Müller, Volkmar

Abstract Background: The current standard of care for first-line (1L) treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) consists of induction chemotherapy combined with trastuzumab (TRAS) and pertuzumab (PERT) followed by maintenance therapy with TRAS + PERT. Although this regimen has been associated with sustained disease control, most patients eventually experience disease progression. The HER2CLIMB-05(NCT05132582) study is investigating the efficacy and safety of adding tucatinib to TRAS + PERT as maintenance therapy in patients with HER2+ MBC after completion of 1L chemotherapy-based induction therapy. Methods: Patients with centrally confirmed HER2+MBC without evidence of progression after 1L induction therapy with 4 to 8cycles of a taxane combined with TRAS + PERT, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and no or asymptomatic brain metastases (BM) were enrolled in HER2CLIMB-05. Contrast-enhanced brain magnetic resonance imaging was performed at screening and regular intervals during the study. Patients were randomly assigned 1:1 to receive either tucatinib 300 mg or placebo twice daily, in combination with either TRAS (6 mg/kg IV or 600 mg SC) plus PERT (420 mg/kg IV) or a SC fixed-dose combination of TRAS, PERT, and hyaluronidase administered every 21 days. Endocrine therapy was permitted for patients with hormone receptor-positive tumors. The primary endpoint is investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints include overall survival (OS), PFS by blinded independent central review, investigator-assessed central nervous system (CNS)-PFS, and safety. Results: Between March 2022 and July 2024, 654 patients were randomly assigned to receive tucatinib (n = 326) or placebo (n = 328) with1L maintenance therapy. All patients were female (median age: 54 years [range, 24-83]);45.0% were White, 35.2% were Asian, 2.9% were Black/African American, and 19.3%were Hispanic/Latino(a)/Spanish origin. Most patients had ECOG PS of 0 (64.1%)and de novo metastatic disease (69.3%). At baseline, 12.4% of patients had presence or history of BM and 52.6% had hormone receptor-positive MBC. As of September5, 2025, PFS was statistically significantly improved with the addition of tucatinib versus placebo to 1L maintenance therapy (hazard ratio [HR] = 0.641 [95%confidence interval (CI), 0.514-0.799]; 2-sided P < 0.0001). All prespecified patient subgroups demonstrated a PFS benefit with tucatinib combination 1L maintenance therapy consistent with the overall population and regardless of presence or absence of BM at baseline or hormone-receptor status. OS is still immature (observed number of deaths = 51;tucatinib arm versus control arm HR = 0.539 [95% CI, 0.303-0.957; 2-sided P= 0.032]). In the safety analysis set, the most common treatment-emergent adverse events (TEAEs) in the tucatinib arm (n = 326) were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (alanine aminotransferase: 28.2%; aspartate aminotransferase:25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1% were, respectively, grade ≥ 3. In the tucatinib arm, 13.5% of patients discontinued tucatinib due to TEAEs. Conclusions: In the HER2CLIMB-05 trial, the addition of tucatinib to TRAS + PERT as 1L maintenance therapy demonstrated a statistically significant and clinically meaningful improvement in PFS with a manageable safety profile in patients with HER2+ MBC. Citation Format: E. Hamilton, G. Curigliano, M. Martin, F. Lerebours, J. Tsurutani, M. Savard, K. Jerzak, X. Hu, L. Martins de Aquino Pimentel, C. O'Sullivan, E. Tokunaga, A. Okines, C. Huang, W. Jacot, J. Sohn, E. Cronemberger Silva, V. Mueller, S. Yang, G. Granata, Q. Shen, L. Santarpia, V. Dieras Her2climb-05: a randomized, double-blind, phase 3 study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as maintenance therapy for her2+ metastatic 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 GS1-01.

