Identifying pathogenic/likely pathogenic variants in high-risk cancer genes is key to cancer risk management.Prophylactic surgeries like RRM and RRSO are guideline-recommended options. This study aims to provide real-world evidence on their clinical implementation. Between 2020 and 2025, 203 women referred for genetic testing at Genekor Medical S.A., were detected with P/LP variants in cancer susceptibility genes, for which risk-reducing surgical options are either recommended or considered for discussion. Referring clinicians were invited to complete a questionnaire to assess whether prophylactic surgical options had been discussed, if the patients had agreed to undergo such procedures, and whether the surgeries have already been performed or postponed. Among the individuals referred for genetic testing, 168(83%) were referred following a cancer diagnosis, while 35(17%) were unaffected individuals referred due to a family history. 153 individuals (76%) harbored BRCA1/2, 31(15%) harbored PALB2, PTEN, TP53 and 19 (9%) harbored BRIP1,RAD51C, RAD51D P/LP variants. RRSO was discussed with 78/153 (51%) of BRCA1/2 carriers and agreed in 60/78 (77%) cases. Addition of hysterectomy to RRSO was discussed in 16/78 (21%) of cases and agreed in 10/16 (63%). RRM was discussed with 113/203 (56%) of patients and agreed in 73/113(65%). In PALB2, PTEN, TP53 carriers, RRM was discussed in 21/31 (68%) cases, and accepted in 9/21 (43%), while in 5 cases both RRM/RRSO were discussed with 3 women agreeing. Finally, for 19 BRIP1,RAD51C, RAD51D carriers, in 9 cases the physician discussed RRSO as an option, with the examinees agreeing in 7 of them and in 5 cases RRM was discussed with agreement to proceed in 2 of them. In all cases, 22 individuals although agreed to proceed with RRM and/or RRSO, decided to postpone the procedure. This study highlights the high awareness and acceptance of surgical management demonstrating the adherence to the recommendations. Age under 35 years and receiving therapy at the time of genetic testing were significant factors in lowering risk reduction RRSO and hysterectomy performance rates. Stage IV cancer was the main reason for not discussing surgical intervention. K. Papazisis, M. Paraskeva, S. Giassas, M. Skondra, R. Iosifidou, C. Tolis, G. Kesisis, E. Zairi, V. Venizelos, C. Markopoulos, I. Natsiopoulos, E. Bleka, I. Xanthakis, A. Ananiadis, D. Matheos, D. Stefanou, A. Adamidis, A. Meintani, G. Kapetsis, D. Bouzarelou, E. Papadopoulou, G. Nasioulas. High-risk cancer susceptibility genes mutation carriers’ compliance with surgical risk reduction for breast and ovarian cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-05-05.
In early-stage estrogen receptor-positive (ER+), HER2-negative (HER2−) breast cancer, the Oncotype DX® Recurrence Score (RS) is a clinically validated 21-gene assay that informs prognosis and predicts the benefit of adding chemotherapy to endocrine therapy. While germline pathogenic variants (PVs) in cancer susceptibility genes may influence tumor biology, treatment response and surgical management, their relationship with RS remains insufficiently explored and has been primarily limited to BRCA1/2 genes. This study investigates the association between Oncotype DX RS and the presence of germline PVs across a broader spectrum of breast cancer predisposition genes. We retrospectively analyzed data from a Greek cohort of early-stage ER+, HER2- breast cancer pts who underwent both germline testing using a 52-gene panel and Oncotype DX testing between 2015 and 2025. Pts were stratified by Oncotype DX Recurrence Score (RS) into low (RS 0-10), intermediate (RS 11-25), and high-risk (RS >25) genomic groups. Germline testing results were categorized into three groups: (a) pathogenic/likely pathogenic (P/LP) variants identified, (b) variants of uncertain significance (VUS), and (c) no variants detected. The P/LP group was further subdivided based on the presence of variants in (a) BRCA1/2, (b) other high-risk genes, (c) moderate-risk genes, and (d) incidental findings in additional genes. A total of 1,465 pts were analyzed. The distribution of Oncotype DX RS across the various germline testing groups is detailed in the table below. The distribution of RS varied notably across genetic variant groups. Pts with BRCA1/2 and other high-risk gene variants exhibited statistically significant higher median RS values (p<0.0001) and higher percentage of pts with RS>25 (p<0.0001) compared to all other subgroups (moderate risk variants, incidental findings, VUS and cases without detected variants). These patterns suggest that pts with germline mutations in high-risk susceptibility genes are more likely to have an unfavorable prognosis for distant recurrence and a greater likelihood of receiving chemotherapy, as indicated by their elevated RS values V. Venizelos, K. Papazisis, C. Markopoulos, G. Xepapadakis, R. Iosifidou, G. Kapetsis, S. Giannoulakis, N. Tsoulos, A. Meintani, D. Bouzarelou, G. Tsaousis, D. Grosomanidis, N. Bredakis, F. Zagouri, C. Christodoulou, K. Anastasakou, M. Paraskeva, D. Mavroudis, N. Michalopoulos, D. Tryfonopoulos, S. Papadopoulos, A. Adamidis, D. Dimas, E. Angelidou, E. Papadopoulou, G. Nasioulas. Association of Oncotype DX Recurrence Score with Germline Mutations in Cancer Susceptibility Genes Including BRCA1/2 in HR+/HER2− Early Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-08-24.
e12548 Background: Germline genetic testing referral of HBOC syndrome and relevant cancer patients is being undertaken using criteria that maximize the probability of finding a disease-causing variant and its actionability. In young onset breast cancer (BC, ≤50 y), invasive epithelial non-mucinous ovarian cancer, metastatic or node positive prostate cancer and exocrine pancreatic cancer, germline genetic testing is universally accepted. Genetic testing in older onset BC patients (>50 y) uses strict clinical criteria like triple negative phenotype or bilateral BC and the presence of family history (FH). This study investigated genetic differences between young- and older-onset HBOC patients to estimate whether the threshold of the likelihood of finding a disease-causing variant can be lowered. Methods: In this study we characterized the mutational landscape of a total of 7.694 suspected HBOC related syndrome individuals, that were referred- regardless of age and FH- for multigene genetic testing using NGS technology, during the period 2020-2024 in GENEKOR MEDICAL S.A. Among the examined individuals, 1,677 (21.8%) were carriers of a pathogenic/likely pathogenic variant and the reason of referral was breast cancer in 90.6%, ovarian cancer in 14.7%, pancreatic cancer in 3.50% and prostate cancer in 1.5% of the cases. Results: Among young BC patients the highest proportion of pathogenic variants were identified in BRCA1 (21%), CHEK2 (17.2%), BRCA2 (14.5%), ATM (5.5%) and PALB2 (3.8%), while FH does not change the landscape of genes mutated. In older BC patients the percentages were modified as following: BRCA2 (14.6%), CHEK2 (14.2%), BRCA1 (13.4%), PALB2 (3.8%) and ATM (5.6%). Even without FH, pathogenic variants, were still detected but in slightly lower percentages in the following genes CHEK2 (7.7%), BRCA1 (7.7%) and PALB2 (7.7%) in this cohort. Conclusions: The results of this study provide some evidence that the mutational landscape among young-onset BC patients is not different from those of older-onset BC patients, even when taking FH into account. Following strictly the age limit cut-off combined with FH as proposed by international guidelines would result in overlooking 1% of gene-testing positive BC patients and defective management of their families.
