Abstract P3-09-02: Mutational assessment of newly diagnosed breast cancer using Germline and tumor genomICs
Authors: Dilanka L De Silva, Anita R Skandarajah, Michelle Sinclair, Maira Kentwell, Lisa Devereux, Magnus Zeethoven, Kirsten Hogg, Luxi Lal, Lesley Stafford, Paul A James, Geoffrey J Lindeman, Gregory B Mann, Ian G Campbell
Journal: Cancer Research (2022)

Abstract Background :For patients with newly diagnosed breast cancer, real-time identification of pathogenic germline mutations in hereditary breast cancer (HBC) genes can provide important information to inform decisions regarding surgery, medical oncology, radiation oncology and to enable activate risk mitigation strategies for unaffected relatives. The potential to dramatically improve outcomes by identifying HBC gene mutation carriers at diagnosis has been demonstrated in the OlympiA. The current strategy of offering germline testing based on NCCN guidelines or validated scores inherently fails to identify all patients with germline HBC gene mutations with adverse consequences for patients and their families. Also, in about 15% of patients without HBC gene mutations, the breast tumors have characteristics suggestive of a more aggressive course. Although universal HBC gene testing has been reported for sub-types of breast cancer or at specialist centers, the MAGIC study is the first prospective trial of unselected invasive breast cancers in general practice combining upfront germline and somatic sequencing with well-validated methods to assess the acceptability of universal testing to patients and clinicians. Methods :This is an Australian multi-center prospective study with 150 consecutive consented patients who are newly diagnosed with nonmetastatic breast cancers. High-grade ductal carcinoma in-situ and pleomorphic lobular cancers were included. Germline testing was performed by whole genome sequencing on DNA from blood or saliva and the data analyzed for actionable HBC gene mutations, including large genomic rearrangements. Whole genome Tumor sequencing was performed on DNA extracted from formalin fixed paraffin-embedded diagnostic tumor and the data analyzed for actionable somatic mutations as well as scoring for homologous recombination deficiency using HRDetect and mutational signatures. The frequency of actionable HBC gene mutations and the number of additional carriers identified compared to standard referral guidelines was the primary objective. For additional analysis, a 3-generation pedigree was done and NCCN, MANCHESTER, and BOADICEA scores were calculated to see whether they would qualify for germline testing according to American and Australian guidelines. Well validated questionnaires were given pre and post-testing for all patients to assess the favorability of universal testing. Health economic analysis will be performed to see the cost vs benefit of offering germline testing. Results :A total of 12 carriers of actionable germline mutations were identified (8.0%) in BRCA1 (n=2), BRCA2 (n=1), PALB2 (n=3), CHEK2 (n=2), ATM (n=2) and PMS2 (n=2). No actionable HBC germline mutations were identified in the 14 cases diagnosed with DCIS only. Only 3 of the 12 mutation positive cases (25%) were referred by the treating clinician for germline testing and including BOADICEA and MANCHESTER scores, would only have identified 6 cases (50%) eligible for germline testing. 9/12 (75%) cases were ER positive including 4 carriers of BRCA1, BRCA2 or PALB2 mutations. Preliminary ascertainment of patient acceptance demonstrates &amp;gt;90% were in favor of universal testing. Among the 12 HBOC gene mutation carriers, the study changed the surgical recommendation for 7 patients (58%) which included the recommendation of B/L salpingo-oophorectomy and radiation management for 3 (25%) patients. Conclusion :Universal germline HBC gene testing is the best method for detecting carriers as over 50% are missed using current. Identifying an actionable mutation in real-time can inform the decision in all specialties involved in the treatment and has a high rate of impacting the clinical decision-making process. This approach was favored by the patients and the clinicians and provided a pathway forward for breast cancer management. Citation Format: Dilanka L De Silva, Anita R Skandarajah, Michelle Sinclair, Maira Kentwell, Lisa Devereux, Magnus Zeethoven, Kirsten Hogg, Luxi Lal, Lesley Stafford, Paul A James, Geoffrey J Lindeman, Gregory B Mann, Ian G Campbell. Mutational assessment of newly diagnosed breast cancer using Germline and tumor genomICs [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-02.