PURPOSE The HER2CLIMB-05 study (ClinicalTrials.gov identifier: NCT05132582 ) is investigating the efficacy and safety of adding tucatinib to trastuzumab and pertuzumab as first-line (1L) maintenance therapy in patients with human epidermal growth factor receptor 2–positive (HER2+) metastatic breast cancer (MBC). METHODS Patients with centrally confirmed HER2+ MBC without evidence of progression post induction therapy and no or asymptomatic brain metastases (BM) were enrolled. Patients were randomly assigned 1:1 to tucatinib (300 mg) or placebo twice a day combined with trastuzumab/pertuzumab. The primary end point is investigator-assessed progression-free survival (PFS); secondary end points include overall survival (OS), PFS per blinded independent central review, CNS-PFS, and safety. RESULTS Between March 2022 and July 2024, 654 patients were randomly assigned to tucatinib (n = 326) and placebo (n = 328) arms. All patients were female (median age, 54 years), 69.3% had de novo MBC, 52.6% were hormone receptor–positive, and 12.4% had presence/history of baseline BM. In this primary analysis, PFS was statistically significantly improved with addition of tucatinib versus placebo (hazard ratio, 0.641 [95% CI, 0.514 to 0.799]; P < .0001; median PFS: 24.9 v 16.3 months); a PFS benefit was seen regardless of the presence/absence of BM or hormone receptor status. OS data remain immature. The most common treatment-emergent adverse events (TEAEs) in the tucatinib arm were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (ALT: 28.2%; AST: 25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1%, respectively, were grade ≥3. In the tucatinib arm, 13.5% discontinued tucatinib because of TEAEs. CONCLUSION Tucatinib addition to trastuzumab and pertuzumab demonstrated improvement in PFS with no new safety signals identified and may be an option for 1L maintenance therapy in patients with HER2+ MBC.

Abstract Purpose: The aim of PREDICT was to confirm clinical validity and the potential for clinical utility of serial circulating tumor cell (CTC) enumeration in patients with metastatic breast cancer, focusing on its prognostic value in different breast cancer subtypes and clinical settings. Experimental Design: In total, 4,436 individual patient-level data with CTC results from both baseline and one follow-up (CellSearch; Menarini Silicon Biosystems) were analyzed to evaluate the association between CTC detection and overall survival (OS) in the full patient cohort and separately for tumor and treatment types. Results: Using the cutoff ≥1 CTC for CTC positivity, 913 (20.6%) patients had 0 CTCs at both time points (neg/neg) and 325 (7.3%) and 1,189 (26.8%) patients converted from CTC negative to CTC positive (neg/pos) or vice versa (pos/neg), whereas 2,009 (45.3%) patients had at least one CTC at both time points (pos/pos). The median OS for the neg/neg, neg/pos, pos/neg, and pos/pos group was 45.6, 26.1, 32.3, and 17.3 months, respectively (P &lt; 0.0001, global log-rank test). CTC responders (pos/neg) showed a lower risk of death compared with CTC nonresponders (pos/pos; HR, 0.48; 95% confidence interval, 0.44–0.53). Similar results were obtained in subgroup analyses according to hormone receptor and HER2 subtype, treatment type, and with a ≥5 CTC cutoff for CTC positivity. Conclusions: Follow-up CTC assessments strongly predict OS independently from tumor subtype and treatment. New randomized trials to define the clinical utility of CTC monitoring for risk stratification and as an early response marker in metastatic breast cancer are urgently needed.

PURPOSE Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome. PATIENTS AND METHODS Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed. RESULTS Germline mutations in 12 established BC predisposition genes (including BRCA1 and BRCA2) were detected in 271 (10.4%) patients. A mutation in BRCA1 or BRCA2 was seen in 129 patients (5.0%). BRCA1 mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% v 6.6%, P < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC. CONCLUSION Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in BRCA1/2 and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.

