Abstract PO1-02-13: Germline mutation status of BRCA1/2 and other breast cancer predisposition genes as predictive and prognostic biomarker: Results of the GeparX study (GeparX-BRCA)
Authors: Schmutzler Rita K. , Link Theresa , Hahnen Eric , Reinisch Mattea , Hauke Jan , Just Marianne , Untch Michael , Ernst Corinna , Stötzer Oliver , Fasching Peter A. , Kayali Mohamad , Wimberger Pauline , Schneeweiss Andreas , Schmidt Sandra , Seiler Sabine , Jackisch Christian , Thill Marc , Rhiem Kerstin , Denkert Carsten , Nekljudova Valentina , Holtschmidt Johannes , Blohmer Jens-Uwe , Loibl Sibylle 
Published: May 2024

Germline mutation status of BRCA1/2 and other breast cancer predisposition genes as predictive and prognostic biomarker: Results of the GeparX study (GeparX-BRCA) Background: There is accumulating evidence that the RANK/RANKL signaling pathway plays a pivotal role in breast tumorigenesis, particularly in the development of BRCA1-mutated tumors. Targeting the RANK pathway has been shown to attenuate breast cancer (BC) proliferation in vitro and in vivo. Studies using bone modifying agents as adjuvant therapy showed reduced rates of bone metastases and improved BC survival, as well as prevention of treatment-induced skeletal events. The GeparX clinical trial assessed the use of denosumab in patients with primary BC as an adjunct to neoadjuvant chemotherapy for its ability to enhance pathological complete response (pCR) rate and improve outcome. The trial randomized 780 patients twice to a total of 4 treatment groups (to receive or not receive denosumab; to receive nab-paclitaxel 125 mg/m2 weekly for 12 weeks or days 1 and 8 every 3 weeks for 4 cycles, both followed by 4 cycles of epirubicin/cyclophosphamide, 90/600 mg/m2 every 2 weeks/every 3 weeks according to the investigator´s choice). Carboplatin was given in triple-negative breast cancer (TNBC), and trastuzumab biosimilar ABP980 plus pertuzumab was given in human epidermal growth factor-2-positive (HER2+) BC. Overall, the pCR (ypT0 ypN0) rate was 41% with denosumab vs 43% without; nab-paclitaxel at a dosage of 125 mg/m2 weekly resulted in a significantly higher pCR rate of 45% vs 39% with a dosage of 125 mg/m2 days 1 and 8 every 3 weeks. Research question: Does the germline mutation status of BRCA1/2 and other BC predisposition genes affect treatment outcome in the GeparX study? Methods: Genetic germline analyses assessing pathogenic variants in BRCA1/2 and 16 other BC predisposition genes were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany; 767 patients were included in this secondary investigation (308 TNBC, 306 HER2-/hormone receptor positive [HR+], 153 HER2+). Findings: Germline BRCA1/2 mutations were present in 91/767 patients (11.9%), with a higher mutation prevalence in TNBC (50/308, 16.2%) and HER2-/HR+ BC (37/306, 12.1%), and a low mutation prevalence in HER2+ BC (4/153, 2.6%). Overall, the pCR rate (ypT0 ypN0) was elevated in BRCA1/2 mutation carriers vs non-carriers (49.5% vs 41.1%, respectively; overall: OR 1.40, 95% CI 0.90-2.17; TNBC: OR 1.24, 95% CI 0.67-2.32; HER2-/HR+: OR 1.83, 95% CI 0.86-3.88). Highest pCR rates were observed in TNBC in BRCA1/2 mutation carriers vs non-carriers (60% vs. 54.7%, respectively). Highest pCR rate differences were observed HER2-/HR+ BC in BRCA1/2 mutation carriers vs non-carriers (32.4% vs. 20.8%, respectively). Regarding treatment arms, both BRCA1/2 mutation carriers and non-carriers benefitted most from nab-paclitaxel at a dosage of 125 mg/m2 weekly vs 125 mg/m2 days 1 and 8 every 3 weeks (BRCA1/2 mutation carriers: 55.3% vs 43.2%, respectively; OR 1.63, 95% CI 0.71-3.73; non-carriers: 43.7% vs 38.6%, respectively; OR 1.24, 95% CI 0.91-1.68). No beneficial effect was observed for denosumab vs no denosumab (51.1% vs 47.8% for BRCA1/2 mutation carriers, respectively; OR 1.14, 95% CI 0.50-2.60; 40.3% vs 41.9% for non-carriers, respectively; OR 0.94, 95% CI 0.69-1.27). Of the 617 BRCA1/2-negative patients, 59 patients carried mutations in other BC predisposition genes which did not predict therapy response compared to patients without any mutation. Conclusions: Irrespective of the treatment arm, higher pCR rates were observed in BRCA1/2 mutations carriers vs non-carriers. Both BRCA1/2 mutation carriers and non-carriers benefitted most from weekly nab-paclitaxel. No pronounced effect was observed for denosumab in either group. Key words: GeparX, denosumab, BRCA1/2 germline mutations, therapy response Funding: GeparX was financially supported by Amgen and BMS (Celgene).

Citation Format: Rita K. Schmutzler, Theresa Link, Eric Hahnen, Mattea Reinisch, Jan Hauke, Marianne Just, Michael Untch, Corinna Ernst, Oliver Stötzer, Peter A. Fasching, Mohamad Kayali, Pauline Wimberger, Andreas Schneeweiss, Sandra Schmidt, Sabine Seiler, Christian Jackisch, Marc Thill, Kerstin Rhiem, Carsten Denkert, Valentina Nekljudova, Johannes Holtschmidt, Jens-Uwe Blohmer, Sibylle Loibl. Germline mutation status of BRCA1/2 and other breast cancer predisposition genes as predictive and prognostic biomarker: Results of the GeparX study (GeparX-BRCA) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-02-13.