The evolution of breast cancer genetic testing: Comparative outcomes of NCCN, ASCO, and universal guidelines in 6,000+ patients.

10619 Background: Germline genetic testing for breast cancer has significantly advanced over the past decade. At King Hussein Cancer Center, 6,336 breast cancer patients underwent genetic testing between 2012 and 2024, transitioning from limited BRCA1/2/PALB2 panels to comprehensive 20-gene and 84-gene panels. Eligibility criteria evolved from strict criteria for testing to broader NCCN and ASCO guidelines by 2024. Universal genetic testing was implemented for all breast cancer cases between April 2021 and September 2022. ASCO guidelines have simpler eligibility criteria, whereas NCCN guidelines are more complex and regularly updated. Methods: This study analyzed genetic testing trends, categorized results by panel type, and compared detection rates of pathogenic/likely pathogenic (P/LP) variants and variants of uncertain significance (VUS). Detection rates were assessed using Chi-square tests, and linear regression calculated annual changes in positive rates. Outcomes were compared between guideline-based (ASCO/NCCN) and universal testing. Results: Of 6,336 patients, 1,731 (27.3%) underwent testing with the 84-gene panel, 3,759 (59.3%) with the 20-gene panel, and 846 (13.4%) with limited testing. Testing volumes increased from 248 cases between 2012-2017 to ~1,000 annually after 2021. Overall, 686 (10.8%) patients had P/LP variants, with higher rates in patients under 30 years (24.4%) and triple-negative breast cancer (20.6%). Among 5490 patients tested with multigene panels, P/LP detection rates were similar: 10.5% (306/2917) for NCCN, 9.4% (87/924) for ASCO, and 9.1% (150/1649) for Universal; p-value was 0.276. No significant difference in P/LP rates was observed between the 84-gene panel 9.2% (160/1,731), and the 20-gene panel 10.2% (383/3,759, p=0.297), but the VUS rate was significantly higher in the 84-gene panel (66.2% vs. 26.2%; p<0.001). Conclusions: Expanded panels (84-gene) did not improve detection of P/LP but significantly increased VUS rates. Universal testing did not lower P/LP detection rates compared to guideline-based testing, and no significant difference was observed between ASCO and NCCN guidelines. ASCO guidelines, offering simpler eligibility criteria, or even universal testing, may be more practical compared to the periodically updated NCCN guidelines and should improve compliance and referral rates. Genetic testing. Genetic testing Number6,336 P/LP p-value VUS p-value Limited test (BRCA1/2, PALB2) 846 143.0 (16.9%) 73.0 (8.6%) Multigene panel (5490) 84-gene panel 1,731 160/1731 (9.2%) 0.297 1146/1731 (66.2%) <0.001^ 20-gene panel 3,759 383/3759 (10.2%) 986/3759 (26.2%) Guidelines* Universal testing 1649 150 (9.1%) 0.276 1131 (68.6%) <0.001^ NCCN Guideline 2917 306 (10.5%) 784 (26.9%) ASCO Guidelines 924 87 (9.4%) 217 (23.5%) *Excluding patients with limited genetic testing. ^Pearson's chi-squared test.