Abstract Background: Several studies suggest clinical utility of serial circulating tumor cell (CTC) enumeration as a means of assessing response status in metastatic breast cancer (MBC). The aim of this study is to conduct a comprehensive pooled analysis comprising globally available data to further define and explore the role of CTC enumeration as a tool for early treatment monitoring in patients with MBC with a focus on the predictive power in different breast cancer subtypes and clinical settings. Methods: In a global effort, peer-reviewed published studies with data on repeated CTC assessments (CellSearch® technology; Menarini Silicon Biosystems; Bologna, Italy) in MBC patients were screened and investigators were asked to provide individual patient data for this pooled analysis. 2761 cases from 32 data sets with data on both baseline and one follow up CTC assessments were included in the analysis (median time interval between the two CTC assessments 35 days). Data were analyzed using log rank tests and Cox regressions to evaluate the association between serial CTC enumeration results and overall survival (OS) in the full patient cohort and defined subgroups. Results: 588 (21.3%) patients had no CTCs at both time points (neg/neg), 236 (8.5%) patients were CTC negative at baseline and CTC positive at follow up (neg/pos), 712 (25.8%) patients converted from CTC positive at baseline to CTC negative (pos/neg), and 1225 (44.4%) patients had at least one CTC at both time points (pos/pos). Log rank tests showed significant differences in OS between these four CTC change groups (p &lt; 0.0001 for all pairwise comparisons except for the comparison between neg/pos and pos/neg, p = 0.015). Median OS for the neg/neg, neg/pos, pos/neg and pos/pos group was 45.6, 26.1, 34.6, and 17.6 months, respectively. Hazard ratios (HR) (reference group neg/neg) were 1.38 (95% CI 1.16 - 1.64) for the pos/neg group, 1.78 (95% CI 1.43 - 2.22) for the neg/pos group, and 3.06 (95% CI 2.63 - 3.56) for the pos/pos group. Results were similar if a cutoff of 5 CTCs was used for CTC positivity (pos/neg group: HR 1.43, 95% CI 1.25 - 1.63; neg/pos group: HR 2.39, 95% CI 1.91 - 2.99; pos/pos group: HR 3.54, 95% CI 3.12 - 4.02). In total, 2586 patients could be assigned to different tumor subtypes based on known hormone receptor (ER) and HER2 status of the primary tumor: 1513 (58.5%) patients had a luminal-like tumor (ER positive, HER2 negative), 682 (26.4%) patients had a HER2-positive tumor, and 391 (15.1%) patients had a triple-negative tumor. In patients with luminal-like tumors, the hazard ratios were 1.67 (95% CI 1.29 - 2.17), 2.01 (95% CI 1.45 - 2.77), and 3.87 (95% CI 3.09 - 4.83) for the pos/neg, neg/pos, and pos/pos group, respectively. In patients with HER2-positive tumors, the neg/pos group (HR 1.68, 95% CI 1.12 - 2.53) and the pos/pos group (HR 2.11, 95% CI 1.58 - 2.83) showed significantly worse OS compared to the neg/neg group, while in triple-negative patients, the pos/pos group had a significantly shorter OS compared to the neg/neg group (HR 2.99, 95% CI 2.11 - 4.24). The results will be up-dated by inclusion of additional large data sets (CALGB 40502, CALGB 40503, COMET, SWOG S0500, TBCRC 001) for the analysis to be presented at SABCS 2020. Conclusion: This large pooled analysis confirms that at a median of 35 days after treatment initiation, follow-up CTC assessments strongly predict overall survival. These results suggest potential clinical utility of CTC monitoring as early response marker in MBC, especially in luminal-like tumors. Citation Format: Wolfgang J Janni, Tracy C. Yab, Daniel F. Hayes, Massimo Cristofanilli, Francois-Clement Bidard, Michail Ignatiadis, Meredith M. Regan, Catherine Alix-Panabières, William E. Barlow, Carlos Caldas, Lisa A. Carey, Luc Dirix, Tanja Fehm, Jose A. Garcia-Saenz, Paola Gazzaniga, Daniele Generali, Lorenzo Gerratana, Rafael Gisbert-Criado, William Jacot, Zefei Jiang, Evi Lianidou, Mark J.M. Magbanua, Luis Manso, Dimitrios Mavroudis, Volkmar Müller, Elisabetta Munzone, Klaus Pantel, Jean-Yves Pierga, Brigitte Rack, Sabine Riethdorf, Hope S. Rugo, Kostandinos Sideras, Stefan Sleijfer, Jeffrey Smerage, Justin Stebbing, Leon W.M.M. Terstappen, José Vidal-Martínez, Rita Zamarchi, Karthik Giridhar, Thomas W.P. Friedl, Minetta C. Liu. Clinical utility of repeated circulating tumor cell (CTC) enumeration as early treatment monitoring tool in metastatic breast cancer (MBC) - a global pooled analysis with individual patient data [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-08.

