance (VUS) compared to pathogenic and likely pathogenic variants (P/LP). To address this gap, we examined the use of breast cancer surveillance and breast surgery in women who underwent multiple gene sequencing in a multicenter cohort of patients. We also expanded the surveillance literature by assessing correlates of breast MRI and mammography among women with VUS and investigating how rates of imaging changed over time after genetic testing. Methods: Using data from two cancer settings, we calculated use of risk reducing mastectomy (RRM) and surveillance for all women at genetically elevated risk of breast cancer, regardless of their personal history of breast cancer, with VUS or P/LP variants in a breast cancer susceptibility gene of high penetrance (BRCA1, BRCA2, PALB2, PTEN, TP53) and moderate penetrance (ATM, CDH1, CHEK2, NBN, NF1, STK11). The primary outcome was longitudinal use of surveillance mammography and breast MRI for women during the 13-month span after genetic testing, and each subsequent 13-month period up to 6 years afterwards. Results: Of 889 women, those with and without personal history of breast cancer were similar with regards to race/ethnicity, marital status, and high- or average-risk status. However, women with a personal history of breast cancer were on average older (54.1 vs 48.2 years), had longer follow-up time since genetic testing (3.4 vs 3.0 years), and were more likely to have VUS (62.5% vs 37.7%) compared to those without personal history of breast cancer. VUS carriers were less likely to undergo RRM compared to those with P/LP (HR=0.17, p=&lt; 0.001) and high-risk women were more likely to undergo RRM than average-risk women (HR=3.91, p=0.005). 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 afterwards. Over the first four years after genetic testing, women with VUS were less likely to undergo annual MRIs compared to P/LP. This observation was true for women without a personal history of breast cancer (OR=0.34, p=0.003; OR=0.37, p=0.03; OR=0.19, p=0.004 for years 1, 2, and 3 respectively) as well as for women with a personal history of breast cancer (OR=0.31, p&lt;=0.001; OR=0.33, p=0.002; OR=0.37, p=0.012; OR=0.3, p=0.14 for years 1, 2, 3, and 4 respectively). Conclusion: In this study of surveillance mammography and breast MRI use among women at elevated risk of breast cancer, we found that women with P/LP variants in breast cancer susceptibility genes are more likely to undergo annual breast MRI compared to those with VUS, whereas there was no difference between the groups in their use of annual surveillance mammography. This study is one of the first to examine maintenance of breast surveillance in a sample of women at elevated risk of breast cancer with non-negative genetic test results in BRCA1/2 as well as non-BRCA1/2 genes, while adjusting for personal and family history of cancer. In addition, we 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 to dispel the myth of VUS-associated mismanagement of care.

Citation Format: Sukh Makhnoon, Minxing Chen, Brooke Levin, Megan Ensinger, Kristin Mattie, Generosa Grana, Sanjay Shete, Banu K. Arun, Susan K. Peterson. Use of breast surveillance between women with pathogenic variants and variants of uncertain significance in breast cancer susceptibility genes [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-04.