1048 Background: Germline BRCA1/2 ( gBRCA) mutations (mt) are some of the few actionable alterations in mBC patients. The PARP inhibitors olaparib/talazoparib are more effective than chemotherapy (ctx) in patients with a gBRCAmt and HER2 negative(-) mBC. In mBC patients the TNT-study suggested a better progression-free survival (PFS) for g BRCA-mt compared to patients with a gBRCA1/2 wildtype (wt) when treated with platinum and not with a taxane. Otherwise little is known about the prognostic effect of g BRCA1/2mt in mBC patients. Methods: PRAEGNANT (NCT02338167) is a prospective mBC registry with a focus on molecular biomarkers. Patients were eligible for this analysis if their mBC was HER2- and treated with ctx for the first time (referred to as first-line ctx). Hormone receptor (HR) positive patients had to have all hormone therapies exhausted. Mutation frequencies and their association with patient and tumor characteristics were analyzed. Multivariable Cox regression models were built with commonly established prognostic factors and g BRCA mutation status as predictors of PFS and overall survival (OS) from first-line ctx. Results: Out of 2932 PRAEGNANT patients, 576 were HER2- and received first-line ctx. Of those 529 patients with g BRCA genotype results and follow up information could be analyzed. 24 patients (4.5%) had a g BRCAmt (11 BRCA1, 13 BRCA2). Mutation rate in HR positive patients was 3.9% (17/432) and 7.2% (7/97) in HR negative patients. Most patients received ctx either as the first treatment in the metastatic setting or after one line of hormone therapy (n=382; 72.2%). Multivariable Cox regression models showed an adjusted hazard ratio for gBRCAmt vs. gBRCAwt patients of 0.70 (95% CI: 0.43-1.15) for PFS and of 0.41 (95% CI: 0.18-0.93) for OS. Most frequent ctx treatments were taxane (52%) or capecitabine based (21%). Additionally, the prevalence of somatic BRCA1/2 mutations in this population will be presented. Conclusions: In this HER2- mBC population under ctx g BRCA mutation rates were within the expected range of about 5%. Within the analyzed population patients with a g BRCA mutation seemed to have a better OS than patients without a mutation. PFS results pointed in the same direction without statistical significance. However, with only 24 mutations replication of these results in additional cohorts is warranted. Clinical trial information: NCT02338167.

Abstract Background New treatment strategies for metastatic breast cancer (mBC) are mainly driven by therapies against specific targets. BRCA mutations are one of the few established actionable targets, with PARP-Inhibitors and Platinum showing high efficacy in mBC. Hereditary cancer testing panels are now broadly used for identification of individuals with BRCA1/2 mutations who may benefit from these therapies. Many of these panels also contain other predisposition genes involved in BRCA-related DNA repair pathways, but the clinical relevance of mutations in these genes remain unclear. The aim of this study was to describe the mutation rates of BRCA1/2 and panel-based predisposition genes, and the associated clinical characteristics of individuals with these mutations, in a prospective cohort of mBC patients. Methods The PRAEGNANT mBC registry (NCT02338167) is a prospective registry for metastatic breast cancer patients with a focus on molecular biomarkers. Patients receiving any therapeutic regimen are eligible for this registry. Germline DNA was collected at study entry and genotyped for 37 cancer predisposition genes including BRCA1 and BRCA2. The frequency of mutations in each gene was determined, and associations between mutations and patient and tumor characteristics, metastatic pattern, and overall survival were assessed. Results Mutations in established high (odds ratio (OR)&gt;5.0) and moderate risk (OR&gt;2.0) breast cancer genes (BRCA1/2, PALB2, CHEK2, ATM, RAD51D, BARD1, and MSH6) were seen in 123 of 1462 tested patients with mBC (8.4%). BRCA1 and BRCA2 mutations were seen in 1.4% and 2.9% of patients respectively. Most frequently mutated non-BRCA panel genes were CHEK2, PALB2 and ATM with 2.8%, 0.8% and 0.6% of patients. Mutation frequency varied with regard to patients who developed brain metastases, visceral metastases or bone only metastases. BRCA1 or BRCA2 mutations were seen frequently in patients with brain (5.3%) or visceral metastases (5.2%), but were present in only 2.5% patients with bone only metastases and 1.5% of patients with lesions in other locations. Panel genes were equally distributed among all metastatic patients. PALB2 mutations (n=11) were only seen in patients with brain (1.9%) and visceral metastases (0.9%), but not in patients with bone metastases or other locations. 36.4% (N=4) of all patients with PALB2 mutations developing a brain metastasis. When adjusted for other mBC prognostic factors, a mutation (all genes) was associated with an unfavorable prognosis (HR: 1.50; 95%CI: 1.04 to 2.30, p=0.03). Mutation frequencies were similar according to therapy lines. All other associations with molecular subtypes and risk factors were similar to primary breast cancer cases. Conclusion Mutations in high and moderate risk breast cancer genes were frequent in metastatic breast cancer patients. The frequency was substantially higher than the 4 to 5% mutation frequency observed among unselected primary breast cancer patients, but is consistent with recent results from studies of metastatic prostate cancer patients. Patients with brain and visceral metastases had the highest BRCA mutation rates. Results suggested that PALB2 mutations may be more frequent in patients with brain metastases. Citation Format: Fasching PA, Hu C, Hart SN, Polley EC, Lee KY, Gnanolivu RD, Lilyquist J, Hartkopf AD, Taran FA, Janni W, Hadji P, Tesch H, Haeberle L, Ettl J, Lux MP, Lueftner D, Wallwiener M, Mueller V, Beckmann MW, Belleville E, Wimberger P, Untch M, Kolberg H-C, Fehm TN, Overkamp F, Wallwiener D, Brucker SY, Schneeweiss A, Couch F. Cancer predisposition genes in metastatic breast cancer – Association with metastatic pattern, prognosis, patient and tumor characteristics [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-02.

Abstract Background: Mutations in BRCA1 and BRCA2 influence the molecular pathogenesis of breast cancer. However, little is known about the association between mutations, response to therapy, and prognosis. We therefore analysed these associations in triple negative breast cancer (TNBC) patients in the neoadjuvant GeparQuinto Study. Methods: The GeparQuinto study recruited 1956 patients with HER2 negative disease including a prespecified group of 671 TNBC patients with untreated breast cancer. Patients were randomized to receive four cycles EC (90/600 mg/m2; q3w) followed by four cycles docetaxel (100 mg/m2; q3w), with or without bevacizumab (15 mg/kg). Here we present the analysis for both randomization arms combined. Sufficient blood was available of 482 TNBC patients. BRCA1 and BRCA2 genotyping was successful in 469 patients with available germline DNA and was conducted by SureSelect custom capture and sequencing on HiSeq 2500. Mutation status was correlated with pathological complete response rates (pCR) and disease free survival (DFS). Results: A total of 74 (15.8%) mutations in BRCA1 (n=61) and BRCA2 (n=13) were detected after initial sequencing. A pCR (ypT0/ypN0) was observed in 50% (n=37) of mutation carriers but only 31.1% (n=123) of patients without mutations (p=0.002). Similar results were observed for pCR (pT0is/pN0) (52.7% vs. 36.5%; p=0.010). pCR (ypT0/ypN0) was predictive of disease free survival (DFS) in all patients (Hazard Ratio, HR=0.23; 95%CI: 0.15-0.37; p&lt;0.001) and in patients without BRCA mutations pCR (ypT0/ypN0) (HR= 0.20; 95%CI: 0.11-0.34; p&lt;0.001). However in mutation carriers this effect was reduced (HR=0.48; 95%CI: 0.18 1.27; p=0.129). Conclusion: TNBC Patients with BRCA mutations showed a higher frequency of pCR than patients without BRCA mutations after treatment with epirubicin, cyclophosphamide and docetaxel (+/ bevacizumab), suggesting that BRCA mutations may influence pCR in response to treatment regimens that do not include platin chemotherapy. pCR as a surrogate marker for DFS was also confirmed in patients without BRCA mutations. In addition, the effect of pCR on prognosis seemed to be smaller among the mutation carriers, although the number of mutation carriers was too low to test for differences between mutation carriers and wildtype patients. The project has partly been funded within NIH-NIGMS U19 GM61388 and the Breast Cancer Research Foundation. Citation Format: Fasching PA, Loibl S, Eidtmann H, Tesch H, Untch M, Hilfrich J, Schem C, Rezai M, Gerber B, Costa SD, Blohmer JU, Fehm TN, Huober J, Liedtke C, Müller V, Nekljudova V, Weber K, Rack B, Rübner M, Wang L, Ingle JN, Weinshilboum RM, von Minckwitz G, Couch F. BRCA mutations, therapy response and prognosis in the neoadjuvant GeparQuinto study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-06.

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression‐free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2‐negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre‐planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF‐A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49–3.75), 1.20 (95% CI, 0.88–1.64) and 0.61 (95% CI, 0.34–1.12). Notably, some SNPs in VEGF‐A exhibited a more pronounced effect in the triple‐negative subgroup. Several SNPs in VEGF‐A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.